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The airways contain a dense subepithelial microvascular plexus that is involved in the supply and clearance of substances to and from the airway wall. We set out to test the hypothesis that airway smooth muscle reactivity to bronchoconstricting agents may be dependent on airway mucosal blood flow. Immunohistochemical staining identified vasoconstrictor and vasodilator nerve fibers associated with subepithelial blood vessels in the guinea pig airways. Intravital microscopy of the tracheal mucosal microvasculature in anesthetized guinea pigs revealed that blockade of α-adrenergic receptors increased baseline arteriole diameter by ~40%, whereas the α-adrenergic receptor agonist phenylephrine produced a modest (5%) vasoconstriction in excess of the baseline tone. In subsequent in vivo experiments, tracheal contractions evoked by topically applied histamine were significantly reduced (P < 0.05) and enhanced by α-adrenergic receptor blockade and activation, respectively. α-Adrenergic ligands produced similar significant (P < 0.05) effects on airway smooth muscle contractions evoked by topically administered capsaicin, intravenously administered neurokinin A, inhaled histamine, and topically administered antigen in sensitized animals. These responses were independent of any direct effect of α-adrenergic ligands on the airway smooth muscle tone. The data suggest that changes in blood flow in the vessels supplying the airways regulate the reactivity of the underlying airway smooth muscle to locally released and exogenously administered agents by regulating their clearance. We speculate that changes in mucosal vascular function or changes in neuronal regulation of the airway vasculature may contribute to airways responsiveness in disease.

In this Commentary, the roles of uridine adenosine tetraphosphate as an endothelium-derived contracting or relaxing factor described in the paper by Tölle et al. are considered and put into the wider context of the mechanisms of control of vascular tone by purinergic signalling via receptors located on both smooth muscle and endothelial cells.

Although the function of rhythmic contractions in the vascular wall - vasomotion - is still under debate, it has been suggested to play a significant role for tissue oxygen homeostasis and under pathological conditions where tissue perfusion is affected. Vasomotion has further been suggested to be important for blood pressure control and has been shown to be reduced in diabetes. Vasomotion is initiated by the coordinated activation of smooth muscle cells (SMCs) in the vascular wall leading to rhythmic contractions. We have suggested the model for generation of this rhythmic activity and have shown that vasomotion initiates via interaction between intracellular calcium released from the sarcoplasmic reticulum and changes in membrane potential. Rhythmic changes in intracellular calcium induce, under certain conditions (in the presence of sufficient concentration of cGMP), changes in membrane potential that lock the electrically-connected SMCs into phase. Synchronized depolarization induces synchronous calcium influx and thus produces rhythmic contraction of blood vessels. I have demonstrated and characterized a new chloride channel in vascular SMCs, which has properties necessary to coordinate SMCs in the vascular wall. Chloride channels have been investigated for many years but remained somewhat in the shadow of cation channels. We know now the molecular structures of some chloride channels, i.e. GABA receptors, "cystic fibrosis transmem-brane conductance regulator" (CFTR) and the ClC chloride channel family. There is one particular group of chloride channels, the calcium activated chloride channels (CaCCs), whose molecular structure is debated still. There are currently no pharmacological tools that activate or inhibit CaCCs with any significant selectivity. The existence of CaCCs in almost all cells in the body has been known for many years based on electrophysiological and other functional studies. CaCCs have been suggested to be important for regulation of membrane potential and cellular volume, as well as for body homeostasis. CaCCs are well characterized in vascular tissues but only at the functional level. The lack of their molecular structure makes it difficult to study the clinical significance of these channels. Based on patch clamp measurements of ion currents, I have previously characterized in SMCs a chloride current with unique properties. This chloride current activated by cGMP, has very high sensitivity to calcium and can be inhibited by low concentrations of zinc ions, while the traditional inhibitors of CaCCs affect this current only at very high concentrations. This cGMP-dependent, calcium-activated chloride current has a linear volt-age-dependence, which differs from previously characterized CaCCs, and it has characteristic anion permeability. This current has been detected in SMCs isolated from a number of different vascular beds but, importantly, it has not been detected in pulmonary arteries. Moreover, this current has been shown in SMCs isolated intestine indicating its broad distribution. Based on unique characteristics I have suggested that the cGMP-dependent calcium-activated chloride current can synchronize SMCs in the vascular wall and that bestrophin protein could be the molecular substrate for this current. Bestrophin has been characterized first as a gene in which mutations cause vitelliform macular dystrophy (VMD) or Best diseases. Based on heterologous expression it has been suggested that bestrophin is a chloride channel. This question is nevertheless controversial since caution should be taken in heterologous expression of calcium-activated chloride channel candidates. The presence of chloride channels in virtually all living cells is an essential problem as well as the dependence of ion channel properties on the complex interaction of many cellular proteins. I was the first who coupled the endogenous chloride current to one of four known bestrophin isoforms. PCR and Western blot studies on different blood vessels demonstrated the presence of bestrophin-3 protein with the exception of pulmonary arteries where the cGMP-dependent current is also absent). There was a strong indication that bestrophin-3 expression could be essential for the cGMP-dependent calcium-activated chloride current. To couple bestrophin-3 expression and this current I have used small interfering RNA (siRNA) technique to downregulate the expression of the candidate (bestrophin-3) and have studied the effect of this specific downregulation on chloride currents. I showed that bestrophin-3 expression is associated with the cGMP-dependent calcium-activated chloride current. This study does not tell us whether bestrophin-3 forms the channel or it is an essential subunit but the previous mutagenic experiments suggested the first possibility. Electrical communication between SMCs is essential for successful synchronization and depends on channels between the cells called gap junctions. The majority of cardiovascular diseases (e.g. hypertension and atherosclerosis) are associated with defects in intercellular communications or in gap junction regulation. The molecular mechanisms responsible for these defects are un-known because of lack of specific experimental tools. Our comprehensive study on the often used gap junction inhibitors heptanol and 18β-glycyrrhetinic acid demonstrated unspecific effects of these drugs at the concentrations where they have no or little gap junctions effects. Other drugs, e.g. 18α-glycyrrhetinic acid and connexin-mimetic peptides are better to inhibit gap junctions but also have demonstrated unspecific effects. Previous studies suggested that channels and transporters in the cell membrane do not function independently but interact as functional units in the spatially restricted areas of the cell. I have demonstrated a close functional interaction between gap junctions and Na+,K+-ATPase, Na+/Ca2+-exchanger and ATP-dependent K+ channels in the spatially restricted manner. I have shown that inhibition of the ouabain-sensitive Na+, K+-ATPase inhibits calcium efflux by the Na+/Ca2+-exchanger and this leads to the local elevation of intracellular calcium and inhibition of intercellular communications. This explains the inhibitory action of ouabain on vasomotion. I have also found that the ATP-dependent K+ channel is an important player in this functional unit and this interaction is reciprocal, since K+ channel supplies Na+, K+-ATPase with K+ ions while the ATP-dependent K+ channel current also regulates the Na+, K+-ATPase. This dissertation is based on nine scientific publications where I have suggested the model for generation of vasomotion and characterized the essential elements of this model.

The endothelium-dependent and myogenic reactions of pia mater arteries of the 1st-5th branching orders were studied in 1-, 3-, and 24-month-old rats by biomicroscopy method. The endothelium-independent (myogenic) reaction predominated in the 1st-3rd order branches and the endothelium-dependent vascular reaction in the 5th order branches of 3-month-old rats. Both regulatory mechanisms were equally developed in the 4th order branches. In 1-month-old rats, the endothelium-dependent reaction was more active in the majority of branches. In 24-month-old rats, this reaction was significantly higher than the endothelium-independent one only in the 4th and 5th order branches. In contrast to 3-month-old rats, the myogenic reaction of 24-month-old animals predominated in the 1st and 2nd order branches and the endothelium-dependent one in the 4th and 5th order branches. Vascular reactivity of 24-month-old rats was lower than in younger rats in all cases.

Brain angiotensin II (Ang II) induces tonic sympathoexcitatory effects through AT1 receptor stimulation of glutamatergic neurons and sympathoinhibitory effects via GABAergic neurons in the rostral ventrolateral medulla, the brainstem 'pressor area'. NADPH-derived superoxide production and reactive oxygen species signalling is critical in these actions, and AT2 receptors in the rostral ventrolateral medulla appear to mediate opposing effects on sympathetic outflow. In the hypothalamic paraventricular nucleus, Ang II has AT1 receptor-mediated sympathoexcitatory effects and enhances nitric oxide formation, which in turn inhibits the Ang II effects through a GABAergic mechanism. Ang II also decreases the tonic sympathoinhibitory effect of gamma amino butyric acid within the paraventricular nucleus. Angiotensin III and Angiotensin IV increase blood pressure via brain AT1 receptor stimulation. Angiotensin (1-7) influences cardiovascular function through a specific Mas-receptor. This review examines the evidence that brain angiotensin peptides, glutamate, gamma amino butyric acid and nitric oxide interact within the rostral ventrolateral medulla and paraventricular nucleus to control sympathetic tone and blood pressure.

Background: Endothelin-1 (ET-1) is considered to be one of the most potent and long-lasting vasoconstrictive peptides, but the mechanisms on the regulation of ET-1 expression are not fully understood., Method and Results: In this study, we found that microRNA (miR)-125a-5p and miR-125b-5p are highly expressed in vascular endothelial cells (VECs), which can be regulated by oxidized low-density lipoprotein (oxLDL). To explore the function of miR-125a/b-5p in VECs, we examined the roles of potential targets of miR-125a/b-5p that could influence endothelium function. We found that both miR-125a/b-5p can suppress oxLDL-induced ET-1 expression by directly targeting 3' untranslated region of prepro-endothelin-1 (preproET-1) mRNA determined by luciferase reporter assay, western blot, and enzyme immunometric assay. Consistently, inhibitors of miR-125a/b-5p can directly enhance preproET-1 expression. The decreased expressions of miR-125a-5p and miR-125b-5p are negatively associated with upregulation of preproET-1 expression in aorta of stroke-prone spontaneously hypertensive rats (SHR-SPs)., Conclusion: Our finding demonstrated that endothelial miR-125a/b-5p inhibits ET-1 expression in VECs, which revealed a novel miRNA-mediated mechanism in vasomotor homeostasis.

Background: Attenuated peripheral perfusion in patients with advanced chronic heart failure (CHF) is partially the result of endothelial dysfunction. This has been causally linked to an impaired endogenous regenerative capacity of circulating progenitor cells (CPC). The aim of this study was to elucidate whether exercise training (ET) affects exercise intolerance and left ventricular (LV) performance in patients with advanced CHF (New York Heart Association class IIIb) and whether this is associated with correction of peripheral vasomotion and induction of endogenous regeneration., Methods and Results: Thirty-seven patients with CHF (LV ejection fraction 24+/-2%) were randomly assigned to 12 weeks of ET or sedentary lifestyle (control). At the beginning of the study and after 12 weeks, maximal oxygen consumption (Vo(2)max) and LV ejection fraction were determined; the number of CD34(+)/KDR(+) CPCs was quantified by flow cytometry and CPC functional capacity was determined by migration assay. Flow-mediated dilation was assessed by ultrasound. Capillary density was measured in skeletal muscle tissue samples. In advanced CHF, ET improved Vo(2)max by +2.7+/-2.2 versus -0.8+/-3.1 mL/min/kg in control (P=0.009) and LV ejection fraction by +9.4+/-6.1 versus -0.8+/-5.2% in control (P<0.001). Flow-mediated dilation improved by +7.43+/-2.28 versus +0.09+/-2.18% in control (P<0.001). ET increased the number of CPC by +83+/-60 versus -6+/-109 cells/mL in control (P=0.014) and their migratory capacity by +224+/-263 versus -12+/-159 CPC/1000 plated CPC in control (P=0.03). Skeletal muscle capillary density increased by +0.22+/-0.10 versus -0.02+/-0.16 capillaries per fiber in control (P<0.001)., Conclusions: Twelve weeks of ET in patients with advanced CHF is associated with augmented regenerative capacity of CPCs, enhanced flow-mediated dilation suggestive of improvement in endothelial function, skeletal muscle neovascularization, and improved LV function. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00176384.

Objectives: We investigated whether menopausal vasomotor symptoms (VMS) are related to an adverse cardiovascular risk profile. Furthermore, we examined the association between estradiol levels and VMS, and whether an association between VMS and cardiovascular risk factors can be explained by estradiol levels., Study Design: We used data from a Swedish population-based sample of 5857 women, aged 50-64 years. Data on VMS and potential confounders were collected by questionnaires., Main Outcome Measures: Body mass index (BMI), waist hip ratio (WHR), glucose, blood pressure, lipid profile and estradiol levels were measured., Results: Symptoms of flushing/sweats were reported by 55% and sweats by 31% of all women. Estradiol concentrations were significantly lower in women with VMS. After multivariate adjustment, women with symptoms of sweats had a statistically significantly higher BMI, waist hip ratio, total cholesterol level, LDL level, triglycerides level, glucose level, systolic and diastolic blood pressure. These patterns did not change after correction for estradiol. The associations between flushing/sweats combined and cardiovascular risk factors were less pronounced., Conclusions: Women with VMS have a less favorable cardiovascular risk profile. Although estradiol levels were significantly lower among women with VMS, the increased cardiovascular risk profile cannot be explained by circulating estradiol levels., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.

We compared the excitability of secretomotor B and vasomotor C neurons using virtual nicotinic synapses implemented with the dynamic clamp technique. In response to fast synaptic conductance (g(syn)) waveforms modeled after B cell synaptic currents, it took 17.1+/-1.2nS to elicit spikes in 104 B cells and 3.3+/-0.3nS in 35 C cells. After normalizing for whole-cell capacitance, C cells were still more excitable than B cells (76+/-5pS/pF vs. 169+/-8pS/pF). Stimulating C cells with slower g(syn) waveforms, identical to synaptic currents in C cells, further accentuated the difference between cell types. The phenotypic excitability difference did not correlate with time in culture (1-12days) and could not be explained by resting potential (B cells: -65.6+/-0.9mV, C cells: -63.1+/-1.6mV) or input conductance density, which was greater in C cells (24.4+/-4.3pS/pF) than B cells (14.5+/-1.5pS/pF). Action potentials elicited by virtual EPSPs had a threshold voltage for firing that was -28.4+/-0.7mV in C cells and -19.7+/-0.4mV B cells, and an upstroke velocity and peak spike potential that were greater in B cells. The repetitive firing properties of B and C cells were similar; 69-78% phasic, 11-16% adapting and 11-15% tonic. We propose that B and C neurons express different types of Na(+) channels that shape how they integrate nicotinic synaptic potentials.

A long-standing, but unproven hypothesis is that menopause symptoms cause cognitive difficulties during the menopause transition. This 6-year longitudinal cohort study of 1,903 midlife US women (2000-2006) asked whether symptoms negatively affect cognitive performance during the menopause transition and whether they are responsible for the negative effect of perimenopause on cognitive processing speed. Major exposures were depressive, anxiety, sleep disturbance, and vasomotor symptoms and menopause transition stages. Outcomes were longitudinal performance in 3 domains: processing speed (Symbol Digit Modalities Test (SDMT)), verbal memory (East Boston Memory Test), and working memory (Digit Span Backward). Adjustment for demographics showed that women with concurrent depressive symptoms scored 1 point lower on the SDMT (P < 0.05). On the East Boston Memory Test, the rate of learning among women with anxiety symptoms tested previously was 0.09 smaller per occasion (P = 0.03), 53% of the mean learning rate. The SDMT learning rate was 1.00 point smaller during late perimenopause than during premenopause (P = 0.04); further adjustment for symptoms did not attenuate this negative effect. Depressive and anxiety symptoms had a small, negative effect on processing speed. The authors found that depressive, anxiety, sleep disturbance, and vasomotor symptoms did not account for the transient decrement in SDMT learning observed during late perimenopause.

The endothelin type A (ETA) receptor was studied in six healthy subjects on two occasions with or without an ETA receptor (BQ-123) blockade. At 40 min of either BQ-123 or NaCl infusion, a concomitant infusion of the endothelin-1 (ET-1) precursor, big ET-1, was initiated to augment ET-1 formation. Blood samples were taken from catheters in a peripheral artery, the renal and femoral veins, and the pulmonary artery. Forty minutes of infusion with BQ-123 alone increased heart rate (P<0.001) and cardiac output (CO; P<0.01) and depressed mean arterial blood pressure (P<0.001) and systemic vascular resistance (SVR; P<0.01). During infusion of big ET-1 alone, CO, stroke volume, and renal blood flow decreased (P<0.01), whereas SVR and pulmonary and renal vascular resistance increased (P<0.05). These responses to big ET-1 were abolished or diminished by BQ-123. Renal ET-1 release was threefold higher when big ET-1 infusion was preceded by BQ-123 infusion (P<0.001). Arterial ET-1 concentrations rose to similar levels after big ET-1 infusion (P<0.01) in both trials because of elevated concomitant pulmonary uptake (P<0.05) after ETA blockade. Although there was no net ET-1 leg exchange, leg ET-1 turnover was higher after big ET-1 was preceded by BQ-123. Gene expression of endothelin-converting enzyme 1 and ET-1 in skeletal muscle remained unaltered on both occasions. Our data demonstrate that the level of circulating ET-1 is regulated by ETA receptor-mediated negative feedback. This mechanism seems to be coupled to increased conversion of big ET-1 and is most potent in the kidneys. This emphasizes the important physiological role of ETA receptors in the kidneys, and the lung seems to be mainly a clearing organ for ET-1.

Objective: To investigate the effects of histamine receptor antagonists on vasoconstriction induced by electrical stimulation (ES) on posterior auricular nerve, and to explore the pre- and post-synaptic effects of sympathetic histamine on the vasomotor responses of vascular smooth muscle in rabbit ear., Methods: ES was applied to posterior auricular nerves of the whole rabbit ear at 10 Hz, 20 Hz and 40 Hz, respectively. Besides, the whole ear was perfused with different histamine receptor antagonists under constant perfusion pressure, and the changes in the flow rate of perfusate were observed., Results: The flow rate of venous outflow was decreased by ES at all the 3 frequencies. The ES-induced vasoconstriction at 20 Hz and 40 Hz could be partly inhibited by H(1) receptor antagonist chlorpheniramine (P < 0.05). After exhaustion of histamine in mast cells by pretreatment with specific mast cell degranulator compound 48/80, chlorpheniramine could still inhibit the ES-induced flow rate reduction. In contrast, H(2) receptor antagonist cimetidine could enhance the 40-Hz ES-induced flow rate reduction (P < 0.05). Moreover, ES-induced vasoconstriction at the 3 frequencies could all be enhanced by H(3) receptor antagonist thioperamide (P < 0.05)., Conclusion: Stimulation on the auricular nerve may evoke histamine release from sympathetic nerves rather than from mast cells. Moreover, the functions of sympathetic histamine vary from pre-synaptic modulation to post-synaptic vasoconstriction or vasodilatation, via activation of different histamine receptors.

Skin problems in children during the first few weeks of life can raise concern, even for experienced neonatologists and paediatric dermatologists. The skin of preterm and term newborn babies has distinct differences from juvenile and adult skin. An understanding of the nature of neonatal skin, the physiological and nonphysiological skin conditions of preterm and term neonates, and skin care are essential in paediatric practice. This article discusses the nature of the neonatal skin and its physiological phenomena.

The aim of human temperature regulation is to protect body processes by establishing a relative constancy of deep body temperature (regulated variable), in spite of external and internal influences on it. This is basically achieved by a distributed multi-sensor, multi-processor, multi-effector proportional feedback control system. The paper explains why proportional control implies inherent deviations of the regulated variable from the value in the thermoneutral zone. The concept of feedback of the thermal state of the body, conveniently represented by a high-weighted core temperature (T (c)) and low-weighted peripheral temperatures (T (s)) is equivalent to the control concept of "auxiliary feedback control", using a main (regulated) variable (T (c)), supported by an auxiliary variable (T (s)). This concept implies neither regulation of T (s) nor feedforward control. Steady-states result in the closed control-loop, when the open-loop properties of the (heat transfer) process are compatible with those of the thermoregulatory processors. They are called operating points or balance points and are achieved due to the inherent property of dynamical stability of the thermoregulatory feedback loop. No set-point and no comparison of signals (e.g. actual-set value) are necessary. Metabolic heat production and sweat production, though receiving the same information about the thermal state of the body, are independent effectors with different thresholds and gains. Coordination between one of these effectors and the vasomotor effector is achieved by the fact that changes in the (heat transfer) process evoked by vasomotor control are taken into account by the metabolic/sweat processor.

Exercise training is known to be an effective means of improving functional capacity and quality of life in patients with peripheral arterial insufficiency (PAI). However, the specific training-induced physiological adaptations occurring within collateral vessels remain to be clearly defined. The purpose of this study was to determine the effect of exercise training on vasomotor properties of isolated peripheral collateral arteries. We hypothesized that daily treadmill exercise would improve the poor vasodilatory capacity of collateral arteries isolated from rats exposed to surgical occlusion of the femoral artery. Following femoral artery ligation, animals were either kept sedentary or exercise trained daily for a period of 3 weeks. Hindlimb collateral arteries were then isolated, cannulated and pressurized via hydrostatic reservoirs to an intravascular pressure of either 45 or 120 cmH(2)O. Non-occluded contralateral vessels of the sedentary animals served as normal Control. Vasodilatory responses to acetylcholine (ACh; 1 x 10(9)-1 x 10(5)m) and sodium nitroprusside (SNP; 1 x 10(9)-1 x 10(4)m), constrictor responses to phenylephrine (PE; 1 x 10(9)-1 x 10(4)m), and flow-induced vasodilatation were determined. Endothelium-mediated vasodilatation responses were significantly greater to either ACh (P < 0.02) or intravascular flow (P < 0.001) in collateral arteries of trained rats. Neither blockade of cyclooxygenase with indomethacin (Indo; 5 microm) nor blockade of endothelial nitric oxide synthase with N(G)-nitro-L-arginine methyl ester (L-NAME; 300 microm) eliminated this ACh- or flow-induced vasodilatation. The depressed vasodilatory response to SNP caused by vascular occlusion was reversed with training. These data indicate that exercise training improves endothelium-mediated vasodilatory capacity of hindlimb collateral arteries, apparently by enhanced production of the putative endothelium-derived hyperpolarizing factor(s). If these findings were applicable to patients with PAI, they could contribute to an improved collateral vessel function and enhance exercise tolerance during routine physical activity.

Tissue blood flow is controlled by a branching network of resistance arteries coupled in series and parallel with one another. To alter organ perfusion during periods of elevated metabolic demand, the arterial segments comprising these networks must dilate in a coordinated manner. Gap junctions are intercellular pores that facilitate arterial coordination by enabling electrical stimuli to conduct among and between endothelial and/or smooth muscle cells. Through this novel perspective, readers will be introduced to the vascular communication field, the process of intercellular conduction, and how key cellular properties influence charge flow. This overview will begin with a brief historical review and then introduce two differing theories on how electrical phenomena moves among and between vascular cells. The basis of the "syncytium" and "differential" hypothesis will be critically discussed within a framework of biophysical and experimental observations. This foundational understanding will be used to extend our mechanistic insight of: (i) "local" and "global" blood flow control; and (ii) debilitating disorders such as arterial vasospasm.

Objectives: Involuntary apnea episodes in obstructive sleep apnea patients result in selective potentiation of peripheral chemoreceptor regulation of sympathetic vasomotor tone. Breath-hold diving is associated with repeated "voluntary" apnea episodes and massive arterial oxygen desaturation, which could also perturb chemoreflex function., Methods: We measured ventilation, heart rate, blood pressure, cardiac stroke volume, and muscle sympathetic nerve activity (MSNA) during isocapnic hypoxia in 11 breath-hold divers and eleven matched control subjects. The study was carried out at least 1 month after intense apnea training., Results: Baseline MSNA frequency was 30 +/- 4 bursts/min in control subjects and 31 +/- 7 bursts/min in divers (ns). During hypoxia MSNA frequency and total activity increased similarly in both groups (30 and 66% in controls and 27 and 60% in divers, respectively). MSNA remained increased after termination of hypoxia and approached baseline measurements after 20 min. Hypoxia-induced stimulation of minute ventilation was similar in both groups, although in divers it was maintained by higher tidal volumes and lower breathing frequency compared with control subjects. In both groups, hypoxia-induced tachycardia drove an increase in cardiac output whereas total peripheral resistance decreased. Blood pressure remained unchanged., Interpretation: We conclude that after the end of intensive training/competition periods, apnea divers show normal peripheral chemoreflex regulation of ventilation and sympathetic vasomotor tone. Although voluntary apnea may not lead to sustained changes in sympathetic nervous system regulation, we cannot exclude the possibility that repeated sympathetic activation elicited by voluntary apnea imposes a burden on the cardiovascular system.

Vasomotor response can be tested by means of transcranial Doppler sonography. It is assumed that flow changes during hyperventilation or breath-holding are due to altered resistance caused by changes in the diameter of vessels distal to the M1 segment of the middle cerebral artery. Evaluating velocities of the M2 and M1 segments together may help elucidate the vasomotor properties of distal segments. We simultaneously evaluated the vasomotor properties of the M1 and M2 segments of the middle cerebral artery in ten healthy volunteers (mean age 21.6 +/- 0.9 years) with breath-holding and hyperventilation. The radius index (RI), defined as the ratio of the M1-M2 segment radii, was estimated after 20 s and after the maximum duration of breath-holding, as well as at the first, second, and third minute of hyperventilation, in relation to velocity ratios. RI values in the resting state were compared with the values after activation procedures. The RI estimated with basal velocities ranged from 0.72 to 0.97 (mean 0.81 +/- 0.07). The RI ranged from 0.73 to 0.97 (mean 0.82 +/- 0.07) after 20 s and 0.75 to 0.90 (mean 0.82 +/- 0.06) after the maximum duration of breath-holding. The RI was 0.72-1.02 (mean 0.85 +/- 0.11), 0.71-1.03 (mean 0.86 +/- 0.12), and 0.71-1.14 (mean 0.88 +/- 0.15) at the first, second, and third minute of hyperventilation, respectively. The differences between RI values in the resting state and during each activation procedure were not statistically significant. These results suggest that the diameter ratio of the M1-M2 segments did not change after vasomotor activation, indicating that the two segments have similar vasomotor properties.

Aims: The study aim was to evaluate the relation between the Framingham risk score (FRS) and the presence of coronary risk factors to coronary microcirculatory vasodilator function in patients with early coronary atherosclerosis., Methods and Results: We evaluated 1063 patients (age: 50 +/- 12 years, 676 (64%) females) without significant narrowing (<30%) on coronary angiography who underwent invasive assessment of coronary endothelial function. Coronary blood flow (CBF) in response to the endothelium-dependent vasodilator acetylcholine was evaluated as well as the microvascular (endothelium-independent) coronary flow reserve (CFR) in response to intracoronary adenosine. Coronary blood flow and CFR were analysed in relation to the FRS and the presence of traditional and novel risk factors. The estimated 10 years risk in this group was 5.4 +/- 5.2%. Higher FRS was associated with lower CBF in men (P = 0.008), and was a univariate predictor of lower CFR (P = 0.012) in all patients. Multivariable analysis identified a higher FRS (P < 0.001), female sex (P < 0.001) and a positive family history of coronary disease (P = 0.043) as independent predictors of reduced CFR., Conclusion: In patients without obstructive coronary disease, a higher FRS was an independent predictor of reduced CFR. The current study provides insight into the relation between cardiac risk profile and coronary microcirculatory function, and suggests that impaired microcirculatory vasodilator function may be present even in patients with a low to intermediate Framingham score.

Extracellular nucleotides transmit signals into the cells through the P2 family of cell surface receptors. These receptors are amply expressed in human blood vessels and participate in vascular tone control; however, their signaling mechanisms remain unknown. Here we show that in smooth muscle cells of isolated human chorionic arteries, the activation of the P2Y(2) receptor (P2Y(2)R) induces not only its partition into membrane rafts but also its rapid internalization. Cholesterol depletion with methyl-beta-cyclodextrin reduced the association of the agonist-activated receptor into membrane rafts but did not affect either the UTP-mediated vasoconstrictions or the vasomotor responses elicited by both serotonin and KCl. Ex vivo perfusion of human chorionic artery segments with 1-10 mum UTP, a selective P2Y(2)R agonist, displaced the P2Y(2)R localization into membrane rafts within 1 min, a process preceded by the activation of both RhoA and Rac1 GTPases. AG1478, a selective and potent inhibitor of the epidermal growth factor receptor tyrosine kinase activity, not only blocked the UTP-induced vasomotor activity but also abrogated both RhoA and Rac1 activation, the P2Y(2)R association with membrane rafts, and its internalization. Altogether, these results show for the first time that the plasma membrane distribution of the P2Y(2)R is transregulated by the epidermal growth factor receptor, revealing an unsuspected functional interplay that controls both the membrane distribution and the vasomotor activity of the P2Y(2)R in intact human blood vessels.

The role of nitric oxide (NO) in the activation-flow coupling (AFC) response to periodic electrical forepaw stimulation was investigated using signal averaged laser Doppler (LD) flowmetry. LD measures of calculated cerebral blood flow (CBF) were obtained both prior and after intra-peritoneal administration of the non-selective nitric oxide synthase (NOS) inhibitor, N(G)-nitro-L-arginine (L-NNA) (40 mg/kg). Characteristic baseline low frequency vasomotion oscillations (0.17 Hz) were observed after L-NNA administration. These LD(CBF) oscillations were synchronous within but not between hemispheres. L-NNA reduced the magnitude of the AFC response (p<0.05) for longer stimuli (1 min) with longer inter-stimulus intervals (2 min). In contrast, the magnitude of the AFC response for short duration stimuli (4 s) with short inter-stimulus intervals (20 s) was augmented (p<0.05) after L-NNA. An interaction occurred between L-NNA induced vasomotion oscillations and the AFC response with the greatest increase occurring at the stimulus harmonic closest to the oscillatory frequency. Nitric oxide may therefore modulate the effects of other vasodilators involved in vasomotion oscillations and the AFC response.

Aims: the present study was performed to evaluate the effects of target disruption of the G-protein-coupled receptor Mas for angiotensin 1-7 [Ang(1-7)] in knockout mice on the course of two-kidney, one-clip (2K1C) Goldblatt hypertension., Methods: knockout and wild-type mice underwent clipping of one renal artery. Blood pressure (BP) was monitored by radiotelemetry. The mice were either untreated or chronically treated with the superoxide (O(2)(-)) scavenger tempol (400 mg/l) or the inhibitor of NADPH oxidase apocynin (1 g/l) administered in drinking water., Results: knockout mice responded to clipping by accelerated increases in BP and the final BP was significantly higher than that in wild-type mice. Chronic treatment with tempol or apocynin elicited similar antihypertensive effects in 2K1C/knockout as in 2K1C/wild-type mice. Acute nitric oxide synthase inhibition caused greater BP increases in 2K1C/wild-type than in 2K1C/knockout mice., Conclusion: our present findings support the notion that the angiotensin-converting enzyme 2-Ang(1-7)-Mas axis serves as an important endogenous physiological counterbalancing mechanism that partially attenuates the hypertensinogenic actions of the activated renin-angiotensin system. The impairment in this axis may contribute to the deterioration of the course of 2K1C Goldblatt hypertension., (2010 S. Karger AG, Basel.)

Pulse pressure analysis algorithms are commonly used to measure cardiac output and to allow for the rational titration of therapy in critically ill patients. The ability of these algorithms to accurately track changes in stroke volume (and cardiac output) is thus very important. Most of the currently available algorithms can provide robust data so long as there is no fundamental change in the vasomotor tone (arterial compliance or impedance). If the tone changes significantly, for instance with vasodilatation or vasoconstriction, then the data become less robust. For this reason, unless there is a mechanism for compensating for changes in vasomotor tone, these algorithms are best used only over short time periods in order to get the most accurate and precise data on changes in cardiac output.

Background: We assess the feasibility of using the newly designed suboccipital probe fixation device (SPFD) as a convenient and reliable tool for simultaneous measurement of vasomotor reactivity (VMR) in the middle cerebral artery (MCA) and basilar artery (BA)., Methods: We analyzed 30 healthy volunteers' VMR values by using both SPFD and conventional handheld method. The VMR values were measured as percentage increase of the mean flow velocity on transcranial Doppler (TCD) in response to hypercapnia induced by the rebreathing method. The VMR tests were performed three times: (1) for both MCAs, (2) for the index MCA (the better signal window) and the BA by using the SPFD, and (3) for the index MCA and the BA by using the handheld technique., Results: The VMR values of the right and left MCAs were similar (P > .05). Although the VMR values of the index MCA and the BA obtained by SPFD application and the handheld technique were similar (P > .05), the correlation coefficient of VMR values obtained by using the SPFD was higher (r= .827, P < .001 vs. r= .568, P= .001)., Conclusion: The SPFD is a convenient and reliable tool for the evaluation of relative VMR between the MCA and BA during TCD monitoring.

Activation of neurons in the dorsomedial hypothalamus (DMH) evokes increases in mean arterial pressure (MAP), sympathetic activity, heart rate (HR) and respiratory activity. Results of previous studies suggest that the DMH-evoked increases in MAP and HR are mediated by neurons within the periaqueductal grey (PAG), but a recent study has proposed that the converse is also true, i.e. that increases in MAP and HR evoked from the PAG depend upon neuronal activity in the DMH. In this study in anaesthetized rats, we examined the functional relationship between the DMH and PAG in regulating renal sympathetic nerve activity (RSNA) and respiratory activity (determined by measuring phrenic nerve activity (PNA)). Bilateral microinjections of the neuronal inhibitor muscimol into the DMH virtually abolished the increases in MAP, RSNA and PNA burst rate and amplitude evoked from the dorsolateral (dl) PAG. In contrast, multiple bilateral injections of much larger (10 times) doses of muscimol or of the local anaesthetic lignocaine into sites in the dlPAG at three different rostrocaudal levels did not reduce the magnitude or duration of the sympathetic vasomotor and respiratory responses evoked by disinhibition of neurons in the DMH. Thus, sympathetic vasomotor and respiratory responses generated from the dlPAG are dependent upon neuronal activity in the DMH, but not the converse. The results of this study together with those of previous studies indicate that the PAG regulates cardiovascular and respiratory function via both ascending projections to the DMH and descending projections to the ventral medulla, that originate from different PAG subregions.

Objective: There is currently a gap in treatment options for menopausal symptoms and a need for comprehensive therapies that are safe and effective for postmenopausal women. This review discusses challenges in the management of menopausal symptoms and the effect of the Women's Health Initiative (WHI) study findings on current treatment patterns. It also examines present and future therapies., Research Design and Methods: A literature search was conducted using Medline, the Cochrane Database, and the National Heart Lung and Blood Institute WHI website with the following search terms: primary care, menopause, vasomotor symptoms, hormone therapy, osteoporosis, and vaginal atrophy. Searches were limited to articles published between 1995 and 2009., Results: Comprehensive therapies that target several aspects of menopause, such as vasomotor symptoms and chronic disease prevention, are currently hormone based. These hormone-based approaches are considered more effective than currently available nonhormonal therapies for the relief of menopausal symptoms. However, hormone therapy is not recommended for women at high risk for venous thromboembolic events, cardiovascular disease, and/or breast cancer. A need exists for novel therapies that mitigate menopausal symptoms, provide protection from osteoporosis, and encourage patient compliance without promoting cancer, heart disease, or stroke. Emerging modalities and strategies, such as the tissue selective estrogen complex (TSEC), Org 50081, MF101, and desvenlafaxine, may provide improved options for postmenopausal women., Conclusions: Several new menopausal therapies that may help to address the ongoing unmet need for safe and effective therapies for postmenopausal women are currently in development. In particular, the TSEC, which provides the benefits of both a selective estrogen receptor modulator and conjugated estrogens with an improved tolerability profile, may offer advantages over currently available treatment options. Limitations of this review include the narrow search criteria and limited search period.

Augmentation index (AIx), a correlate of mortality, is thought to be influenced by left ventricular contractility and wave reflections. However, the relationship of AIx with left ventricular contractility changes has never been assessed, and the wave reflection theory has recently been questioned. This study sought to examine arterial waveform changes in response to reduced "wave reflection" and increased left ventricular contractility induced by dobutamine. Simultaneous radial tonometry (for AIx) and tissue Doppler echocardiography (for peak longitudinal systolic strain rate [SR] as an analogue of left ventricular contractility) were recorded at rest and peak dobutamine-induced stress in 50 patients (41 men; aged 62+/-10 years). From baseline to peak stress there was an increase in heart rate (70+/-11 to 127+/-17 bpm; P<0.001) and SR (-0.88+/-0.23 to -1.81+/-0.43 1/s; P<0.001), whereas AIx decreased (27+/-9% to -7+/-15%; P<0.001). There was also a greater increase in the systolic (compared with diastolic) pressure-time integral relative to cardiac cycle length (3.2+/-1.9 versus 1.8+/-1.1 mm Hg; P<0.001), indicating that wave reflection was not shifted into diastole as per the current belief. AIx was significantly associated with ejection duration (r=0.88), heart rate (r=-0.81), and SR (r=0.72; P<0.001 for all). However, when SR was heart rate corrected, there was no significant association with AIx (r=0.18; P=0.11). The strongest independent correlate of AIx was ejection duration, accounting for 78% variance (beta=0.88; model R2=0.77; P<0.001). Neither SR (beta=0.12; P=0.18) nor heart rate-corrected SR (beta=0.02; P=0.72) was associated with AIx. We conclude that AIx is determined by chronotropic rather than inotropic effects, as well as factors other than wave reflection.

Purpose: To investigate the relative impacts of age and cigarette smoking on cutaneous blood flow and flow motion., Experimental Design: Skin blood flux was measured before and during the hyperaemic response to thermal warming of the skin to 43 degrees C using laser Doppler fluximetry (LDF) in 28 habitual smokers (5.4 [11.4] (median [IQR]) pack years; pack years = packs/day x duration of smoking habit), aged between 18 and 63 years and their age, sex and body mass index. Flow motion was assessed using Fourier analysis of the LDF signal., Results: Mean and total hyperaemic (area under the flux curve, AUC(10)) response during warming were reduced in smokers compared with their non-smoking controls (P<0.05). Attenuation of the response to warming in smokers was associated with a reduction in relative spectral power around 0.01 Hz, reflecting a reduced endothelial/metabolic activity (P<0.04). In regression modelling with AUC(10) as the outcome, and smoking (yes/no), age, sex and BMI, as explanatory variables, age (P<0.0001) and smoking (P=0.018) were independently associated with the hyperaemic response and together accounted for 31% of the variance in AUC(10)., Conclusions: Age and smoking are associated with approximately one-third of the variance in the endothelium-associated microvascular vasomotor activity in habitual smokers.

Both autoregulation and CO(2) reactivity are known to have significant effects on cerebral blood flow and thus on the transport of oxygen through the vasculature. In this paper, a previous model of the autoregulation of blood flow in the cerebral vasculature is expanded to include the dynamic behavior of oxygen transport through binding with hemoglobin. The model is used to predict the transfer functions for both oxyhemoglobin and deoxyhemoglobin in response to fluctuations in arterial blood pressure and arterial CO(2) concentration. It is shown that only six additional nondimensional groups are required in addition to the five that were previously found to characterize the cerebral blood flow response. A resonant frequency in the pressure-oxyhemoglobin transfer function is found to occur in the region of 0.1 Hz, which is a frequency of considerable physiological interest. The model predictions are compared with results from the published literature of phase angle at this frequency, showing that the effects of changes in breathing rate can significantly alter the inferred phase dynamics between blood pressure and hemoglobin. The question of whether dynamic cerebral autoregulation is affected under conditions of stenosis or stroke is then examined.

The ventral medulla oblongata is critical for cardiorespiratory regulation. Here we review previous literature relating to sites within the ventral medulla that have been identified as having a 'cardiovascular' or 'respiratory' function. Together with the maps generated here, of sites from which cardiovascular and respiratory responses were evoked by glutamate microinjection, specific 'cardiovascular' regions have been defined and delineated. Commonly investigated regions, including the vasopressor rostral ventrolateral medulla (RVLM) and vasodepressor caudal ventrolateral medulla (CVLM), or areas only described by others, such as the medullary cerebral vasodilator area, are included for completeness. Emphasis is given to the caudal medulla, where three pressor regions, the caudal pressor area (CPA), the intermediate pressor area (IPA) and the medullo-cervical pressor area (MCPA), caudal to the vasodepressor CVLM were defined in the original data provided. The IPA is most responsive under pentobarbitone rather than urethane anaesthesia clearly delineating it from both the rostrally located CPA and the caudally located MCPA. The description of these multiple pressor areas appears to clarify the confusion that surrounds the identification of the 'CPA'. Also noted is a vasopressor region adjacent to the vasodepressor CVLM. Apart from the well described ventral respiratory column, a region medial to the pre-Bötzinger is described, from which increases in both phrenic nerve frequency and amplitude were evoked. Limitations associated with the technique of glutamate microinjection to define functionally specific regions are discussed. Particular effort has been made to define and delineate the regions with respect to ventrally located anatomical landmarks rather than the commonly used ventral surface or dorsal landmarks such as the obex or calamus scriptorius that may vary with the brain orientation or histological processing. This should ensure that a region can easily be defined by all investigators. Study of defined regions will help expedite the identification of the role of the multiple cell groups with diverse neurotransmitter complements that exist even within each of the regions described, in coordinating the delivery of oxygenated blood to the tissues.

Background: We investigated the role of calcium-activated potassium (K(Ca)) channel activation in myogenic tone in human peripheral microvasculature after heart surgery., Methods: Human skeletal muscle arterioles (90-180microm diameter) were dissected from tissue harvested pre- and post-cardiopulmonary bypass (CPB) during cardiac surgery. Myogenic reactivity in response to stepwise increases in intraluminal pressure was studied between pressure steps. Microvessel tone was determined pre-CPB, post-CPB, and after blockade of K(Ca) channels. Expression and localization of large conductance (BK) K(Ca) channels in the coronary microvasculature was assessed by immunoblot and immunofluorescence photomicroscopy., Results: Myogenic tone of skeletal muscle arterioles was significantly reduced post-CPB compared with pre-CPB. Decrease in myogenic tone after CPB was reflected by the increase in microvessel internal diameter. Myogenic tone of post-CPB microvessels was significantly increased after treatment with BK(Ca)-blocker iberiotoxin, but unchanged in the combined presence of the blockers of intermediate (IK(Ca)) and small conductance (SK(Ca)) K(Ca) channels, TRAM34/apamin. The increases in myogenic tone after iberiotoxin treatment were demonstrated as a decrease in microvessel internal diameter. No significant differences in BK(Ca) protein levels were noted comparing pre- and post-CPB conditions judged by immunoblot and by immunofluorescence staining of skeletal muscle microvessels. Prominent staining for BK(Ca)-alpha and BK(Ca)-beta(1) subunits localized to the microvascular smooth muscle., Conclusion: CPB-associated decrease in peripheral myogenic reactivity is likely due to activation of BK(Ca), but not IK(Ca) or SK(Ca). CPB may increase BK(Ca) activity without increasing BK polypeptide level.

Increased wave reflection is an independent factor associated with cardiovascular diseases, risk, and mortality. The influence of the menstrual cycle on wave reflections and particularly on the reproducibility of their measurement has never been examined. The aim of the present study was to examine the reproducibility and variability of wave reflection indices in premenopausal healthy women during their menstrual cycle. Thirty-two women were examined at 3 phases of their menstrual cycle: days 1 to 2 (menstrual phase), days 6 to 14 (late follicular), and days 4 to 7 after ovulation (early luteal phase). Applanation tonometry of the radial artery and aortic pulse wave analysis were performed for the calculation of augmentation pressure, augmentation index, and timing of reflected waves. Reproducibility of these measures was evaluated by intraclass correlation coefficient and Bland-Altman analysis, whereas ANOVA was performed to assess their variability during the menstrual cycle. The SD of augmentation index differences between repeated measurements within the menstrual cycle ranged from 7.6% to 9.9%. Bland-Altman analysis indicated no evidence of systemic bias and no trend for the reproducibility of measurements to vary with their underlying mean value. Intraclass correlation coefficient indicated a moderate reproducibility of augmentation index and augmentation pressure (>0.80) and a rather low reproducibility for timing of reflected waves (0.43). Mean augmentation pressure, augmentation index, and timing of reflected waves did not vary significantly during the menstrual cycle (ANOVA). Measurement of wave reflections at the same phase of the menstrual cycle or statistical adjustment could be suggested for optimal study design and data interpretation.

Objective: We conducted a randomized, double-blind, placebo-controlled, parallel group trial of the efficacy and tolerability of Cimicifuga racemosa (black cohosh) extract for the treatment of anxiety disorder due to menopause. We hypothesized that black cohosh would be superior to placebo in reducing anxiety symptoms of menopause, with a comparable tolerability profile to placebo., Materials and Methods: Subjects were randomized to therapy with either pharmaceutical-grade black cohosh extract (n = 15) or placebo (n = 13) for up to 12 weeks. The primary outcome measure was changed over time in total Hamilton Anxiety Rating Scale (HAM-A) scores. Secondary outcomes included a change in scores on the Beck Anxiety Inventory, Green Climacteric Scale (GCS), and Psychological General Well-Being Index (PGWBI) and the proportion of patients with a change of 50% or higher in baseline HAM-A scores., Results: There was neither a significant group difference in change over time in total HAM-A scores (P = 0.294) nor a group difference in the proportion of subjects with a reduction of 50% or higher in baseline HAM-A scores at study end point (P = 0.79). There was a significantly greater reduction in the total GCS scores during placebo (vs black cohosh; P = 0.035) but no group difference in change over time in the GCS subscale scores or in the PGWBI (P = 0.140). One subject (3.6%) taking black cohosh discontinued treatment because of adverse events., Conclusions: We found no statistically significant anxiolytic effect of black cohosh (vs placebo). However, small sample size, choice of black cohosh preparation, and dosage used may have been limiting factors producing negative results.

Several forms of experimental evidence gathered in the last 37 years have unequivocally established that the medulla oblongata harbors the main neural circuits responsible for generating the vasomotor tone and regulating arterial blood pressure. Our current understanding of this circuitry derives mainly from the studies of Pedro Guertzenstein, a former student who became Professor of Physiology at UNIFESP later, and his colleagues. In this review, we have summarized the main findings as well as our collaboration to a further understanding of the ventrolateral medulla and the control of arterial blood pressure under normal and pathological conditions.

Mastication has been proven to enhance the systemic circulation, with circulatory responses seeming to be largely regulated by autonomic nervous activity via a more complex regulatory system than those of other activities. However, few studies have examined the relationships between changes in autonomic nervous activity and the systemic circulation that are induced by masticatory movement. We investigated changes in the systemic circulation and autonomic nervous activity during gum chewing to clarify the influence of mastication. Electrocardiograms, arterial blood pressure, and masseter electromyograms were taken while chewing gum continuously as indicators of systemic circulation in 10 healthy subjects with normal dentition. Cardiac sympathetic activity and vagus nervous activity, as well as vasomotor sympathetic nervous activity, were evaluated by fluctuation analysis of heart rate and blood pressure. Repeated analysis of variance and multiple comparisons were performed to determine chronological changes in each indicator during gum chewing. Gum chewing increased the heart rate and the mean arterial pressure. Although cardiac sympathetic activity and vagus nervous activity showed significant changes, vasomotor sympathetic nervous activity did not. These results suggest that changes in the autonomic nervous activity of the heart are mainly involved in the enhancement of systemic circulation with gum chewing. This explains some characteristics of autonomic nervous regulation in masticatory movement.

Although the full physiological significance of vasomotion is still debated, it is generally thought to have a role in optimizing tissue oxygenation parameters. We study the effect of vasomotion rhythm in skeletal muscle on oxygen transport using a computational model. The model is used: (i) to test a novel hypothesis that "vasomotors" form a chemical network in which the rhythm adapts to meet oxygen demand in skeletal muscle and (ii) to study the contribution of desynchronized/chaotic vasomotion in optimizing oxygen delivery to skeletal muscle. We formulate a 2D grid model of skeletal muscle consisting of an interleaved arrangement of vessels and muscle fibers fired by a motor neuronal network. The vasomotors too form a network interacting by chemical means. When positive (negative) synapses dominate, the neuronal network exhibits synchronized (desynchronized) activity. Similarly, when positive (negative) chemical interactions dominate, the vessels exhibit synchronized (desynchronized) activity. Optimal oxygenation is observed when both neuronal network and vasomotor network exhibit desynchronous activity. Muscle oxygenation is thought to result by interactions between the fiber/neuron network and the vessel network; optimal oxygenation depends on precise rhythm-related conditions on the two networks. The model provides interesting insights into the phenomenon of muscle fatigue.

The actions of oxygen in the body are extremely complex, and are also involved in various signalling pathways. Hyperbaric oxygen is known to contribute to the improvement of conditions where tissue circulation is suboptimal, and has considerable usage in different treatment protocols and experimental investigations. However, the precise mechanism by which hyperbaric oxygen changes the functioning of coordinated blood vessel systems and microcirculation is still unknown. Taking into account the known facts, we suggest that hyperbaric oxygen induces changes in conducted vasomotor responses, and in that way influences vascular sensitivity and reactivity to vasodilators and vasoconstrictors. Conducted vasomotor responses are constrictions and dilations that are propagated along the vessel, leading to changes in vessel diameter on a certain distance of the initial site of vasoactive substance activity. Because these vascular responses are of substantial significance in physiological processes, their modification would subsequently cause alterations of blood vessel function and tissue perfusion that could explain observed effects of hyperbaric oxygen. We also discuss potential molecular targets of hyperbaric oxygen, investigation of which could presumably help in the eventual clarification of hyperbaric oxygen action.

Background: FTO is the first gene established as contributing to common forms of obesity. The gene is highly expressed in the hypothalamus and is thought to mediate this effect through its influence on energy homeostasis. The hypothalamus, however, also regulates blood pressure (BP). Therefore, we investigated whether the FTO-risk variant is associated not only with increased adiposity but also with elevated BP and whether the latter may be mediated, in part, by increased sympathetic modulation of vasomotor tone., Methods and Results: The primary study was carried out in 485 adolescents recruited from a French Canadian founder population who underwent detailed body-composition and cardiovascular phenotyping. Body fat was examined with MRI, bioimpedance, and anthropometry. BP was recorded beat to beat at rest and during physical and mental challenges. Sympathetic modulation of vasomotor tone was assessed with power spectral analysis of BP. We found that individuals with the FTO-risk genotype compared with those without it demonstrate greater adiposity, including the amount of intra-abdominal fat (by 38%). They also showed higher systolic BP throughout the entire protocol, with a maximum difference during a mental stress (6.4 [1.5 to 11.3] mm Hg). The difference in BP was accompanied by elevated index of sympathetic modulation of vasomotor tone. A replication in an independent sample of adults from the same founder population confirmed the association between FTO and BP., Conclusions: These results suggest that, in a French Canadian founder population, FTO may increase not only risk for obesity, as demonstrated in other populations, but also for hypertension. The latter may be related, at least in part, to the regulation of sympathetic vasomotor tone.

Aims: The aim of this study was to evaluate coronary vasomotor function in cardiac transplant recipients maintained on sirolimus (SRL)- or cyclosporin (CyA)-based immunosuppression., Methods and Results: Endothelium-independent response to intracoronary nitroglycerin and adenosine and endothelium-dependent response to intracoronary acetylcholine (Ach) were assessed in 15 SRL- and 21 CyA- treated subjects with angiographically normal coronary arteries. Baseline mean blood pressure was lower in the SRL group (85.6 +/- 10.3 vs. 105.2 +/- 8.7 mmHg, P = 0.002). There was no difference between the groups in coronary flow reserve after adenosine administration in multivariable analysis (P = 0.34). Nitroglycerin administration resulted in increase in coronary artery diameter in the SRL compared with the CyA groups (2.79 +/- 0.54 vs. 2.57 +/- 0.61, P = 0.0036). In 13 SRL-treated subjects without evidence of cardiac allograft vasculopathy (CAV), Ach administration resulted in less epicardial vasoconstriction compared with CyA-treated subjects (2.7 +/- 17.7 vs. -15.6 +/- 17.2%, P = 0.005). Two SRL-treated subjects with three-dimensional intravascular ultrasound evidence of CAV developed coronary spasm in response to Ach 10(-4). Microvascular endothelial function did not differ between the groups., Conclusion: Sirolimus immunosuppression is associated with less pronounced coronary epicardial endothelial dysfunction compared with CyA immunosuppression. Improvement of coronary vasomotor function with SRL may be an important mechanism for the prevention of CAV.

Objective: Repetitive Transcranial Magnetic Stimulation (rTMS) has been recently employed as a therapeutic strategy for stroke, although its effects on cerebral hemodynamics has been poorly investigated. This study aims to examine the impact of high frequency rTMS on cerebral vasomotor reactivity (VMR)., Methods: Twenty-nine healthy subjects were randomly assigned to real (19) or sham 17-Hz rTMS, applied on primary motor cortex (M1) of the dominant hemisphere. All subjects underwent Transcranial Doppler of the middle cerebral arteries to evaluate mean flow velocity and VMR before (T(0)) and within 10 min (T(1)) following rTMS. Four subjects underwent further VMR evaluations at 2 (T(2)), 5 (T(3)) and 24 h (T(4)) after rTMS. As a control condition, 10 subjects underwent real (5) or sham rTMS on calcarine cortex. In addition, five acute stroke patients underwent five daily rTMS sessions on the affected hemisphere mimicking a therapeutic trial., Results: Following real rTMS on M1 (p=0.002) and calcarine cortex (p<0.001) VMR decreased with respect to T(0) in both hemispheres, while no change was observed after sham rTMS (p>0.6). VMR tended to remain lower than T(0) until T(3.) Cerebral VMR decreased independently of the stimulated side also in the patients' group., Conclusions: High frequency rTMS reduces cerebral VMR, possibly as a secondary effect on autonomic control of cerebral hemodynamics., Significance: The effect of rTMS on cerebral hemodynamics should be carefully considered before proceeding toward a therapeutic application in stroke patients.