Skeletal Muscle Vascular Resistance Research Articles

Abstract 58: The 5-HT7 receptor contributes to increased hindquarter blood flow caused by skeletal muscle contraction

Exogenous serotonin (5-hydroxytryptamine, 5-HT) causes a reproducible decrease in blood pressure in normotensive and hypertensive rats. This is associated with dilation of arterioles in skeletal muscle. The 5-HT7 receptor KO rat strain allowed us to test the role of this receptor in both responses as well as the effects of endogenous 5-HT -- acting at 5-HT7 receptors -- on normal circulatory regulation. First, we hypothesized that the 5-HT7 receptor KO rat would have a higher hindquarter (HQ) vascular resistance (HQVR) than wildtype (WT) because of loss of this receptor. In rats anesthetized with isoflurane, instrumented with arterial catheters and flow probes on the terminal aorta, male KO rats had significantly higher resting HQVR [mm Hg/ml/min; KO (16.0±2.0) vs WT (10.8±0.6.0), p = 0.04] and lower HQ blood flow than normal Sprague-Dawley (SD) rats. No differences in resting HQVR or HQ flow were observed in female rats. Intravenous infusion of 5-HT (50 ug/kg/min) reduced systemic blood pressure and HQVR; these parameters were significantly attenuated (~56%) in male KO rats versus WT and SD animals. In females, falls in systemic blood pressure and HQVR were absent in both KO and WT rats. Second, as 5-HT has been implicated in the pathophysiology of heart failure (HF), a left anterior descending artery ligation model of HF was used to investigate the potential role of 5-HT7 regulation of HQ flow in HF-associated exercise intolerance. The ability of hindlimb muscle stimulation to increase blood flow using transdermal neuromuscular electrical stimulation was tested (NMES). M and F KO rats showed a reduced ability to increase HQ flow during muscle contraction vs WT (% over basal: M WT = 118±18 vs KO =14.6±7.1; F WT= 101±12 vs KO = 7.6±6) rats. This was observed in both intact and HF rats (in which flow changes were already impaired). Acute administration of the 5-HT7 receptor antagonist SB269970 abolished the ability of NMES to increase HQ flow in normal SD rats. Importantly, the microcirculatory capacity, visualized by Lectin-594, was not significantly different in the gastrocnemius muscle of WT (arbitrary fluorescence units/area: 946±40) vs KO (914±69). These data support that the 5-HT7 receptor, likely activated by endogenous 5-HT, is an important regulator of skeletal muscle vascular resistance. Thus, 5-HT may have a larger role in normal and pathophysiological regulation of the circulation than has previously been appreciated.

Control of blood pressure in the cold: differentiation of skin and skeletal muscle vascular resistance.

What is the central question of this study? Why does blood pressure increases during cold air exposure? Specifically, what is the contribution of skin and skeletal muscle vascular resistance during whole body versus isolated face cooling? What is the main finding and its importance? Whole-body cooling caused an increase in blood pressure through an increase in skeletal muscle and cutaneous vascular resistance. However, isolated mild face cooling caused an increase in blood pressure predominately via an increase in cutaneous vasoconstriction. The primary aim of this investigation was to determine the individual contribution of the cutaneous and skeletal muscle circulations to the cold-induced pressor response. To address this, we examined local vascular resistances in the cutaneous and skeletal muscle of the arm and leg. Thirty-four healthy individuals underwent three different protocols, whereby cold air to clamp skin temperature (27°C) was passed over (1) the whole-body, (2) the whole-body, but with the forearm pre-cooled to clamp cutaneous vascular resistance, and (3) the face. Cold exposure applied to the whole body or isolated to the face increased mean arterial pressure (all, P<0.001) and total peripheral resistance (all, P<0.047) compared to thermal neutral baseline. Whole-body cooling increased femoral (P<0.005) and brachial artery resistance (P<0.003) compared to thermoneutral baseline. Moreover, when the forearm was pre-cooled to remove the contribution of cutaneous resistance (P=0.991), there was a further increase in lower arm vasoconstriction (P=0.036) when whole-body cooling was superimposed. Face cooling also caused a reflex increase in lower arm cutaneous (P=0.009) and brachial resistance (P=0.050), yet there was no change in femoral resistance (P=0.815) despite a reflex increase in leg cutaneous resistance (P=0.010). Cold stress causes an increase in blood pressure through a change in total peripheral resistance that is largely due to cutaneous vasoconstriction with face cooling, but there is additional vasoconstriction in the skeletal muscle vasculature with whole-body cooling.

Abstract MP19: Endogenous 5-hydroxytryptamine May Regulate Skeletal Muscle Vascular Resistance In Normal Healthy Rats

Infusing low doses of 5-hydroxytryptamine (5-HT) into normal rats causes chronic (weeks to months) hypotension and a fall in total peripheral resistance. These effects are mediated by activation of 5-HT 7 receptors. Therefore, we generated 5-HT 7 receptor knockout rats (5-HT 7 KO) to explore possible cardiovascular effects of 5-HT 7 receptors under normal and pathophysiological conditions. We previously reported that healthy 5-HT 7 KO rats have normal blood pressure and total peripheral resistance at rest. This suggested that 5-HT 7 receptors plays no role in cardiovascular regulation under normal conditions. But total peripheral resistance is determined by multiple vascular beds that differ in their sensitivity to 5-HT. Others have indicated that 5-HT 7 receptors in the skeletal muscle vasculature are particularly sensitive to the effects of 5-HT. Therefore, we hypothesized that 5-HT 7 KO rats would show both reduced responsiveness to exogenous 5-HT and increased resting skeletal muscle vascular resistance. Experiments were performed in isoflurane-anesthetized, male Sprague-Dawley (SD) (n=6), 5-HT 7 wild-type (5-HT 7 WT) (n=5) and 5-HT 7 KO (n=6) rats at 7-8 months of age. Arterial pressure was measured with an aortic catheter. Blood flow to the hindquarters (mostly skeletal muscle) was measured with transit-time, ultrasound flowmetry. After 10 minutes of baseline hemodynamic measurements were obtained, 5-HT was infused iv at a rate of 25 μg/kg/min for 15 minutes, followed by a 15-minute recovery period. As expected, 5-HT 7 KO rats did not show a significant fall in hindquarter vascular resistance (HQVR) during 5-HT infusion, while SD and 5-HT 7 WT did. More importantly, HQVR at baseline was significantly (p &lt; 0.05) higher in 5-HT 7 KO rats (16.0 ± 2.0 mmHg/ml/min) than in 5-HT 7 WT rats (10.9 ± 0.06 mmHg/ml/min) or SD rats (7.0 ± 0.03 mmHg/ml/min). These results support our hypothesis that in healthy (albeit anesthetized) rats, 5-HT 7 receptors reduce skeletal muscle vascular resistance.

Reduction in Hindquarter Vascular Resistance Supports 5-HT7 Receptor Mediated Hypotension.

The 5-HT7 receptor is the primary mediator of both the acute (<hours) and chronic (day-week) decreases in mean arterial pressure (MAP) during low dose 5-HT infusion in rats. Previous data show the hypotensive response during chronic 5-HT infusion is due to a decrease total peripheral resistance (TPR) and specifically splanchnic vascular resistance. We hypothesized that changes in vascular resistance in both the splanchnic and skeletal muscle vascular beds are critical to the cardiovascular effects mediated by the 5-HT7 receptor. Systemic and regional hemodynamic data were collected in conscious and anesthetized male rats using radiotelemetry, vascular catheters and transit-time flowmetry. Reversible antagonism of the 5-HT7 receptor was achieved with the selective antagonist SB269970 (33 μg/kg, iv). From the very beginning and throughout the duration (up to 5 days) of a low dose (25 μg/kg) infusion of 5-HT, TPR, and MAP were decreased while cardiac output (CO) was increased. In a separate group of rats, the contribution of the 5-HT7 receptor to the regional hemodynamic response was tested during 5-HT-induced hypertension. The decrease in MAP after 24 h of 5-HT (saline 83 ± 3 vs. 5-HT 72 ± 3 mmHg) was associated with a significant decrease in skeletal muscle vascular resistance (saline 6 ± 0.2 vs. 5-HT 4 ± 0.4 mmHg/min/mL) while splanchnic vascular resistance was similar in 5-HT and saline-treated rats. When SB269970 was administered acutely, MAP and skeletal muscle vascular resistance rapidly increased, whereas splanchnic resistance was unaffected. Our work suggests the most prominent regional hemodynamic response to 5-HT7 receptor activation paralleling the fall in MAP is a decrease in skeletal muscle vascular resistance.

Effects of aging, TNF-α, and exercise training on angiotensin II-induced vasoconstriction of rat skeletal muscle arterioles

Skeletal muscle vascular resistance during physical exertion is higher with old age. The purpose of this study was to determine whether 1) aging enhances angiotensin II (ANG II)-induced vasoconstriction; 2) the proinflammatory cytokine tumor necrosis factor (TNF)-α contributes to alterations in ANG II-mediated vasoconstriction with aging; 3) exercise training attenuates putative age-associated increases in ANG II-mediated vasoconstriction; and 4) the mechanism(s) through which aging and exercise training alters ANG II-induced vasoconstriction in skeletal muscle arterioles. Male Fischer 344 rats were assigned to four groups: young sedentary (4 mo), old sedentary (24 mo), young trained, and old trained. In a separate group of young sedentary and old sedentary animals, a TNF type 1 receptor inhibitor was administered subcutaneously for 10 wk. First-order arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Old age augmented ANG II-induced vasoconstriction in both soleus (young: 27 ± 3%; old: 38 ± 4%) and gastrocnemius (young: 42 ± 6%; old: 64 ± 9%) muscle arterioles; this augmented vasoconstriction was abolished with the removal of the endothelium, N(G)-nitro-l-arginine methyl ester, and chronic inhibition of TNF-α. In addition, exercise training ameliorated the age-induced increase in ANG II vasoconstriction. These findings demonstrate that old age enhances and exercise training diminishes ANG II-induced vasoconstrictor responses in skeletal muscle arterioles through an endothelium-dependent nitric oxide synthase signaling pathway. In addition, the enhancement of ANG II vasoconstriction with old age appears to be related to a proinflammatory state.

Endothelin and Aged Blood Vessels

Age is one of the most important risk factors for cardiovascular disease. For example, a 30-year-old male smoker with untreated hypertension, diabetes, dyslipidemia, and a strong family history of premature coronary heart disease (CHD) would have a 10-year coronary heart disease event rate of only 16% (“intermediate risk”) by Framingham criteria; however, given exactly the same risk profile for a 60-year-old, the risk climbs to >50%. Aging, particularly sedentary aging, leads not only to the development of atherosclerosis but also to ventricular and arterial stiffening.1 This reduces functional capacity and contributes to chronic diseases of the elderly, such as systolic hypertension or heart failure with a preserved ejection fraction. In the search for the underlying mechanism for this effect of sedentary aging, one common feature that has been identified universally in older men is an increased baseline vascular tone,2 which has both hemodynamic and metabolic consequences.3 Although this age-related increase in vascular tone is mediated in part by a chronically elevated sympathetic α-adrenergic vasoconstriction,2 endothelial function also plays a critical role in vascular stability and the regulation of vasomotor function. The endothelium regulates vascular tone through the release of dilator and constrictor substances. Endothelin (ET)-1 is the most potent endothelium-derived constricting factor and influences peripheral vascular tone by interacting with ETA and ETB receptors on smooth muscle cells and the endothelium.4 Several animal studies have examined the profound effects of vascular aging on the ET-1 pathway and support a central role for ET-1 to explain the age-related increase in vascular tone.5–7 In the present issue of Hypertension , Van Guilder et al8 present new and important information regarding the role of aging and physical fitness on the vasomotor effects of ET-1. Using a cross-sectional design in a small but carefully studied …

Vasopeptidase inhibition with omapatrilat increases fluid and protein microvascular permeability in cat skeletal muscle.

BACKGROUND Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. OBJECTIVE To analyse the effects of vasopeptidase inhibition on permeability. DESIGN The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. METHODS Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. RESULTS After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. CONCLUSIONS A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.

Vasopeptidase inhibition with omapatrilat increases fluid and protein microvascular permeability in cat skeletal muscle.

Vasopeptidase inhibition is a new antihypertensive approach combining inhibition of angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), but severe oedema, mainly angio-oedema, has been reported. As ACE and NEP catalyse degradation of the permeability-increasing peptide bradykinin, and NEP also catalyses degradation of permeability-increasing peptides such as atrial natriuretic peptide, substance P, endothelin-1 and angiotensin II, vasopeptidase inhibition may increase microvascular permeability. To analyse the effects of vasopeptidase inhibition on permeability. The study was performed on the autoperfused cat calf skeletal muscle, evaluating the effects on fluid and protein permeability of a clinically relevant dose of the vasopeptidase inhibitor, omapatrilat. The effects were compared with those of the vehicle, of selective ACE and NEP inhibition, and of omapatrilat during bradykinin receptor blockade. Effects on fluid permeability were determined with a capillary filtration coefficient (CFC) technique, and effects on protein permeability were assessed from changes in the osmotic reflection coefficient for albumin. After 1.5 h of intravenous infusion of omapatrilat (0.35 mg/kg per hour), mean arterial pressure was reduced from 114 mmHg to 86 mmHg (P < 0.01) and skeletal muscle vascular resistance was reduced from 14.5 peripheral resistance units (PRU) to 11.5 PRU (P < 0.05). CFC was increased by 22% (P < 0.01) and the reflection coefficient was decreased by 17% (P < 0.01). Infusion of vehicle had no effects. Inhibition of NEP increased permeability without affecting blood pressure, whereas ACE inhibition decreased blood pressure without affecting permeability. The increase in permeability associated with omapatrilat was reduced by bradykinin blockade. A clinically relevant antihypertensive dose of omapatrilat reduces vascular resistance and increases fluid and protein permeability, the permeability effect more by inhibition of NEP than by inhibition of ACE, by a mechanism involving bradykinin.

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A novel assay for determination of diadenosine polyphosphates in human platelets: studies in normotensive subjects and in patients with essential hypertension.

Diadenosine polyphosphates (APnAs, n = 3-6) are a family of endogenous vasoactive purine dinucleotides which have been isolated from thrombocytes. Diadenosine pentaphosphate (AP5A) and diadenosine hexaphosphate (AP6A) are more potent than diadenosine tetraphosphate (AP4A) and diadenosine triphosphate (AP3A) and cause skeletal muscle vasoconstriction in rats. Little is known about their physiological and pathophysiological significance in humans. The aims of the present study were to compare thrombocyte APnA concentrations in patients with essential hypertension (HYP) and in healthy normotensive humans (CON) using a novel quantitative assay and to assess a possible relationship between thrombocyte APnA concentrations and skeletal muscle vascular resistance. We describe a novel assay for quantification of APnAs in human platelets, involving platelet isolation from human blood, a solid-phase extracting procedure with a derivatized resin, desalting and quantitative determination of the substances with an ion-pair reversed-phase high-performance liquid chromatography (HPLC) system. The structural integrity of the isolated APnAs was confirmed by mixed assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) measurements and co-elution with added standards. The detection threshold for all four APnAs was 1 pmol/l and the inter-assay coefficients of variation were < 11% (n = 12). After venous blood sampling, mean arterial blood pressure (MAP) and forearm blood flow (FBF, using venous occlusion plethysmography) were measured in HYP and CON. Forearm vascular resistance (FVR) was calculated as MAP/FBF. significantly differ in platelet AP3A and AP4A content, but HYP had significantly higher thrombocyte concentrations of AP5A (56 +/- 7 versus 32 +/- 3 ng/microg beta-thromboglobulin, P = 0.003) and AP6A (10 +/- 1 versus 6 +/- 1 ng/microg beta-thromboglobulin, P = 0.015) than CON. HYP had significantly elevated FVR (50 +/- 6 versus 33 +/- 2 arbitrary units, P = 0.01) compared to CON. Significant correlations were found between AP5A and FVR (p = 0.38, P = 0.04) as well as between AP6A and FVR (p = 0.42, P = 0.02). In contrast, there were no significant correlations between APnAs and MAP. The study shows that thrombocyte concentrations of AP5A and AP6A are elevated in patients with essential hypertension. Vasoconstriction caused by release of AP5A and AP6A from thrombocytes may contribute to the increase of vascular resistance in hypertensive patients.

Adenosine and nitric oxide regulate regional vascular resistance via interdependent and independent mechanisms during sepsis.

Adenosine receptor blockade increases regional resting vascular resistance during sepsis. In healthy subjects, part of adenosine's actions are mediated via stimulation of nitric oxide synthase. Because nitric oxide synthase activity is thought to be a major contributor to altered vascular tone in sepsis, we tested the hypothesis that some of the nitric oxide-mediated resting regional resistance during sepsis is secondary to endogenous adenosine stimulation of nitric oxide synthase. Prospective, randomized, controlled experiment. Shock-trauma and basic science laboratory. Male Sprague-Dawley rats. Twenty-four hours after sepsis or sham induction, rats were separated into two groups (n = 6 to 10 in each group). Group 1 received a 10-min infusion of the adenosine antagonist 8-sulfophenyltheophylline (0.9 mg/kg x min) followed by a 10-min infusion of L-nitro-arginine-methyl ester (0.5 mg/kg x min). Group 2 similarly received L-nitro-arginine-methyl ester followed by 8-sulfophenyltheophylline in the presence of L-nitro-arginine-methyl ester. Hemodynamic and blood flow measurements (microspheres) were made before infusions, 10 mins after the administration of each single-agent infusion, and 10 mins after combined-agent infusions were administered. No significant resistance alterations were observed in nonseptic rats. In septic rats, adenosine receptor blockade alone increased hepatosplanchnic and skeletal muscle vascular resistance, but no further increases were seen when L-nitro-arginine-methyl ester was added. Nitric oxide synthase inhibition alone increased hepatosplanchnic and skeletal muscle vascular resistances. When 8-sulfophenyltheophylline was added to the infusion, skeletal muscle vascular resistance increased significantly more than with L-nitro-arginine-methyl ester alone, but there were no further increases in hepatosplanchnic resistance. Renal and adipose vascular resistances increased with L-nitro-arginine-methyl ester infusions, and 8-sulfophenyltheophylline produced no effect. During sepsis, nitric oxide caused resting vasodilation independent of adenosine in the renal and adipose vasculature. In the hepatosplanchnic circulation, there is reciprocal adenosine-nitric oxide interaction in maintaining resting regional resistance. Skeletal muscle displayed a dual adenosine-mediated (nitric oxide-independent) and nitric oxide-mediated (adenosine receptors required) interaction to regulate resting resistance during sepsis. These data indicate that in the hepatosplanchnic and skeletal muscle vasculature, all of the resting nitric oxide-mediated vasodilation is secondary to endogenous adenosine action, but in adipose and renal vasculature, resting nitric oxide mediated vasodilation is independent of adenosine. Endogenous adenosine also appears to play a significant role in determining resting skeletal muscle resistance that is independent of nitric oxide synthase during sepsis.

Forearm vascular and neuroendocrine responses to graded water immersion in humans.

The hypothesis that graded expansion of central blood volume by water immersion to the xiphoid process and neck would elicit a graded decrease in forearm vascular resistance was tested. Central venous pressure increased (P < 0.05) by 4.2 +/- 0.4 mmHg (mean +/- SEM) during xiphoid immersion and by 10.4 +/- 0.5 mmHg during neck immersion. Plasma noradrenaline was gradually suppressed (P < 0.05) by 62 +/- 8 and 104 +/- 11 pg mL-1 during xiphoid and neck immersion, respectively, indicating a graded suppression of sympathetic nervous activity. Plasma concentrations of arginine vasopressin were suppressed by 1.5 +/- 0.5 pg mL-1 (P < 0.05) during xiphoid immersion and by 2.0 +/- 0.5 pg mL-1 during neck immersion (P < 0.05 vs. xiphoid immersion). Forearm subcutaneous vascular resistance decreased to the same extent by 26 +/- 9 and 28 +/- 4% (P < 0.05), respectively, during both immersion procedures, whereas forearm skeletal muscle vascular resistance declined only during neck immersion by 27 +/- 6% (P < 0.05). In conclusion, graded central blood volume expansion initiated a graded decrease in sympathetic nervous activity and AVP-release. Changes in forearm subcutaneous vascular resistance, however, were not related to the gradual withdrawal of the sympathetic and neuroendocrine vasoconstrictor activity. Forearm skeletal muscle vasodilatation exhibited a more graded response with a detectable decrease only during immersion to the neck. Therefore, the forearm subcutaneous vasodilator response reaches saturation at a lower degree of central volume expansion than that of forearm skeletal muscle.

Differential Responses in Human Subcutaneous and Skeletal Muscle Vascular Beds to Critical Limb Ischaemia

Objectives to investigate the effects of chronic ischaemia on the subcutaneous and the skeletal muscle resistance vasculature. To understand the redistribution of available blood in the ischaemic limb. Methods human subcutaneous and skeletal muscle resistance arteries were obtained from limbs amputated for critical limb ischaemia and studied under isobaric conditions using pressure myography. Morphological measurements of wall and lumen were analysed using light microscopy and image analysis. Vasoconstrictor responses to potassium and adrenoceptor agonists were used to measure functional status. Noradrenaline re-uptake mechanisms and α1-selectivity were investigated. Results both human skeletal muscle and subcutaneous resistance arteries undergo a severe atrophy of the arterial wall in ischaemic conditions. However, whereas subcutaneous resistance arteries become less able to vasoconstrict to adrenoceptor stimulation, the response of skeletal muscle resistance arteries becomes exaggerated and significantly augmented. This is true in response to both the endogenous vasoconstrictor noradraline and the α1-selective adrenoceptor agonist phenylephrine. Conclusions hypersensitivity to circulating catecholamines in the skeletal muscle vascular resistance bed may contribute to the progression of ischaemic disease by differentially diverting available blood to the subcutaneous tissue to the detriment of skeletal muscle perfusion.

Modification of the cardiovascular response to hemorrhage by somatic afferent nerve stimulation with special reference to gut and skeletal muscle blood flow.

Tissue injury modifies heart rate and blood pressure responses to hemorrhage. The effect of concomitant injury on the hemorrhage-induced redistribution of cardiac output is much less clear. However, if injury elicits the visceral alerting response of the defense reaction, then a change in this redistribution of peripheral blood flow might be expected. If such a change compromised the gut circulation, then it might explain the deleterious effects of injury on the ability to withstand hemorrhage. Immature pigs anesthetized with Saffan were bled 30% of blood volume with or without concomitant somatic afferent (brachial) nerve stimulation (to mimic injury). In addition to global cardiovascular and oxygen transport variables, blood flow was measured in the cranial mesenteric (gut) and right femoral (skeletal muscle) arteries after a 60-minute stabilization period after surgery, at the end of the 30-minute hemorrhage, and after a 30-minute shock period. Hemorrhage induced the expected cardiovascular and oxygen transport changes accompanied by a reduction in skeletal muscle blood flow and a 55% increase in skeletal muscle vascular resistance, but gut blood flow and vascular resistance were unchanged. However, in the presence of brachial nerve stimulation, the pattern of response to hemorrhage was modified, such that gut blood flow was now reduced and gut vascular resistance increased. The sparing of the gut circulation after hemorrhage was abolished in the presence of "injury." This finding is consistent with injury eliciting the defense reaction and may help explain the deleterious effects of injury on resistance to hypovolemia.

Reversal of peripheral microvascular dysfunction during long-term treatment with the angiotensin converting enzyme inhibitor fosinopril in congestive heart failure

Background: Treatment with angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure (CHF) improves cardiac and peripheral hemodynamic function and exercise performance. However, studies on the effects of long-term treatment with an ACE inhibitor on the neurogenic and nonneurogenic regulation and structural microangiopathy of the peripheral microvasculature in CHF are lacking. Methods and Results: We investigated the effect of 12 weeks of treatment with the ACE inhibitor fosinopril on peripheral microvascular function in a double-blind, placebo-controlled study of 12 patients treated with fosinopril and 10 patients treated with placebo. All had moderate CHF. Microvascular blood flow and resistance were calculated after application of the local isotope washout method in relaxed and nonrelaxed calf vascular beds in the supine position and during head-up tilt. Skeletal muscle vascular resistance was reduced in the fosinopril group (46 ± 6 to 30 ± 1 mm Hg · mL −1 · 100 g · min ± standard error; P < .05) and differed compared with the effect of placebo ( P < .05) where no change was seen (37 ± 11 to 55 ± 13 mm Hg · mL −1 · 100 g · min; not significant [NS]). Also, skin minimal vascular resistance was reduced during fosinopril treatment (13 ± 0.6 to 11 ± 0.7 mm Hg · mL −1 · 100 g · min; ( P < .05) and differed compared with the effect of placebo ( P < .05) with absence of change (12 ± 1.6 to 14 ± 1.4 mm Hg · mL −1 · 100 g · min; NS). Conclusions: These results suggest that long-term ACE inhibitor treatment with fosinopril in patients with CHF improves hemodynamic status to as far as the peripheral microvascular level in both the relaxed and nonrelaxed microcirculation of the lower leg.

Changes in skeletal muscle vascular resistance with weight gain: associations with insulin and sympathetic activity.

This study was designed to characterize changes in peripheral vascular resistance with weight gain, and whether these changes are correlated with insulin and/or sympathetic activity. Femoral vascular resistance (FVR), mean arterial pressure, heart rate, and plasma insulin were measured before and during overfeeding in seven dogs with unilateral lumbar ganglionectomy (L3 to L6). Measurements were taken standing and while walking on a treadmill. There was a significant main effect of weight gain to increase mean arterial pressure (16.5+/-8.4 mmHg and 12.5+/-6.8 mmHg increase for standing and walking baseline, respectively) and heart rate (increase from week 1 of 31.6+/-10.6 beats/minute standing and 38.3+/-9.1 walking beat/minute). FVR increased immediately with overfeeding/ weight gain [standing: denervated (DNX):1.32+/-0.3 to 2.34+/-0.5; intact: 0.88+/-0.17 to 1.9+/-0.33 mmHg/mL.min(-1)], but returned to baseline with continued weight gain. Return of FVR to baseline occurred between weeks 2 and 3 of overfeeding in the DNX limb, but did not return to baseline until week 6 in the innervated limb. These changes were not correlated with plasma insulin levels. These data suggest that vascular resistance may be normal in the obese, but increases in vascular resistance occur early with weight gain (before changes in arterial pressure). This initial increase in vascular resistance could initiate the series of events leading to obesity-associated hypertension. Additionally, changing vascular resistance during weight gain may be influenced by sympathetic activity, because DNX limb FVR returned to baseline approximately 3 weeks earlier than the innervated limb.

Endothelial modulation of neural sympathetic vascular tone in canine skeletal muscle.

The effect of nitric oxide synthase (NOS) inhibition and endothelin-A (ETA)-receptor blockade on neural sympathetic control of vascular tone in the gastrocnemius muscle was examined in anesthetized dogs under conditions of constant flow. Muscle perfusion pressure (MPP) was measured before and after NOS inhibition (Nomega-nitro-L-arginine methyl ester; L-NAME) and ETA-receptor blockade [cyclo-(D-Trp-d-Asp-Pro-D-Val-Leu); BQ-123]. Zero and maximum sympathetic nerve activities were achieved by sciatic nerve cold block and stimulation, respectively. In group 1 (n = 6), MPP was measured 1) before nerve cold block, 2) during nerve cold block, and 3) during nerve stimulation. Measurements under these conditions were repeated after L-NAME and then BQ-123. The same protocol was followed in group 2 (n = 6) except that the order of L-NAME and BQ-123 was reversed. MPP and muscle vascular resistance (MVR) increased after L-NAME and then decreased to control values after BQ-123. MVR decreased after BQ-123 alone and, with the addition of L-NAME, increased to a level not different from that observed during the control period. MVR fell during nerve cold block. This response was not affected by administration of L-NAME followed by BQ-123, but it was attenuated by administration of BQ-123 before L-NAME. The constrictor response during sympathetic nerve stimulation was enhanced by L-NAME; no further effect was observed with BQ-123, nor was the response affected when BQ-123 was given first. These findings indicate that endothelin contributes to 1) basal vascular tone in skeletal muscle and 2) the increase in skeletal muscle vascular resistance after NOS inhibition. Finally, nitric oxide "buffers" the degree of constriction in skeletal muscle vasculature during maximal sympathetic stimulation.

Effects of nitric oxide synthase inhibition and endothelin ETA receptor blockade on haemodynamics in hypertensive rats.

1. The objectives of the present study were to study regional differences in haemodynamics between spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats induced by the nitric oxide synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA) and the endothelin ETA receptor antagonist BQ 123 in vivo in tissues known to be important for blood pressure (BP) regulation (heart, kidney and skeletal muscle). Furthermore, the effect of acetylcholine (ACh) infusion (2 micrograms/kg per min) was examined after L-NMMA or BQ 123. The microsphere method was used for determinations of cardiac index (CI) and regional haemodynamics. 2. NG-Monomethyl-L-arginine (20 mg/kg) increased BP (26-48%; P < 0.01) and reduced CI in both rat strains. BQ 123 (1 mg/kg) reduced BP slightly (-4 to 11%; P < 0.05). 3. NG-Monomethyl-L-arginine significantly increased myocardial and skeletal muscle vascular resistance in SHR only; however, in the kidney, L-NMMA reduced blood flow and increased vascular resistance in both rat strains. 4. BQ 123 induced minor changes in regional haemodynamics that were not significantly different between the two strains. 5. Acetylcholine following BQ 123 induced an increase in myocardial blood flow in WKY rats, but decreased blood flow in SHR. Acetylcholine following L-NMMA reduced myocardial blood flow in both strains. 6. Acetylcholine following BQ 123 induced renal vasodilation in WKY rats but, following L-NMMA, ACh did not induce renal vasodilation in either rat strain. In contrast, L-NMMA did not abolish the vasodilation of acetylcholine in skeletal muscle in WKY rats. 7. In conclusion, the contribution of nitric oxide to basal vessel tone was not impaired in the heart, skeletal muscle and kidney in SHR. Antagonism of ETA receptors caused similar haemodynamic responses in both rat strains in these organs. Furthermore, NOS inhibition, but not ETA blockade, blunted the expected ACh-induced vasodilation in the heart and kidney in WKY rats, but not in skeletal muscle in both strains.

Differential effects of training on the control of skeletal muscle perfusion.

Endurance and high-intensity sprint training have been shown to alter skeletal muscle blood flow and factors that govern muscle perfusion under various conditions. Neither endurance nor sprint training alter skeletal muscle perfusion at rest but can result in an increase in muscle blood flow during the anticipation of exercise. The magnitude of the anticipatory increases in muscle blood flow is dependent on the intensity and duration of the prior training bouts and results from elevations in mean arterial pressure and decreases in vascular resistance in skeletal muscle. The decrements in skeletal muscle vascular resistance appear to be mediated through increases in muscle sympathetic cholinergic nerve activity or decreases in muscle sympathetic adrenergic nerve activity. During submaximal exercise, total muscle blood flow is either unchanged or slightly lower. However, a redistribution of muscle blood flow may occur following aerobic training, resulting in an enhanced perfusion of high-oxidative skeletal muscles and less flow going to low-oxidative muscles. The increased perfusion of the high-oxidative muscles may result from various factors including: a) increased recruitment of high-oxidative motor units, b) increased local release of metabolic vasodilator substances, c) qualitative changes in the metabolic substances released, d) decreased muscle sympathetic nerve activity, e) diminished sensitivity of the arterial vasculature to norepinephrine or other vasoconstrictor agents, f) enhanced endothelium-mediated dilation in the resistance vasculature, and g) an increased effectiveness of the skeletal muscle pump. Conversely, the decreases in blood flow to low-oxidative muscles may result from an enhanced autoregulatory responsiveness of the resistance vasculature. Endurance and sprint training increase muscle perfusion during exercise at VO2max: this primarily appears to be the result of an enhanced pumping capacity of the heart to increase in maximal cardiac output. Many of the training-induced alterations in muscle blood flow and vascular structure are localized in the muscles that are most active during the training bouts. Therefore, differences in muscle recruitment patterns that occur with low-intensity endurance exercise and high-intensity sprint exercise may account for differences observed between these two training regimens.

Effects of insulin-like growth factor-I and LR3IGF-I on regional blood flow in normal rats.

Two studies were conducted to investigate the haemodynamic effects of IGF-I and its analogue LR3IGF-I in normal anaesthetised rats. Infusion of IGF-I intravenously, at a dose of 125 micrograms/kg/h, for 20 min in the first study resulted in renal blood flow being significantly elevated by 35% above baseline. Mean arterial blood pressure (MABP) at this IGF-I dose fell by 18% of baseline, with LR3IGF-I also causing a significant decline in MABP (by 15%) at the dose of 125 micrograms/kg/h. In the second study the intravenous administration of IGF-I or LR3IGF-I, at a dose of 125 micrograms/kg/h, over a period of 60 min, resulted in MABP being significantly lowered by 25% of baseline values. Regional blood flow rates were determined using radioactive microspheres, 15 microns in diameter, injected systemically at the end of the peptide infusion period. The gastrocnemius, a representative skeletal muscle, was the only vascular region to show a significant increase in blood flow after IGF-I (by 58%) or LR3IGF-1 (by 308%) infusion. Vascular resistance in the brain was significantly reduced after infusion of IGF-I (by 60%) or LR3IGF-I (by 48%) as compared with vehicle. Skeletal muscle vascular resistance was also reduced by IGF-I (by 41%) and more particularly by LR3IGF-I (by 77%) in comparison to vehicle. These alterations to vascular tone produced by IGF infusion may be related to the central nervous system and systemic cardiovascular side-effects that have been reported during IGF-I administration in humans.