Vasoconstriction in active skeletal muscles: a potential role for P2X purinergic receptors?

There is evidence that ATP acts as a neurotransmitter in vascular smooth muscle and is coreleased with norepinephrine from sympathetic nerves. We hypothesized that P2X-receptor stimulation with the selective P2X-receptor agonist alpha,beta-methylene ATP would produce vasoconstriction in resting and exercising skeletal muscle. Six mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. The selective P2X agonist alpha,beta-methylene ATP was infused as a bolus into the femoral artery catheter at rest and during mild, moderate, and heavy exercise. Intra-arterial infusions of alpha,beta-methylene ATP elicited reductions in vascular conductance of 54 +/- 5, 49 +/- 8, 39 +/- 8, and 30 +/- 6% at rest, 3 miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. The agonist infusions did not affect blood flow in the contralateral iliac artery. To examine whether nitric oxide is responsible for the attenuated vasoconstrictor response to P2X stimulation, the infusions were repeated in the presence of NG-nitro-l-arginine methyl ester. After nitric oxide synthase blockade, intra-arterial infusions of alpha,beta-methylene ATP elicited reductions in vascular conductance of 56 +/- 7, 61 +/- 8, 52 +/- 9, and 40 +/- 7% at rest, 3 miles/h, 6 miles/h, and 6 miles/h at a 10% grade, respectively. P2X-receptor responsiveness was attenuated during exercise compared with rest. Blockade of nitric oxide production did not affect the attenuation of P2X-receptor responsiveness during exercise. These data support the hypothesis that P2X purinergic receptors can produce vasoconstriction in exercising skeletal muscle.     

Vasoconstriction in exercising skeletal muscles: a potential role for neuropeptide Y?

There is evidence that neuropeptide Y (NPY) acts as a neurotransmitter in vascular smooth muscle and is released with norepinephrine from sympathetic nerves. We hypothesized that NPY Y(1) receptor stimulation would produce vasoconstriction in resting and exercising skeletal muscle. Nine mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. The selective NPY Y(1) receptor agonist [Leu(31),Pro(34)]NPY was infused as a bolus into the femoral artery catheter at rest and during mild, moderate, and heavy exercise. Intra-arterial infusions of [Leu(31),Pro(34)]NPY elicited reductions (P < 0.05) in vascular conductance of 38 +/- 3, 25 +/- 2, 17 +/- 1, and 11 +/- 1% at rest, 3 miles/h, 6 miles/h, and 6 miles/h and 10% grade, respectively. The agonist infusions did not affect (P > 0.05) blood flow in the contralateral iliac artery. To examine whether nitric oxide (NO) is responsible for the attenuated vasoconstrictor response during exercise to NPY Y(1) receptor stimulation, the infusions were repeated after NO synthase blockade. These infusions yielded reductions (P < 0.05) in vascular conductance of 47 +/- 3, 23 +/- 2, 19 +/- 3, and 12 +/- 2% at rest, 3 miles/h, 6 miles/h, and 6 miles/h and 10% grade, respectively. NPY Y(1) receptor responsiveness was attenuated (P < 0.05) during exercise compared with rest. Blockade of NO production did not affect (P > 0.05) the attenuation of NPY Y(1) receptor responsiveness during exercise. These data support the hypothesis that NPY Y(1) receptors can produce vasoconstriction in exercising skeletal muscle.     

Role of nitric oxide in exercise sympatholysis.

The production of nitric oxide is the putative mechanism for the attenuation of sympathetic vasoconstriction (sympatholysis) in working muscles during exercise. We hypothesized that nitric oxide synthase blockade would eliminate the reduction in alpha-adrenergic-receptor responsiveness in exercising skeletal muscle. Ten mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. The selective alpha(1)-adrenergic agonist (phenylephrine) or the selective alpha(2)-adrenergic agonist (clonidine) was infused as a bolus into the femoral artery catheter at rest and during mild and heavy exercise. Before nitric oxide synthase inhibition with N(G)-nitro-l-arginine methyl ester (l-NAME), intra-arterial infusions of phenylephrine elicited reductions in vascular conductance of -91 +/- 3, -80 +/- 5, and -75 +/- 6% (means +/- SE) at rest, 3 miles/h, and 6 miles/h and 10% grade, respectively. Intra-arterial clonidine reduced vascular conductance by -65 +/- 6, -39 +/- 4, and -30 +/- 3%. After l-NAME, intra-arterial infusions of phenylephrine elicited reductions in vascular conductance of -85 +/- 5, -85 +/- 5, and -84 +/- 5%, whereas clonidine reduced vascular conductance by -67 +/- 5, -45 +/- 3, and -35 +/- 3%, at rest, 3 miles/h, and 6 miles/h and 10% grade. alpha(1)-Adrenergic-receptor responsiveness was attenuated during heavy exercise. In contrast, alpha(2)-adrenergic-receptor responsiveness was attenuated even at a mild exercise intensity. Whereas the inhibition of nitric oxide production eliminated the exercise-induced attenuation of alpha(1)-adrenergic-receptor responsiveness, the attenuation of alpha(2)-adrenergic-receptor responsiveness was unaffected. These results suggest that the mechanism of exercise sympatholysis is not entirely mediated by the production of nitric oxide.     

Do P2X purinergic receptors regulate skeletal muscle blood flow during exercise?

Although there is evidence that sympathetic nerves release ATP as a neurotransmitter to produce vasoconstriction via P2X purinergic receptors, the role of these receptors in the regulation of blood flow to exercising skeletal muscle has yet to be determined. We hypothesized that there is tonic P2X receptor-mediated vasoconstriction in exercising skeletal muscle. To test this hypothesis, the effect of P2X receptor blockade on skeletal muscle blood flow was examined in six exercising mongrel dogs. P2X receptor antagonism was accomplished with pyridoxal-phosphate-6-azophenyl-2'4'-disulfonic acid (PPADs). Animals were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. PPADs (40 mg) was infused as a bolus into the femoral artery catheter during steady-state exercise at 6 miles/h. Intra-arterial infusion of PPADs increased iliac blood flow from 542 +/- 55 to 677 +/- 69 ml/min (P < 0.05) and iliac vascular conductance from 5.17 +/- 0.62 to 6.53 +/- 0.80 ml.min(-1).mmHg(-1). The PPADs infusion did not affect blood flow in the contralateral iliac artery. These data support the hypothesis that P2X purinergic receptors produce vasoconstriction in exercising skeletal muscle.     

Neuropeptide Y1 receptor vasoconstriction in exercising canine skeletal muscles.

Existing evidence suggests that neuropeptide Y (NPY) acts as a neurotransmitter in vascular smooth muscle and is coreleased with norepinephrine from sympathetic nerves. We hypothesized that release of NPY stimulates NPY Y(1) receptors in the skeletal muscle vasculature to produce vasoconstriction during dynamic exercise. Eleven mongrel dogs were instrumented chronically with flow probes on the external iliac arteries of both hindlimbs and a catheter in one femoral artery. In resting dogs (n = 4), a 2.5-mg bolus of BIBP-3226 (NPY Y(1) antagonist) infused into the femoral artery increased external iliac conductance by 150 +/- 82% (1.80 +/- 0.44 to 3.50 +/- 0.14 ml.min(-1).mmHg(-1); P < 0.05). A 10-mg bolus of BIBP-3226 infused into the femoral artery in dogs (n = 7) exercising on a treadmill at a moderate intensity (6 miles/h) increased external iliac conductance by 28 +/- 6% (6.00 +/- 0.49 to 7.64 +/- 0.61 ml.min(-1).mmHg(-1); P < 0.05), whereas the solvent vehicle did not (5.74 +/- 0.51 to 5.98 +/- 0.43 ml.min(-1).mmHg(-1); P > 0.05). During exercise, BIBP-3226 abolished the reduction in conductance produced by infusions of the NPY Y(1) agonist [Leu(31),Pro(34)]NPY (-19 +/- 3 vs. 0.5 +/- 1%). Infusions of BIBP-3226 (n = 7) after alpha-adrenergic receptor antagonism with prazosin and rauwolscine also increased external iliac conductance (6.82 +/- 0.43 to 8.22 +/- 0.48 ml.min(-1).mmHg(-1); P < 0.05). These data support the hypothesis that NPY Y(1) receptors produce vasoconstriction in exercising skeletal muscle. Furthermore, the NPY Y(1) receptor-mediated tone appears to be independent of alpha-adrenergic receptor-mediated vasoconstriction.     

Alpha-adrenergic receptor-mediated restraint of skeletal muscle blood flow during prolonged exercise.

Sympathetic nervous system restraint of skeletal muscle blood flow during dynamic exercise has been well documented. However, whether sympathetic restraint of muscle blood flow persists and is constant throughout prolonged exercise has not been established. We hypothesized that both alpha1- and alpha2-adrenergic receptors would restrain skeletal muscle blood flow throughout prolonged constant-load exercise and that the restraint would increase as a function of exercise duration. Mongrel dogs were instrumented chronically with transit-time flow probes on the external iliac arteries and an indwelling catheter in a branch of the femoral artery. Flow-adjusted doses of selective alpha1- (prazosin) and alpha2-adrenergic receptor (rauwolscine) antagonists were infused after 5, 30, and 50 min of treadmill exercise at 3 and 6 miles/h. During mild-intensity exercise (3 miles/h), prazosin infusion resulted in a greater (P < 0.05) increase in vascular conductance (VC) after 5 [42% (SD 6)], compared with 30 [28% (SD 6)] and 50 [28% (SD 8)] min of running. In contrast, prazosin resulted in a similar increase in VC after 5 [29% (SD 10)], 30 [24% (SD 9)], and 50 [22% (SD 9)] min of moderate-intensity (6 miles/h) exercise. Rauwolscine infusion resulted in a greater (P < 0.05) increase in VC after 5 [39% (SD 14)] compared with 30 [26% (SD 9)] and 50 [22% (SD 4)] min of exercise at 3 miles/h. Rauwolscine infusion produced a similar increase in VC after 5 [19% (SD 3)], 30 [15% (SD 6)], and 50 [16% (SD 2)] min of exercise at 6 miles/h. These results suggest that the ability of alpha1- and alpha2-adrenergic receptors to produce vasoconstriction and restrain blood flow to active muscles may be influenced by both the intensity and duration of exercise.     

Carotid baroreflex pressor responses at rest and during exercise: cardiac output vs. regional vasoconstriction

The arterial baroreflex mediates changes in arterial pressure via reflex changes in cardiac output (CO) and regional vascular conductance, and the relative roles may change between rest and exercise and across workloads. Therefore, we quantified the contribution of CO and regional vascular conductances to carotid baroreflex-mediated increases in mean arterial pressure (MAP) at rest and during mild to heavy treadmill exercise (3.2 kph; 6.4 kph, 10% grade; and 8 kph, 15% grade). Dogs (n = 8) were chronically instrumented to measure changes in MAP, CO, hindlimb vascular conductance, and renal vascular conductance in response to bilateral carotid occlusion (BCO). At rest and at each workload, BCO caused similar increases in MAP (average 35 +/- 2 mmHg). In response to BCO, neither at rest nor at any workload were there significant increases in CO; therefore, the pressor response occurred via peripheral vasoconstriction. At rest, 10.7 +/- 1.4% of the rise in MAP was due to vasoconstriction in the hindlimb, whereas 4.0 +/- 0.7% was due to renal vasoconstriction. Linear regression analysis revealed that, with increasing workloads, relative contributions of the hindlimb increased and those of the kidney decreased. At the highest workload, the decrease in hindlimb vascular conductance contributed 24.3 +/- 3.4% to the pressor response, whereas the renal contribution decreased to only 1.6 +/- 0.3%. We conclude that the pressor response during BCO was mediated solely by peripheral vasoconstriction. As workload increases, a progressively larger fraction of the pressor response is mediated via vasoconstriction in active skeletal muscle and the contribution of vasoconstriction in inactive beds (e.g., renal) becomes progressively smaller.     

Muscle metaboreflex attenuates spontaneous heart rate baroreflex sensitivity during dynamic exercise

Hypoperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex. Dynamic exercise attenuates spontaneous baroreflex sensitivity (SBRS) in the control of heart rate (HR) during rapid, spontaneous changes in blood pressure (BP). Our objective was to determine whether muscle metaboreflex activation (MRA) further diminishes SBRS. Conscious dogs were chronically instrumented for measurement of HR, cardiac output, mean arterial pressure, and left ventricular systolic pressure (LVSP) at rest and during mild (3.2 km/h) or moderate (6.4 km/h at 10% grade) dynamic exercise before and after MRA (via partial reduction of hindlimb blood flow). SBRS was evaluated as the slopes of the linear relations (LRs) between HR and LVSP during spontaneous sequences of at least three consecutive beats when HR changed inversely vs. pressure (expressed as beats x min(-1) x mmHg(-1)). During mild exercise, these LRs shifted upward, with a significant decrease in SBRS (-3.0 +/- 0.4 vs. -5.2 +/- 0.4, P<0.05 vs. rest). MRA shifted LRs upward and rightward and decreased SBRS (-2.1 +/- 0.1, P<0.05 vs. mild exercise). Moderate exercise shifted LRs upward and rightward and significantly decreased SBRS (-1.2 +/- 0.1, P<0.05 vs. rest). MRA elicited further upward and rightward shifts of the LRs and reductions in SBRS (-0.9 +/- 0.1, P<0.05 vs. moderate exercise). We conclude that dynamic exercise resets the arterial baroreflex to higher BP and HR as exercise intensity increases. In addition, increases in exercise intensity, as well as MRA, attenuate SBRS.     

Leg vasoconstriction during dynamic exercise with reduced cardiac output.

We evaluated whether a reduction in cardiac output during dynamic exercise results in vasoconstriction of active skeletal muscle vasculature. Nine subjects performed four 8-min bouts of cycling exercise at 71 +/- 12 to 145 +/- 13 W (40-84% maximal oxygen uptake). Exercise was repeated after cardioselective (beta 1) adrenergic blockade (0.2 mg/kg metoprolol iv). Leg blood flow and cardiac output were determined with bolus injections of indocyanine green. Femoral arterial and venous pressures were monitored for measurement of heart rate, mean arterial pressure, and calculation of systemic and leg vascular conductance. Leg norepinephrine spillover was used as an index of regional sympathetic activity. During control, the highest heart rate and cardiac output were 171 +/- 3 beats/min and 18.9 +/- 0.9 l/min, respectively. beta 1-Blockade reduced these values to 147 +/- 6 beats/min and 15.3 +/- 0.9 l/min, respectively (P < 0.001). Mean arterial pressure was lower than control during light exercise with beta 1-blockade but did not differ from control with greater exercise intensities. At the highest work rate in the control condition, leg blood flow and vascular conductance were 5.4 +/- 0.3 l/min and 5.2 +/- 0.3 cl.min-1.mmHg-1, respectively, and were reduced during beta 1-blockade to 4.8 +/- 0.4 l/min (P < 0.01) and 4.6 +/- 0.4 cl.min-1.mmHg-1 (P < 0.05). During the same exercise condition leg norepinephrine spillover increased from a control value of 2.64 +/- 1.16 to 5.62 +/- 2.13 nM/min with beta 1-blockade (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Heart failure alters the strength and mechanisms of arterial baroreflex pressor responses during dynamic exercise

Arterial baroreflex function is well preserved during dynamic exercise in normal subjects. In subjects with heart failure (HF), arterial baroreflex ability to regulate blood pressure is impaired at rest. However, whether exercise modifies the strength and mechanisms of baroreflex responses in HF is unknown. Therefore, we investigated the relative roles of cardiac output and peripheral vasoconstriction in eliciting the pressor response to bilateral carotid occlusion (BCO) in conscious, chronically instrumented dogs at rest and during treadmill exercise ranging from mild to heavy workloads. Experiments were performed in the same animals before and after rapid ventricular pacing-induced HF. At rest, the pressor response to BCO was significantly attenuated in HF (33.3 +/- 1.2 vs. 18.7 +/- 2.7 mmHg), and this difference persisted during exercise in part due to lower cardiac output responses in HF. However, both before and after the induction of HF, the contribution of vasoconstriction in active skeletal muscle toward the pressor response became progressively greater as workload increased. We conclude that, although there is an impaired ability of the baroreflex to regulate arterial pressure at rest and during exercise in HF, vasoconstriction in active skeletal muscle becomes progressively more important in mediating the baroreflex pressor response as workload increases with a pattern similar to that observed in normal subjects.     

alpha 1-Adrenergic-receptor responsiveness in skeletal muscle during dynamic exercise

Attenuation of sympathetic vasoconstriction(sympatholysis) in working muscles during dynamic exercise iscontroversial. One potential mechanism is a reduction in₁-adrenergic-receptorresponsiveness. The purpose of this study was to examine₁-adrenergic-receptor-mediated vasoconstriction in resting and working skeletal muscles by using intra-arterial infusions of a selective agonist. Seven mongrel dogswere instrumented chronically with flow probes on the external iliacarteries of both hindlimbs and a catheter in one femoral artery. Aselective ₁-adrenergic-receptoragonist (phenylephrine) was infused as a bolus into the femoral arterycatheter at rest and during exercise. All dogs ran on amotorized treadmill at two exercise intensities (3 and 6 miles/h).Intra-arterial infusions of the same effective concentration ofphenylephrine elicited reductions in vascular conductance of 76 ± 4, 76 ± 6, and 67 ± 5% (P > 0.05) at rest, 3 miles/h, and 6 miles/h, respectively. Systemic bloodpressure and blood flow in the contralateral iliac artery wereunaffected by phenylephrine. These results do not demonstrate anattenuation of vasoconstriction to a selective ₁-agonist during exercise anddo not support the concept of sympatholysis.

     

Cardiovascular effects of the respiratory muscle metaboreflexes in dogs: rest and exercise.

In awake dogs, lactic acid was injected into the phrenic and deep circumflex iliac arteries to elicit the diaphragm and abdominal muscle metaboreflexes, respectively. At rest, injections into the phrenic or deep circumflex iliac arteries significantly increased mean arterial blood pressure 21 +/- 7% and reduced cardiac output 6 +/- 2% and blood flow to the hindlimbs 20 +/- 9%. Simultaneously, total systemic, hindlimb, and abdominal expiratory muscle vascular conductances were reduced. These cardiovascular responses were not accompanied by significant changes in the amplitude or timing of the diaphragm electromyogram. During treadmill exercise that increased cardiac output, hindlimb blood flow, and vascular conductance 159 +/- 106, 276 +/- 309, and 299 +/- 90% above resting values, lactic acid injected into the phrenic or deep circumflex iliac arteries also elicited pressor responses and reduced hindlimb blood flow and vascular conductance. Adrenergic receptor blockade at rest eliminated the cardiovascular effects of the respiratory muscle metaboreflex. We conclude that the cardiovascular effects of respiratory muscle metaboreflex activation are similar to those previously reported for limb muscles. When activated via metabolite production, the respiratory muscle metaboreflex may contribute to the increased sympathetic tone and redistribution of blood flow during exercise.     

Strength training reduces arterial blood pressure but not sympathetic neural activity in young normotensive subjects.

The effects of resistance training on arterial blood pressure and muscle sympathetic nerve activity (MSNA) at rest have not been established. Although endurance training is commonly recommended to lower arterial blood pressure, it is not known whether similar adaptations occur with resistance training. Therefore, we tested the hypothesis that whole body resistance training reduces arterial blood pressure at rest, with concomitant reductions in MSNA. Twelve young [21 +/- 0.3 (SE) yr] subjects underwent a program of whole body resistance training 3 days/wk for 8 wk. Resting arterial blood pressure (n = 12; automated sphygmomanometer) and MSNA (n = 8; peroneal nerve microneurography) were measured during a 5-min period of supine rest before and after exercise training. Thirteen additional young (21 +/- 0.8 yr) subjects served as controls. Resistance training significantly increased one-repetition maximum values in all trained muscle groups (P < 0.001), and it significantly decreased systolic (130 +/- 3 to 121 +/- 2 mmHg; P = 0.01), diastolic (69 +/- 3 to 61 +/- 2 mmHg; P = 0.04), and mean (89 +/- 2 to 81 +/- 2 mmHg; P = 0.01) arterial blood pressures at rest. Resistance training did not affect MSNA or heart rate. Arterial blood pressures and MSNA were unchanged, but heart rate increased after 8 wk of relative inactivity for subjects in the control group (61 +/- 2 to 67 +/- 3 beats/min; P = 0.01). These results indicate that whole body resistance exercise training might decrease the risk for development of cardiovascular disease by lowering arterial blood pressure but that reductions of pressure are not coupled to resistance exercise-induced decreases of sympathetic tone.     

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.     

Effect of morphine on sympathetic nerve activity in humans.

There are conflicting reports for the role of endogenous opioids on sympathetic and cardiovascular responses to exercise in humans. A number of studies have utilized naloxone (an opioid-receptor antagonist) to investigate the effect of opioids during exercise. In the present study, we examined the effect of morphine (an opioid-receptor agonist) on sympathetic and cardiovascular responses at rest and during isometric handgrip (IHG). Eleven subjects performed 2 min of IHG (30% maximum) followed by 2 min of postexercise muscle ischemia (PEMI) before and after systemic infusion of morphine (0.075 mg/kg loading dose + 1 mg/h maintenance) or placebo (saline) in double-blinded experiments on separate days. Morphine increased resting muscle sympathetic nerve activity (MSNA; 17 +/- 2 to 22 +/- 2 bursts/min; P < 0.01) and increased mean arterial pressure (MAP; 87 +/- 2 to 91 +/- 2 mmHg; P < 0.02), but it decreased heart rate (HR; 61 +/- 4 to 59 +/- 3; P < 0.01). However, IHG elicited similar increases for MSNA, MAP, and HR between the control and morphine trial (drug x exercise interaction = not significant). Moreover, responses to PEMI were not different. Placebo had no effect on resting, IHG, and PEMI responses. We conclude that morphine modulates cardiovascular and sympathetic responses at rest but not during isometric exercise.     

Short-term exercise training augments sympathetic vasoconstrictor responsiveness and endothelium-dependent vasodilation in resting skeletal muscle

We tested the hypotheses that 4 wk of exercise training would diminish the magnitude of vasoconstriction in response to sympathetic nerve stimulation and augment endothelium-dependent vasodilation (EDD) in resting skeletal muscle in a training intensity-dependent manner. Sprague-Dawley rats were randomly assigned to sedentary time-control (S), mild- (M; 20 m/min, 5% grade), or heavy-intensity (H; 40 m/min, 5% grade) treadmill exercise groups. Animals trained 5 days/wk for 4 wk with training volume matched between groups. Rats were anesthetized and instrumented for study 24 h after the last training session. Arterial pressure and femoral artery blood flow were measured, and femoral vascular conductance (FVC) was calculated. Lumbar sympathetic chain stimulation was delivered continuously at 2 Hz and in patterns at 20 and 40 Hz. EDD was assessed by the vascular response to intra-arterial bolus injections of ACh. The response (% change FVC) to sympathetic stimulation increased (P < 0.05) in a training intensity-dependent manner at 2 Hz (S: -20.2 ± 9.8%, M: -34.0 ± 6.7%, and H: -44.9 ± 2.0%), 20 Hz (S: -22.0 ± 10.6%, M: -31.2 ± 8.4%, and H: -42.8 ± 5.9%), and 40 Hz (S: H -24.5 ± 8.5%, M: -35.1 ± 8.9%, H: -44.9 ± 6.5%). The magnitude of EDD also increased in a training intensity-dependent manner (P < 0.05). These data demonstrate that short-term exercise training augments the magnitude of vasoconstriction in response to sympathetic stimulation and EDD in resting skeletal muscle in a training intensity-dependent manner.     

Differential sympathetic outflow and vasoconstriction responses at kidney and skeletal muscles during fictive locomotion

We compared sympathetic and circulatory responses between kidney and skeletal muscles during fictive locomotion evoked by electrical stimulation of the mesencephalic locomotor region (MLR) in decerebrate and paralyzed rats (n = 8). Stimulation of the MLR for 30 s at 40-microA current intensity significantly increased arterial pressure (+38 +/- 6 mmHg), triceps surae muscle blood flow (+17 +/- 3%), and both renal and lumbar sympathetic nerve activities (RSNA +113 +/- 16%, LSNA +31 +/- 7%). The stimulation also significantly decreased renal cortical blood flow (-18 +/- 6%) and both renal cortical and triceps surae muscle vascular conductances (RCVC -38 +/- 5%, TSMVC -17 +/- 3%). The sympathetic and vascular conductance changes were significantly dependent on current intensity for stimulation at 20, 30, and 40 microA. The changes in LSNA and TSMVC were significantly less than those in RSNA and RCVC, respectively, at all current intensities. At the early stage of stimulation (0-10 s), decreases in RCVC and TSMVC were significantly correlated with increases in RSNA and LSNA, respectively. These data demonstrate that fictive locomotion induces less vasoconstriction in skeletal muscles than in kidney because of less sympathetic activation. This suggests that a neural mechanism mediated by central command contributes to blood flow distribution by evoking differential sympathetic outflow during exercise.     

Sympathetic restraint of muscle blood flow at the onset of dynamic exercise.

Little attention has focused on sympathetic influences on skeletal muscle blood flow at the onset of exercise. We hypothesized that 1) the sympathetic nervous system constrains muscle blood flow and 2) the decline from peak blood flow is mediated by increasing sympathetic vasoconstrictor tone. Mongrel dogs (n = 7) ran on a treadmill after intra-arterial infusion of saline (control) or combined alpha(1)- and alpha(2)-adrenergic blockade (prazosin and rauwolscine). Immediate and rapid increases in hindlimb blood flow occurred at commencement of exercise with peak iliac blood flows averaging 933 +/- 79 and 1,227 +/- 90 ml/min during control and blockade conditions, respectively. At 1 min of exercise, hindlimb blood flow had decreased to 629 +/- 54 and 1,057 +/- 89 ml/min. In the absence of sympathetic vasoconstrictor tone, there was an enhanced peak blood flow at the onset of exercise. In addition, alpha-blockade attenuated the overshoot of hindlimb blood flow compared with the control condition. These data suggest that an immediate and sustained increase in sympathetic outflow restrains hindlimb blood flow at the onset of exercise and is responsible, at least in part, for an overshoot of blood flow to exercising skeletal muscle.     

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.     

Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans

It is now generally accepted that alpha-adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of nonadrenergic vasoconstrictor pathways during exercise remains unclear. Thus, in eight young (23 +/- 1 yr), healthy volunteers, we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the alpha(1)-adrenoreceptor agonist phenylephrine (PE) with that of the nonadrenergic endothelin A (ET(A))/ET(B) receptor agonist ET-1. Heart rate, arterial blood pressure, common femoral artery diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20%, 40%, and 60% of maximal work rate (WR(max)). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng x ml(-1) x min(-1)) provoked a rapid and significant decrease in leg blood flow (-51 +/- 3%) within 2.5 min. Resting ET-1 infusion (40 pg x ml(-1) x min(-1)) significantly decreased leg blood flow within 5 min, reaching a maximal vasoconstriction (-34 +/- 3%) after 25-30 min of continuous infusion. Compared with rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 +/- 5%, -7 +/- 2%, and -1 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 +/- 3%, -7 +/- 4%, and 2 +/- 3% change in leg blood flow at 20%, 40%, and 60% of WR(max), respectively). These findings support a significant contribution of ET-1 and alpha-adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest and suggest a similar, intensity-dependent "lysis" of peripheral ET and alpha-adrenergic vasoconstriction during dynamic exercise.