Dilatation Of Resistance Vessels Research Articles

Deficiency of T-type voltage-gated calcium channels results in attenuated weight gain and improved endothelium-dependent dilatation of resistance vessels induced by a high-fat diet in mice.

The deletion of T-type Cav3.1 channels may reduce high-fat diet (HFD)-induced weight gain, which correlates positively with obesity and endothelial dysfunction. Therefore, experiments were designed to study the involvement of T-type Cav3.1 channels in HFD-induced endothelial dysfunction in mice. Wildtype (WT) and Cav3.1-/- mice were fed either a normal diet (ND) or an HFD for 8weeks. Body composition was assessed, and thoracic aortae and mesenteric arteries were harvested for myography to assess endothelium-dependent responses. Changes in intracellular calcium were measured by fluorescence imaging, and behavior was assessed with the open-field test. Cav3.1-/- mice had attenuated HFD-induced weight gain and lower total fat mass compared with WT mice. Cav3.1-/- mice on an HFD had reduced plasma cholesterol levels compared with WT mice on the same diet. Increased feeding efficiency, independent of food intake, was observed in WT mice on an HFD compared with an ND, but no difference in feeding efficiency between diets was observed for Cav3.1-/- mice. Nitric oxide-dependent dilatation was increased in mesenteric arteries of Cav3.1-/- mice compared with WT mice on an HFD, with no difference observed in aortae. No differences in mouse locomotor activity were observed between the experimental groups. Mice on an HFD lacking T-type channels have reduced weight gain, lower total cholesterol levels, and increased dilatation of resistance vessels compared with WT mice on an HFD, suggesting that Cav3.1 deletion protects against endothelial dysfunction in resistance vessels but not in large conduit vessels.

The role of vascular endothelium in nitroglycerin-mediated vasodilation.

Nitroglycerin (or glyceryl trinitrate, GTN) has been long considered an endothelium-independent vasodilator because GTN vasodilation is intact in the absence of the endothelium and in the presence of endothelial dysfunction. However, in animal and in vitro models, GTN has been shown to stimulate the release of certain endothelium-derived vasodilators such as nitric oxide (NO) and prostacyclin (PGI2 ). In addition, chronic GTN therapy leads to endothelial dysfunction. In this series of experiments, we explored how GTN might interact with the vascular endothelium in normal humans, without cardiovascular disease or risk factors associated with abnormalities in vascular function. We examined the effect of inhibition of NO, PGI2 , and epoxyeicosatrienoic acids (EETs, a class of endothelium-derived hyperpolarizing factor) on GTN-mediated vasodilation. We measured arterial blood flow responses to brachial artery infusions of GTN in the absence and presence of L-NMMA (n=13), ketorolac (n=14) and fluconazole (n=16), which are inhibitors of endothelium-derived NO, PGI2 and EETs, respectively, in healthy volunteers. Our results demonstrate that inhibition of endothelium-dependent vasodilator mechanisms does not alter forearm resistance vessel responses to GTN. We conclude that GTN-mediated dilation of forearm resistance vessels is largely independent of vascular endothelium.

The Role of Vascular Endothelium in Nitroglycerin-Mediated Vasodilation

Aims Nitroglycerin (or glyceryl trinitrate, GTN) has been long considered an endothelium-independent vasodilator because GTN vasodilation is intact in the absence of the endothelium and in the presence of endothelial dysfunction. However, in animal and in vitro models, GTN has been shown to stimulate the release of certain endothelium-derived vasodilators such as nitric oxide (NO) and prostacyclin (PGI2 ). In addition, chronic GTN therapy leads to endothelial dysfunction. In this series of experiments, we explored how GTN might interact with the vascular endothelium in normal humans, without cardiovascular disease or risk factors associated with abnormalities in vascular function. Methods We examined the effect of inhibition of NO, PGI2 , and epoxyeicosatrienoic acids (EETs, a class of endothelium-derived hyperpolarizing factor) on GTN-mediated vasodilation. We measured arterial blood flow responses to brachial artery infusions of GTN in the absence and presence of L-NMMA (n = 13), ketorolac (n = 14) and fluconazole (n = 16), which are inhibitors of endothelium-derived NO, PGI2 and EETs, respectively, in healthy volunteers. Results Our results demonstrate that inhibition of endothelium-dependent vasodilator mechanisms does not alter forearm resistance vessel responses to GTN. Conclusion We conclude that GTN-mediated dilation of forearm resistance vessels is largely independent of vascular endothelium.

Distinct Regulatory Effects of Myeloid Cell and Endothelial Cell NAPDH Oxidase 2 on Blood Pressure

Hypertension caused by increased renin-angiotensin system activation is associated with elevated reactive oxygen species production. Previous studies implicate NADPH oxidase (Nox) proteins as important reactive oxygen species sources during renin-angiotensin system activation, with different Nox isoforms being potentially involved. Among these, Nox2 is expressed in multiple cell types, including endothelial cells, fibroblasts, immune cells, and microglia. Blood pressure (BP) is regulated at the central nervous system, renal, and vascular levels, but the cell-specific role of Nox2 in BP regulation is unknown. We generated a novel mouse model with a floxed Nox2 gene and used Tie2-Cre, LysM Cre, or Cdh5-CreERT2 driver lines to develop cell-specific models of Nox2 perturbation to investigate its role in BP regulation. Unexpectedly, Nox2 deletion in myeloid but not endothelial cells resulted in a significant reduction in basal BP. Both Tie2-CreNox2 knockout (KO) mice (in which Nox2 was deficient in both endothelial cells and myeloid cells) and LysM CreNox2KO mice (in which Nox2 was deficient in myeloid cells) had significantly lower BP than littermate controls, whereas basal BP was unaltered in Cdh5-CreERT2 Nox2KO mice (in which Nox2 is deficient only in endothelial cells). The lower BP was attributable to an increased NO bioavailability that dynamically dilated resistance vessels in vivo under basal conditions without a change in renal function. Myeloid-specific Nox2 deletion had no effect on angiotensin II-induced hypertension, which, however, was blunted in Tie2-CreNox2KO mice, along with preservation of endothelium-dependent relaxation during angiotensin II stimulation. We identify a hitherto unrecognized modulation of basal BP by myeloid cell Nox2, whereas endothelial cell Nox2 regulates angiotensin II-induced hypertension. These results identify distinct cell-specific roles for Nox2 in BP regulation.

Corrigendum to “Induction of resistance vessel dilation by ginger root juice, possibly through extracellular signal-regulated kinase 1/2 and endothelial nitric oxide synthase activation in endothelial cells” [Family Medicine and Community Health (2013) 1(3), 12‐18

Corrigendum to “Induction of resistance vessel dilation by ginger root juice, possibly through extracellular signal-regulated kinase 1/2 and endothelial nitric oxide synthase activation in endothelial cells” [Family Medicine and Community Health (2013) 1(3), 12‐18

Cardiohemodynamic and electrophysiological effects of a selective EP4 receptor agonist ONO­-AE1­-329 in the halothane-anesthetized dogs

Cardiovascular effects of a highly selective prostaglandin E2 type 4 (EP4) receptor agonist ONO-AE1-329 were assessed with the halothane-anesthetized dogs (n=6). ONO-AE1-329 was intravenously infused in three escalating doses of 0.3, 1 and 3ng/kg/min for 10min with a pause of 20min between the doses. The low dose of 0.3ng/kg/min significantly increased maximum upstroke velocity of left ventricular pressure by 18% at 20min, indicating increase of ventricular contractility. The middle dose of 1ng/kg/min significantly decreased total peripheral resistance by 24% and left ventricular end-diastolic pressure by 32% at 10min, indicating dilation of arteriolar resistance vessels and venous capacitance ones, respectively; and increased cardiac output by 25% at 10min in addition to the change induced by the low dose. The high dose of 3ng/kg/min increased heart rate by 34% at 10min; decreased mean blood pressure by 14% at 10min and atrioventricular nodal conduction time by 13% at 5min; and shortened left ventricular systolic period by 8% at 10min and electromechanical coupling defined as an interval from completion of repolarization to the start of ventricular diastole by 39% at 10min in addition to the changes induced by the middle dose. No significant change was detected in a ventricular repolarization period. These results indicate that ONO-AE1-329 may possess a similar cardiovascular profile to typical phosphodiesterase 3 inhibitors as an inodilator, and suggest that EP4 receptor stimulation can become an alternative strategy for the treatment of congestive heart failure.

Morphology and function of cerebral arteries in adults with pompe disease.

Cerebrovascular abnormalities have been reported in adult patients with Pompe disease. The objective was to study these abnormalities by (1) determining the diameter and mean flow velocity (MFV) of large cerebral arteries and (2) estimating cerebral blood flow (CBF), resistance index (RI) and cerebrovascular reactivity (CVR) as functions of resistance vessels. In ten adults with Pompe disease and twenty controls, the diameter, peak systolic (PSV) and end-diastolic velocities (EDV) of arteries supplying the brain were quantified by MR angiography and sonography. MFV, RI and CBF were calculated. CVR in the middle cerebral artery (MCA) was determined by hyperventilation and acetazolamide injection. MR angiography revealed dilation of cerebral arteries predominantly in the posterior circulation. Dilative arteriopathy was found in three patients; two of them showed vertebrobasilar dolichoectasia. Despite of the dilative arteriopathy, the MFV was normal, indicating increased CBF and dilated resistance vessels. RI of all examined arteries and CVR of MCA were normal. The data suggest that dilation of small and large cerebral arteries is a common feature in adults with Pompe disease. Increased CBF might be the consequence of dilated resistance vessels. However, dysfunction of resistance vessels was rarely found. In adults with Pompe disease, dilation of small and large cerebral arteries is a common feature and might be associated with increased cerebral blood flow.

Induction of resistance vessel dilation by ginger root juice, possibly through extracellular signal-regulated kinase 1/2 and endothelial nitric oxide synthase activation in endothelial cells

<h3>Objective</h3> To investigate the effects of ginger root juice on contractibility of resistance blood vessels from mice and on activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and endothelial nitric oxide synthase (eNOS) in human endothelial cells. <h3>Methods</h3> Juice was prepared from semi-dry ginger roots. Mesenteric artery rings were dissected from healthy adult C57BL/J6 mice. Primary human umbilical vein endothelial cells (HUVECs) were isolated from umbilical cords of normal full-term babies. The contractibility of the dissected vessel rings in the presence or absence of ginger root juice at 0.1% (v/v) after potassium (100 mM KCL) stimulation was measured by wire myography. The phosphorylation levels of ERK1/2 and eNOS in the presence of ginger root juice in the culture medium at 0, 0.025%, 0.05%, 0.1%, and 0.2% (v/v) in HUVECs were assessed by western blotting analysis. <h3>Results</h3> An immediate sharp increase in the contractile activity was observed in mesenteric artery rings in response to KCL stimulation. Ginger root juice effectively attenuated the KCL-mediated vessel contraction. Moreover, ginger root juice significantly increased phosphorylation of ERK1/2 and eNOS in a dose-dependent manner. <h3>Conclusions</h3> Ginger root juice is capable of relaxing resistance blood vessels. Activation of ERK1/2 and eNOS through phosphorylation in endothelial cells may be a mechanism underlying the vasodilator activity of ginger root.

Phosphodiesterase 5 inhibition-induced coronary vasodilation is reduced after myocardial infarction

The balance between the production and removal of cGMP in coronary vascular smooth muscle is of critical importance in determining coronary vasomotor tone and thus in the regulation of coronary blood flow. cGMP production by soluble guanylyl cyclase is activated by nitric oxide (NO), whereas cGMP breakdown occurs through phosphodiesterase 5 (PDE5). We hypothesized that myocardial infarction (MI) alters the balance between the production and removal of cGMP in the coronary vasculature and thereby alters the control of coronary vasomotor tone. Chronically instrumented swine with and without a 2-wk-old MI were exercised on a treadmill in the absence and presence of the PDE5 inhibitor EMD-360527 (300 μg·kg(-1)·min(-1) iv). Inhibition of PDE5 produced coronary resistance vessel dilation, which was more pronounced at rest than during exercise in normal swine. PDE5 gene expression was markedly reduced in coronary resistance vessels isolated from the remote myocardium of MI swine, which was accompanied by a similarly marked attenuation of coronary vasodilation by PDE5 inhibition in MI swine. The coronary vasoconstriction produced by inhibition of NO synthesis with N(ω)-nitro-L-arginine (20 mg/kg iv) was only slightly smaller in swine with MI. Interestingly, inhibition of NO synthesis reduced the vasodilator response to subsequent PDE5 inhibition in normal swine but not in MI swine. Conversely, PDE5 inhibition enhanced the coronary vasoconstriction produced by NO synthesis inhibition in normal swine but not in MI swine, suggesting that downregulation of PDE5 mitigated the loss of NO vasodilator influence. In conclusion, the expression and vasoconstrictor influence of PDE5 are markedly attenuated in coronary resistance vessels in the remote myocardium after MI, which appears to serve as a compensatory mechanism to mitigate the loss of NO vasodilator influence.

Endocrine Nitric Oxide Bioactivity and Hypoxic Vasodilation by Inhaled Nitric Oxide

Inhaled nitric oxide (iNO) is approved by the Food and Drug Administration for the treatment of persistent pulmonary hypertension of the newborn, largely as a result of the pioneering research efforts of Warren Zapol. Inhaled nitric oxide (NO) dilates pulmonary resistance vessels to improve ventilation–perfusion matching before being inactivated by reactions with hemoglobin (Hb) in blood exiting the lung. Inhaled NO therefore is a selective pulmonary vasodilator.1 Notwithstanding the validity of this model, investigators including Claes Frostell2 and David Wessel3 noted early on that high therapeutic doses of iNO led to subtle decreases in blood pressure. It had recently been discovered that albumin could be S-nitrosylated by NO,4 endowing it with long-lived vasodilatory activity. So, when presented with the quandary of systemic effects, it was quickly demonstrated that iNO could S-nitrosylate plasma proteins,5 potentially providing systemic vasodilatory activity6 and thus acting in an endocrine-like manner. S-nitrosoalbumin since has been implicated in protection by iNO against reperfusion injury in systemic vessels,7,8 but also may form within airways of iNO-treated patients,5,9 potentially contributing to “pulmonary selectivity.” In subsequent studies, the family of circulating S-nitrosylated proteins (SNO-proteins) was expanded to include S-nitrosohemoglobin (SNO-Hb),10 which exhibits the remarkable ability to mediate hypoxic vasodilation,11 the selective vasodilation in proportion to degree of hypoxemia. A number of recent studies have provided evidence that iNO may utilize SNO-based pathways12 to confer protection against ischemic insults8,13–18—none more remarkable than the report by Terpolilli et al19 in this issue of Circulation Research , which illustrates beautifully in cerebral vessels the principles of endocrine NO bioactivity and hypoxia-coupled delivery of NO bioactivity. Their demonstration that iNO promotes dilation of cerebral resistance vessels selectively in hypoperfused tissue, without changes …

Pharmacological studies with SK&F 94120, a novel positive inotropic agent with vasodilator activity.

The pharmacological properties of SK&F 94120 on the cardiovascular system have been studied in laboratory animal species. The compound was shown to have positive inotropic activity on hearts from guinea-pig, cat, dog and marmoset in-vitro and in cat and dog in-vivo. These responses in-vivo occurred in association with minimal changes in heart rate. Positive inotropic activity was not caused by SK&F 94120 in rat or hamster hearts in-vitro, thereby indicating a species dependence in myocardial response. SK&F 94120 was shown to have vasodilator activity in cats in-vivo. Detailed studies carried out on anaesthetized cats indicated that the compound caused a balanced dilatation of both resistance and capacitance blood vessels. Haemodynamic studies in anaesthetized cats indicated that, as a consequence of the positive inotropic and vasodilator actions, SK&F 94120 causes significant increases in cardiac output and stroke volume. Studies in conscious dogs showed the compound to be active as a positive inotrope after oral administration. The above properties suggest that this compound possesses useful haemodynamic properties for the treatment of congestive heart failure.

Do engineered natriuretic peptides have greater therapeutic potential than do native peptides?

This editorial refers to ‘A novel chimeric natriuretic peptide reduces cardiomyocyte hypertrophy through the NHE-1–calcineurin pathway’ by A. Kilic et al. , doi:10.1093/cvr/cvq254. As is well known, intravenously infused nesiritide [a recombinant form of brain-type natriuretic peptide (BNP)] antagonizes renin–angiotensin–aldosterone system activation and induces natriuresis, diuresis, and venous and arterial dilation. When administered to patients with acutely decompensated heart failure, a rapid reduction of pulmonary capillary pressure and consequent relief of dyspnoea often results. However, BNP-induced dilation of resistance (arterioles) and capacitance (veins) vessels taken together with the diuresis-associated reduction of blood (plasma) volume causes clinically significant systemic hypotension in some patients. Unfortunately, this hypotension can be associated with decreased renal perfusion and worsening of renal function, and the latter has been associated with increased morbidity and mortality in some clinical trials.1 The hypotension and consequent complications can be attenuated by reducing the dose of nesiritide being administered.1 Recently, Burnett and colleagues speculated that they might be able to improve the therapeutic properties of natriuretic peptides by modifying their structures. Their goal was to generate a natriuretic peptide that retained the biological activities of BNP sans the capacity to dilate resistance vessels. Their first engineered chimeric natriuretic peptide (CD-NP) comprised the 15-amino acid C-terminus of the Dendroaspis peptide (a snake-derived natriuretic peptide) and the peptide ring component of the cardiac-type natriuretic peptide (CNP). CNP lacks renal actions but retains veno-dilator capacity and has only modest dilatory effects … *Corresponding author. Tel: +1 612 626 2001; fax: +1 612 626 2004, Email: fromx001{at}umn.edu

The muscle metaboreflex: reining in the heart?

the muscle metaboreflex, also known as the muscle chemoreflex, is one of the principal mediators of the cardiovascular exercise response. This reflex is thought to be triggered by metabolic by-products of ischemia that stimulate afferent nerve endings in skeletal muscle and leads to an increase in

The shear stress of keeping cool: why being in the ‘hot seat’ might actually be good for your blood vessels

An automobile comes off the assembly line stuck with its particular structural and functional traits which may remain inadequate or even dysfunctional in responding to driving challenges, unless public outcry and media coverage demands a recall. Thankfully, biological organisms are capable of constantly modifying themselves to better deal with both external and internal stresses that challenge their structural and functional capacity to maintain homeostasis. How are these stresses coupled to biological structural and functional adaptation? This remains a quintessential question in integrative physiology. Reductionist approaches have done much to identify specifics of signalling pathways that translate a given challenge into adaptations in the functional and structural building blocks of organism response capacity. However, the resurgence of innovative, integrative human in vivo studies in recent years demonstrates the critical contribution this type of research can play in advancing new perspectives on the underpinnings of physiological adaptation. The recent Journal of Physiology study by Green et al. (2010) is a case in point. These investigators set out to test the hypothesis that it is shear stress which couples repeated bouts of local heating (challenge to temperature homeostasis) to improvements in microvascular structure and function (biological response adaptation). The notion that mechanical stresses of blood flow can be a stimulus for vascular adaptation is nothing new and a wealth of findings from reductionist studies demonstrate this (for review see Hudlicka & Brown, 2009). However, no human study designs have been able to demonstrate such a cause–effect in the microvasculature in vivo. Green et al. (2010) measured the forearm skin blood flow response to incremental local heating, which is largely nitric oxide dependent, both before and after 4 and 8 weeks of 30-min-3-times-per-week repeated bilateral forearm heating challenges via water immersion (heat ‘training’). The frequency and duration could be compared to a moderate exercise training intensity for aerobic fitness improvement in sedentary persons. A cuff around the elbow in one arm was inflated during heat training to minimize the increase in skin perfusion during the heating bouts, isolating the impact of skin microvascular hyperaemia and attendant shear stress elevation on microvascular adaptation. Heat training increased the skin blood flow response to incremental heating, but only in the arm which was allowed to experience normal elevations in microvascular perfusion. Some additional key observations should be noted. First, during the heat training challenges skin vasodilatation in the cuffed arm was not different from that in the non-cuffed arm. So, local heating was evoking the normal vasodilatory response even when perfusion was restricted. Yet, the coupling of local temperature change to improvements in microvascular dilatation response did not occur unless mechanical forces of blood flow increased. Second, while the cuff substantially attenuated the increase in skin blood flow with local heating, the increase was still ∼40% of that in the uncuffed arm (∼4-fold vs.∼7-fold), suggesting a threshold shear stress for adaptation. However, it should be acknowledged that shear increase would not be proportional to flow increase because non-shear-mediated dilatation of resistance vessels would attenuate the actual shear experienced. Therefore, it remains to be confirmed what the actual threshold shear for adaptation would be. So why does this study warrant our close attention? First, it has identified increased shear as a stimulus for improving microvascular function in humans, and thereby focuses attention on finding ways to target increased blood flow to vascular regions as part of vascular disease prevention and treatment. But this is not all! This experimental model will allow examination of microvascular adaptations via skin biopsy and microdialysis. An innovative review by Martinez-Lemus and Meininger (Martinez-Lemus et al. 2009) summarizes evidence for repositioning and alignment of vascular smooth muscle cells and cytoskeleton protein rearrangement that rapidly (within a few days) redesigns the mechanical and structural characteristics of the vessel wall to optimize vasoregulatory responsiveness to a new ‘normal’. The approach developed by Green et al. (2010) will allow us to answer the question ‘What is the impact of the type of heat training bouts on structural and functional adaptation and their respective timelines?’ and significantly advance the use of shear stress as a therapeutic approach for vascular health. Second, the lack of vascular adaptation to local heating alone is particularly intriguing. Local heating represents an externally imposed challenge to regulation of temperature. Increases in microvascular perfusion represent a biological response aimed at limiting hyperthermia. Yet, it is coincident shear stress and not heating per se that appears essential for improving microvascular responsiveness to an external heating challenge. So, what aspect(s) of a given challenge to homeostasis actually represent the stimulus for adaptation? This is a question that is sorely lacking answers across a wide range of physiological systems. Perhaps, when investigating this question, the answers will not be found in obvious places.

Divergent effects of low-O2tension and iloprost on ATP release from erythrocytes of humans with type 2 diabetes: implications for O2supply to skeletal muscle

Erythrocytes release both O(2) and a vasodilator, ATP, when exposed to reduced O(2) tension. We investigated the hypothesis that ATP release is impaired in erythrocytes of humans with type 2 diabetes (DM2) and that this defect compromises the ability of these cells to stimulate dilation of resistance vessels. We also determined whether a general vasodilator, the prostacyclin analog iloprost (ILO), stimulates ATP release from healthy human (HH) and DM2 erythrocytes. Finally, we used a computational model to compare the effect on tissue O(2) levels of increases in blood flow directed to areas of increased O(2) demand (erythrocyte ATP release) with nondirected increases in flow (ILO). HH erythrocytes, but not DM2 cells, released increased amounts of ATP when exposed to reduced O(2) tension (Po(2) < 30 mmHg). In addition, isolated hamster skeletal muscle arterioles dilated in response to similar decreases in extraluminal O(2) when perfused with HH erythrocytes, but not when perfused with DM2 erythrocytes. In contrast, both HH and DM2 erythrocytes released ATP in response to ILO. In the case of DM2 erythrocytes, amounts of ATP released correlated inversely with glycemic control. Modeling revealed that a functional regulatory system that directs blood flow to areas of need (low O(2)-induced ATP release) provides appropriate levels of tissue oxygenation and that this level of the matching of O(2) delivery with demand in skeletal muscle cannot be achieved with a general vasodilator. These results suggest that the inability of erythrocytes to release ATP in response to exposure to low-O(2) tension could contribute to the peripheral vascular disease of DM2.

Cardiovascular hyporesponsiveness in sepsis is associated with G-protein receptor kinase expression via a nitric oxide-dependent mechanism

Septic shock is characterized by cardiac collapse and decreased peripheral resistance due to systemic resistance vessel dilatation, generally induced by large nitric oxide (NO). G-protein-coupled receptor (GPCR) kinases (GRKs), specific kinases interacting with GPCR proteins, induce receptor phosphorylation and thereby signal desensitization in the continuing agonist presence. Then, an increased expression of GRKs could augment adrenergic receptor desensitization and in turn reduce cardiovascular responses. Thus, we hypothesized that the hyporesponsiveness observed in sepsis could result from signal adrenergic receptor desensitization mediated by GRK2 via a NO-dependent mechanism.

Both β1- and β2-adrenoceptors contribute to feedforward coronary resistance vessel dilation during exercise

During exercise, beta-feedforward coronary vasodilation has been shown to contribute to the matching of myocardial oxygen supply with the demand of the myocardium. Since both beta(1)- and beta(2)-adrenoceptors are present in the coronary microvasculature, we investigated the relative contribution of these subtypes to beta-feedforward coronary vasodilation during exercise as well as to infusion of the beta(1)-agonist norepinephrine and the beta(1)- and beta(2)-agonist isoproterenol. Chronically instrumented swine were studied at rest and during graded treadmill exercise (1-5 km/h) under control conditions and after beta(1)-blockade with metoprolol (0.5 mg/kg iv) and beta(1)/beta(2)-blockade with propranolol (0.5 mg/kg iv). The selectivity and degree of beta-blockade of metoprolol and propranolol were confirmed using isoproterenol infusion (0.05-0.4 microg. kg(-1).min(-1)) under resting conditions. Isoproterenol-induced coronary vasodilation was mediated through the beta(2)-adrenoceptor, whereas norepinephrine-induced coronary vasodilation was principally mediated through the beta(1)-adrenoceptor. Exercise resulted in a significant increase in left ventricular norepinephrine release and epinephrine uptake. beta(1)-Adrenoceptor blockade with metoprolol had very little effect under resting conditions. However, during exercise, metoprolol attenuated the increase in myocardial oxygen supply in excess of the reduction in myocardial oxygen demand, as evidenced by a progressive decrease in coronary venous Po(2). Consequently, metoprolol caused a clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). Additional beta(2)-adrenoceptor blockade with propranolol further inhibited myocardial oxygen supply during exercise, resulting in a further clockwise rotation of the relationship between myocardial oxygen consumption and coronary venous Po(2). In conclusion, both beta(1)- and beta(2)-adrenoceptors contribute to the beta-feedforward coronary resistance vessel dilation during exercise.

Vasomotion and insulin‐mediated capillary recruitment – part of the explanation?

Vasomotion and insulin‐mediated capillary recruitment – part of the explanation?

Vascular nitric oxide: effects of exercise training in animals

Exercise training is known to induce several adaptations in the cardiovascular system, one of which is increased skeletal muscle blood flow at maximal exercise. Improved muscle blood flow, in turn, could in part be accounted for by augmented endothelium-dependent, nitric oxide (NO)-mediated vasodilation. Studies have indeed demonstrated that endothelium-dependent, NO-mediated dilation of conductance-type vessels is augmented after endurance exercise training; recently, this adaptation has been extended into resistance-type vessels within rodent skeletal muscle. With the latter, however, it appears that only resistance vessels supplying muscle active during training sessions exhibit this adaptation. These findings in rats are in contrast to those from human studies, in which increased endothelium-dependent dilation has been observed in vasculatures not associated with elevated blood flow during exercise. Increased expression of endothelial NO synthase (eNOS) appears to underlie enhanced endothelium-dependent, NO-mediated dilation of both conductance and resistance vessels. Greater eNOS expression may also underlie the preventive and (or) rehabilitative effect(s) of exercise training on atherosclerosis, given that NO inhibits several steps of the atherosclerotic disease process. Thus, exercise training may induce adaptations that benefit both vasodilation and vascular health.

Hypoxic Modulation of Exogenous Nitrite-Induced Vasodilation in Humans

It has been proposed that under hypoxic conditions, nitrite may release nitric oxide, which causes potent vasodilation. We hypothesized that nitrite would have a greater dilator effect in capacitance than in resistance vessels because of lower oxygen tension and that resistance-vessel dilation should become more pronounced during hypoxemia. The effect of intra-arterial infusion of nitrite on forearm blood flow and forearm venous volumes was assessed during normoxia and hypoxia. Forty healthy volunteers were studied. After baseline infusion of 0.9% saline, sodium nitrite was infused at incremental doses from 40 nmol/min to 7.84 mumol/min. At each stage, forearm blood flow was measured by strain-gauge plethysmography. Forearm venous volume was assessed by radionuclide plethysmography. Changes in forearm blood flow and forearm venous volume in the infused arm were corrected for those in the control arm. The peak percentage of venodilation during normoxia was 35.8+/-3.4% (mean+/-SEM) at 7.84 micromol/min (P<0.001) and was similar during hypoxia. In normoxia, arterial blood flow, assessed by the forearm blood flow ratio, increased from 1.04+/-0.09 (baseline) to 1.62+/-0.18 (nitrite; P<0.05) versus 1.07+/-0.09 (baseline) to 2.37+/-0.15 (nitrite; P<0.005) during hypoxia. This result was recapitulated in vitro in vascular rings. Nitrite is a potent venodilator in normoxia and hypoxia. Arteries are modestly affected in normoxia but potently dilated in hypoxia, which suggests the important phenomenon of hypoxic augmentation of nitrite-mediated vasodilation in vivo. The use of nitrite as a selective arterial vasodilator in ischemic territories and as a potent venodilator in heart failure has therapeutic implications.