Effect of the renin-angiotensin system on limb circulation and metabolism during exercise in patients with heart failure

The maximal aerobic exercise capacity of patients with chronic heart failure is frequently decreased because of inadequate blood flow to working skeletal muscle. To investigate whether this reduced flow is in part due to interference by angiotensin II with arteriolar dilation in working muscle, the effect of the angiotensin-converting enzyme inhibitor captopril on leg blood flow, leg vascular resistance, leg oxygen consumption (VO2) and leg lactate release during maximal upright bicycle exercise was examined in 12 patients with heart failure (maximal VO2 10.7 +/- 3.1 ml/min per kg). Captopril decreased leg resistance at rest (258 +/- 115 to 173 +/- 67 U, p less than 0.01) and maximal exercise (68 +/- 69 to 45 +/- 29 U, p less than 0.01) associated with proportionately similar decreases in systemic vascular resistance. However, maximal exercise duration and maximal VO2 were unchanged and, at identical peak exercise work times, there was no improvement in leg blood flow (2.0 +/- 0.9 to 2.0 +/- 1.1 liters/min, p = NS), leg VO2 (261 +/- 104 to 281 +/- 157 ml/min, p = NS) or leg lactate release (269 +/- 149 to 227 +/- 151 mg/min, p = NS). These data suggest that, during exercise in patients with heart failure, angiotensin II does not interfere with blood flow to working skeletal muscle.     

Sympathetic vasoconstriction during exercise in ambulatory patients with left ventricular failure

In patients with heart failure, exercise is thought to increase sympathetic vasoconstrictor tone. To investigate the extent of this sympathetic activation, we studied the effect of maximal exercise on nonexercising vascular beds in 35 patients with left ventricular failure (ejection fraction, 21 +/- 8%; peak exercise oxygen uptake (VO2), 12.3 +/- 3.5 ml/min/kg). In 28 patients, cardiac output and leg blood flow were measured during maximal upright bicycle exercise. Total flow to nonexercising tissue was then calculated as cardiac output--(2 x leg flow). In seven patients and six normal subjects, forearm blood flow was measured during supine bicycle exercise before and after alpha-adrenergic blockade with intravenous phentolamine. Maximal upright exercise increased the vascular resistance of nonexercising tissue from 34 +/- 16 units at upright rest to 45 +/- 25 units (p less than 0.02) but did not affect total flow to nonexercising tissue (rest, 2.9 +/- 1.0; maximal exercise, 2.8 +/- 1.4 l/min; p = NS). Supine exercise had no significant effect on forearm blood flow or vascular resistance in the normal subjects. In the patients with heart failure, supine exercise increased forearm vascular resistance from 45 +/- 17 to 58 +/- 25 mm Hg/ml/min/100 ml (p less than 0.02), again with no change in tissue flow (rest, 2.4 +/- 0.1; maximal exercise, 2.4 +/- 0.9 ml/min/100 ml; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

Relation between central and peripheral hemodynamics during exercise in patients with chronic heart failure. Muscle blood flow is reduced with maintenance of arterial perfusion pressure

We studied the central hemodynamic, leg blood flow, and metabolic responses to maximal upright bicycle exercise in 30 patients with chronic heart failure attributable to severe left ventricular dysfunction (ejection fraction, 24 +/- 8%) and in 12 normal subjects. At peak exercise, patients demonstrated reduced oxygen consumption (15.1 +/- 4.8 vs. 32.1 +/- 9.9 ml/kg/min, p less than 0.001), cardiac output (8.7 +/- 3.2 vs. 18.6 +/- 4.4 l/min, p less than 0.001), and mean systemic arterial blood pressure (116 +/- 15 vs. 135 +/- 13 mm Hg, p less than 0.01) compared with normal subjects. Leg blood flow was decreased in patients versus normal subjects at rest and matched submaximal work rates and maximal exercise (2.1 +/- 1.9 vs. 6.4 +/- 1.4 l/min, all p less than 0.01). Mean systemic arterial blood pressure was no different in the two groups at rest or at matched submaximal work rates, whereas leg vascular resistance was higher in patients compared with normal subjects at rest, submaximal, and maximal exercise (all p less than 0.01). Although nonleg blood flow was decreased at rest in patients, it did not decrease significantly during exercise in either group. Peak exercise leg blood flow was related to peak exercise cardiac output in patients (r = 0.66, p less than 0.01) and normal subjects (r = 0.67, p less than 0.01). In patients, leg vascular resistance was not related to mean arterial blood pressure, pulmonary capillary wedge pressure, arterial catecholamines, arterial lactate, or femoral venous pH at rest or during exercise. Compared with normal subjects during submaximal exercise, patients demonstrated increased leg oxygen extraction and lactate production accompanied by decreased leg oxygen consumption. Thus, in patients with chronic heart failure compared with normal subjects, skeletal muscle perfusion is decreased at rest and during submaximal and maximal exercise, and local vascular resistance is increased. Our data indicate that nonleg blood flow and arterial blood pressure were preferentially maintained during exercise at the expense of leg hypoperfusion in our patients. This was associated with decreased leg oxygen utilization and increased leg oxygen extraction when compared to normal subjects, providing further evidence that reduced perfusion of skeletal muscle is important in causing early anaerobic skeletal muscle metabolism during exercise in subjects with this disorder.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential regional haemodynamic changes during mineralocorticoid hypertension

BACKGROUND: Primary aldosteronism is a cause of hypertension in up to 10% of hypertensive patients, but the mechanisms by which excess aldosterone raises arterial pressure remain unclear. OBJECTIVE: To investigate the systemic and regional haemodynamic changes during the development and maintenance of aldosterone-induced hypertension and the effect of sympathetic and vasopressin blockade. METHODS: Responses to intravenous infusion of aldosterone (10 microg/h) for 4 weeks were determined in five conscious sheep. The effects of sympathetic blockade with propranolol and phentolamine or vasopressin V1-receptor blockade with SR59049 were investigated in six further sheep infused with aldosterone. RESULTS: Aldosterone progressively increased the mean arterial pressure by 20 mmHg over 4 weeks (P < 0.001). The changes in cardiac output were variable between animals, resulting in no overall significant change. Total peripheral conductance was significantly decreased due to selective reductions in mesenteric conductance (from 6.17 +/- 0.27 to 4.46 +/- 0.15 ml/min per mmHg, P < 0.001) and iliac conductance (from 1.54 +/- 0.21 to 1.27 +/- 0.15 ml/min per mmHg, P < 0.001). In contrast, renal and coronary conductance were unchanged and renal blood flow increased from 290 +/- 17 to 350 +/- 28 ml/min (P < 0.01) and coronary blood flow from 34.7 +/- 3.0 to 44.6 +/- 2.5 ml/min (P < 0.05). These aldosterone-induced changes were not inhibited by sympathetic or vasopressin V1-receptor blockade. CONCLUSION: Excess aldosterone caused a slow progressive increase in arterial pressure, which in the long term depended on reduced total peripheral conductance. This resulted from vasoconstriction in the gut and skeletal muscle, but not the kidney. These effects were not mediated by the sympathetic nervous system or vasopressin.     

Failure to augment maximal limb blood flow in response to one-leg versus two-leg exercise in patients with severe heart failure

Lower limb blood flow, oxygen uptake, and femoral vein O2 content were measured at rest and during maximal bicycle exercise, performed with two legs and one leg, in four normal subjects and in five patients with severe congestive heart failure. While in normal subjects femoral vein blood flow and lower limb vascular conductance were significantly greater during one-leg exercise than during two-leg exercise (6084 +/- 745 vs 5370 +/- 803 ml/min, p less than .05, and 52.3 +/- 8.0 vs 45.1 +/- 8.2 U X 10(3), p less than .05, respectively), in patients with severe congestive heart failure these values were similar during the two forms of exercise (1082 +/- 459 vs 1053 +/- 479 ml/min and 9.6 +/- 3.7 vs 9.4 +/- 3.5 U X 10(3), respectively). In five additional patients, one-leg maximal bicycle exercise was performed before and after administration of phentolamine into the femoral artery of the active leg. Regional alpha-adrenergic blockade with phentolamine did not alter maximal oxygen uptake attained during one-leg bicycle exercise (9.8 +/- 1.5 vs 10.3 +/- 1.9 ml/kg). Lower limb blood flow and femoral vein O2 content attained during maximal one-leg exercise were also similar before and after phentolamine. Thus, in contrast with normal subjects, patients with severe congestive heart failure were unable to further increase limb blood flow during one-leg bicycle exercise. Moreover, local alpha-adrenergic blockade does not augment blood flow to the active limb during maximal one-leg bicycle exercise. This suggests that the ability of the muscular vasculature to vasodilate during exercise is impaired and may be a limiting factor to maximal exercise capacity in such patients.     

Dependence of enhanced maximal exercise performance on increased peak skeletal muscle perfusion during long-term captopril therapy in heart failure

Maximal oxygen uptake (VO2), skeletal muscle blood flow by xenon-133 washout technique and femoral vein arteriovenous oxygen difference and lactate were measured at rest and during maximal bicycle exercise in eight patients with severe congestive heart failure before and after 8 weeks of therapy with captopril. During therapy, skeletal muscle blood flow at rest increased significantly from 1.5 +/- 0.6 to 2.6 +/- 1.0 ml/100 g per min (p less than 0.05), with a concomitant decrease in the femoral arteriovenous oxygen difference from 10.0 +/- 1.7 to 8.3 +/- 1.9 ml/100 ml (p less than 0.05). Maximal VO2 increased significantly from 13.4 +/- 3.0 to 15.5 +/- 4.1 ml/kg per min (p less than 0.05). In four patients, the increase in maximal VO2 averaged 3.7 ml/kg per min (range 2.7 to 4.9), whereas in the remaining four patients, it was less than 1 ml/kg per min. Overall, peak skeletal muscle blood flow attained during exercise did not change significantly during long-term therapy with captopril (19.6 +/- 6.2 versus 27.6 +/- 14.3 ml/100 g per min, p = NS). However, the four patients with a significant increase in maximal VO2 experienced substantial increases in peak skeletal muscle blood flow and the latter changes were linearly correlated with changes in maximal VO2 (r = 0.95, p less than 0.001). Femoral arteriovenous oxygen difference at peak exercise was unchanged (12.6 +/- 2.6 versus 12.6 +/- 2.4 ml/100 ml). Thus, improvement in maximal VO2 produced by long-term therapy with captopril is associated with an increased peripheral vasodilatory response to exercise, and this improvement only occurs when the peak blood flow is augmented.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood flow redistribution and exercise intolerance in chronic heart failure]

We examined blood flow redistribution during exercise and its significance on exercise intolerance in chronic heart failure. Sixty-three patients with chronic heart diseases underwent symptom-limited maximal multistage exercise using a supine ergometer. We measured oxygen intake (VO2) and cardiac index (CI) using Fick's principle and leg flow with the thermodilution method at rest and during exercise. Patients were categorized in 5 groups according to their VO2 max; i.e., control group (n = 12), having normal right-sided cardiac pressure during exercise; A group (n = 8), having an abnormal right-sided pressure elevation, but normal exercise tolerance VO2 max greater than 20 ml/min/kg; B group (n = 19) VO2 max 20-15; C group (n = 17) also 15-10; and D group (n = 7), VO2 less than 10 ml/min/kg. At maximal exercise, the CI max and leg flow max were similar between the control and A groups; whereas, they decreased in the order of groups B, C and D. The ratio of leg flow/CI increased by 5 times from rest to maximal exercise in all groups, although the values at rest and at maximal exercise were similar among all groups. The relationship between CI and leg flow during exercise was linear in each individual patient. The coefficient of this regression line was extremely high (r = 0.98 +/- 0.02). Therefore, we calculated each regression line, leg flow = (a).CI +/- (b), with the gradient (a) as an index of blood flow redistribution to working skeletal muscles.(ABSTRACT TRUNCATED AT 250 WORDS)     

Use of maximal bicycle exercise testing with respiratory gas analysis to assess exercise performance in patients with congestive heart failure secondary to coronary artery disease or to idiopathic dilated cardiomyopathy

Analysis of respiratory gases during maximal treadmill exercise testing has been used in patients with congestive heart failure (CHF) to detect the lactate threshold, presumed to reflect the onset of skeletal muscle underperfusion, and maximal oxygen consumption (VO2), the point at which VO2 plateaus with increasing work due to exhaustion of peripheral oxygen delivery capacity. To determine if this approach is also useful during maximal bicycle exercise testing, ventilatory, hemodynamic and systemic lactate responses to bicycle exercise were measured in 48 patients with CHF. Ventilatory responses also were assessed in 12 normal subjects. Exercise increased VO2 to 24.8 +/- 3.9 ml/min/kg in normal subjects and 13.9 +/- 3.7 ml/min/kg in patients with CHF (p less than 0.001). In all but 1 patient the VO2 increment over the last 3 minutes of exercise was comparable to that in normal subjects exercising over identical work times, suggesting that maximal VO2 was not achieved. Moreover, in patients who exercised for less than 6 minutes, a ventilatory lactate threshold could not be identified. In the 33 patients who exercised longer, a ventilatory lactate threshold was identified in 31 and correlated well (r = 0.81) with blood lactate threshold, as defined by the VO2 at which lactate increased 5 mg/dl over rest levels. However, the 95% confidence limit for predicting blood lactate threshold from ventilatory data was +/- 200 ml/min, a large range relative to the measured ventilatory threshold (570 +/- 132 ml/min). These data suggest that in patients with CHF, respiratory gas analysis during maximal bicycle exercise cannot be used to measure maximal VO2 and provides only a general index of blood lactate behavior.     

Dissociation between sympathetic nerve traffic and sympathetically mediated vascular tone in normotensive human obesity

Obesity increases the risk of hypertension and its cardiovascular complications. This has been partly attributed to increased sympathetic nerve activity, as assessed by microneurography and catecholamine assays. However, increased vasoconstriction in response to obesity-induced sympathoactivation has not been unequivocally demonstrated in obese subjects without hypertension. We evaluated sympathetic alpha-adrenergic vascular tone in the forearm by brachial arterial infusion of the alpha-adrenoreceptor antagonist phentolamine (120 microg/min) in normotensive obese (daytime ambulatory arterial pressure: 123+/-1/77+/-1 mm Hg; body mass index: 35+/-1 kg/m(2)) and lean (daytime ambulatory arterial pressure: 123+/-2/77+/-2 mm Hg; body mass index: 22+/-1 kg/m(2)) subjects (n=25 per group) matched by blood pressure, age, and gender. Microneurographic sympathetic nerve activity to skeletal muscle was significantly higher in obese subjects (30+/-3 versus 22+/-1 bursts per minute; P=0.02). Surprisingly, complete alpha-adrenergic receptor blockade by phentolamine (at concentrations sufficient to completely inhibit norepinephrine and phenylephrine-induced vasoconstriction) caused equivalent vasodilatation in obese (-57+/-2%) and lean subjects (-57+/-3%; P=0.9). In conclusion, sympathetic vascular tone in the forearm circulation is not increased in obese normotensive subjects despite increased sympathetic outflow. Vasodilator factors or mechanisms occurring in obese normotensive subjects could oppose the vasoconstrictor actions of increased sympathoactivation. Our findings may help to explain why some obese subjects are protected from the development of hypertension.     

Exercise training in patients with severe left ventricular dysfunction. Hemodynamic and metabolic effects

We studied the effects of exercise training in patients with chronic heart failure attributed to left ventricular dysfunction (ejection fraction, 24 +/- 10%). Twelve ambulatory patients with stable symptoms underwent 4-6 months of conditioning by exercising 4.1 +/- 0.6 hr/wk at a heart rate corresponding to 75% of peak oxygen consumption. Before and after training, patients underwent maximal bicycle exercise testing with direct measurement of central hemodynamic, leg blood flow, and metabolic responses. Exercise training resulted in a decrease in heart rate at rest and submaximal exercise and a 23% increase in peak oxygen consumption from 16.8 +/- 3.8 to 20.6 +/- 4.7 ml/kg/min (p less than 0.01). Heart rate, arterial lactate, and respiratory exchange ratio were unchanged at peak exercise after training. Maximal cardiac output tended to increase from 8.9 +/- 2.7 to 9.9 +/- 3.2 1/min and contributed to improved peak oxygen consumption in some patients, although this change did not reach statistical significance (p = 0.13). Rest and exercise measurements of left ventricular ejection fraction, left ventricular end-diastolic volume, and left ventricular end-systolic volume were unchanged. Right atrial, pulmonary arterial, pulmonary capillary wedge, and systemic arterial pressures were not different after training. Training induced several important peripheral adaptations that contributed to improved exercise performance. At peak exercise, systemic arteriovenous oxygen difference increased from 13.1 +/- 1.4 to 14.6 +/- 2.3 ml/dl (p less than 0.05). This increase was associated with an increase in peak-exercise leg blood flow from 2.5 +/- 0.7 to 3.0 +/- 0.8 l/min (p less than 0.01) and an increase in leg arteriovenous oxygen difference from 14.5 +/- 1.3 to 16.1 +/- 1.9 ml/dl (p = 0.07). Arterial and femoral venous lactate levels were markedly reduced during submaximal exercise after training, even though cardiac output and leg blood flow were unchanged at these workloads. Thus, ambulatory patients with chronic heart failure can achieve a significant training effect from long-term exercise. Peripheral adaptations, including an increase in peak blood flow to the exercising leg, played an important role in improving exercise tolerance.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of local sympathetic blockade on forearm blood flow and glucose uptake during hypoglycemia

During hypoglycemia, hepatic glucose production increases and peripheral glucose utilization decreases. Systemic beta-adrenergic blockade during hypoglycemia increases peripheral glucose utilization. To explore the local effects of increased alpha- and beta-adrenergic activity on skeletal muscle glucose utilization, we measured arterial and venous plasma glucose concentrations, forearm blood flow (FBF), and forearm glucose uptake (FGU) during a hyperinsulinemic (40 mU/m2/min) stepped-hypoglycemic clamp with intrabrachial artery infusion of saline, phentolamine, propranolol, or combined phentolamine and propranolol. A control study was also performed with a euglycemic clamp and intraarterial saline. During hypoglycemia with saline and phentolamine, there were significant increases in FBF (130% +/- 38% and 180% +/- 35%, respectively) and FGU (120% +/- 51% and 230% +/- 150%, respectively). During hypoglycemia with propranolol and phentolamine + propranolol, FBF remained constant. FGU during hypoglycemia with propranolol was not different versus hypoglycemia with saline. No differences were found in these studies for forearm lactate output (FLO) or venous free fatty acid concentrations. These results demonstrate that local, as opposed to systemic, blockade during hypoglycemia does not alter peripheral glucose utilization.     

Inhibitory effects of procainamide on sympathetic nerve activity in humans

In experimental animals, procainamide causes hypotension and reductions in efferent vasoconstrictor sympathetic outflow that may result from ganglionic blockade or central nervous system sympathetic inhibition. To test the hypothesis that procainamide decreases sympathetic nerve activity (SNA) in humans, we recorded postganglionic SNA in seven normal subjects in the baseline state and during infusions of procainamide HCl at 50 mg/min (loading) and 8 mg/min (maintenance). At the end of the loading infusion, mean arterial pressure (MAP) had decreased from 88.5 +/- 2.4 (mean +/- SEM) to 81.5 +/- 3.2 mm Hg (p less than 0.05), central venous pressure from 6.7 +/- 0.7 to 5.4 +/- 0.9 mm Hg (p less than 0.05), forearm vascular resistance (FVR) from 28 +/- 4.8 to 22.3 +/- 5.1 resistance units (p less than 0.05), and SNA from 259 +/- 47 to 94 +/- 26 units/min (p less than 0.05). These changes persisted during the maintenance infusion. Increased levels of SNA, FVR, and MAP provoked by the cold pressor test were reduced significantly by intravenous procainamide. In eight other subjects, intravenous procainamide HCl (15 mg/kg at 50 mg/min) caused dose-dependent inhibition of SNA that reversed as blood concentrations fell during drug washout. To determine if procainamide causes direct vasodilation, in nine subjects, graded infusions were delivered into the brachial artery at doses that produced no systemic effect. Ipsilateral FVR tended to increase during local intra-arterial infusion of procainamide. These data show that intravenous procainamide causes hypotension, vasodilation, and sympathetic withdrawal. Vasodilation does not result from a direct vasorelaxant effect of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of partial neuromuscular blockade on sympathetic nerve responses to static exercise in humans

We used intraneural recordings of sympathetic nerve activity in conscious humans to determine if central command increases sympathetic discharge to resting skeletal muscle during static exercise. In nine healthy subjects, we measured arterial pressure, heart rate, and muscle sympathetic nerve activity with microelectrodes in the peroneal nerve of the resting leg during 1) static handgrip at 15% and 30% maximal voluntary contraction and 2) attempted handgrip during partial neuromuscular blockade produced by systemic administration of tubocurarine chloride (0.075 mg/kg i.v.). During curare, subjects reported that they used near-maximal motor effort to attempt a sustained handgrip contraction, but they generated almost no force. Without sustained contraction, the intent to exercise alone, that is, central command, caused statistically significant (p less than 0.05) increases in muscle sympathetic nerve activity as well as in arterial pressure and heart rate. However, the increases in muscle sympathetic nerve activity (+ 56 +/- 16% over control) and in mean arterial pressure (+ 12 +/- 2 mm Hg) during attempted handgrip were much smaller (p less than 0.05) than the sympathetic nerve response (+ 217 +/- 37% over control) and pressor response (+ 25 +/- 3 mm Hg) during an actual static handgrip at 30% maximal voluntary contraction. In contrast, heart rate increased as much during the attempted contraction (+ 18 +/- 2 beats/min) as during the actual contraction at 30% maximal voluntary contraction (+ 16 +/- 4 beats/min). In 11 additional subjects, the heart rate responses during curare were greatly attenuated (p less than 0.05) by atropine but were not significantly affected by propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of dobutamine on skeletal muscle metabolism in patients with congestive heart failure

Dobutamine is known to increase leg blood flow during exercise in patients with heart failure. However, it is uncertain whether the increased flow is delivered to working skeletal muscle. In 7 patients with heart failure, the effects of dobutamine were examined on calf phosphorus-31 magnetic resonance spectroscopy (MRS) spectra and femoral vein blood flow during rest and upright plantar flexion. During upright plantar flexion every 3 seconds, dobutamine increased femoral venous blood flow (control 1.7 +/- 0.1; dobutamine 2.1 +/- 1.0 liters/min; p less than 0.05) and increased femoral venous O2 saturation (control 24 +/- 5%; dobutamine 31 +/- 2%; p less than 0.05), indicating improved total leg blood flow. However, dobutamine did not change the slope of the relation between systemic VO2 and the calf inorganic phosphate to phosphocreatine relation (control 0.0054 +/- 0.0039; dobutamine 0.0056 +/- 0.0032; difference not significant) and did not change muscle pH, suggesting no improvement in blood flow to active skeletal muscle. These findings suggest that dobutamine does not improve oxygen delivery to working skeletal muscle in patients with heart failure, despite its ability to increase cardiac output and limb blood flow.     

Skeletal muscle metaboreceptor stimulation opposes peak metabolic vasodilation in humans

The total blood flow requirements of a large muscle mass can exceed the maximal cardiac output generated by the heart during exercise. Therefore, to maintain blood pressure, muscle vasodilation must be opposed by sympathetic vasoconstriction. The primary neural signal that increases sympathetic outflow is unclear. In an effort to isolate the vasoconstricting mechanism that opposes vasodilation, we measured the peak forearm vascular conductance response after the release of 10 minutes of forearm circulatory arrest under five separate study conditions: 1) no leg exercise, 2) low-level supine leg exercise, 3) low-level supine leg exercise with leg circulatory arrest after exercise, 4) high-level supine leg exercise, and 5) high-level supine leg exercise with leg circulatory arrest after exercise. We found that both high-workload conditions reduced peak forearm conductance below the no-leg exercise condition (a 34% reduction during leg exercise and a 52% reduction during leg exercise followed by leg circulatory arrest). In addition, at each workload, leg circulatory arrest after exercise, which isolated the skeletal muscle metaboreceptor contribution to vasoconstriction, reduced forearm conductance by approximately 20% below the values noted for leg exercise alone (combined central command and metaboreceptor stimulation). In a separate group of subjects, peak forearm blood flow was measured during lower-body negative pressure to levels up to -40 mm Hg, a maneuver that unloads high- and low-pressure baroreceptors. This intervention did not affect peak forearm blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute moderate-intensity exercise induces vasodilation through an increase in nitric oxide bioavailiability in humans

BACKGROUND: Long-term moderate-intensity exercise augments endothelium-dependent vasodilation through an increase in nitric oxide (NO) production. The purpose of this study was to determine the effects of different intensities of acute exercise on hemodynamics in humans. METHODS: We evaluated forearm blood flow (FBF) responses to different intensities of exercise (mild, 25% maximum oxygen consumption [VO2max]; moderate, 50% VO2max; and high, 75% VO2max; bicycle ergometer, for 30 min) in eight healthy young men. The FBF was measured by using a strain-gauge plethysmography. RESULTS: After exercise began, moderate-intensity exercise, but not mild-intensity exercise, promptly increased FBF from 2.8+/-1.1 mL/min/100 mL to a plateau at 5.4+/-1.6 mL/min/100 mL at 5 min (P<.01) and increased mean arterial pressure from 84.7+/-11.8 mm Hg to a plateau at 125.7+/-14.3 mm Hg at 5 min (P<.01). Moderate-intensity exercise decreased forearm vascular resistance (FVR) from 29.2+/-5.4 to 16.8+/-3.2 mm Hg/mL/min/100 mL tissue (P<.01). The administration of NG-monomethyl-L-arginine, an NO synthase inhibitor, abolished moderate exercise-induced augmentation of vasodilation. Although we were not able to measure FBF during high-intensity exercise because of large body motion, high-intensity exercise markedly increased mean arterial pressure from 82.6+/-12.2 to 146.8+/-19.8 mm Hg. High-intensity exercise, but not mild-intensity or moderate-intensity exercise, increased plasma concentration of 8-isoprostane, an index of oxidative stress, from 24.1+/-10.8 to 40.2+/-16.7 pg/mL (P<.05) at 10 min after the end of exercise. CONCLUSIONS: These findings suggest that acute moderate-intensity exercise induces vasodilation through an increase in NO bioavailability in humans and that high-intensity exercise increases oxidative stress.     

Evidence for cholinergically mediated vasodilation at the beginning of isometric exercise in humans

Vasodilation occurs in the nonexercising forearm at the beginning of isometric handgrip despite activation of sympathetic vasoconstrictor reflexes. The mechanism of this response remains unclear. In 33 normal humans, age 24 +/- 1 years (mean +/- SEM), we measured mean arterial pressure, heart rate, and forearm blood flow (plethysmography) in the nonexercising arm during sustained contralateral isometric handgrip at 30% maximal voluntary contraction. Sympathetic nerve activity to calf muscles (microneurography) was also measured in 15 subjects. Handgrip resulted in increases in arterial pressure from 86 +/- 2 to 97 +/- 3 mm Hg (p less than 0.05). Despite increases in nerve activity to calf muscles from 229 +/- 43 to 337 +/- 66 units (p less than 0.005), which would be expected to produce forearm vasoconstriction, forearm vascular resistance in the contralateral resting arm decreased from 20 +/- 3 to 18 +/- 2 units (p less than 0.05). To determine the mechanism of this vasodilatory influence, additional studies were performed with regional autonomic blockade with intra-arterial administration of atropine (0.8 mg, 10 subjects) or propranolol (2.0 mg, eight subjects) into the nonexercising forearm before contraction. Propranolol and vehicle had no effect on forearm vascular responses in the resting arm during SHG in the other arm. In contrast, atropine blocked the vasodilatory response in the resting arm during contraction (delta forearm vascular resistance during contraction, control = -2.1 +/- 0.6 units; postatropine = +0.2 +/- 0.9 units, p less than 0.05). Atropine did not attenuate the vasodilator response to isoproterenol or the vasoconstrictor response to norepinephrine. We conclude 1) a dissociation exists between sympathetic neural and forearm vascular responses to isometric exercise; 2) the vasodilatory response in the nonexercising forearm is not due to sympathetic withdrawal or beta 2-adrenergic-mediated vasodilation; and 3) this response is mediated primarily by cholinergic mechanisms. These studies provide the first direct evidence for active, cholinergically mediated vasodilation during exercise in humans.     

Effects of nisoldipine on systemic and leg blood flow, oxygen transport and metabolism, and hemodynamics during exercise in effort angina pectoris

The acute effects of 10 mg of oral nisoldipine on hemodynamics, oxygen transport and metabolism, and distribution of cardiac output, at rest and during semiupright bicycle exercise, were evaluated in 10 men with effort angina receiving long-term beta 1 blockade. Cardiac output and leg blood flow were measured using the thermodilution technique. At rest, nisoldipine decreased systemic resistance from 18.9 +/- 1.0 to 15.9 +/- 1.2 dynes.s.cm-5.10(2) (p less than 0.05) and cardiac output increased from 4.8 +/- 0.2 to 5.3 +/- 0.3 liters/min (p less than 0.05) without changing leg blood flow. During maximal exercise with nisoldipine, systemic resistance was reduced (10.6 +/- 0.9 to 8.6 +/- 0.5 dynes.s.cm-5.10(2), p less than 0.05) and cardiac output increased 18% (10.3 +/- 0.7 to 12.2 +/- 0.6 liters/min, p less than 0.05) when compared with control values. Exercise heart rate was higher with nisoldipine (113 +/- 4 vs 106 +/- 4 beats/min, p less than 0.01), but the mean arterial pressure was not significantly changed, giving a higher rate-pressure product. The increase in mean pulmonary artery wedge pressure was attenuated (26 +/- 3 vs 30 +/- 3 mm Hg during control exercise, p less than 0.05), but ST depression was unaltered. Exercise leg flow was reduced by nisoldipine from 4.3 +/- 0.4 to 3.9 +/- 0.3 liters/min (p = 0.07) and the proportion of cardiac output distributed to the legs was reduced from 42 +/- 3 to 33 +/- 3% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exercise stress-induced changes in systemic arterial potassium in angina pectoris

Large fluctuations in systemic arterial potassium have been found during and after exercise in normal subjects. To determine whether similar changes occur in patients with angina pectoris, arterial potassium levels were measured before, during and immediately after maximal bicycle exercise in 20 patients with exertional angina. In 10 of these patients, leg blood flow and arteriovenous potassium levels also were measured. During exercise, arterial potassium increased significantly both from rest to submaximal exercise (4.3 +/- 0.1 to 4.7 +/- 0.1 mmol/liter, p less than 0.01) and from submaximal to maximal exercise (5.4 +/- 0.1 mmol/liter, p less than 0.01). Within 1 minute of cessation of exercise, arterial potassium had decreased to 4.7 +/- 0.1 mmol/liter (p less than 0.001) and continued to decrease to a minimum of 4.1 +/- 0.1 mmol/liter between 3 and 5 minutes after exercise, significantly less than the rest value (p less than 0.05). At maximal exercise (99 +/- 9 watts), the calculated release of potassium from each leg reached 2.7 +/- 1.3 mmol/min. Four minutes after exercise, the leg muscles were resorbing potassium at 0.24 mmol/min. In these patients with exertional myocardial ischemia, the magnitude and rapidity of arterial potassium changes during and after exercise resemble those found in normal subjects, but occurred at much lower workloads. Release and resorption of potassium by exercising muscle in patients with angina pectoris may cause potentially arrhythmogenic arterial potassium fluctuations.     

Altered skeletal muscle metabolic response to exercise in chronic heart failure. Relation to skeletal muscle aerobic enzyme activity

BACKGROUND. Exertional fatigue, which frequently limits exercise in patients with chronic heart failure, is associated with early anaerobic metabolism in skeletal muscle. The present study was designed to examine the skeletal muscle metabolic response to exercise in this disorder and determine the relation of reduced muscle blood flow and skeletal muscle biochemistry and histology to the early onset of anaerobic metabolism in patients. METHODS AND RESULTS. We evaluated leg blood flow, blood lactate, and skeletal muscle metabolic responses (by vastus lateralis biopsies) during upright bicycle exercise in 11 patients with chronic heart failure (ejection fraction 21 +/- 8%) and nine normal subjects. In patients compared to normal subjects, peak exercise oxygen consumption was decreased (13.0 +/- 3.3 ml/kg/min versus 30.2 +/- 8.6 ml/kg/min, p less than 0.01), whereas peak respiratory exchange ratio and femoral venous oxygen content were not different (both p greater than 0.25), indicating comparable exercise end points. At rest in patients versus normals, there was a reduction in the activity of hexokinase (p = 0.08), citrate synthetase (p less than 0.02), succinate dehydrogenase (p = 0.0007), and 3-hydroxyacyl CoA dehydrogenase (p = 0.04). In patients, leg blood flow was decreased at rest, submaximal, and maximal exercise when compared to normal subjects (all p less than 0.05), and blood lactate accumulation was accelerated. In patients, during submaximal exercise blood lactate levels were not closely related to leg blood flow but were inversely related to rest citrate synthetase activity in skeletal muscle (r = -0.74, p less than 0.05). At peak exercise there were no intergroup differences in skeletal muscle glycolytic intermediates, adenosine nucleotides, or glycogen, whereas in patients compared to normal subjects less lactate accumulation and phosphocreatine depletion were noted (both p less than 0.05), suggesting that factors other than the magnitude of phosphocreatine depletion or lactate accumulation may influence skeletal muscle fatigue in this disorder. CONCLUSIONS. The results of the present study suggest that in patients with chronic heart failure reduced aerobic activity in skeletal muscle plays an important role in mediating the early onset of anaerobic metabolism during exercise. Our findings are consistent with the concept that reduced aerobic enzyme activity in skeletal muscle is, in part, responsible for determining exercise tolerance and possibly the response to chronic intervention in patients with chronic heart failure.