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Background: Orally administered second-generation gepants are effective for the treatment of migraine. The intranasal administration of the third-generation gepant zavegepant might have additional benefits including a rapid onset of action, but it is not clear yet to which extent this has clinical relevance. Methods: We examined the effect of zavegepant on the relaxations induced by calcitonin gene-related peptide (CGRP) in human isolated middle meningeal arteries. Furthermore, we connected the pharmacodynamics and pharmacokinetics of gepants by combining data from clinical and basic research. Results: We showed that 10 nM zavegepant potently antagonized the functional response to CGRP. We also showed that all gepants are effective at inhibiting functional responses to CGRP at their therapeutic plasma concentrations. Conclusions: The relatively low predicted potency of zavegepant to inhibit CGRP-induced relaxation at therapeutic systemic plasma concentrations may point to the relevance of local delivery to the trigeminovascular system through intranasal administration. This approach may have additional benefits for various groups of patients, including overweight patients. [ABSTRACT FROM AUTHOR]

Vacuolar H+‐ATPase (V‐ATPase) is a multisubunit protein complex which, along with its accessory proteins, resides in almost every eukaryotic cell. It acts as a proton pump and as such is responsible for regulating pH in lysosomes, endosomes, and the extracellular space. Moreover, V‐ATPase has been implicated in receptor‐mediated signaling. Although numerous studies have explored the role of V‐ATPase in cancer, osteoporosis, and neurodegenerative diseases, research on its involvement in vascular disease remains limited. Vascular diseases pose significant challenges to human health. This review aimed to shed light on the role of V‐ATPase in hypertension and atherosclerosis. Furthermore, given that vascular complications are major complications of diabetes, this review also discusses the pathways through which V‐ATPase may contribute to such complications. Beginning with an overview of the structure and function of V‐ATPase in hypertension, atherosclerosis, and diabetes, this review ends by exploring the pharmacological potential of targeting V‐ATPase. [ABSTRACT FROM AUTHOR]

Background Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age. Methods Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m.sup.2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone. Conclusions This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients., Author(s): Daan H. H. M. Viering [sup.1] , Anneke P. Bech [sup.2] , Jeroen H. F. de Baaij [sup.1] , Eric J. Steenbergen [sup.3] , A. H. Jan Danser [sup.4] [...]

Cardiovascular diseases are the number one cause of death globally. The most important determinant of cardiovascular health is a person's age. Aging results in structural changes and functional decline of the cardiovascular system. DNA damage is an important contributor to the aging process, and mice with a DNA repair defect caused by Ercc1 deficiency display hypertension, vascular stiffening, and loss of vasomotor control. To determine the underlying cause, we compared important hallmarks of vascular aging in aortas of both Ercc1Δ/− and age‐matched wildtype mice. Additionally, we investigated vascular aging in 104 week old wildtype mice. Ercc1Δ/− aortas displayed arterial thickening, a loss of cells, and a discontinuous endothelial layer. Aortas of 24 week old Ercc1Δ/− mice showed phenotypical switching of vascular smooth muscle cells (VSMCs), characterized by a decrease in contractile markers and a decrease in synthetic markers at the RNA level. As well as an increase in osteogenic markers, microcalcification, and an increase in markers for damage induced stress response. This suggests that Ercc1Δ/− VSMCs undergo a stress‐induced contractile‐to‐osteogenic phenotype switch. Ercc1Δ/− aortas showed increased MMP activity, elastin fragmentation, and proteoglycan deposition, characteristic of vascular aging and indicative of age‐related extracellular matrix remodeling. The 104 week old WT mice showed loss of cells, VSMC dedifferentiation, and senescence. In conclusion, Ercc1Δ/− aortas rapidly display many characteristics of vascular aging, and thus the Ercc1Δ/− mouse is an excellent model to evaluate drugs that prevent vascular aging in a short time span at the functional, histological, and cellular level. [ABSTRACT FROM AUTHOR]

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and β-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of β-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a β-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS. [ABSTRACT FROM AUTHOR]

The article discusses the phenomenon of cryoactivation, which refers to a cold-induced change in prorenin, the inactive precursor of renin. The authors explain that storing plasma samples at low temperatures for a long time can lead to the inactivation of serine protease inhibitors, resulting in the generation of kallikrein, which can cleave the prosegment of prorenin. The authors argue that storing samples at -20 °C is sufficient and that there is no advantage to storing them at -70 °C. They also mention that renin inhibitors can bind to the active site of prorenin, leading to overestimation of renin levels in certain assays. [Extracted from the article]