Skeletal Muscle Vascular Conductance Research Articles

Passive leg movement-induced vasodilation and exercise-induced sympathetic vasoconstriction.

The role of nitric oxide (NO) as a modulator of functional sympatholysis has been debated in the literature, but the preponderance of evidence suggests that the magnitude of NO-mediated dilation is restrained by sympathetic vasoconstriction. Therefore, we hypothesized that passive leg movement (PLM)-induced vasodilation, which is predominantly NO-mediated, would be attenuated by an exercise-induced increase in muscle sympathetic nerve activity (MSNA). To test this hypothesis, MSNA, leg blood flow (LBF), and mean arterial blood pressure (MAP) were measured and leg vascular conductance (LVC) calculated in 9 healthy subjects (30±3yr), during PLM with and without sympathoexcitation evoked by arm-cranking exercise (ACE), at 25, 50, and 75% of maximal capacity. During this incremental intensity ACE, MSNA increased significantly (26±2, 34±3, and 41±5 bursts/100 HB, respectively). LVC during PLM fell markedly (~1.2ml/min/mmHg) with each increase in ACE intensity, and there was a strong relationship (r=0.92; p<0.05) between ∆MSNA and ∆Peak LVC induced by the three intensities of ACE. Thus, as anticipated, this study reveals that the, NO-mediated, PLM-induced vasodilation, is significantly and proportionally attenuated by exercise-induced MSNA. This finding highlights the dominant role of MSNA in regulating skeletal muscle vascular conductance.

Mechanisms of sympathetic restraint in human skeletal muscle during exercise: role of α-adrenergic and nonadrenergic mechanisms.

Sympathetic vasoconstriction is mediated by α-adrenergic receptors under resting conditions. During exercise, increased sympathetic nerve activity (SNA) is directed to inactive and active skeletal muscle; however, it is unclear what mechanism(s) are responsible for vasoconstriction during large muscle mass exercise in humans. The aim of this study was to determine the contribution of α-adrenergic receptors to sympathetic restraint of inactive skeletal muscle and active skeletal muscle during cycle exercise in healthy humans. In ten male participants (18-35 yr), mean arterial pressure (intra-arterial catheter) and forearm vascular resistance (FVR) and conductance (FVC) were assessed during cycle exercise (60% total peak workload) alone and during combined cycle exercise + handgrip exercise (HGE) before and after intra-arterial blockade of α- and β-adrenoreceptors via phentolamine and propranolol, respectively. Cycle exercise caused vasoconstriction in the inactive forearm that was attenuated ~80% with adrenoreceptor blockade (%ΔFVR, +81.7 ± 84.6 vs. +9.7 ± 30.7%; P = 0.05). When HGE was performed during cycle exercise, the vasodilatory response to HGE was restrained by ~40% (ΔFVC HGE, +139.3 ± 67.0 vs. cycle exercise: +81.9 ± 66.3 ml·min-1·100 mmHg-1; P = 0.03); however, the restraint of active skeletal muscle blood flow was not due to α-adrenergic signaling. These findings highlight that α-adrenergic receptors are the primary, but not the exclusive mechanism by which sympathetic vasoconstriction occurs in inactive and active skeletal muscle during exercise. Metabolic activity or higher sympathetic firing frequencies may alter the contribution of α-adrenergic receptors to sympathetic vasoconstriction. Finally, nonadrenergic vasoconstrictor mechanisms may be important for understanding the regulation of blood flow during exercise.NEW & NOTEWORTHY Sympathetic restraint of vascular conductance to inactive skeletal muscle is critical to maintain blood pressure during moderate- to high-intensity whole body exercise. This investigation shows that cycle exercise-induced restraint of inactive skeletal muscle vascular conductance occurs primarily because of activation of α-adrenergic receptors. Furthermore, exercise-induced vasoconstriction restrains the subsequent vasodilatory response to hand-grip exercise; however, the restraint of active skeletal muscle vasodilation was in part due to nonadrenergic mechanisms. We conclude that α-adrenergic receptors are the primary but not exclusive mechanism by which sympathetic vasoconstriction restrains blood flow in humans during whole body exercise and that metabolic activity modulates the contribution of α-adrenergic receptors.

Attenuated Leg Vascular Conductance Responses To Dynamic Knee Extension Exercise In Young Black Men

Our group recently showed a blunted increase in skeletal muscle vascular conductance and blood flow during rhythmic handgrip exercise in young black (i.e. African American) individuals with no overt cardiovascular diseases compared with white (i.e. Caucasian American) individuals. These findings, along with reduced endothelium‐dependent forearm vasodilation and augmented forearm vasoconstriction to phenylephrine at rest, suggest that vascular alterations occur early in the lifetime of black individuals, possibly predisposing this population to develop cardiovascular diseases. Notably, research on racial differences in vascular responses has almost exclusively examined upper limbs. However, lower limb vascular diseases are more prevalent and cause more adverse events in the black population than in any other racial group in the U.S. Therefore, for a better understanding of racial differences in vascular health, we tested the hypothesis that vascular responses to lower limb exercise would be attenuated in black individuals compared with their white counterparts. Six black (21 ± 1 years; 23 ± 2 kg/m2) and 4 white (21 ± 0 years; 21 ± 1 kg/m2) healthy men performed dynamic knee extension exercise at the workloads of 10, 20, and 30 watts (W) in an upright sitting position on a custom ergometer. Each exercise trial lasted for 3 min with a minimum rest interval of 5 min. Knee extension cadence was 50 repetitions per min, provided by a metronome and real‐time visual feedback. Common femoral artery blood flow (FABF, Doppler ultrasound) and mean arterial pressure (MAP, finger photoplethysmography) were continuously measured, and leg vascular conductance (LVC) was calculated as FABF/MAP. The participants reported a rating of perceived exertion (Borg Scale 6 – 20) at the end of each trial. Both groups presented LVC increases from rest during dynamic knee extension. While this response was similar between groups at 10 W (White: +1970 ± 138 vs. Black: +1666 ± 173 mL/min/100 mmHg; P = 0.407), the increases in LVC were significantly attenuated in black individuals (mixed‐model ANOVA interaction P = 0.026) at the workloads of 20 W (Whites: +2550 ± 105 vs. Blacks: +1829 ± 179 mL/min/100 mmHg; P = 0.025) and 30 W (Whites: +2528 ± 248 vs. Blacks: +1850 ± 152 mL/min/100 mmHg; P = 0.035). Similarly, FABF responses to dynamic knee extension were lower in black individuals compared with their white counterparts (Interaction P = 0.011). In contrast, increases in MAP were similar between groups (Interaction P = 0.271). The groups reported similar ratings of perceived exertion among trials (Interaction P = 0.817) and achieved similar peak workloads in a dynamic knee extension maximal exercise test (Whites: 48 ± 8 W vs. Blacks: 49 ± 3 W; P = 0.883). These preliminary findings suggest a blunted vasodilator response during leg exercise in black men, further highlighting the early occurrence of vascular alterations in this population.Support or Funding InformationUTA Center of Research and Scholarship Pilot Grant;NIH (1R15HL130906‐01)

Integrated Effects of Sympathetic Vasoconstriction and Local Vasodilation in Human Skeletal Muscle and Skin Microvasculature

Both sympathetic vasoconstriction and locally-mediated vasodilation play important roles in regulation of blood flow to skeletal muscle and skin during exercise. However, the integrated effects of these two vascular regulatory mechanisms in microcirculation are unclear. PURPOSE: We aimed to investigate integration of sympathetic vasoconstriction and local vasodilation in the skeletal muscle and skin microvasculature in humans. METHODS: In 39 healthy volunteers, we measured blood flow index of flexor carpi radialis muscle using diffuse correlation spectroscopy and monitored skin blood flow at the proximal site by laser-Doppler flowmetry, simultaneously. We examined the effects of acute sympathoexcitation by forehead cooling on relatively weak or robust vasodilatory responses during post-occlusive reactive hyperemia (PORH) induced by 70 s or 10 min arterial occlusion at upper arm, respectively. To increase sympathetic tone during PORH, forehead cooling was begun 60 s before the occlusion release and ended 60 s after the release. RESULTS: The acute sympathoexcitation diminished the peak and duration of vasodilation in both skeletal muscle and skin in 70 s occlusion trials [peak skeletal muscle vascular conductance (MVC): 5.6 ± 0.4 vs. 4.1 ± 0.3, peak cutaneous vascular conductance (CVC): 3.4 ± 0.2 vs. 2.9 ± 0.2 AU, 50 % decay time of MVC: 19 ± 0.8 vs. 13 ± 0.6, 50 % decay time of CVC: 17 ± 1.0 vs. 14 ± 1.0 s, p < 0.05]. The sympathetic inhibition of vasodilation was blunted under robust vasodilatory stimuli produced by 10 min occlusion. This blunt of the sympathetic inhibition was greater in skeletal muscle than in skin, especially in those initial and peak vasodilation. Indeed, the sympathoexcitation reduced the peak vasodilation only in skin (peak MVC: 10.2 ± 0.9 vs. 9.7 ± 0.9, p > 0.05, peak CVC: 7.7 ± 0.5 vs. 6.5 ± 0.5 AU, p < 0.05) while it accelerated the initial vasodilation selectively in skeletal muscle (area of MVC during first 15 s of PORH: 75.2 ± 6.5 vs. 83.0 ± 6.9, p < 0.05, area of CVC: 51.6 ± 2.7 vs. 51.7 ± 3.4 AUs, p > 0.05). CONCLUSION: We conclude that, in humans, the integration of sympathetic vasoconstriction and local vasodilation has different effects in skeletal muscle and skin. Such different effects would be importantly involved in selective control of perfusion in microcirculation of different tissues.

Aging alters the contribution of nitric oxide to regional muscle hemodynamic control at rest and during exercise in rats

Advanced age is associated with altered skeletal muscle hemodynamic control during the transition from rest to exercise. This study investigated the effects of aging on the functional role of nitric oxide (NO) in regulating total, inter-, and intramuscular hindlimb hemodynamic control at rest and during submaximal whole body exercise. We tested the hypothesis that NO synthase inhibition (N(G)-nitro-l-arginine methyl ester, l-NAME; 10 mg/kg) would result in attenuated reductions in vascular conductance (VC) primarily in oxidative muscles in old compared with young rats. Total and regional hindlimb muscle VCs were determined via radiolabeled microspheres at rest and during treadmill running (20 m/min, 5% grade) in nine young (6-8 mo) and seven old (27-29 mo) male Fisher 344 × Brown Norway rats. At rest, l-NAME increased mean arterial pressure (MAP) significantly by ∼17% and 21% in young and old rats, respectively. During exercise, l-NAME increased MAP significantly by ∼13% and 19% in young and old rats, respectively. Compared with young rats, l-NAME administration in old rats evoked attenuated reductions in 1) total hindlimb VC during exercise (i.e., down by ∼23% in old vs. 43% in young rats; P < 0.05), and 2) VC in predominantly oxidative muscles both at rest and during exercise (P < 0.05). Our results indicate that the dependency of highly oxidative muscles on NO-mediated vasodilation is markedly diminished, and therefore mechanisms other than NO-mediated vasodilation control the bulk of the increase in skeletal muscle VC during the transition from rest to exercise in old rats. Reduced NO contribution to vasomotor control with advanced age is associated with blood flow redistribution from highly oxidative to glycolytic muscles during exercise.

Acute antioxidant supplementation and skeletal muscle vascular conductance in aged rats: role of exercise and fiber type

Age-related increases in oxidative stress contribute to impaired skeletal muscle vascular control. However, recent evidence indicates that antioxidant treatment with tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) attenuates flow-mediated vasodilation in isolated arterioles from the highly oxidative soleus muscle of aged rats. Whether antioxidant treatment with tempol evokes similar responses in vivo at rest and during exercise in senescent individuals and whether this effect varies based on muscle fiber type composition are unknown. We tested the hypothesis that redox modulation via acute systemic tempol administration decreases vascular conductance (VC) primarily in oxidative hindlimb locomotor muscles at rest and during submaximal whole body exercise (treadmill running at 20 m/min, 5% grade) in aged rats. Eighteen old (25-26 mo) male Fischer 344 x Brown Norway rats were assigned to either rest (n = 8) or exercise (n = 10) groups. Regional VC was determined via radiolabeled microspheres before and after intra-arterial administration of tempol (302 μmol/kg). Tempol decreased mean arterial pressure significantly by 9% at rest and 16% during exercise. At rest, similar VC in 26 out of 28 individual hindlimb muscles or muscle parts following tempol administration compared with control resulted in unchanged total hindlimb muscle VC (control: 0.18 ± 0.02; tempol: 0.17 ± 0.05 ml·min(-1)·100 g(-1)·mmHg(-1); P > 0.05). During exercise, all individual hindlimb muscles or muscle parts irrespective of fiber type composition exhibited either an increase or no change in VC with tempol (i.e., ↑11 and ↔17 muscles or muscle parts), such that total hindlimb VC increased by 25% (control: 0.93 ± 0.04; tempol: 1.15 ± 0.09 ml·min(-1)·100 g(-1)·mmHg(-1); P ≤ 0.05). These results demonstrate that acute systemic administration of the antioxidant tempol significantly impacts the control of regional vascular tone in vivo presumably via redox modulation and improves skeletal muscle vasodilation independently of fiber type composition during submaximal whole body exercise in aged rats.

Exercising an option to prevent age related decline of vascular BH4 and uncoupling of eNOS

It is well documented that skeletal muscle vascular conductance and endothelium-dependent vasodilatation are reduced with ageing. Studies utilizing isolated skeletal muscle arterioles reveal that age-related deficits involve, at least in part, alterations in the NO signalling pathway (Muller-Delp et al. 2002; Delp et al. 2008). Although manifold factors could contribute to age-related declines in NO-mediated function, recent studies highlight the potential importance of tetrahydrobiopterin (BH4), a nitric oxide synthase (NOS) cofactor. When BH4 is limited, eNOS can become uncoupled and produce superoxide instead of NO. Thus, BH4 is potentially of junctional importance in the link between NO, reactive oxygen species (ROS) and vascular function. In humans, a single oral dose of BH4 restored endothelium-dependent dilatation in the conduit brachial artery of sedentary older men (Eskurza et al. 2005). Furthermore, Delp et al. (2008) demonstrated that age-related declines in flow-mediated dilatation of rat soleus muscle arterioles resulted, at least in part, from limitations in availability of the eNOS cofactor tetrahydrobiopterin (BH4), and that administration of the BH4 precursor sepiapterin improved flow-induced dilatation in vessels from aged rats. These results collectively support the argument that interventions to preserve vascular BH4 may be a therapeutic option for age-related vascular dysfunction (Pierce & LaRocca, 2008). In the current issue of The Journal of Physiology, Sindler et al. proposed to determine if age-related declines in vascular BH4 were associated with eNOS uncoupling and ROS production, and whether these age-related changes could be reversed by a therapeutic exercise training intervention. Aerobic exercise training has previously been shown to blunt or eliminate age-dependent declines in NO-mediated endothelium-dependent dilatation and to improve skeletal muscle blood flow in a variety of models (Seals et al. 2008), and the study of Sindler et al. proposes to add novel understanding of the underlying mechanisms related to BH4. The approach is integrative, combining functional assessment of vasodilatation with biochemical measurements of BH4, NO and ROS production, all in isolated arterioles from the soleus muscle under a number of controlled pharmacological conditions. As expected, flow-mediated dilatation was impaired with ageing and restored by exercise training; novel observations point to potential underlying mechanisms: age-related reduction in BH4 occurred in conjunction with decline in flow-induced NO signalling, and increase in superoxide production (eNOS uncoupling); and exercise training prevented the age-related loss of BH4 and improved NO bio-availability by balancing accelerated NO and ROS production. These results extend the appreciation of oxidative stress impacting NO bio-availability and vasomotor function beyond the traditional, but insufficient, concept of NO destruction by ROS (Rush et al. 2005). The findings of the study of Sindler et al. are timely, reported roughly contemporaneously with identification of the need for pharmacological therapies directed toward a similar result, the restoration of BH4 in aged blood vessels. This creates a discovery environment in which potential pharmacological- and exercise-oriented approaches to the problem will undoubtedly co-evolve. The findings of Sindler et al. additionally serve as a progenitor for many hypotheses regarding BH4 in vascular adaptations to age and exercise. Fundamental questions raised include those related to identifying the cellular mechanisms accounting for age-related declines and exercise-related restoration of vascular BH4. In this regard, emerging data suggest that H2O2 is a regulatory factor controlling BH4 synthesis in vascular cells via induction of the enzyme GTP-cyclohydrolase I (GTPCH; Shimizu et al. 2003). The data of Sindler et al. indicate that H2O2 contributes to flow-induced dilatation of skeletal muscle arterioles of young sedentary animals and that, like the flow-induced dilatation functional response itself, this H2O2 signalling declines with age but is restored by exercise training. Is it possible that this same pattern of H2O2 signalling could contribute to maintenance of BH4 in young arterioles, its loss with age, and its restoration with exercise in aged arterioles, consistent with the indicated effect of H2O2 on GTPCH expression and BH4 synthesis? If so, H2O2 takes on another important role in the acute and chronic regulation of vascular function. A recurring theme in vascular biology is heterogeneity in phenotype and function depending on vessel type (conduit vs. resistance), location (vascular bed), and physiological circumstances (e.g. other conditions in vivo). While these considerations are in part cautionary regarding the global interpretation of the results of Sindler et al., they can more appropriately be seen as an invitation for additional studies designed to create a more integrative understanding of cellular mechanisms of vascular ageing and the therapeutic effects of exercise. The study of Sindler et al. creates a new paradigm justifying such an invitation with respect to BH4, vasomotor function and the regulation of skeletal muscle blood flow.

Integrative control of the skeletal muscle microcirculation in the maintenance of arterial pressure during exercise.

Skeletal muscle blood flow and vascular conductance are influenced by numerous factors that can be divided into two general categories: central cardiovascular control mechanisms and local vascular control mechanisms. Central cardiovascular control mechanisms are thought to be designed primarily for the maintenance of arterial pressure and central cardiovascular homeostasis, whereas local vascular control mechanisms are thought to be designed primarily for the maintenance of muscle homeostasis. To support the high metabolic rates that can be generated during muscle contraction, skeletal muscle has a tremendous capacity to vasodilate and increase oxygen and nutrient delivery. During whole body dynamic exercise at maximal oxygen consumption (VO2 max), the skeletal muscle receives 85-90% of cardiac output. Yet despite receiving such a large fraction of cardiac output during high-intensity exercise, a vasodilator reserve remains with the potential to produce further elevations in skeletal muscle vascular conductance and blood flow. However, because maximal cardiac output is reached during exercise at VO2 max, further elevations in muscle vascular conductance would produce a fall in arterial pressure. Therefore, limits on muscle perfusion must be imposed during whole body exercise to prevent such drops in pressure. Effective arterial pressure control in response to a potentially hypotensive challenge during high-intensity exercise occurs primarily through reflex-mediated increases in sympathetic nerve activity, which are capable of modulating vasomotor tone of the skeletal muscle resistance vasculature. Thus skeletal muscle vascular conductance and perfusion are primarily mediated by local factors at rest and during exercise, but other centrally mediated control systems are superimposed on the dominant local control mechanisms to provide an integrated regulation of both arterial pressure and skeletal muscle vascular conductance and perfusion during whole body dynamic exercise.

Regional hemodynamics during postexercise hypotension. I. Splanchnic and renal circulations.

Moderate exercise elicits a relative postexercise hypotension that is caused by an increase in systemic vascular conductance. Previous studies have shown that skeletal muscle vascular conductance is increased postexercise. It is unclear whether these hemodynamic changes are limited to skeletal muscle vascular beds. The aim of this study was to determine whether the splanchnic and/or renal vascular beds also contribute to the rise in systemic vascular conductance during postexercise hypotension. A companion study aims to determine whether the cutaneous vascular bed is involved in postexercise hypotension (Wilkins BW, Minson CT, and Halliwill JR. J Appl Physiol 97: 2071-2076, 2004). Heart rate, arterial pressure, cardiac output, leg blood flow, splanchnic blood flow, and renal blood flow were measured in 13 men and 3 women before and through 120 min after a 60-min bout of exercise at 60% of peak oxygen uptake. Vascular conductances of leg, splanchnic, and renal vascular beds were calculated. One hour postexercise, mean arterial pressure was reduced (79.1 +/- 1.7 vs. 83.4 +/- 1.8 mmHg; P < 0.05), systemic vascular conductance was increased by approximately 10%, leg vascular conductance was increased by approximately 65%, whereas splanchnic (16.0 +/- 1.8 vs. 18.5 +/- 2.4 ml.min(-1).mmHg(-1); P = 0.13) and renal (20.4 +/- 3.3 vs. 17.6 +/- 2.6 ml.min(-1).mmHg(-1); P = 0.14) vascular conductances were unchanged compared with preexercise. This suggests there is neither vasoconstriction nor vasodilation in the splanchnic and renal vasculature during postexercise hypotension. Thus the splanchnic and renal vascular beds neither directly contribute to nor attenuate postexercise hypotension.

Maximal muscular vascular conductances during whole body upright exercise in humans.

That muscular blood flow may reach 2.5 l kg(-1) min(-1) in the quadriceps muscle has led to the suggestion that muscular vascular conductance must be restrained during whole body exercise to avoid hypotension. The main aim of this study was to determine the maximal arm and leg muscle vascular conductances (VC) during leg and arm exercise, to find out if the maximal muscular vasodilatory response is restrained during maximal combined arm and leg exercise. Six Swedish elite cross-country skiers, age (mean +/-s.e.m.) 24 +/- 2 years, height 180 +/- 2 cm, weight 74 +/- 2 kg, and maximal oxygen uptake (VO(2,max)) 5.1 +/- 0.1 l min(-1) participated in the study. Femoral and subclavian vein blood flows, intra-arterial blood pressure, cardiac output, as well as blood gases in the femoral and subclavian vein, right atrium and femoral artery were determined during skiing (roller skis) at approximately 76% of VO(2,max) and at VO(2,max) with different techniques: diagonal stride (combined arm and leg exercise), double poling (predominantly arm exercise) and leg skiing (predominantly leg exercise). During submaximal exercise cardiac output (26-27 l min(-1)), mean blood pressure (MAP) (approximately 87 mmHg), systemic VC, systemic oxygen delivery and pulmonary VO2(approximately 4 l min(-1)) attained similar values regardless of exercise mode. The distribution of cardiac output was modified depending on the musculature engaged in the exercise. There was a close relationship between VC and VO2 in arms (r= 0.99, P < 0.001) and legs (r= 0.98, P < 0.05). Peak arm VC (63.7 +/- 5.6 ml min(-1) mmHg(-1)) was attained during double poling, while peak leg VC was reached at maximal exercise with the diagonal technique (109.8 +/- 11.5 ml min(-1) mmHg(-1)) when arm VC was 38.8 +/- 5.7 ml min(-1) mmHg(-1). If during maximal exercise arms and legs had been vasodilated to the observed maximal levels then mean arterial pressure would have dropped at least to 75-77 mmHg in our experimental conditions. It is concluded that skeletal muscle vascular conductance is restrained during whole body exercise in the upright position to avoid hypotension.

Interactions between angiotensin II and nitric oxide during exercise in normal and heart failure rats.

We hypothesized that nitric oxide (NO) opposes ANG II-induced increases in arterial pressure and reductions in renal, splanchnic, and skeletal muscle vascular conductance during dynamic exercise in normal and heart failure rats. Regional blood flow and vascular conductance were measured during treadmill running before (unblocked exercise) and after 1) ANG II AT(1)-receptor blockade (losartan, 20 mg/kg ia), 2) NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME); 10 mg/kg ia], or 3) ANG II AT(1)-receptor blockade + NOS inhibition (combined blockade). Renal conductance during unblocked exercise (4.79 +/- 0.31 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased after ANG II AT(1)-receptor blockade (6.53 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.12 +/- 0.20 ml x 100 g(-1) x min(-1) x mmHg(-1)) and combined inhibition (3.96 +/- 0.57 ml x 100 g(-1) x min(-1) x mmHg(-1); all P < 0.05 vs. unblocked). In heart failure rats, renal conductance during unblocked exercise (5.50 +/- 0.66 ml x 100 g(-1) x min(-1) x mmHg(-1)) was increased by ANG II AT(1)-receptor blockade (8.48 +/- 0.83 ml x 100 g(-1) x min(-1) x mmHg(-1)) and decreased by NOS inhibition (2.68 +/- 0.22 ml x 100 g(-1) x min(-1) x mmHg(-1); both P < 0.05 vs. unblocked), but it was unaltered during combined inhibition (4.65 +/- 0.51 ml x 100 g(-1) x min(-1) x mmHg(-1)). Because our findings during combined blockade could be predicted from the independent actions of NO and ANG II, no interaction was apparent between these two substances in control or heart failure animals. In skeletal muscle, L-NAME-induced reductions in conductance, compared with unblocked exercise (P < 0.05), were abolished during combined inhibition in heart failure but not in control rats. These observations suggest that ANG II causes vasoconstriction in skeletal muscle that is masked by NO-evoked dilation in animals with heart failure. Because reductions in vascular conductance between unblocked exercise and combined inhibition were less than would be predicted from the independent actions of NO and ANG II, an interaction exists between these two substances in heart failure rats. L-NAME-induced increases in arterial pressure during treadmill running were attenuated (P < 0.05) similarly in both groups by combined inhibition. These findings indicate that NO opposes ANG II-induced increases in arterial pressure and in renal and skeletal muscle resistance during dynamic exercise.

Control of skeletal muscle perfusion at the onset of dynamic exercise

At the onset of exercise there is a rapid increase in skeletal muscle vascular conductance and blood flow. Several mechanisms involved in the regulation of muscle perfusion have been proposed to initiate this hyperemic response, including neural, metabolic, endothelial, myogenic, and muscle pump mechanisms. Investigators utilizing pharmacological blockade of cholinergic muscarinic receptors and sympathectomy have concluded that neither sympathetic cholinergic nor adrenergic neural mechanisms are involved in the initial hyperemia. Studies have also shown that the time course for vasoactive metabolite release, diffusion, accumulation, and action is too long to account for the rapid increase in vascular conductance at the initiation of exercise. Furthermore, there is little or no evidence to support an endothelium or myogenic mechanism as the initiating factor in the muscle hyperemia. Thus, the rise in muscle blood flow does not appear to be explained by known neural, metabolic, endothelial, or myogenic influences. However, the initial hyperemia is consistent with the mechanical effects of the muscle pump to increase the arteriovenous pressure gradient across muscle. Because skeletal muscle blood flow is regulated by multiple and redundant mechanisms, it is likely that neural, metabolic, and possibly endothelial factors become important modulators of mechanically induced exercise hyperemia following the first 5-10 s of exercise.

Vascular conductance and aerobic power in sedentary and active subjects and heart failure patients

The relationship between peak aerobic power and a strain-gauge determination of local skeletal muscle vascular conductance 10-13 s after calf exercise to fatigue was examined in 21 middle-aged adults (age 38.1 +/- 2.5 yr): seven physically active men (A), seven sedentary men (S), and six men and one woman with compensated idiopathic heart failure (HF). The three subgroups were chosen as differing widely in peak O2 intake [48.2 +/- 1.2, 32.9 +/- 1.6, and 16.1 +/- 1.3 (SE) ml.kg-1 x min-1, respectively]. Calf vascular conductance showed a gradation with aerobic power: 64.8 +/- 3.8, 40.7 +/- 4.3, and 30.7 +/- 6.1 (SE) ml/min local flow per 10 liters of tissue per unit of blood pressure. There was a strong positive correlation between O2 intake and vascular conductance for the overall group (VO2 = 0.614 G + 3.5; r = 0.75, P < 0.001) and for the 14 normal subjects (VO2 = 0.377 G + 20.6; r = 0.74, P < 0.002). The mean conductance was smaller in HF (P < 0.001), with no significant slope in relation to O2 intake. There was no relationship between the resting cardiac ejection fraction [74.4 +/- 4.1% (SE) for A, 74.3 +/- 4.2% for S, and 25.8 +/- 5.2% for HF] and either peak aerobic power or calf vascular conductance. We conclude that peak aerobic power is strongly associated with local vascular conductance during peripherally limited exercise involving the calf muscles of one leg and that vascular conductance is particularly low in subjects with compensated idiopathic heart failure.

Skeletal muscle blood flow capacity: role of muscle pump in exercise hyperemia.

An appreciation for the potential of skeletal muscle vascular beds for blood flow (blood flow capacity) is required if one is to understand the limits of the cardiorespiratory system in exercise. To assess this potential, an index of blood flow capacity that can be objectively measured is required. One obvious index would be to measure maximal muscle blood flow (MBF). However, a unique value for maximal MBF cannot be measured, since once maximal vasodilation is attained MBF is a function of perfusion pressure. Another approach would be to measure maximal or peak vascular conductance. However, peak vascular conductance is different among skeletal muscles composed of different fiber types and is a function of perfusion pressure during peak vasodilation within muscle composed of a given fiber type. Also, muscle contraction can increase or decrease blood flow and/or the apparent peak vascular conductance depending on the experimental preparation and the type of muscle contraction. Blood flows and calculated values of conductance appear to be greater during rhythmic contractions (with the appropriate frequency and duration) than observed in resting muscle during what is called "maximal" vasodilation. Moreover, dynamic exercise in conscious subjects produces the greatest skeletal muscle blood flows. The purpose of this review is to consider the interaction of the determinants of muscle blood flow during locomotory exercise. Emphasis is directed toward the hypothesis that the "muscle pump" is an important determinant of perfusion of active skeletal muscle. It is concluded that, during normal dynamic exercise, MBF is determined by skeletal muscle vascular conductance, the perfusion pressure gradient, and the efficacy of the muscle pump.