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Patients who initially survive the rupture and repair of a brain aneurysm often take a devastating turn for the worse some days later and die or suffer permanent neurologic deficits. This catastrophic sequela is attributed to a delayed phase of global cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH), but we lack effective treatment. Here we present our view, based on 20 years of research, that the initial drop in blood flow at the time of rupture triggers genomic responses throughout the brain vasculature that manifest days later as increased vasoconstriction and decreased cerebral blood flow. We propose a novel treatment strategy to prevent DCI by early inhibition of the vascular mitogen-activated protein kinase (MAPK) pathway that triggers expression of vasoconstrictor and inflammatory mediators. We summarize evidence from experimental SAH models showing early treatment with MAPK inhibitors "switches off" these detrimental responses, maintains flow, and improves neurological outcome. This promising therapy is currently being evaluated in clinical trials.

The choroid is the thin, vasculature-filled layer of the eye situated between the sclera and the retina, where it serves the metabolic needs of the light-sensing photoreceptors in the retina. Illumination of the interior surface of the back of the eye (fundus) is a critical regulator of subretinal fluid homeostasis, which determines the overall shape of the eye, but it is also important for choroidal perfusion. Noted for having some of the highest blood flow rates in the body, the choroidal vasculature has been reported to lack intrinsic, intravascular pressure-induced (myogenic) autoregulatory mechanisms. Here, we ask how light directly regulates choroid perfusion and ocular fluid homeostasis, testing the hypothesis that light facilitates ocular fluid absorption by directly increasing choroid endothelial permeability and decreasing choroid perfusion. Utilizing ex vivo pressurized whole-choroid and whole-eye preparations from mice expressing cell-specific Ca2+ indicators, we found that the choroidal vasculature has two intrinsically light-sensitive Ca2+-signaling mechanisms: One increases Ca2+-dependent production of nitric oxide in choroidal endothelial cells; the other promotes vasoconstriction through Ca2+ elevation in vascular smooth muscle cells. In addition, we found that choroidal flow, or pressure, modulates endothelial and smooth muscle photosensitivity and trans-retinal absorption of fluid into the choroid. These results collectively suggest that the choroid vasculature exhibits an inverted form of autoregulatory control, where pressure-and light-induced mechanisms work in opposition to regulate blood flow and maintain fluid balance in response to changes in light and dark, aligning with the metabolic needs of photoreceptors. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusions and Implications In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho‐inhibition and sympatho‐excitation, mainly via 5‐HT1D/1A and 5‐HT3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5‐HT sympatho‐modulatory role in female rats, characterising the 5‐HT receptors involved.Female Wistar (14‐ to 16‐week‐old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1–5 Hz) or i.v. noradrenaline (0.01–0.5 μg·kg−1). 5‐HT‐related drug effects on adrenergic system were determined. Age‐matched male rats were used as control.Basal MBP in females was lower than in male rats, whereas electrical‐induced increases in MBP were similar. In females, 5‐HT exerted a dose‐dependent inhibition on the sympathetic‐evoked vasoconstrictions, that was reproduced by some agonists; 5‐CT (5‐HT1/5/7) and L‐694,247 (5‐HT1D), whereas the selective 5‐HT2A/2B/2C (α‐methyl‐5‐HT) and 5‐HT3 agonist (1‐PBG) increased the electrically‐produced vasopressor responses. None of the other drugs tested (targeting 5‐HT1A/1B/1F, 5‐HT2B/2C, 5‐HT4, 5‐HT5A or 5‐HT7) modified these vasoconstrictions. Only 1‐PBG (5‐HT3) modified the vasoconstrictions induced by exogenous noradrenaline.In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5‐HT1D receptor activation, whereas pre and/or postjunctional 5‐HT3 and prejunctional 5‐HT2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex‐differential therapeutic strategies for treating cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Focused ultrasound can non-invasively modulate neural activity, but whether effective stimulation parameters generalize across brain regions and cell types remains unknown. We used focused ultrasound coupled with fiber photometry to identify optimal neuromodulation parameters for four different arousal centers of the brain in an effort to yield overt changes in behavior. Applying coordinate descent, we found that optimal parameters for excitation or inhibition are highly distinct, the effects of which are generally conserved across brain regions and cell types. Optimized stimulations induced clear, target-specific behavioral effects, whereas non-optimized protocols of equivalent energy resulted in substantially less or no change in behavior. These outcomes were independent of auditory confounds and, contrary to expectation, accompanied by a cyclooxygenase-dependent and prolonged reduction in local blood flow and temperature with brain-region-specific scaling. These findings demonstrate that carefully tuned and targeted ultrasound can exhibit powerful effects on complex behavior and physiology. [Display omitted] • Optimal ultrasound neuromodulation parameters generalize across neuronal cell types • Distinct parameters for excitation and inhibition are identified • Targeted stimulation induces site-specific behavioral changes • COX2-dependent vasoconstriction and brain cooling occur with excitatory protocols The field of focused ultrasound (FUS) neuromodulation is undergoing rapid growth but is limited by our understanding of effective waveform parameters and cell-type effects. Murphy et al. combine deep-brain optical readouts with FUS technology to uncover waveforms for inducing powerful, bidirectional neuromodulation across a collection of therapeutically important brain cell types. [ABSTRACT FROM AUTHOR]

Introduction: Laparoscopic myomectomy is a commonly performed operation with fast recovery and excellent results. However, haemorrhagic nature of the operation mandates us to use variety of vasoconstrictive and uterotonic agents. Amongst which, one of them is vasopressin. It is a synthetic antidiuretic hormone analogue which has been in common use as a vasoconstrictive agent in various surgical procedures including laparoscopic myomectomy. Methods: A meta‑analysis of randomised controlled trials published from 2013 to 2023 (10 years) comparing the use of vasopressin against other drug or placebo or different doses of vasopressin was performed. The outcome measures were intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct). Results: We identified 176 articles through the study search, amongst which 12 articles were included for the meta‑analysis. There was a significant heterogeneity in the studies with moderate risk of bias in eight studies and low risk of bias in four studies. Compared to placebo, vasopressin showed significantly lower odds need of blood transfusion (odds ratio [OR] 0.28, 95% confidence interval [CI]: 0.13–0.61, P = 0.002) and significantly lower pre–post fall in Hb (OR −3.12, 95% CI: −4.63–−1.60, P < 0.0001). However, there was no statistically significant difference in intraoperative blood loss (OR −0.56 (95% CI: −2.04–0.92, P = 0.46) and pre–post fall in Hct (OR −0.94, 95% CI: −1.96–0.07, P > 0.05). Compared to other drug (epinephrine, misoprostol and octreotide acetate), vasopressin showed no significant superiority in controlling blood loss (P > 0.05). Even the two doses of vasopressin (dilute vs. concentrated) showed no statistically significant difference between surgical blood loss and need for blood transfusion (P > 0.05). Conclusion: Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement and maintaining Hb and Hct during laparoscopic myomectomy. [ABSTRACT FROM AUTHOR]

Background: Epinephrine (EPI) or norepinephrine (NOR) is widely used to treat cardiovascular collapse during lipid emulsion (LE) resuscitation for drug toxicity. However, the effect of LE on the vasoconstriction caused by EPI or NOR remains unknown. The purpose of this study was to examine the effect of an LE (Intralipid) on the vasoconstriction caused by EPI and NOR in isolated rat aorta. Methods: The effect of LE on the vasoconstriction caused by EPI or NOR in isolated rat aorta was examined. Additionally, the effect of LE on the calcium increase caused by EPI or NOR was investigated. The distribution constant (KD: lipid to aqueous phase) of EPI or NOR between a LE (1%) and an aqueous phase was determined. Results: LE (1 and 2%) did not significantly alter vasoconstriction caused by EPI or NOR in isolated endothelium-intact aorta. Moreover, the LE did not significantly alter the increased calcium level caused by EPI or NOR. The log KD of EPI in the LE (1%) was -0.71, -0.99, and -1.00 at 20, 50, and 100 mM ionic strength, respectively. The log KD of NOR in the LE (1%) was -1.22, -1.25, and -0.96 at 20, 50, and 100 mM ionic strength, respectively. Conclusions: Taken together, the Intralipid emulsion did not alter vasoconstriction induced by EPI or NOR that seems to be due to the hydrophilicity of EPI or NOR, leading to sustained hemodynamic support produced by EPI or NOR used during LE resuscitation. [ABSTRACT FROM AUTHOR]

The myocardium and vascular system are influenced by the neurological, paracrine and endocrine systems to control blood pressure in health. Blood pressure control is crucial to maintain adequate organ perfusion and function. In disease, the homeostatic mechanisms that control these systems are dysregulated, which can lead to organ failure. Therefore, understanding the means of manipulating these systems using anaesthesia is important. The central nervous system, cardiac muscle and vascular smooth muscle all have physiological processes which can be targeted to reduce the stress response associated with their derangement. This article reviews the different pharmacological means of altering cardiac function and blood vessel calibre to improve organ perfusion. [ABSTRACT FROM AUTHOR]

Objectives: An excessive and abrupt increase in cerebral blood flow may cause blood vessel damage, leading to stroke. Therefore, appropriate methods to immediately regulate blood flow velocity are important. Through an analysis of 31 healthy adults, we therefore investigated whether stimulating the common carotid artery (CCA) using transcutaneous electrical nerve stimulation (TENS) could modulate blood flow velocity in the CCA. Methods: Three stimulation intensities (below-threshold, threshold, and above-threshold) were applied in a random order. Blood velocity changes were examined by the measurement of peak systolic velocity (PSV) with Doppler ultrasound before, during, and after TENS stimulation. To evaluate arterial stiffness, pulse wave velocity (PWV) was calculated using CCA diameter, and blood pressure was measured before and after stimulation. Results: PSV changes in the below-threshold level were significant (p = 0.028). The PSV after below-threshold stimulation was significantly decreased by 2.23% compared to that before stimulation (p = 0.031). PWV showed no significant differences; however, a nonsignificant increase was observed immediately after stimulation only in the above-threshold condition. Above-threshold stimulation can increase vascular tone by activating the sympathetic nerve, possibly triggering vasoconstriction. Conclusions: A decrease in blood flow velocity may not be expected upon the above-threshold stimulation. In contrast, the below-threshold stimulation immediately reduces blood flow velocity, without significantly affecting hemodynamic function, such as arterial flexibility. Therefore, this short-term and low electrical stimulation technique can help to lower vascular resistance and prevent vascular damage from rapid blood flow velocity. [ABSTRACT FROM AUTHOR]

Purpose of review: Congenital diaphragmatic hernia (CDH) remains a significant challenge, particularly in severe cases with persistent pulmonary hypertension (PPHN) and hypoplastic lungs and heart. For patients unresponsive to conventional therapies, ECMO is required. While the surgical repair is relatively simple, determining the optimal timing for surgery in patients requiring ECMO is particularly challenging. This review explores the dilemma of surgical timing and proposes a two-staged approach: a reduction in herniated organs and the creation of a silo to relieve abdominal pressure before initiating ECMO, with defect closure following ECMO decannulation. Recent Findings: Studies support pre-, on-, and post-ECMO repair, each with its own risks and benefits. Pre-ECMO repair may enhance ECMO efficacy by relieving organ compression but poses risks due to instability. Post-ECMO repair is safer but may result in losing the chance to repair. On-ECMO repair has significant hemorrhage risks, but early repair with careful anticoagulation management is currently recommended. Recently, the author reported a successful case using a two-staged approach—reducing herniated organs and creating a silo before ECMO, followed by defect closure after ECMO decannulation—which suggests a potential alternative strategy for managing severe CDH. Summary: A two-staged approach may offer a solution for severe CDH patients requiring ECMO. [ABSTRACT FROM AUTHOR]

Introduction: In the field of sports and exercise science researchers are exploring methods to enhance recovery after training sessions. One popular approach that has gained attention is the use of ice baths. Purpose: This review examines how ice baths impact muscle recovery time following high intensity workouts looking at both the effects and practical considerations with a focus, on Delayed Onset Muscle Soreness (DOMS). The PubMed database was used in this study. A literature review was conducted using the keywords: "cold water", "muscle regeneration", "muscle soreness", "DOMS" and "ice bathing". State of Knowledge: Ice baths have been found to trigger vasoconstriction reduce inflammation and alleviate muscle soreness. However, their effectiveness in reducing exercise-induced inflammation and muscle soreness remains uncertain. The impact on DOMS varies among individuals due to factors like genetics, age, gender and health conditions. This variability highlights the challenges of incorporating ice baths into workout recovery routines. Summary: The use of ice baths in post-exercise recovery presents a complex landscape with diverse physiological responses and variable outcomes. While practical guidelines exist for the application of ice baths in high-intensity training, debates persist regarding their efficacy on DOMS compared to active recovery. While ice baths are incorporated into holistic recovery strategies conflicting research casts doubt on their standalone effectiveness prompting further exploration of how they complement other recovery methods. Moreover, potential drawbacks and conflicting evidence regarding their influence on long-term training adaptations raise questions about the overall costs and benefits. [ABSTRACT FROM AUTHOR]

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine-induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham = −7.499, LogIC50 Stroke = −7.350, p = 0.0132, n = 19, 31 respectively). The vasodilatory responses to SNP were identical in the isolated aortas in the sham and stroke groups. Phenylephrine-induced vasoconstriction was impaired in the aortas isolated from the stroke animals in comparison to their sham treatment counterparts (Sham LogEC50= −6.652 vs. Stroke LogEC50 = −6.475, p < 0.001). Our study demonstrates that 24 h post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. The aortas from the stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while the endothelium-independent vasodilatory responses were preserved. Since both the vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke. [ABSTRACT FROM AUTHOR]

The establishment of a peripheral ECMO circuit can lead to significant arterial and venous complications in 10–30% of patients. Vascular complications, particularly acute limb ischemia, are associated with worsening overall outcomes. Limb ischemia occurs significantly more frequently in the early stages of VA ECMO than in VV ECMO. Mechanisms of limb ischemia include arterial obstruction, cannulation injury, loss of pulsatile flow, thromboembolism, venous stasis from compressive obstruction with large venous cannulas, and systemic vasoconstriction due to shock and pharmacologic vasoconstriction. The care team may use several mitigation strategies to prevent limb ischemia. Arterial and venous complications can be mitigated by careful access site selection, minimizing cannula size, placement of distal perfusion and/or outflow catheter(s), and continuous NIRS monitoring. Rapid intervention, when ischemia or compartment syndrome occurs, can reduce limb loss but may not affect the mortality and morbidity of the ECMO patient in the long term due to their underlying conditions and the etiology of the ECMO need. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. METHODS: We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. RESULTS: This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm−5 (interquartile range, 870–1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0–0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm−5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P=0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P<0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P=0.003). CONCLUSIONS: Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm−5, high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed. [ABSTRACT FROM AUTHOR]

Introduction Laparoscopic myomectomy is a commonly performed operation with fast recovery and excellent results. However, haemorrhagic nature of the operation mandates us to use variety of vasoconstrictive and uterotonic agents. Amongst which, one of them is vasopressin. It is a synthetic antidiuretic hormone analogue which has been in common use as a vasoconstrictive agent in various surgical procedures including laparoscopic myomectomy. Methods A meta-analysis of randomised controlled trials published from 2013 to 2023 (10 years) comparing the use of vasopressin against other drug or placebo or different doses of vasopressin was performed. The outcome measures were intraoperative blood loss, need for blood transfusion, difference in the haemoglobin (Hb) and haematocrit (Hct). Results We identified 176 articles through the study search, amongst which 12 articles were included for the meta-analysis. There was a significant heterogeneity in the studies with moderate risk of bias in eight studies and low risk of bias in four studies. Compared to placebo, vasopressin showed significantly lower odds need of blood transfusion (odds ratio [OR] 0.28, 95% confidence interval [CI]: 0.13–0.61, P = 0.002) and significantly lower pre–post fall in Hb (OR −3.12, 95% CI: −4.63–−1.60, P < 0.0001). However, there was no statistically significant difference in intraoperative blood loss (OR −0.56 (95% CI: −2.04–0.92, P = 0.46) and pre–post fall in Hct (OR −0.94, 95% CI: −1.96–0.07, P > 0.05). Compared to other drug (epinephrine, misoprostol and octreotide acetate), vasopressin showed no significant superiority in controlling blood loss (P > 0.05). Even the two doses of vasopressin (dilute vs. concentrated) showed no statistically significant difference between surgical blood loss and need for blood transfusion (P > 0.05). Conclusion Vasopressin is an efficacious drug to be used for controlling blood loss, decreasing blood transfusion requirement and maintaining Hb and Hct during laparoscopic myomectomy.

Abstract 18 Participants were randomized to receive 30 ml/kg bodyweight Ringer’s Lactate at 37° or 15 °C over 30 min. In a second session, participants were crossed over. Over a 120 min period after starting the fluid bolus we measured mean arterial pressure (MAP), cardiac output, systemic vascular resistance, and catecholamine levels. After infusion with cold fluids, the absolute increase in MAP at 45 min was significantly higher at + 6.5 mmHg (95% CI 4.8–8.2) compared with warm fluids (+ 0.6 mmHg, 95% CI, − 1.6 to 2.8; p

High systolic blood pressure and increased blood pressure variability after the onset of ischemic stroke are associated with poor clinical outcomes. One of the key determinants of blood pressure is arteriolar size, determined by vascular smooth muscle tone and vasodilatory and vasoconstrictor substances that are released by the endothelium. The aim of this study is to outline alterations in vasomotor function in isolated peripheral arteries following ischemic stroke. The reactivity of thoracic aortic segments from male C57BL/6 mice to dilators and constrictors was quantified using wire myography. Acetylcholine-induced endothelium-dependent vasodilation was impaired after ischemic stroke (LogIC50 Sham = −7.499, LogIC50 Stroke = −7.350, p = 0.0132, n = 19, 31 respectively). The vasodilatory responses to SNP were identical in the isolated aortas in the sham and stroke groups. Phenylephrine-induced vasoconstriction was impaired in the aortas isolated from the stroke animals in comparison to their sham treatment counterparts (Sham LogEC50= −6.652 vs. Stroke LogEC50 = −6.475, p < 0.001). Our study demonstrates that 24 h post-ischemic stroke, peripheral vascular responses are impaired in remote arteries. The aortas from the stroke animals exhibited reduced vasoconstrictor and endothelium-dependent vasodilator responses, while the endothelium-independent vasodilatory responses were preserved. Since both the vasodilatory and vasoconstrictor responses of peripheral arteries are impaired following ischemic stroke, our findings might explain increased blood pressure variability following ischemic stroke.

Humans and mice with mutations in COL4A1 and COL4A2 manifest hallmarks of cerebral small vessel disease (cSVD). Mice with a missense mutation in Col4a1 at amino acid 1344 (Col4a1+/G1344D) exhibit age-dependent intracerebral hemorrhages (ICHs) and brain lesions. Here, we report that this pathology was associated with the loss of myogenic vasoconstriction, an intrinsic vascular response essential for the autoregulation of cerebral blood flow. Electrophysiological analyses showed that the loss of myogenic constriction resulted from blunted pressure-induced smooth muscle cell (SMC) membrane depolarization. Furthermore, we found that dysregulation of membrane potential was associated with impaired Ca2+-dependent activation of large-conductance Ca2+-activated K+ (BK) and transient receptor potential melastatin 4 (TRPM4) cation channels linked to disruptions in sarcoplasmic reticulum (SR) Ca2+ signaling. Col4a1 mutations impair protein folding, which can cause SR stress. Treating Col4a1+/G1344D mice with 4-phenylbutyrate, a compound that promotes the trafficking of misfolded proteins and alleviates SR stress, restored SR Ca2+ signaling, maintained BK and TRPM4 channel activity, prevented loss of myogenic tone, and reduced ICHs. We conclude that alterations in SR Ca2+ handling that impair ion channel activity result in dysregulation of SMC membrane potential and loss of myogenic tone and contribute to age-related cSVD in Col4a1+/G1344D mice.

Summary: There have been increasing concerns about the great risks posed by petroleum products which contribute to the progression endothelial renal vasoconstriction and hypertension. This study aims to investigate the modulatory effects of Roasted cashew nut on rats induced with endothelial renal vasoconstriction syndrome upon exposure to mixed fractionated petroleum products (MFPP). Seventy male albino rats were randomized into seven (n=10) groups. Group I (normal control) was given distilled water. Group II was administered with MFPP (20 %/day). Group III was administered with MFPP (20 %/day) + atenolol (50 mg/kg). Group IV was administered with MFPP (20 %/day) + 10 % roasted cashew nut (10 %RCN). Group V was administered with MFPP (20 %/day) + (20 %RCN). Group VI was treated with 10 %RCN while Group VII was treated with 20 %RCN. Data were analyzed using one-way analysis of variance (ANOVA) and Duncan's multiple range test with P

Anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies that target CGRP ligands or receptors, may cause a very rare side effect of reversible cerebral vasoconstriction syndrome (RCVS). This study is a case report of a patient who developed cerebral artery vasoconstriction documented on serial brain magnetic resonance angiography (MRA) scans without the typical manifestations of RCVS following galcanezumab loading dose. Case report: A 40-year-old female patient with high-frequency episodic migraine with visual aura on topiramate 100 mg/day developed transient numbness of the right upper and lower extremities and right face without headache and a normal neurological examination 10 min after a loading dose of galcanezumab, which resolved over the next 2 days. Magnetic resonance angiography brain imaging showed segmental arterial constriction of both middle cerebral arteries in the M1–2 segments and both posterior cerebral arteries in the P1–2 segments, which partial resolved in a subsequent study by the end of 6 months. There were no other supporting examination data, such as transcranial Doppler, which might provide additional information on the progression and improvement of the vasoconstriction. Her differential diagnosis included prolonged migraine sensory aura without headache, RCVS, or cerebral vasoconstriction secondary to the effect of an anti-CGRP monoclonal antibody. Further research needs to be conducted. Plain Language Summary: We report a case with numbness on the right upper and lower extremities and right face without headache 10 min after the loading dose of galcanezumab. These stroke-like symptoms resolved within 2 days. Cerebral blood vessels showed narrowing and then dilatation with residual narrowing of two or more vessels. The differential diagnosis is prolonged migraine aura without headache, reversible cerebral vasoconstriction syndrome, or cerebral vasoconstriction due to the effects of galcanezumab. [ABSTRACT FROM AUTHOR]

Abstract Background Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. Case presentation A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. Conclusion Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties.

Abstract Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH.

Andreas Clipet-Jensen, Hans Fjeldsøe-Nielsen, Peter Roy Kirkegaard Department of Anesthesiology and Intensive Care Medicine, Zealand University Hospital, Nykøbing, DenmarkCorrespondence: Andreas Clipet-Jensen, Email andreas.clipet-jensen.01@regionh.dk; a.clipet.jensen@gmail.comAbstract: Although peripheral nerve blocks are deemed very safe, a significant number of patients for whom this anesthetic technique may be particularly appealing to apply may present with preexisting peripheral neuropathies, putting them at risk for further nerve damage. We present a case with a 74-year-old male with several risk factors for peripheral neuropathy who developed a foot drop following a popliteal sciatic nerve block with ropivacaine. We suggest that the vasoconstrictive properties of ropivacaine may have contributed to a preexisting neuronal ischemia, thus further damaging an already compromised nerve.Keywords: peripheral nerve block, peripheral neuropathy, vasoconstriction, local anesthetics

Individuals with posttraumatic stress disorder (PTSD) face an increased risk of cardiovascular disease, but the mechanisms linking PTSD to cardiovascular disease remain incompletely understood. We used a co-twin control study design to test the hypothesis that individuals with PTSD exhibit augmented peripheral and systemic vasoconstriction during a personalized trauma recall task. In 179 older male twins from the Vietnam Era Twin Registry, lifetime history of PTSD and current (last month) PTSD symptoms were assessed. Participants listened to neutral and personalized trauma scripts while peripheral vascular tone (Peripheral Arterial Tone ratio) and systemic vascular tone (e.g., total vascular conductance) were measured. Linear mixed-effect models were used to assess the within-pair relationship between PTSD and vascular tone indices. The mean age of participants was 68 years, and 19% had a history of PTSD. For the Peripheral Arterial Tone ratio analysis, 32 twins were discordant for a history of PTSD, and 46 were discordant for current PTSD symptoms. Compared with their brothers without PTSD, during trauma recall, participants with a history of PTSD had greater increases in peripheral (β = −1.01, 95% CI [−1.72, −0.30]) and systemic (total vascular conductance: β = −1.12, 95% CI [−1.97, −0.27]) vasoconstriction after adjusting for cardiovascular risk factors. Associations persisted after adjusting for antidepressant medication use and heart rate and blood pressure during the tasks. Analysis of current PTSD symptom severity showed consistent results. PTSD is associated with exaggerated peripheral and systemic vasoconstrictor responses to traumatic stress reminders, which may contribute to elevated risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Background: Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by diffuse, multifocal segmental narrowing of cerebral arteries and can result in ischaemic stroke. Causal factors, identified in 60% of cases, include immunosuppressant pharmacotherapy. The few reports following heart transplantation are almost all in Asian recipients. We report on a Caucasian Australian patient with immunotherapy induced RCVS post heart transplantation to highlight the state of knowledge of the condition and the treatment dilemma it poses. Case presentation: A 51-year-old female underwent orthotopic heart transplantation at our institution. Induction immunotherapy comprised basiliximab, mycophenolate mofetil and methylprednisolone. On day 6 post-transplantation the patient was transitioned to oral prednisolone and tacrolimus. On day 7 the patient began to experience bilateral, severe, transient occipital and temporal headaches. On day 9 tacrolimus dose was up-titrated. A non-contrast computed tomography brain (CTB) was normal. Endomyocardial biopsy on day 12 demonstrated moderate Acute Cellular Rejection (ACR), which was treated with intravenous methylprednisolone. That evening the patient experienced a 15-minute episode of expressive dysphasia. The following morning she became confused, aphasic, and demonstrated right sided neglect and right hemianopia. A CT cerebral perfusion scan demonstrated hypoperfusion in the left middle cerebral artery (MCA) territory and cerebral angiography revealed widespread, focal multi-segmental narrowing of the anterior and posterior circulations. A diagnosis of RCVS was made, and nimodipine was commenced. As both steroids and tacrolimus are potential triggers of RCVS, cyclosporin replaced tacrolimus and methylprednisolone dose was reduced. A further CTB demonstrated a large left MCA territory infarct with left M2 MCA occlusion. The patient made steady neurological improvement. She was discharged 34 days post-transplantation with mild residual right lower limb weakness and persistent visual field defect on verapamil, cyclosporine, everolimus, mycophenolate mofetil and prednisolone. Conclusion: Reversible cerebral vasoconstriction syndrome is rare after orthotopic heart transplantation. Until now, RCVS has been almost exclusively described in Asian recipients, and is typically caused by immunotherapy. The condition may lead to permanent neurological deficits, and in the absence of definitive treatments, early recognition and imaging based diagnosis is essential to provide the opportunity to remove the causal agent(s). Co-existent ACR, can pose unique treatment difficulties. [ABSTRACT FROM AUTHOR]

Objective • The objective of this study is to evaluate the effectiveness of targeted nursing measures in relieving swollen limb pain after extremity fractures. The term “targeted nursing measures” refers to specific nursing interventions and care strategies that are designed to address the issue of swollen limb pain in patients with extremity fractures. Methods • Patients with extremity fractures treated in our hospital between January 2020 and December 2021 were recruited for eligibility assessment, and 100 patients were eventually included and assigned alternately at the time of admission to receive routine care, namely standard nursing interventions commonly provided to individuals with extremity fractures (These interventions included preoperative assessment, vital sign monitoring, postoperative status monitoring, local ice application, elevation of the affected limb, functional exercise, pain relief measures, postoperative nutrition, medication administration, and general health instruction) (routine group) or targeted care, namely care measures tailored to address swollen limb pain. (These targeted care measures included health education regarding the causes of limb fractures, precautions, causes of swollen limb pain after fractures, and treatment methods, decongestion care, ice compresses to promote vasoconstriction and reduce pain and swelling, psychological counseling to relieve negative emotions, and targeted rehabilitation training supervision) (targeted group), with 50 patients in each group. Outcome measures included swelling, pain, emotional state, and nursing satisfaction. Results • Targeted care resulted in better mitigation of swelling versus routine care (P < .05). Patients with targeted care had significantly lower visual analog scale (VAS) scores, self-rating anxiety scale (SAS) scores, and Hamilton depression scale (HAMD) scores, and higher Connor-Davidson resilience scale (CD-RISC) scores versus those with routine care (P < .05). Targeted care was associated with significantly higher nursing satisfaction versus routine care (P < .05). Conclusion • Targeted care rapidly relieves the degree of swelling and pain of patients with extremity fractures and ameliorates their emotional state, thereby promoting health recovery and effectively improving patient satisfaction. [ABSTRACT FROM AUTHOR]

Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano‐molecular programs that orchestrate region‐ and layer‐specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single‐cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T‐lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo‐1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno‐mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi‐gerogenic signals priming to disease development. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a life-threatening disease with limited survival. Herein, we propose the pharmacological inhibition of Gq proteins as a novel concept to counteract pulmonary vasoconstriction and proliferation/migration of pulmonary artery smooth muscle cells (PASMCs) in PAH. We demonstrate that the specific pan-Gq inhibitor FR900359 (FR) induced a strong vasorelaxation in large and small pulmonary arteries in mouse, pig, and human subjects ex vivo. Vasorelaxation by FR proved at least as potent as the currently used triple therapy. We also provide in vivo evidence that local pulmonary application of FR prevented right ventricular systolic pressure increase in healthy mice as well as in mice suffering from hypoxia (Hx)-induced pulmonary hypertension (PH). In addition, we demonstrate that chronic application of FR prevented and also reversed Sugen (Su)Hx-induced PH in mice. We also demonstrate that Gq inhibition reduces proliferation and migration of PASMCs in vitro. Thus, our work illustrates a dominant role of Gq proteins for pulmonary vasoconstriction as well as remodeling and proposes direct Gq inhibition as a powerful pharmacological strategy in PH. Synopsis: This study highlights the decisive role of Gq proteins in pulmonary vasoconstriction and vascular remodeling, the main hallmarks of pulmonary hypertension (PH), and introduces the pharmacological pan-Gq inhibitor FR900359 (FR) as a potential therapeutic compound. Gq inhibition by FR induced strong pulmonary vasorelaxation in mice, pigs, and humans ex vivo. Gq inhibition by FR reduced cell growth and migration of pulmonary artery smooth muscle cells in vitro. FR prevented and reversed hypoxia-induced PH in mice in vivo. This study highlights the decisive role of Gq proteins in pulmonary vasoconstriction and vascular remodeling, the main hallmarks of pulmonary hypertension (PH), and introduces the pharmacological pan-Gq inhibitor FR900359 (FR) as a potential therapeutic compound. [ABSTRACT FROM AUTHOR]

This study investigated the effects of chronic crowding-induced social stress and dimethyl fumarate (DMF) on borderline hypertensive rats, focusing on the transcription nuclear factor (erythroid-derived 2)-like 2 (NRF2) gene Nfe2l2, on the expression of selected NFR2-mediated gene expressions in the heart, and on vascular function. Rats were exposed to chronic crowding, DMF treatment (30 mg/kg/day, p.o.), or a combination of both for six weeks. Blood pressure (BP) was measured non-invasively, gene expressions were analysed using RT-qPCR, and vascular function was assessed by measuring noradrenaline (NA)-induced vasoconstriction and endothelium-dependent and -independent relaxations in the femoral arteries using a wire myograph. Chronic stress increased BP, Nfe2l2 expression, and NA-induced vasoconstriction, though it did not affect relaxation responses nor the left heart ventricle-to-body weight (LHV/BW) ratio. DMF elevated Nfe2l2 expression (as the main effect) in the heart but did not alter BP and vascular functions vs. control when administered alone. Interestingly, DMF increased the LHV/BW ratio, supposedly due to reductive stress induced by continuous NRF2 activation. When combined with stress, DMF treatment prevented stress-induced hypertension and mitigated NA-induced vasoconstriction without altering relaxation functions. In addition, the combination of stress and DMF increased Tnf and Nos2 expression and the expressions of several genes involved in iron metabolism. In conclusion, these findings suggest that DMF can prevent chronic stress-induced hypertension by reducing vascular contractility. Moreover, DMF itself may produce reductive stress in the heart and induce inflammation when combined with stress. This indicates a need for the careful consideration of long-term DMF treatment considering its impact on the heart. [ABSTRACT FROM AUTHOR]

A variety of ion channels regulate membrane potential and calcium influx in arterial smooth muscle and endothelial cells to modify vascular functions, including contractility. The current (I) generated by a population of ion channels is equally dependent upon their number (N), open probability (Po) and single channel current (i), such that I = N.PO.i. A conventional view had been that ion channels traffic to the plasma membrane in a passive manner, resulting in a static surface population. It was also considered that channels assemble with auxiliary subunits prior to anterograde trafficking of the multimeric complex to the plasma membrane. Recent studies have demonstrated that physiological stimuli can regulate the surface abundance (N) of several different ion channels in arterial smooth muscle and endothelial cells to control arterial contractility. Physiological stimuli can also regulate the number of auxiliary subunits present in the plasma membrane to modify the biophysical properties, regulatory mechanisms and physiological functions of some ion channels. Furthermore, ion channel trafficking becomes dysfunctional in the vasculature during hypertension, which negatively impacts the regulation of contractility. The temporal kinetics of ion channel and auxiliary subunit trafficking can also vary depending on the signalling mechanisms and proteins involved. This review will summarize recent work that has uncovered the mechanisms, functions and pathological modifications of ion channel trafficking in arterial smooth muscle and endothelial cells. [ABSTRACT FROM AUTHOR]

Although the gasotransmitter hydrogen sulfide (H2S) is well known for its vasodilatory effects, H2S also exhibits vasoconstricting properties. Herein, it is demonstrated that administration of H2S as intravenous sodium sulfide (Na2S) increased blood pressure in sheep and rats, and this effect persisted after H2S has disappeared from the blood. Inhibition of the L‐type calcium channel (LTCC) diminished the hypertensive effects. Incubation of Na2S with whole blood, red blood cells, methemoglobin, or oxyhemoglobin produced a hypertensive product of H2S, which is not hydrogen thioperoxide, metHb‐SH− complexes, per‐/poly‐ sulfides, or thiolsulfate, but rather a labile intermediate. One‐electron oxidation of H2S by oxyhemoglobin generated its redox cousin, sulfhydryl radical (HS•). Consistent with the role of HS• as the hypertensive intermediate, scavenging HS• inhibited Na2S‐induced vasoconstriction and activation of LTCCs. In conclusion, H2S causes vasoconstriction that is dependent on the activation of LTCCs and generation of HS• by oxyhemoglobin. [ABSTRACT FROM AUTHOR]

Reversible cerebral vasoconstriction syndrome (RCVS) is a clinical radiographic phenomenon characterized by thunderclap headaches and transient vasoconstriction of cerebral vessels, which typically resolve within 3 months of symptom onset. Although RCVS has been extensively studied in adults, research on this condition in pediatric populations is limited, likely due to its perceived rarity. This comprehensive review aims to bridge the knowledge gap by examining the clinical presentation, diagnostic methods, treatment strategies, and prognostic outcomes of pediatric RCVS cases, including two case reports contributed by the authors. This study demonstrates an inconclusive sex distribution of RCVS in children, attributed to the scarcity of comprehensive studies of this demographic. Additionally, we identified several predictors of adverse neurological outcomes in children with RCVS, including motor deficits, aphasia, hypertension, and renal disease. This study offers a thorough overview of RCVS in the pediatric population, providing valuable insights to inform future research in this area. [ABSTRACT FROM AUTHOR]

The TMEM16A calcium-activated chloride channel is a promising therapeutic target for various diseases. Niclosamide, an anthelmintic medication, has been considered a TMEM16A inhibitor for treating asthma and chronic obstructive pulmonary disease (COPD) but was recently found to possess broad-spectrum off-target effects. Here, we show that, under physiological Ca2+ (200-500 nM) and voltages, niclosamide acutely potentiates TMEM16A. Our computational and functional characterizations pinpoint a putative niclosamide binding site on the extracellular side of TMEM16A. Mutations in this site attenuate the potentiation. Moreover, niclosamide potentiates endogenous TMEM16A in vascular smooth muscle cells, triggers intracellular calcium increase, and constricts the murine mesenteric artery. Our findings advise caution when considering clinical applications of niclosamide as a TMEM16A inhibitor. The identification of the putative niclosamide binding site provides insights into the mechanism of TMEM16A pharmacological modulation and provides insights into developing specific TMEM16A modulators to treat human diseases. [ABSTRACT FROM AUTHOR]

Patients with heart failure with reduced ejection fraction (HFrEF) have exaggerated sympathoexcitation and impaired peripheral vascular conductance. Evidence demonstrating consequent impaired functional sympatholysis is limited in HFrEF. This study aimed to determine the magnitude of reduced limb vascular conductance during sympathoexcitation and whether functional sympatholysis would abolish such reductions in HFrEF. Twenty patients with HFrEF and 22 age-matched controls performed the cold pressor test (CPT) [left foot 2-min in −0.5 (1)°C water] alone and with right handgrip exercise (EX + CPT). Right forearm vascular conductance (FVC), forearm blood flow (FBF), and mean arterial pressure (MAP) were measured. Patients with HFrEF had greater decreases in %ΔFVC and %ΔFBF during CPT (both P < 0.0001) but not EX + CPT (P = 0.449, P = 0.199) compared with controls, respectively. %ΔFVC and %ΔFBF decreased from CPT to EX + CPT in patients with HFrEF (both P < 0.0001) and controls (P = 0.018, P = 0.015), respectively. MAP increased during CPT and EX + CPT in both groups (all P < 0.0001). MAP was greater in controls than in patients with HFrEF during EX + CPT (P = 0.025) but not CPT (P = 0.209). In conclusion, acute sympathoexcitation caused exaggerated peripheral vasoconstriction and reduced peripheral blood flow in patients with HFrEF. Handgrip exercise abolished sympathoexcitatory-mediated peripheral vasoconstriction and normalized peripheral blood flow in patients with HFrEF. These novel data reveal intact functional sympatholysis in the upper limb and suggest that exercise-mediated, local control of blood flow is preserved when cardiac limitations that are cardinal to HFrEF are evaded with dynamic handgrip exercise. NEW & NOTEWORTHY: Patients with HFrEF demonstrate impaired peripheral blood flow regulation, evidenced by heightened peripheral vasoconstriction that reduces limb blood flow in response to physiological sympathoexcitation (cold pressor test). Despite evidence of exaggerated sympathetic vasoconstriction, patients with HFrEF demonstrate a normal hyperemic response to moderate-intensity handgrip exercise. Most importantly, acute, simultaneous handgrip exercise restores normal limb vasomotor control and vascular conductance during acute sympathoexcitation (cold pressor test), suggesting intact functional sympatholysis in patients with HFrEF. [ABSTRACT FROM AUTHOR]

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Background: Prenatal hypoxia, a common pregnancy complication, leads to impaired cardiovascular outcomes in the adult offspring. It results in impaired vasodilation in coronary and mesenteric arteries of the adult offspring, due to reduced nitric oxide (NO). Thromboxane A2 (TxA2) is a potent vasoconstrictor increased in cardiovascular diseases, but its role in the impact of prenatal hypoxia is unknown. To prevent the risk of cardiovascular disease by prenatal hypoxia, we have tested a maternal treatment using a nanoparticle-encapsulated mitochondrial antioxidant (nMitoQ). We hypothesized that prenatal hypoxia enhances vascular TxA2 responses in the adult offspring, due to decreased NO modulation, and that this might be prevented by maternal nMitoQ treatment. Methods: Pregnant Sprague–Dawley rats received a single intravenous injection (100 µL) of vehicle (saline) or nMitoQ (125 µmol/L) on gestational day (GD)15 and were exposed to normoxia (21% O2) or hypoxia (11% O2) from GD15 to GD21 (term = 22 days). Coronary and mesenteric arteries were isolated from the 4-month-old female and male offspring, and vasoconstriction responses to U46619 (TxA2 analog) were evaluated using wire myography. In mesenteric arteries, L-NAME (pan-NO synthase (NOS) inhibitor) was used to assess NO modulation. Mesenteric artery endothelial (e)NOS, and TxA2 receptor expression, superoxide, and 3-nitrotyrosine levels were assessed by immunofluorescence. Results: Prenatal hypoxia resulted in increased U46619 responsiveness in coronary and mesenteric arteries of the female offspring, and to a lesser extent in the male offspring, which was prevented by nMitoQ. In females, there was a reduced impact of L-NAME in mesenteric arteries of the prenatal hypoxia saline-treated females, and reduced 3-nitrotyrosine levels. In males, L-NAME increased U46619 responses in mesenteric artery to a similar extent, but TxA2 receptor expression was increased by prenatal hypoxia. There were no changes in eNOS or superoxide levels. Conclusions: Prenatal hypoxia increased TxA2 vasoconstrictor capacity in the adult offspring in a sex-specific manner, via reduced NO modulation in females and increased TP expression in males. Maternal placental antioxidant treatment prevented the impact of prenatal hypoxia. These findings increase our understanding of how complicated pregnancies can lead to a sex difference in the programming of cardiovascular disease in the adult offspring. Highlights: Prenatal hypoxia increases thromboxane-mediated vasoconstrictor responses in both coronary and mesenteric arteries from the adult female and male offspring. This was more pronounced in females, and was prevented by maternal placental antioxidant treatment in pregnancy. The mechanisms for the increased thromboxane-mediated vasoconstrictor responses by prenatal hypoxia exposure were sex-specific, where females had reduced nitric oxide modulation of vasoconstriction, while males had increased thromboxane receptor expression. There are sex-specific differences on how prenatal hypoxia impairs vascular function in the adult offspring. Placenta-targeted therapies in pregnancy should be considered to improve cardiovascular outcomes in the offspring later life but should take the sex of the fetus into consideration. Plain language summary: Prenatal hypoxia, when the fetus does not receive enough oxygen, is a common problem during pregnancy that impacts the developing fetus. It is associated with an increased risk of cardiovascular disease in the offspring in adulthood. While the mechanisms are not fully understood, the blood vessel function in the offspring may be impacted by prenatal hypoxia. We hypothesize that prenatal hypoxia increases the constriction of the blood vessels in the offspring. The placenta, an essential organ for fetal development, supplies oxygen and nutrients to the fetus. In prenatal hypoxia pregnancies, the placenta does not work properly. We have been studying a placental treatment (called nMitoQ) to improve placenta function and thereby the blood vessel function of the offspring. We used a rat model of prenatal hypoxia, where pregnant rats (dams) were placed in a low oxygen environment (hypoxia) during the last trimester of pregnancy. Control rats were kept in normal oxygen conditions. The dams were treated with nMitoQ, or with saline (control). Next, we studied the blood vessels of the offspring in adulthood. We found that prenatal hypoxia increases the constriction of the blood vessels, which was prevented by treating the dams with nMitoQ. Interestingly, this impact was more severe in females compared to males, and the mechanisms were different between the sexes. This study helps in the understanding of how complicated pregnancies can impair cardiovascular health in the offspring, and in a potential development of targeted and sex-specific therapies for those offspring at high risk for future cardiovascular disease. [ABSTRACT FROM AUTHOR]

This case addressed patient and free flap survival after cardiac arrest with the contentious use of vasopressors amid concerns about potential vasoconstrictive effects on flap vitality. A 59-year-old male with mucoepidermoid carcinoma underwent post-total maxillectomy and double free flap reconstruction (free fibular flap and anterolateral thigh free flap). Intraoperatively, he experienced cardiac arrest after anastomosis due to hypovolemia or hypoxia, requiring external cardiac massage and vasopressor administration. Despite the initial restoration of circulation, subsequent cardiac arrest ensued, necessitating further resuscitation. Postoperatively, vasopressors were also administered due to hemodynamic instability. Contrary to concerns, both flaps demonstrated sustained vitality, challenging prevailing apprehensions about vasopressor-induced vasoconstriction compromising flap viability. This observation suggests that vasopressors may not significantly threaten flap viability, prompting reconsideration of hesitations and encouraging further investigation. The study advocates for a judicious evaluation of vasopressor administration in free flap procedures, enriching clinical considerations for optimal patient care. [ABSTRACT FROM AUTHOR]

Horiuchi, Masahiro, Satomi Mitsui, and Tadashi Uno. Influence of smoking and alcohol habits on symptoms of acute mountain sickness on Mount Fuji: a questionnaire survey-based pilot study. High Alt Med Biol 00:000–000, 2024. Background: Acute cigarette smoking or alcohol intake would cause opposing vasculature effects that may influence acute mountain sickness (AMS). The present study aimed to investigate the effects of smoking and alcohol consumption behaviors, and acute smoking and consuming alcohol during ascent on AMS on Mount Fuji. Methods: This questionnaire survey study included 887 participants who climbed Mount Fuji and obtained information regarding sex, age, and smoking and alcohol habits, including behavior during ascent. Results: AMS prevalence was 45% for all participants. A univariate analysis revealed that younger participants (20–29 years) were associated with increased AMS prevalence (effect size [ES] = 0.102, p = 0.057) and severity (ES = 0.18, p = 0.01). A prediction model using multiple logistic regression indicated that several factors influenced AMS risk: younger age (p = 0.001), daily smoking habits (p = 0.021), no smoking (p = 0.033), or alcohol consumption during ascent (p = 0.096). Alcohol consumption during ascent had no effect on the increased AMS risk in younger participants (20–29 years), while alcohol consumption during ascent increased AMS risk for middle-age participants (50–59 years). Conclusion: Younger individuals are more likely to experience AMS. Smoking habits are associated with an increased AMS risk. It may be recommended that middle-aged climbers should ascend without consuming alcohol. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a patient with intravascular large B-cell lymphoma (IVLBCL) who developed reversible cerebral vasoconstriction syndrome (RCVS) after receiving immunochemotherapy. IVLBCL is a rare subtype of large B-cell lymphoma that can present with neurological symptoms. The patient experienced sudden blindness and was diagnosed with RCVS based on neurological symptoms and imaging findings. The article explores the potential triggers and pathogenesis of RCVS in IVLBCL patients and highlights the importance of considering RCVS as a differential diagnosis in these cases. Treatment with nimodipine and continuation of immunochemotherapy resulted in the resolution of symptoms and improvement in vision. [Extracted from the article]

Migraine is a form of primary headache that affects at least 10% of the world's population. In addition to advising patients to modify their lifestyles, the management of migraine includes terminating ongoing attacks and/or preventing attacks from occurring. Pharmacological agents of both nonspecific (for example, non-narcotic analgesics), and specific actions can be used for the abortive treatment of this form of headache. Specific treatments include, in particular, serotoninergic agents: triptans (selective 5-HT1B/1D receptor agonists), ditans (selective 5-HT1F-mimetics) and ergot alkaloids (non-selective modulators of various subtypes of 5-HT receptor). This review presents the currently known results from many basic and applied studies of drugs from these groups, identifying the neuronal and vascular components of their anti-migraine pharmacodynamics. Significant quantities of these data were obtained in vivo in a variety of experimental models of migraine based on the trigeminovascular theory of its pathogenesis. Other information is based on ex vivo work on isolated tissues and cell cultures. Analysis of results from these studies yielded evidence in favor of the notion that the anti-migraine potential of members of all of these pharmacological classes is mediated by similar mechanisms, whereby neurotropic activity dominates over direct intervention in vascular tone. Special attention is paid to uncertain and controversial issues in this area, whose successful solution is key to further progress in the pharmacotherapy of migraine. [ABSTRACT FROM AUTHOR]

Topical corticosteroids manage inflammatory skin conditions via their action on the immune system. An effect of application of corticosteroids to the skin is skin blanching caused by peripheral vasoconstriction. This has been used to characterize, in some cases relative potency and also as a way to compare skin penetration. Chromameters have been used to assess skin blanching—the outcome of vasoconstriction caused by topical corticosteroids—but do not directly measure vasoconstriction. Here, we demonstrate quantitative volumetric photoacoustic microscopy (PAM) as a tool for directly assessing the vasoconstriction followed by topical corticosteroid application, noninvasively visualizing skin vasculature without any exogeneous contrast agent. We photoacoustically differentiated the vasoconstrictive ability of four topical corticosteroids in small animals through multiparametric analyses, offering detailed 3D insights into vasoconstrictive mechanisms across different skin depths. Our findings highlight the potential of PAM as a noninvasive tool for measurement of comparative vasoconstriction with potential for clinical, pharmaceutical, and bioequivalence applications.

Background: Chronic obstructive lung disease (COPD) has diverse molecular pathomechanisms and clinical courses which, however, are not fully mirrored by current therapy. Intermittent hypoxemia is a driver of lung function decline and poor outcome, e.g., in patients with concomitant obstructive sleep apnea. Transient hypoxemia during physical exercise has been suggested to act in a similar manner. The PROSA study is designed to prospectively assess whether the clinical course of COPD patients with or without exertional desaturation differs, and to address potential pathophysiological mechanisms and biomarkers. Methods: 148 COPD patients (GOLD stage 2–3, groups B or C) will undergo exercise testing with continuous pulse oximetry. They will be followed for 36 months by spirometry, echocardiography, endothelial function testing, and biomarker analyses. Exercise testing will be performed by comparing the 6-min walk test (6MWT), bicycle ergometry, and a 15-sec breath-hold test. Exertional desaturation will be defined as SpO2 < 90% or delta-SpO2 ≥ 4% during the 6MWT. The primary endpoint will be the rate of decline of FEV1(LLN) between COPD patients with and without exertional desaturation. Discussion: The PROSA Study is an investigator-initiated prospective study that was designed to prove or dismiss the hypothesis that COPD patients with exertional desaturation have a significantly more rapid rate of decline of lung function as compared to non-desaturators. A 20% difference in the primary endpoint was considered clinically significant; it can be detected with a power of 90%. If the primary endpoint will be met, exercise testing with continuous pulse oximetry can be used as a ubiquitously available, easy screening tool to prospectively assess the risk of rapid lung function decline in COPD patients at an early disease stage. This will allow to introduce personalized, risk-adapted therapy to improve COPD outcome in the long run. PROSA is exclusively funded by public funds provided by the European Research Council through an ERC Advanced Grant. Patient recruitment is ongoing; the PROSA results are expected to be available in 2028. Trial registration: The PROSA Study has been prospectively registered at clinicaltrials.gov (register no. NCT06265623, dated 09.02.2024). [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a rare subtype of group 1 pulmonary hypertension (PH) diseases, characterized by high pulmonary artery pressure leading to right ventricular dysfunction and potential life-threatening consequences. PAH involves complex mechanisms: vasoconstriction, vascular remodeling, endothelial dysfunction, inflammation, oxidative stress, fibrosis, RV remodeling, cellular hypoxia, metabolic imbalance, and thrombosis. These mechanisms are mediated by several pathways, involving molecules like nitric oxide and prostacyclin. PAH diagnosis requires clinical evaluation and right heart catheterization, confirming a value of mPAP ≥ 20 mmHg at rest and often elevated pulmonary vascular resistance (PVR). Even if an early and accurate diagnosis is crucial, PAH still lacks effective biomarkers to assist in its diagnosis and prognosis. Biomarkers could contribute to arousing clinical suspicion and serve for prognosis prediction, risk stratification, and dynamic monitoring in patients with PAH. The aim of the present review is to report the main novelties on new possible biomarkers for the diagnosis, prognosis, and treatment monitoring of PAH. [ABSTRACT FROM AUTHOR]

Background: The intramuscular (IM) administration of 7.5-10 mg/kg of alfaxalone produces anesthetic effects that enable endotracheal intubation with mild cardiorespiratory depression in dogs. However, the effects of IM co-administration of medetomidine, butorphanol, and alfaxalone on cardiorespiratory function under inhalation anesthesia have not been studied. Aim: To assess the cardiorespiratory function following the IM co-administration of 5 µg/kg of medetomidine, 0.3 mg/kg of butorphanol, and 2.5 mg/kg of alfaxalone (MBA) in dogs anesthetized with sevoflurane. Methods: Seven intact healthy Beagles (three males and four females, aged 3-6 years old and weighing 10.0-18.1 kg) anesthetized with a predetermined minimum alveolar concentration (MAC) of sevoflurane were included in this study. The baseline cardiorespiratory variable values were recorded using the thermodilution method with a pulmonary artery catheter after stabilization for 15 minutes at 1.3 times their individual sevoflurane MAC. The cardiorespiratory variables were measured again following the IM administration of MBA. Data are expressed as median [interquartile range] and compared with the corresponding baseline values using the Friedman test and Sheff's method. A p < 0.05 was considered statistically significant. Results: The intramuscular administration of MBA transiently decreased the cardiac index [baseline: 3.46 (3.18-3.69), 5 minutes: 1.67 (1.57-1.75) l/minute/m2: p < 0.001], respiratory frequency, and arterial pH. In contrast, it increased the systemic vascular resistance index [baseline: 5,367 (3,589-6,617), 5 minutes:10,197 (9,955-15,005) dynes second/cm5/m2: p = 0.0092], mean pulmonary arterial pressure, and arterial partial pressure of carbon dioxide. Conclusion: The intramuscular administration of MBA in dogs anesthetized with sevoflurane transiently decreased cardiac output due to vasoconstriction. Although spontaneous breathing was maintained, MBA administration resulted in respiratory acidosis due to hypoventilation. Thus, it is important to administer MBA with caution to dogs with insufficient cardiovascular function. In addition, ventilatory support is recommended. [ABSTRACT FROM AUTHOR]

Hormone-sensitive lipase (HSL) is active throughout the brain and its genetic ablation impacts brain function. Its activity in the brain was proposed to regulate bioactive lipid availability, namely eicosanoids that are inflammatory mediators and regulate cerebral blood flow (CBF). We aimed at testing whether HSL deletion increases susceptibility to neuroinflammation and impaired brain perfusion upon diet-induced obesity. HSL−/−, HSL+/−, and HSL+/+ mice of either sex were fed high-fat diet (HFD) or control diet for 8 weeks, and then assessed in behavior tests (object recognition, open field, and elevated plus maze), metabolic tests (insulin and glucose tolerance tests and indirect calorimetry in metabolic cages), and CBF determination by arterial spin labeling (ASL) magnetic resonance imaging (MRI). Immunofluorescence microscopy was used to determine coverage of blood vessels, and morphology of astrocytes and microglia in brain slices. HSL deletion reduced CBF, most prominently in cortex and hippocampus, while HFD feeding only lowered CBF in the hippocampus of wild-type mice. CBF was positively correlated with lectin-stained vessel density. HSL deletion did not exacerbate HFD-induced microgliosis in the hippocampus and hypothalamus. HSL−/− mice showed preserved memory performance when compared to wild-type mice, and HSL deletion did not significantly aggravate HFD-induced memory impairment in object recognition tests. In contrast, HSL deletion conferred protection against HFD-induced obesity, glucose intolerance, and insulin resistance. Altogether, this study points to distinct roles of HSL in periphery and brain during diet-induced obesity. While HSL−/− mice were protected against metabolic syndrome development, HSL deletion reduced brain perfusion without leading to aggravated HFD-induced neuroinflammation and memory dysfunction. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been increasingly used in the clinical treatment of neoplastic, inflammatory and infectious skin diseases. However, the generation of reactive oxygen species (ROS) may induce undesired side effects in normal tissue surrounding the treatment lesion, which is a big challenge for the clinical application of PDT. To date, (–)-Epigallocatechin gallate (EGCG) has been widely proposed as an antiangiogenic and antitumor agent for the protection of normal tissue from ROS-mediated oxidative damage. This study evaluates the regulation ability of EGCG for photodynamic damage of blood vessels during hematoporphyrin monomethyl ether (Hemoporfin)-mediated PDT. The quenching rate constants of EGCG for the triplet-state Hemoporfin and photosensitized 1O2 generation are determined to be 6. 8 × 1 0 8 M−1S−1 and 1. 5 × 1 0 8 M−1S−1, respectively. The vasoconstriction of blood vessels in the protected region treated with EGCG hydrogel after PDT is lower than that of the control region treated with pure hydrogel, suggesting an efficiently reduced photodamage of Hemoporfin for blood vessels treated with EGCG. This study indicates that EGCG is an efficient quencher for triplet-state Hemoporfin and 1O2, and EGCG could be potentially used to reduce the undesired photodamage of normal tissue in clinical PDT. [ABSTRACT FROM AUTHOR]

Background: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) may cause ischaemic stroke and intracranial haemorrhage. The aim of our study was to assess the frequency of the afore‐mentioned outcomes. Methods: We performed a PROSPERO‐registered (CRD42022355704) systematic review and meta‐analysis accessing PubMed until 7 November 2022. The inclusion criteria were: (1) original publication, (2) adult patients (≥18 years), (3) enrolling patients with PRES and/or RCVS, (4) English language and (5) outcome information. Outcomes were frequency of (1) ischaemic stroke and (2) intracranial haemorrhage, divided into subarachnoid haemorrhage (SAH) and intraparenchymal haemorrhage (IPH). The Cochrane Risk of Bias tool was used. Results: We identified 848 studies and included 48 relevant studies after reviewing titles, abstracts and full text. We found 11 studies on RCVS (unselected patients), reporting on 2746 patients. Among the patients analysed, 15.9% (95% CI 9.6%–23.4%) had ischaemic stroke and 22.1% (95% CI 10%–39.6%) had intracranial haemorrhage. A further 20.3% (95% CI 11.2%–31.2%) had SAH and 6.7% (95% CI 3.6%–10.7%) had IPH. Furthermore, we found 28 studies on PRES (unselected patients), reporting on 1385 patients. Among the patients analysed, 11.2% (95% CI 7.9%–15%) had ischaemic stroke and 16.1% (95% CI 12.3%–20.3%) had intracranial haemorrhage. Further, 7% (95% CI 4.7%–9.9%) had SAH and 9.7% (95% CI 5.4%–15%) had IPH. Conclusions: Intracranial haemorrhage and ischaemic stroke are common outcomes in PRES and RCVS. The frequency reported in the individual studies varied considerably. [ABSTRACT FROM AUTHOR]