Sympathetic activation restrains endothelium-mediated muscle vasodilatation in heart failure patients

Although the vasodilatory response during mental stress is blunted in heart failure (HF), the mechanisms underlying this phenomenon are not fully understood. We tested the hypothesis that sympathetic activity limits the endothelium-dependent vasodilatation during mental stress in chronic HF patients. Twenty-one HF patients (age 45 +/- 2 yr, functional classes III and IV, New York Heart Association) and 22 age-matched normal controls (NC; age 42 +/- 2 yr, P = 0.13) were studied at rest and during 4 min of Stroop color-word test with brachial intra-arterial saline, acetylcholine (endothelium dependent), phentolamine (alpha-blocker), and phentolamine plus acetylcholine infusion. Forearm blood flow was measured by venous occlusion plethysmography. Baseline forearm vascular conductance (FVC) was significantly lower in HF patients (2.18 +/- 0.12 vs. 3.66 +/- 0.22 units, P = 0.001). During mental stress with saline, the changes in FVC were significantly blunted in HF patients compared with NC (0.92 +/- 0.20 vs. 2.13 +/- 0.39 units, P = 0.001). In HF, the vasodilatation with acetylcholine was similar to saline control and significantly lower than in NC. In HF patients, phentolamine significantly increased FVC responses (1.16 +/- 0.20 vs. 2.09 +/- 0.29 units, P = 0.001), and the difference between HF patients and NC tended to decrease (2.09 +/- 0.29 vs. 3.61 +/- 0.74 units, P = 0.052). The vasodilatation with phentolamine plus acetylcholine was similar between HF and NC (4.23 +/- 0.73 vs. 4.76 +/- 1.03 units, P = 0.84). In conclusion, sympathetic activation mediates the blunted muscle endothelium-mediated vasodilatation during mental stress in HF patients.     

In vivo and in vitro evidence for ACh-stimulated L-arginine uptake

Whereas L-arginine is clearly recognized as the precursor for nitric oxide synthesis, and its entry into endothelial cells via system y(+) transport is established, few data exist regarding the acute regulation of this transport process. We specifically investigated the effect of ACh and isoprenaline (Iso) on L-arginine uptake in the human forearm and in cultured bovine aortic endothelial cells (BAEC). Sixteen healthy males were studied. During a steady-state intra-arterial infusion of [(3)H]L-arginine (100 nCi/min), the effects of ACh (9.25 and 37 microg/min), Iso (25-50 and 200 microg/min), and sodium nitroprusside (SNP) (1-2 and 8 microg/min) on forearm plasma flow (FPF), L-[(3)H]arginine uptake, and L-[(3)H]citrulline release were determined. In parallel experiments, the effects of ACh, Iso, and SNP on L-[(3)H]arginine uptake were studied in BAEC. L-Arginine uptake was inversely related to FPF (r = -0.50; P < 0.005). At a similar FPF (ACh 56.82 +/- 9.25, Iso 58.49 +/- 5.56, SNP 57.92 +/- 4.96 ml/min; P = ns), intra-arterial ACh significantly increased forearm uptake of L-[(3)H]arginine (54,655 +/- 8,018 dpm/min), compared with that observed with either Iso (40,517.23 +/- 6,841 dpm/min; P = 0.01) or SNP (36,816 +/- 4,650 dpm/min; P = 0.011). This was associated with increased ACh-induced L-[(3)H]citrulline release compared with Iso and SNP (P = 0.046). Similarly, in BAEC, ACh significantly increased L-[(3)H]arginine uptake compared with control, Iso, or SNP (ACh 12.0 x 10(7) +/- 1.83 x 10(7) vs. control 6.67 x 10(7) +/- 1.16 x 10(7) vs. Iso 7.35 x 10(7) +/- 1.63 x 10(7) vs. SNP 6.01 x 10(7) +/- 1.11 x 10(7) fmol.min(-1).mg(-1) at 300 micromol/l L-arginine; P = 0.043). Taken together, these data indicate that ACh stimulates L-arginine uptake in cultured endothelial cells and in human forearm circulation, indicating the potential for acute modulation of endothelial L-arginine uptake.     

Impact of combined NO and PG blockade on rapid vasodilation in a forearm mild-to-moderate exercise transition in humans

We tested the hypothesis that nitric oxide (NO) and prostaglandins (PGs) contribute to the rapid vasodilation that accompanies a transition from mild to moderate exercise. Nine healthy volunteers (2 women and 7 men) lay supine with forearm at heart level. Subjects were instrumented for continuous brachial artery infusion of saline (control condition) or combined infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) and ketorolac (drug condition) to inhibit NO synthase and cyclooxygenase, respectively. A step increase from 5 min of steady-state mild (5.4 kg) rhythmic, dynamic forearm handgrip exercise (1 s of contraction followed by 2 s of relaxation) to moderate (10.9 kg) exercise for 30 s was performed. Steady-state forearm blood flow (FBF; Doppler ultrasound) and forearm vascular conductance (FVC) were attenuated in drug compared with saline (control) treatment: FBF = 196.8 +/- 30.8 vs. 281.4 +/- 34.3 ml/min and FVC = 179.3 +/- 29.4 vs. 277.8 +/- 34.8 ml.min(-1).100 mmHg(-1) (both P < 0.01). FBF and FVC increased from steady state after release of the initial contraction at the higher workload in saline and drug conditions: DeltaFBF = 72.4 +/- 8.7 and 52.9 +/- 7.8 ml/min, respectively, and DeltaFVC = 66.3 +/- 7.3 and 44.1 +/- 7.0 ml.min(-1).100 mmHg(-1), respectively (all P < 0.05). The percent DeltaFBF and DeltaFVC were not different during saline infusion or combined inhibition of NO and PGs: DeltaFBF = 27.2 +/- 3.1 and 28.1 +/- 3.8%, respectively (P = 0.78) and DeltaFVC = 25.7 +/- 3.2 and 26.0 +/- 4.0%, respectively (P = 0.94). The data suggest that NO and vasodilatory PGs are not obligatory for rapid vasodilation at the onset of a step increase from mild- to moderate-intensity forearm exercise. Additional vasodilatory mechanisms not dependent on NO and PG release contribute to the immediate and early increase in blood flow in an exercise-to-exercise transition.     

Effect of aerobic and resistance exercise training on vascular function in heart failure

Exercise training of a muscle group improves local vascular function in subjects with chronic heart failure (CHF). We studied forearm resistance vessel function in 12 patients with CHF in response to an 8-wk exercise program, which specifically excluded forearm exercise, using a crossover design. Forearm blood flow (FBF) was measured using strain-gauge plethysmography. Responses to three dose levels of intra-arterial acetylcholine were significantly augmented after exercise training when analyzed in terms of absolute flows (7.0 +/- 1.8 to 10.9 +/- 2.1 ml x 100 ml(-1) x min(-1) for the highest dose, P < 0.05 by ANOVA), forearm vascular resistance (21.5 +/- 5.0 to 15.3 +/- 3.9 ml x 100 ml forearm(-1) x min(-1), P < 0.01), or FBF ratios (P < 0.01, ANOVA). FBF ratio responses to sodium nitroprusside were also significantly increased after training (P < 0.05, ANOVA). Reactive hyperemic flow significantly increased in both upper limbs after training (27.9 +/- 2.7 to 33.5 +/- 3.1 ml x 100 ml(-1) x min(-1), infused limb; P < 0.05 by paired t-test). Exercise training improves endothelium-dependent and -independent vascular function and peak vasodilator capacity in patients with CHF. These effects on the vasculature are generalized, as they were evident in a vascular bed not directly involved in the exercise stimulus.     

Forearm vascular resistance increases during static exercise in heart transplant recipients.

In heart transplant recipients but not in normal humans, total peripheral vascular resistance increases during static exercise. To determine whether this augmented vasoconstriction limits the vasodilation normally seen in the nonexercising forearm, we measured arterial pressure, heart rate, and forearm blood flow during 30% maximal static handgrip in 9 heart transplant recipients and 10 control subjects. Handgrip evoked comparable increases in mean arterial pressure in the transplant recipients and control subjects (+19 +/- 2 vs. +20 +/- 2 mmHg). Heart rates increased by 14 +/- 3 beats/min in the control subjects but did not change in the transplant recipients. Directionally opposite patterns of forearm vascular resistance were observed in the two groups. In the control subjects, forearm resistance fell during handgrip (-8.8 +/- 1.9 units, P less than 0.05). In contrast, in the transplant recipients, forearm resistance rose during this intervention (+9.0 +/- 2.9 units, P less than 0.05). Thus the vasodilation that normally occurs in the nonexercising forearm during static handgrip is reversed in heart transplant recipients. Vasoconstriction in the forearm contributes to the increase in total peripheral resistance that occurs during static exercise in these individuals.     

Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training

Forearm endothelium-dependent vasodilation is impaired with age in sedentary, but not endurance-trained, men. The purpose of this investigation was to determine whether these age- and physical activity-related differences in endothelium-dependent vasodilation also occur in the leg. Brachial and common femoral arterial blood flow were measured with Doppler ultrasound during increasing doses of acetylcholine (1, 4, and 16 microg.100 ml limb tissue(-1).min(-1)), substance P (8, 31, and 125 pg.100 ml limb tissue(-1).min(-1)), and sodium nitroprusside (0.063, 0.25, and 1 microg.100 ml limb tissue(-1).min(-1)) in 23 healthy men (8 younger sedentary, 8 older sedentary, and 7 older endurance trained). Increases in forearm blood flow to the highest dose of acetylcholine and sodium nitroprusside were smaller (P < 0.05) in older sedentary (841 +/- 142%, 428 +/- 74%) compared with younger sedentary (1,519 +/- 256%, 925 +/- 163%) subjects. Similarly, increases in forearm blood flow to sodium nitroprusside (1 microg.100 ml limb tissue(-1).min(-1)) were smaller (P < 0.05) in older endurance-trained (505 +/- 110%) compared with younger sedentary (925 +/- 163%) subjects. In contrast, no differences in leg blood flow responses to intra-arterial infusions of acetylcholine, substance P, or sodium nitroprusside were noted between subject groups. These results demonstrate that 1) acetylcholine- and sodium nitroprusside-induced vasodilation are attenuated in the forearm vasculature and preserved in the leg vasculature of older sedentary subjects and 2) sodium nitroprusside-induced vasodilation remains attenuated in the forearm vasculature of healthy older endurance-trained men but preserved in the leg vasculature of these men.     

Adenosine contributes to hypoxia-induced forearm vasodilation in humans.

In humans, hypoxia leads to increased sympathetic neural outflow to skeletal muscle. However, blood flow increases in the forearm. The mechanism of hypoxia-induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is cholinergically mediated or is due to local release of adenosine, normal subjects were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately 20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm tissue(-1)) was infused into the brachial artery to block adenosine receptors (n = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg over 4 min) infused into the brachial artery (n = 8). The responses of forearm blood flow (plethysmography) and forearm vascular resistance to hypoxia in the infused and opposite (control) forearms were compared. During hypoxia (arterial O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P < 0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P < 0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data suggest that adenosine contributes to hypoxia-induced vasodilation, whereas cholinergic vasodilation does not play a role.     

Characterization of endothelium-derived hyperpolarizing factor in the human forearm microcirculation

The identity of endothelium-dependent hyperpolarizing factor (EDHF) in the human circulation remains controversial. We investigated whether EDHF contributes to endothelium-dependent vasomotion in the forearm microvasculature by studying the effect of K+ and miconazole, an inhibitor of cytochrome P-450, on the response to bradykinin in healthy human subjects. Study drugs were infused intra-arterially, and forearm blood flow was measured using strain-gauge plethysmography. Infusion of KCl (0.33 mmol/min) into the brachial artery caused baseline vasodilation and inhibited the vasodilator response to bradykinin, but not to sodium nitroprusside. Thus the incremental vasodilation induced by bradykinin was reduced from 14.3 +/- 2 to 7.1 +/- 2 ml x min(-1) x 100 g(-1) (P < 0.001) after KCl infusion. A similar inhibition of the bradykinin (P = 0.014), but not the sodium nitroprusside (not significant), response was observed with KCl after the study was repeated during preconstriction with phenylephrine to restore resting blood flow to basal values after KCl. Miconazole (0.125 mg/min) did not inhibit endothelium-dependent or -independent responses to ACh and sodium nitroprusside, respectively. However, after inhibition of cyclooxygenase and nitric oxide synthase with aspirin and NG-monomethyl-L-arginine, the forearm blood flow response to bradykinin (P = 0.003), but not to sodium nitroprusside (not significant), was significantly suppressed by miconazole. Thus nitric oxide- and prostaglandin-independent, bradykinin-mediated forearm vasodilation is suppressed by high intravascular K+ concentrations, indicating a contribution of EDHF. In the human forearm microvasculature, EDHF appears to be a cytochrome P-450 derivative, possibly an epoxyeicosatrienoic acid.     

Metabolic forearm vasodilation is enhanced following Bier block with phentolamine

The extent to which sympathetic nerve activity restrains metabolic vasodilation in skeletal muscle remains unclear. We determined forearm blood flow (FBF; ultrasound/Doppler) and vascular conductance (FVC) responses to 10 min of ischemia [reactive hyperemic blood flow (RHBF)] and 10 min of systemic hypoxia (inspired O(2) fraction = 0.1) before and after regional sympathetic blockade with the alpha-receptor antagonist phentolamine via Bier block in healthy humans. In a control group, we performed sham Bier block with saline. Consistent with alpha- receptor inhibition, post-phentolamine, basal FVC (FBF/mean arterial pressure) increased (pre vs. post: 0.42 +/- 0.05 vs. 1.03 +/- 0.21 units; P < 0.01; n = 12) but did not change in the saline controls (pre vs. post: 0.56 +/- 0.14 vs. 0.53 +/- 0.08 units; P = not significant; n = 5). Post-phentolamine, total RHBF (over 3 min) increased substantially (pre vs. post: 628 +/- 75 vs. 826 +/- 92 ml/min; P < 0.01) but did not change in the controls (pre vs. post: 618 +/- 66 vs. 661 +/- 35 ml/min; P = not significant). In all conditions, compared with peak RHBF, peak skin reactive hyperemia was markedly delayed. Furthermore, post-phentolamine (pre vs. post: 0.43 +/- 0.06 vs. 1.16 +/- 0.17 units; P < 0.01; n = 8) but not post-saline (pre vs. post: 0.93 +/- 0.16 vs. 0.87 +/- 0.19 ml/min; P = not significant; n = 5), the FVC response to hypoxia (arterial O(2) saturation = 77 +/- 1%) was markedly enhanced. These data suggest that sympathetic vasoconstrictor nerve activity markedly restrains skeletal muscle vasodilation induced by local (forearm ischemia) and systemic (hypoxia) vasodilator stimuli.     

Low-dose estrogen therapy does not change postexercise hypotension, sympathetic nerve activity reduction, and vasodilation in healthy postmenopausal women

The aim of this study was to determine whether estrogen therapy enhances postexercise muscle sympathetic nerve activity (MSNA) decrease and vasodilation, resulting in a greater postexercise hypotension. Eighteen postmenopausal women received oral estrogen therapy (ET; n=9, 1 mg/day) or placebo (n=9) for 6 mo. They then participated in one 45-min exercise session (cycle ergometer at 50% of oxygen uptake peak) and one 45-min control session (seated rest) in random order. Blood pressure (BP, oscillometry), heart rate (HR), MSNA (microneurography), forearm blood flow (FBF, plethysmography), and forearm vascular resistance (FVR) were measured 60 min later. FVR was calculated. Data were analyzed using a two-way ANOVA. Although postexercise physiological responses were unaltered, HR was significantly lower in the ET group than in the placebo group (59+/-2 vs. 71+/-2 beats/min, P<0.01). In both groups, exercise produced significant decreases in systolic BP (145+/-3 vs. 154+/-3 mmHg, P=0.01), diastolic BP (71+/-3 vs. 75+/-2 mmHg, P=0.04), mean BP (89+/-2 vs. 93+/-2 mmHg, P=0.02), MSNA (29+/-2 vs. 35+/-1 bursts/min, P<0.01), and FVR (33+/-4 vs. 55+/-10 units, P=0.01), whereas it increased FBF (2.7+/-0.4 vs. 1.6+/-0.2 ml x min(-1) x 100 ml(-1), P=0.02) and did not change HR (64+/-2 vs. 65+/-2 beats/min, P=0.3). Although ET did not change postexercise BP, HR, MSNA, FBF, or FVR responses, it reduced absolute HR values at baseline and after exercise.     

Muscle metaboreflex-induced increases in cardiac sympathetic activity vasoconstrict the coronary vasculature.

Ischemia of active skeletal muscle evokes a powerful blood pressure-raising reflex termed the muscle metaboreflex (MMR). MMR activation increases cardiac sympathetic nerve activity, which increases heart rate, ventricular contractility, and cardiac output (CO). However, despite the marked increase in ventricular work, no coronary vasodilation occurs. Using conscious, chronically instrumented dogs, we observed MMR-induced changes in arterial pressure, CO, left circumflex coronary blood flow (CBF), and coronary vascular conductance (CVC) before and after alpha1-receptor blockade (prazosin, 100 microg/kg iv). MMR was activated during mild treadmill exercise by partially reducing hindlimb blood flow. In control experiments, MMR activation caused a substantial pressor response-mediated via increases in CO. Although CBF increased (+28.1 +/- 3.7 ml/min; P < 0.05), CVC did not change (0.45 +/- 0.05 vs. 0.47 +/- 0.06 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P > 0.05). Thus all of the increase in CBF was due to the increase in arterial pressure. In contrast, after prazosin, MMR activation caused a greater increase in CBF (+55.9 +/- 17.1 ml/min; P < 0.05 vs. control) and CVC rose significantly (0.59 +/- 0.08 vs. 0.81 +/- 0.17 ml x min(-1) x mmHg(-1), exercise vs. exercise with MMR activation, respectively; P < 0.05). A greater increase in CO also occurred (+2.01 +/- 0.1 vs. +3.27 +/- 1.1 l/min, control vs. prazosin, respectively; P < 0.05). We conclude that the MMR-induced increases in sympathetic activity to the heart functionally restrain coronary vasodilation, which may limit increases in ventricular function.     

Local prostaglandin blockade attenuates muscle mechanoreflex-mediated renal vasoconstriction during muscle stretch in humans

During exercise, muscle mechanoreflex-mediated sympathoexcitation evokes renal vasoconstriction. Animal studies suggest that prostaglandins generated within the contracting muscle sensitize muscle mechanoreflexes. Thus we hypothesized that local prostaglandin blockade would attenuate renal vasoconstriction during ischemic muscle stretch. Eleven healthy subjects performed static handgrip before and after local prostaglandin blockade (6 mg ketorolac tromethamine infused into the exercising forearm) via Bier block. Renal blood flow velocity (RBV; Duplex Ultrasound), mean arterial pressure (MAP; Finapres), and heart rate (HR; ECG) were obtained during handgrip, post-handgrip muscle ischemia (PHGMI) followed by PHGMI with passive forearm muscle stretch (PHGMI + stretch). Renal vascular resistance (RVR, calculated as MAP/RBV) was increased from baseline during all paradigms except during PHGMI + stretch after the ketorolac Bier block trial where RVR did not change from baseline. Before Bier block, RVR rose more during PHGMI + stretch than during PHGMI alone (P < .01). Similar results were found after a saline Bier block trial (Delta53 +/- 13% vs. Delta35 +/- 10%; P < 0.01). However, after ketorolac Bier block, RVR was not greater during PHGMI + stretch than during PHGMI alone [Delta39 +/- 8% vs. Delta40 +/- 12%; P = not significant (NS)]. HR and MAP responses were similar during PHGMI and PHGMI + stretch (P = NS). Passive muscle stretch during ischemia augments renal vasoconstriction, suggesting that ischemia sensitizes mechanically sensitive afferents. Inhibition of prostaglandin synthesis eliminates this mechanoreceptor sensitization-mediated constrictor responses. Thus mechanoreceptor sensitization in humans is linked to the production of prostaglandins.     

Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits.

Exercise training is known to improve vasodilating mechanisms mediated by endothelium-dependent relaxing factors in the cardiac and skeletal muscle vascular beds. However, the effects of exercise training on visceral vascular reactivity, including the renal circulation, are still unclear. We used the experimental model of the isolated perfused rabbit kidney, which involves both the renal macro- and microcirculation, to test the hypothesis that exercise training improves vasodilator mechanisms in the entire renal circulation. New Zealand White rabbits were pen confined (Sed; n = 24) or treadmill trained (0% grade) for 5 days/wk at a speed of 18 m/min during 60 min over a 12-wk period (ExT; n = 24). Kidneys isolated from Sed and ExT rabbits were continuously perfused in a nonrecirculating system under conditions of constant flow and precontracted with norepinephrine (NE). We assessed the effects of exercise training on renal vascular reactivity using endothelial-dependent [acetylcholine (ACh) and bradykinin (BK)] and -independent [sodium nitroprusside (SNP)] vasodilators. ACh induced marked and dose-related vasodilator responses in kidneys from Sed rabbits, the reduction in perfusion pressure reaching 41 +/- 8% (n = 6; P < 0.05). In the kidneys from ExT rabbits, vasodilation induced by ACh was significantly enhanced to 54 +/- 6% (n = 6; P < 0.05). In contrast, BK-induced renal vasodilation was not enhanced by training [19 +/- 8 and 13 +/- 4% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P > 0.05)]. Continuous perfusion of isolated kidneys from ExT animals with N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM), an inhibitor of nitric oxide (NO) biosynthesis, completely blunted the additional vasodilation elicited by ACh [reduction in perfusion pressure of 54 +/- 6 and 38 +/- 5% for ExT and L-NAME + ExT, respectively (n = 6; P < 0.05)]. On the other hand, L-NAME infusion did not affect ACh-induced vasodilation in Sed animals. Exercise training also increased renal vasodilation induced by SNP [36 +/- 7 and 45 +/- 10% reduction in perfusion pressure for Sed and ExT rabbits, respectively (n = 6; P < 0.05)]. It is concluded that exercise training alters the rabbit kidney vascular reactivity, enhancing endothelium-dependent and -independent renal vasodilation. This effect seems to be related not only to an increased bioavailability of NO but also to the enhanced responsiveness of the renal vascular smooth muscle to NO.     

Direct effect of ethanol on human vascular function

Epidemiological studies indicate that moderate ethanol consumption reduces cardiovascular mortality. Cellular and animal data suggest that ethanol confers beneficial effects on the vascular endothelium and increases the bioavailability of nitric oxide. The purpose of this study was to assess the effect of ethanol on endothelium-dependent, nitric oxide-mediated vasodilation in healthy human subjects. Forearm blood flow (FBF) was determined by venous occlusion plethysmography in healthy human subjects during intra-arterial infusions of either methacholine (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), nitroprusside (0.3, 1.0, 3.0, and 10.0 mcg/min, n = 9), or verapamil (10, 30, 100, and 300 mcg/min, n = 8) before and during the concomitant intra-arterial infusions of ethanol (10% ethanol in 5% dextrose). Additionally, a time control experiment was conducted, during which the methacholine dose-response curve was measured twice during vehicle infusions (n = 5). During ethanol infusion, mean forearm and systemic alcohol levels were 227 +/- 30 and 6 +/- 0 mg/dl, respectively. Ethanol infusion alone reduced FBF (2.5 +/- 0.1 to 1.9 +/- 0.1 ml.dl(-1).min(-1), P < 0.05). Despite initial vasoconstriction, ethanol augmented the FBF dose-response curves to methacholine, nitroprusside, and verapamil (P < 0.01 by ANOVA for each). To determine whether this augmented FBF response was related to shear-stress-induced release of nitric oxide, FBF was measured during the coinfusion of ethanol and N(G)-nitro-L-arginine (L-NAME; n = 8) at rest and during verapamil-induced vasodilation. The addition of L-NAME did not block the ability of ethanol to augment verapamil-induced vasodilation. Ethanol has complex direct vascular effects, which include basal vasoconstriction as well as potentiation of both endothelium-dependent and -independent vasodilation. None of these effects appear to be mediated by an increase in nitric oxide bioavailability, thus disputing findings from preclinical models.     

Evidence of sustained forearm vasodilatation after brief isocapnic hypoxia.

Healthy subjects exposed to 20 min of hypoxia increase ventilation and muscle sympathetic nerve activity (MSNA). After return to normoxia, although ventilation returns to baseline, MSNA remains elevated for up to an hour. Because forearm vascular resistance is not elevated after hypoxic exposure, we speculated that the increased MSNA might be a compensatory response to sustained release of endogenous vasodilators. We studied the effect of isocapnic hypoxia (mean arterial oxygen saturation 81.6 +/- 4.1%, end-tidal Pco2 44.7 +/- 6.3 Torr) on plethysmographic forearm blood flow (FBF) in eight healthy volunteers while infusing intra-arterial phentolamine to block local alpha-receptors. The dominant arm served as control. Forearm arterial vascular resistance (FVR) was calculated as the mean arterial pressure (MAP)-to-FBF ratio. MAP, heart rate (HR), and FVR were reported at 5-min intervals at baseline, then while infusing phentolamine during room air, isocapnic hypoxia, and recovery. Despite increases in HR during hypoxia, there was no change in MAP throughout the study. By design, FVR decreased during phentolamine infusion. Hypoxia further decreased FVR in both forearms. With continued phentolamine infusion, FVR after termination of the exposure (17.47 +/- 6.3 mmHg x min x ml(-1) x 100 ml of tissue) remained lower than preexposure baseline value (23.05 +/- 8.51 mmHg x min x ml(-1) x 100 ml of tissue; P < 0.05). We conclude that, unmasked by phentolamine, the vasodilation occurring during hypoxia persists for at least 30 min after the stimulus. This vasodilation may contribute to the sustained MSNA rise observed after hypoxia.     

Skeletal muscle beta-receptors and isoproterenol-stimulated vasodilation in canine heart failure

To investigate whether heart failure alters beta-adrenergic receptors on skeletal muscle and its associated vasculature, the density of beta-adrenergic receptors, isoproterenol-stimulated adenylate cyclase activity, and coupling of the guanine nucleotide-binding regulatory protein were compared in 18 control dogs and 16 dogs with heart failure induced by 5-8 wk of ventricular pacing at 260 beats/min. Hindlimb vascular responses to isoproterenol were compared in eight controls and eight of the dogs with heart failure. In dogs with heart failure, the density of beta-receptors on skeletal muscle was reduced in both gastrocnemius (control: 50 +/- 5; heart failure: 33 +/- 8 fmol/mg of protein) and semitendinosus muscle (control: 43 +/- 9; heart failure: 27 +/- 9 fmol/mg of protein, both P less than 0.05). Receptor coupling to the ternary complex, as determined by isoproterenol competition curves with and without guanosine 5'-triphosphate (GTP), was unchanged. Isoproterenol-stimulated adenylate cyclase activity was significantly decreased in semitendinosus muscle (control: 52.4 +/- 4.6; heart failure: 36.5 +/- 9.5 pmol.mg-1.min-1; P less than 0.05) and tended to be decreased in gastrocnemius muscle (control: 40.1 +/- 8.5; heart failure: 33.5 +/- 4.5 pmol.mg-1.min-1; P = NS). Isoproterenol-induced hindlimb vasodilation was not significantly different in controls and in dogs with heart failure. These findings suggest that heart failure causes downregulation of skeletal muscle beta-adrenergic receptors, probably due to receptor exposure to elevated catecholamine levels, but does not reduce beta-receptor-mediated vasodilation in muscle.     

Effects of chronic sympathectomy on vascular function in the human forearm.

To determine whether endothelial function is altered by chronic surgical sympathectomy, we infused ACh, isoproterenol, nitroprusside (NTP), and the nitric oxide synthase inhibitor NG-mono-methyl-L-arginine (L-NMMA) into the brachial arteries of nine patients 5-64 mo after thoracic sympathectomy for hyperhidrosis. Age- and gender-matched controls were also studied. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. Lower body negative pressure was used to assess reflex vasoconstrictor responses. Tyramine, which acts locally and causes norepinephrine release from sympathetic nerves, was also administered via the brachial artery. FBF at rest was 2.5 +/- 0.4 ml x dl-1 x min-1 in the patients and 2.5 +/- 0.3 ml x dl-1 x min-1 in the controls (P = 0.95). The normal vasoconstrictor responses to lower body negative pressure were abolished in the patients. By contrast, tyramine produced dose-dependent vasoconstriction in the patients that was identical to that of controls. The dose-response curves to ACh were similar in patients and controls, with maximum values of 19.3 +/- 4.4 vs. 25.5 +/- 2.8 ml x dl-1 x min-1, respectively. L-NMMA reduced baseline FBF similarly and reduced the maximal FBF response to ACh in both groups (patients 8.9 +/- 3.5 vs. controls 9.7 +/- 2.5 ml x dl-1 x min-1). The vasodilation to isoproterenol was similar and blunted to the same extent in both groups by L-NMMA. The responses to NTP in patients and controls were similar and not affected by L-NMMA. We conclude that, in humans, chronic surgical sympathectomy does not cause major disruptions in vascular function in the forearm. The normal vasoconstrictor responses to tyramine indicate that there were viable sympathetic nerves in the forearm that were not engaged by LBNP.     

Forearm neurovascular responses during mental stress and vestibular activation

Autonomic responses may underlie associations among anxiety, vestibular dysfunction, and unexplained syncope. Mental stress (MS), an anxiety-inducing stimulus, causes forearm vasodilation, whereas the vestibulosympathetic reflex (VSR) causes forearm vasoconstriction. The purpose of this study was to examine the combined effects of mental and vestibular stimulation on neurovascular control in the forearm. Heart rate, arterial pressure (Finapres), and forearm blood flow (Doppler) were measured in 10 healthy volunteers in the prone position during 1) head-down rotation (HDR), 2) MS (mental arithmetic), and 3) HDR + MS. Forearm vascular resistance (FVR) increased during HDR (from 232 +/- 40 to 319 +/- 53 units) and decreased during MS (from 260 +/- 57 to 154 +/- 22 units). During HDR + MS, FVR did not change [change (Delta) = -31 +/- 50 units] and was not significantly different from the algebraic sum of each trial performed alone (Delta = -20 +/- 42 units). Arm muscle sympathetic nerve activity (MSNA; microneurography) was measured in seven additional subjects. MSNA increased during HDR (from 13 +/- 2 to 17 +/- 2 bursts/min) and HDR + MS (from 11 +/- 2 to 16 +/- 2 bursts/min). Increases in MSNA during HDR + MS (Delta = 5 +/- 2 bursts/min) were not different from the algebraic sum of each trial performed alone (Delta = 6 +/- 2 bursts/min). We conclude that an additive neurovascular interaction exists between MS and the VSR in the forearm. Activation of the VSR prevented forearm vasodilation during MS, suggesting that activation of the VSR may help protect against stress-induced syncope.     

Exercise throughout 6 degrees head-down tilt bed rest preserves thermoregulatory responses.

Spaceflight and its bed rest analog [6 degrees head-down tilt (HDT)] decrease plasma and blood volume and aerobic capacity. These responses may be associated with impaired thermoregulatory responses observed during exercise and passive heating after HDT exposure. This project tested the hypothesis that dynamic exercise during 13 days of HDT bed rest preserves thermoregulatory responses. Throughout HDT bed rest, 10 subjects exercised for 90 min/day (75% of pre-HDT maximum heart rate; supine). Before and after HDT bed rest, each subject exercised in the supine position at the same workload in a 28 degrees C room. The internal temperature (Tcore) threshold for the onset of sweating and cutaneous vasodilation, as well as the slope of the relationship between the elevation in Tcore relative to the elevation in sweat rate (SR) and cutaneous vascular conductance (CVC; normalized to local heating maximum), were quantified pre- and post-HDT. Tcore thresholds for the onset of cutaneous vasodilation on the chest and forearm (chest: 36.79 +/- 0.12 to 36.94 +/- 0.13 degrees C, P = 0.28; forearm: 36.76 +/- 0.12 to 36.91 +/- 0.11 degrees C, P = 0.16) and slope of the elevation in CVC relative to Tcore (chest: 77.9 +/- 14.2 to 80.6 +/- 17.2%max/ degrees C; P = 0.75; forearm: 76.3 +/- 11.8 to 67.5 +/- 14.3%max/ degrees C, P = 0.39) were preserved post-HDT. Moreover, the Tcore threshold for the onset of SR (36.66 +/- 0.12 to 36.74 +/- 0.10 degrees C; P = 0.36) and the slope of the relationship between the elevation in SR and the elevation in Tcore (1.23 +/- 0.19 to 1.01 +/- 0.14 mg x cm(-2) x min(-1) x degrees C(-1); P = 0.16) were also maintained. Finally, after HDT bed rest, peak oxygen uptake and plasma and blood volumes were not different relative to pre-HDT bed rest values. These data suggest that dynamic exercise during this short period of HDT bed rest preserves thermoregulatory responses.     

Rapid blunting of sympathetic vasoconstriction in the human forearm at the onset of exercise.

The purpose of this study was to test the hypothesis that sympathetic vasoconstriction is rapidly blunted at the onset of forearm exercise. Nine healthy subjects performed 5 min of moderate dynamic forearm handgrip exercise during -60 mmHg lower body negative pressure (LBNP) vs. without (control). Beat-by-beat forearm blood flow (Doppler ultrasound), arterial blood pressure (finger photoplethysmograph), and heart rate were collected. LBNP elevated resting heart rate by approximately 45%. Mean arterial blood pressure was not significantly changed (P = 0.196), but diastolic blood pressure was elevated by approximately 10% and pulse pressure was reduced by approximately 20%. At rest, there was a 30% reduction in forearm vascular conductance (FVC) during LBNP (P = 0.004). The initial rapid increase in FVC with exercise onset reached a plateau between 10 and 20 s of 126.6 +/- 4.1 ml. min(-1). 100 mmHg(-1) in control vs. only 101.6 +/- 4.1 ml. min(-1). 100 mmHg(-1) in LBNP (main effect of condition, P = 0.003). This difference was quickly abolished during the second, slower phase of adaptation in forearm vascular tone to steady state. These data are consistent with a rapid onset of functional sympatholysis, in which local substances released with the onset of muscle contractions impair sympathetic neural vasoconstrictor effectiveness.