WISE 2005: vascular responses to 60-day bed rest in women

WISE-2005 studied 24 women during a 60-day head down bed rest (HDBR) who look part in an exercise countermeasure (LBNP-treadmill plus flywheel, EX) and no-exercise (No-EX). We conducted a series of experiments to explore changes in cardiovascular function and the ability of EX to prevent these changes. Resting arterial diameter in the arm was not affected but the leg arteries (femoral and popliteal) were significantly reduced in Np-EX, but was increased in EX. In this study we report on drug stimulated responses with sublingual nitroglycerin and infused isoproterenol. Heart rate increased in response to nitroglycerin with larger increases in No-EX after HDBR. Likewise during isoproterenol infusion the HR increase was greater after HDBR in the No-EX group. In all cases, the higher HR was associated with lower stroke volume in No-EX while stroke volume was protected in EX. These data do not support a change in sensitivity of beta-adrenergic receptors after HDBR. The leg vascular resistance decreased in response to isoproterenol and it decreased to a greater extent in No-EX than EX. These data were consistent with observations of lower leg vascular resistance during orthostatic challenge tests after HDBR. We conclude that consistent changes in cardiovascular function in the No-EX were detected by different methods that point to mechanisms contributing to orthostatic intolerance after HDBR.     

Vascular adaptation to deconditioning and the effect of an exercise countermeasure: results of the Berlin Bed Rest study.

Deconditioning is a risk factor for cardiovascular disease. The physiology of vascular adaptation to deconditioning has not been elucidated. The purpose of the present study was to assess the effects of bed rest deconditioning on vascular dimension and function of leg conduit arteries. In addition, the effectiveness of resistive vibration exercise as a countermeasure for vascular deconditioning during bed rest was evaluated. Sixteen healthy men were randomly assigned to bed rest (BR-Ctrl) or to bed rest with resistive vibration exercise (BR-RVE). Before and after 25 and 52 days of strict horizontal bed rest, arterial diameter, blood flow, flow-mediated dilatation (FMD), and nitroglycerin-mediated dilatation were measured by echo Doppler ultrasound. In the BR-Ctrl group, the diameter of the common femoral artery decreased by 13 +/- 3% after 25 and 17 +/- 1% after 52 days of bed rest (P < 0.001). In the BR-RVE group this decrease in diameter was significantly attenuated (5 +/- 2% after 25 days and 6 +/- 2% after 52 days, P < 0.01 vs. BR-Ctrl). Baseline blood flow did not change after bed rest in either group. After 52 days of bed rest, FMD and nitroglycerin-mediated dilatation of the superficial femoral artery were increased in both groups, possibly by increased nitric oxide sensitivity. In conclusion, bed rest deconditioning is accompanied by a reduction in the diameter of the conduit arteries and by an increased reactivity to nitric oxide. Resistive vibration exercise effectively attenuates the diameter decrease of leg conduit arteries after bed rest.     

Effect of rowing ergometry and oral volume loading on cardiovascular structure and function during bed rest

This study examined the effectiveness of a short-duration but high-intensity exercise countermeasure in combination with a novel oral volume load in preventing bed rest deconditioning and orthostatic intolerance. Bed rest reduces work capacity and orthostatic tolerance due in part to cardiac atrophy and decreased stroke volume. Twenty seven healthy subjects completed 5 wk of -6 degree head down bed rest. Eighteen were randomized to daily rowing ergometry and biweekly strength training while nine remained sedentary. Measurements included cardiac mass, invasive pressure-volume relations, maximal upright exercise capacity, and orthostatic tolerance. Before post-bed rest orthostatic tolerance and exercise testing, nine exercise subjects were given 2 days of fludrocortisone and increased salt. Sedentary bed rest led to cardiac atrophy (125 ± 23 vs. 115 ± 20 g; P < 0.001); however, exercise preserved cardiac mass (128 ± 38 vs. 137 ± 34 g; P = 0.002). Exercise training preserved left ventricular chamber compliance, whereas sedentary bed rest increased stiffness (180 ± 170%, P = 0.032). Orthostatic tolerance was preserved only when exercise was combined with volume loading (-10 ± 22%, P = 0.169) but not with exercise (-14 ± 43%, P = 0.047) or sedentary bed rest (-24 ± 26%, P = 0.035) alone. Rowing and supplemental strength training prevent cardiovascular deconditioning during prolonged bed rest. When combined with an oral volume load, orthostatic tolerance is also preserved. This combined countermeasure may be an ideal strategy for prolonged spaceflight, or patients with orthostatic intolerance.     

High K(+)-induced membrane depolarization attenuates endothelium-dependent pulmonary vasodilation

Impairment of endothelium-dependent pulmonary vasodilation has been implicated in the development of pulmonary hypertension. Pulmonary vascular smooth muscle cells and endothelial cells communicate electrically through gap junctions; thus, membrane depolarization in smooth muscle cells would depolarize endothelial cells. In this study, we examined the effect of prolonged membrane depolarization induced by high K(+) on the endothelium-dependent pulmonary vasodilation. Isometric tension was measured in isolated pulmonary arteries (PA) from Sprague-Dawley rats, and membrane potential was measured in single PA smooth muscle cells. Increase in extracellular K(+) concentration from 4.7 to 25 mM significantly depolarized PA smooth muscle cells. The 25 mM K(+)-mediated depolarization was characterized by an initial transient depolarization (5-15 s) followed by a sustained depolarization that could last for up to 3 h. In endothelium-intact PA rings, ACh (2 microM), levcromakalim (10 microM), and nitroprusside (10 microM) reversibly inhibited the 25 mM K(+)-mediated contraction. Functional removal of endothelium abolished the ACh-mediated relaxation but had no effect on the levcromakalim- or the nitroprusside-mediated pulmonary vasodilation. Prolonged ( approximately 3 h) membrane depolarization by 25 mM K(+) significantly inhibited the ACh-mediated PA relaxation (-55 +/- 4 vs. -29 +/- 2%, P < 0.001), negligibly affected the levcromakalim-mediated pulmonary vasodilation (-92 +/- 4 vs. -95 +/- 5%), and slightly but significantly increased the nitroprusside-mediated PA relaxation (-80 +/- 2 vs. 90 +/- 3%, P < 0. 05). These data indicate that membrane depolarization by prolonged exposure to high K(+) concentration selectively inhibited endothelium-dependent pulmonary vasodilation, suggesting that membrane depolarization plays a role in the impairment of pulmonary endothelial function in pulmonary hypertension.     

Exercise within lower body negative pressure partially counteracts lumbar spine deconditioning associated with 28-day bed rest.

Astronauts experience spine deconditioning during exposure to microgravity due to the lack of axial loads on the spine. Treadmill exercise in a lower body negative pressure (LBNP) chamber provides axial loads on the lumbar spine. We hypothesize that daily supine LBNP exercise helps counteract lumbar spine deconditioning during 28 days of microgravity simulated by bed rest. Twelve sets of healthy, identical twins underwent 6 degrees head-down-tilt bed rest for 28 days. One subject from each set of twins was randomly assigned to the exercise (Ex) group, whereas their sibling served as a nonexercise control (Con). The Ex group exercised in supine posture within a LBNP chamber for 45 min/day, 6 days/wk. All subjects underwent magnetic resonance imaging of their lumbar spine before and at the end of bed rest. Lumbar spinal length increased 3.7 +/- 0.5 mm in the Con group over 28-day bed rest, whereas, in the Ex group, lumbar spinal length increased significantly less (2.3 +/- 0.4 mm, P = 0.01). All lumbar intervertebral disk heights (L5-S1, L4-5, L3-4, L2-3, and L1-2) in the Con group increased significantly over the 28-day bed rest (P < 0.05). In the Ex group, there were no significant increases in L5-S1 and L4-5 disk heights. Lumbar lordosis decreased significantly by 3.3 +/- 1.2 degrees during bed rest in the Con group (P = 0.02), but it did not decrease significantly in the Ex group. Our results suggest that supine LBNP treadmill exercise partially counteracts lumbar spine lengthening and deconditioning associated with simulated microgravity.     

Acute vascular responses to isometric handgrip exercise and effects of training in persons medicated for hypertension

Previous work from our laboratory demonstrated that isometric handgrip (IHG) training improved local, endothelium-dependent vasodilation in medicated hypertensives [McGowan CL (PhD Thesis), 2006; McGowan et al. Physiologist 47: 285, 2004]. We investigated whether changes in the capacity of smooth muscle to dilate (regardless of endothelial factors) influenced this training-induced change, and we examined the acute vascular responses to a single bout of IHG. Seventeen subjects performed four 2-min unilateral IHG contractions at 30% of maximal voluntary effort, three times a week for 8 wk. Pre- and posttraining, brachial artery flow-mediated dilation (FMD, an index of endothelium-dependent vasodilation) and nitroglycerin-mediated maximal vasodilation (an index of endothelium-independent vasodilation) were measured in the exercised arm by using ultrasound before and immediately after acute IHG exercise. IHG training resulted in improved resting brachial FMD (P < 0.01) and no change in nitroglycerin-mediated maximal vasodilation. Pre- and posttraining, brachial artery FMD decreased following an acute bout of IHG exercise (normalized to peak shear rate, pre-, before IHG exercise: 0.01 +/- 0.002, after IHG exercise: 0.008 +/- 0.002%/s(-1); post-, before IHG exercise: 0.020 +/- 0.003, after IHG exercise: 0.010 +/- 0.003%/s(-1); P < 0.01). Posttraining, resting brachial artery FMD improved yet nitroglycerin-mediated maximal vasodilation was unchanged in persons medicated for hypertension. This suggests that the training-induced improvements in the resting brachial artery FMD were not due to underlying changes in the forearm vasculature. Acute IHG exercise attenuated brachial artery FMD, and although this impairment may be interpreted as hazardous to medicated hypertensives with already dysfunctional endothelium, the effects appear transient as repeated exposure to the IHG stimulus improved resting endothelium-dependent vasodilation.     

Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide

This study is aimed to test the hypothesis, that short-term daily bouts of exercise alter the endothelial regulation of peripheral vascular resistance by nitric oxide. Rats ran on a treadmill once a day, 5 days a week, for an average of three weeks with gradually increasing intensity (EX), while a control group remained sedentary (SED). Dose dependent reductions in mean arterial blood pressure (resting MABP; SED: 120.0 +/- 3.4 and EX: 127.8 +/- 4.0 mm Hg) of pentobarbital anesthetized rats to intravenous endothelium independent dilator sodium nitropmsside (SNP; 0.6-3.0 microg/kg) were not different in EX and SED animals. In contrast, dose dependent reductions in MABP to endothelium dependent dilator acetylcholine (ACh) were significantly enhanced in EX compared to those in SED rats (at 0.5 and 1.0 microg/kg ACh: 60.3 +/- 2.4 and 66.5 +/- 1.8 vs 52.8 +/- 2.0 and 59.8 +/- 1.7 mmHg, respectively, p<0.01). There was no significant difference in the heart rate (HR) response to ACh and SNP in the two groups of rats. Intravenous administration of 20 mg/kg Nomega-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor) elicited a similar increase (approximately 30%) in the MABP in the two groups and eliminated the difference between ACh-induced blood pressure lowering responses in EX and SED rats (at 0.5 and 1.0 microg/kg ACh: 44.6 +/- 4.7 and 56.3 +/- 4.4 vs 50.9 +/- 4.5 and 59.4 +/- 3.6 mm Hg, respectively). Thus, we suggest that the enhanced acetylcholine-induced decrease in systemic blood pressure following regular daily exercise is primarily due to the augmented synthesis of nitric oxide in the endothelium of peripheral vasculature. This change in the function of endothelium could be important in the adaptation of circulation to exercise training.     

Supine lower body negative pressure exercise during bed rest maintains upright exercise capacity.

Bed rest and spaceflight reduce exercise fitness. Supine lower body negative pressure (LBNP) treadmill exercise provides integrated cardiovascular and musculoskeletal stimulation similar to that imposed by upright exercise in Earth gravity. We hypothesized that 40 min of supine exercise per day in a LBNP chamber at 1.0-1.2 body wt (58 +/- 2 mmHg LBNP) maintains aerobic fitness and sprint speed during 15 days of 6 degrees head-down bed rest (simulated microgravity). Seven male subjects underwent two such bed-rest studies in random order: one as a control study (no exercise) and one with daily supine LBNP treadmill exercise. After controlled bed-rest, time to exhaustion during an upright treadmill exercise test decreased 10%, peak oxygen consumption during the test decreased 14%, and sprint speed decreased 16% (all P < 0.05). Supine LBNP exercise during bed rest maintained all the above variables at pre-bed-rest levels. Our findings support further evaluation of LBNP exercise as a countermeasure against long-term microgravity-induced deconditioning.     

Dimethylarginine dimethylaminohydrolase and endothelial dysfunction in failing hearts

Congestive heart failure (CHF) is associated with impaired endothelium-dependent nitric oxide (NO)-mediated vasodilation (endothelial dysfunction). We hypothesized that coronary endothelial dysfunction in CHF may be due in part to decreased dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades endogenous inhibitors of NO synthase (NOS), including asymmetric dimethylarginine. Coronary blood flow and the endothelium-dependent vasodilator response to acetylcholine were studied in dogs in which CHF was produced by rapid ventricular pacing for 4 wk. Coronary flow and myocardial O2 consumption at rest and during treadmill exercise were decreased after development of CHF, and the vasodilator response to intracoronary acetylcholine (75 microg/min) was decreased by 39 +/- 5%. DDAH activity and DDAH isoform 2 (DDAH-2) protein content were decreased by 53 +/- 13% and 58 +/- 14%, respectively, in hearts with CHF, whereas endothelial NOS and DDAH isoform 1 (DDAH-1) were increased. Caveolin-1 and protein arginine N-methyltransferase 1, the enzyme that produces asymmetric dimethylarginine, were unchanged. Immunohistochemical staining showed DDAH-1 strongly expressed in coronary endothelium and smooth muscle and in the sarcolemma of cardiac myocytes. In cultured human endothelial cells, DDAH-1 was uniformly distributed in the cytosol and nucleus, whereas DDAH-2 was found only in the cytosol. Decreased DDAH activity and DDAH-2 protein expression may cause accumulation of endogenous inhibitors of endothelial NOS, thereby contributing to endothelial dysfunction in the failing heart.     

Repeat exercise normalizes the gas-exchange impairment induced by a previous exercise bout in asthmatic subjects.

Twenty-one subjects with asthma underwent treadmill exercise to exhaustion at a workload that elicited approximately 90% of each subject's maximal O2 uptake (EX1). After EX1, 12 subjects experienced significant exercise-induced bronchospasm [(EIB+), %decrease in forced expiratory volume in 1.0 s = -24.0 +/- 11.5%; pulmonary resistance at rest vs. postexercise = 3.2 +/- 1.5 vs. 8.1 +/- 4.5 cmH2O.l(-1).s(-1)] and nine did not (EIB-). The alveolar-to-arterial Po2 difference (A-aDo2) was widened from rest (9.1 +/- 6.7 Torr) to 23.1 +/- 10.4 and 18.1 +/- 9.1 Torr at 35 min after EX1 in subjects with and without EIB, respectively (P < 0.05). Arterial Po2 (PaO2) was reduced in both groups during recovery (EIB+, -16.0 +/- -13.0 Torr vs. baseline; EIB-, -11.0 +/- 9.4 Torr vs. baseline, P < or = 0.05). Forty minutes after EX1, a second exercise bout was completed at maximal O2 uptake. During the second exercise bout, pulmonary resistance decreased to baseline levels in the EIB+ group and the A-aDo2 and PaO2 returned to match the values seen during EX1 in both groups. Sputum histamine (34.6 +/- 25.9 vs. 61.2 +/- 42.0 ng/ml, pre- vs. postexercise) and urinary 9alpha,11beta-prostaglandin F2 (74.5 +/- 38.6 vs. 164.6 +/- 84.2 ng/mmol creatinine, pre- vs. postexercise) were increased after exercise only in the EIB+ group (P < 0.05), and postexercise sputum histamine was significantly correlated with the exercise PaO2 and A-aDo2 in the EIB+ subjects. Thus exercise causes gas-exchange impairment during the postexercise period in asthmatic subjects independent of decreases in forced expiratory flow rates after the exercise; however, a subsequent exercise bout normalizes this impairment secondary in part to a fast acting, robust exercise-induced bronchodilatory response.     

Impaired endothelium-dependent vasodilation in overweight and obese adult humans is not limited to muscarinic receptor agonists

Muscarinic receptor agonists have primarily been used to characterize endothelium-dependent vasodilator dysfunction with overweight/obesity. Reliance on a single class of agonist, however, yields limited, and potentially misleading, information regarding endothelial vasodilator capacity. The aims of this study were to determine 1) whether the overweight/obesity-related reduction in endothelium-dependent vasodilation extends beyond muscarinic receptor agonists and 2) whether the contribution of nitric oxide (NO) to endothelium-dependent vasodilation is reduced in overweight/obese adults. Eighty-six middle-aged and older adults were studied: 42 normal-weight (54 +/- 1 yr, 21 men and 21 women, body mass index = 23.4 +/- 0.3 kg/m(2)) and 44 overweight/obese (54 +/- 1 yr, 28 men and 16 women, body mass index = 30.3 +/- 0.6 kg/m(2)) subjects. Forearm blood flow (FBF) responses to intra-arterial infusions of acetylcholine in the absence and presence of the endothelial NO synthase inhibitor N(G)-monomethyl-l-arginine, methacholine, bradykinin, substance P, isoproterenol, and sodium nitroprusside were measured by strain-gauge plethysmography. FBF responses to each endothelial agonist were significantly blunted in the overweight/obese adults. Total FBF (area under the curve) to acetylcholine (50 +/- 5 vs. 79 +/- 4 ml/100 ml tissue), methacholine (55 +/- 4 vs. 86 +/- 5 ml/100 ml tissue), bradykinin (62 +/- 5 vs. 85 +/- 4 ml/100 ml tissue), substance P (37 +/- 4 vs. 57 +/- 5 ml/100 ml tissue), and isoproterenol (62 +/- 4 vs. 82 +/- 6 ml/100 ml tissue) were 30%-40% lower in the overweight/obese than normal-weight adults. N(G)-monomethyl-l-arginine significantly reduced the FBF response to acetylcholine to the same extent in both groups. There were no differences between the groups in the FBF responses to sodium nitroprusside. These results indicate that agonist-stimulated endothelium-dependent vasodilation is universally impaired with overweight/obesity. Moreover, this impairment appears to be independent of NO.     

Endothelial function during stimulation of renin-angiotensin system by low-sodium diet in humans

We examined whether physiological stimulation of the endogenous renin-angiotensin system results in impaired endothelium-dependent vasodilatation in forearm resistance vessels of healthy subjects and whether this impairment can be prevented by angiotensin II type 1 receptor blockade. A low-sodium diet was administered to 27 volunteers who were randomized to concomitant treatment with losartan (100 mg once daily) or matched placebo in a double-blind fashion. Forearm blood flow was assessed by venous occlusion plethysmography at baseline and after 5 days. Endothelium-dependent and -independent vasodilation was assessed by intra-arterial infusion of methacholine and verapamil, respectively. The low-sodium diet resulted in significantly decreased urine sodium excretion (placebo: 146 +/- 64 vs. 10 +/- 9 meq/24 h, P < 0.001; losartan: 141 +/- 56 vs. 14 +/- 14 meq/24 h, P < 0.001) and increased plasma renin activity (placebo: 1.0 +/- 0.5 vs. 5.0 +/- 2.5 ng x ml(-1) x h(-1), P < 0.001; losartan: 3.8 +/- 7.2 vs. 19.1 +/- 11.2 ng x ml(-1) x h(-1), P = 0.006) in both the losartan and placebo groups. With the baseline study as the reference, the diet intervention was not associated with any significant change in endothelium-dependent vasodilation to methacholine in either the placebo (P = 0.74) or losartan (P = 0.40) group. We conclude that short-term physiological stimulation of the renin-angiotensin system does not cause clinically significant endothelial dysfunction. Losartan did not influence endothelium-dependent vasodilation in humans with a stimulated renin-angiotensin system.     

WISE 2005: flow and nitroglycerin mediated dilation following 56 days of head down tilt bed rest with and without an exercise countermeasure

This investigation set out to determine the effect of 56 days of head-down tilt bed rest (HDBR) and an exercise countermeasure on endothelial dependent and independent vascular function. 24women took part in this study. 8 subjects completed lower body resistance and aerobic exercise (EX, treadmill running 3-4 days per week for 40-min followed by 10-min of static LBNP, and resistive exercise on a flywheel device every 3rd day) and 16 subjects were considered as non-exercisers in a control group and a protein supplement group. FMD was induced by release of distal limb ischemia and NMD by sublingual administration of 0.3 mg of nitroglycerin before and after HDBR. Preliminary results of this study suggest that HDBR without EX results in a decreased resting diameter of the popliteal while EX increased the diameter. It is also suggested that FMD was elevated without exercise in both brachial and popliteal arteries, while pre-HDBR FMD was preserved by EX in the popliteal, but not the brachial artery. NMD appears to be elevated in the popliteal and femoral in the absence of exercise, but unchanged in the brachial artery or at any site for EX.     

Insulin sensitivity is preserved despite disrupted endothelial function

It is well established that endothelial dysfunction and insulin resistance go hand in hand. However, it is unclear whether endothelial dysfunction per se is sufficient to impair insulin-mediated glucose uptake. We have previously reported that 4 wk of administration of the human immunodeficiency virus (HIV)-1 protease inhibitor indinavir to HIV-negative subjects induces endothelial dysfunction. Hence, we hypothesized that indinavir-induced endothelial dysfunction was associated with impaired insulin-mediated glucose disposal. We measured insulin-mediated glucose disposal at the level of the whole body, skeletal muscle, and vasculature by performing hyperinsulinemic euglycemic clamp, and vascular function studies, in a separate group of HIV-negative healthy nonobese subjects (n = 13) before and after 4 wk of daily oral indinavir. Four weeks of indinavir resulted in a 113 +/- 29% (P < 0.01) reduction of endothelium-dependent vasodilation, consistent with our earlier findings. In addition, there was a significant impairment of insulin-mediated vasodilation (101 +/- 14% before indinavir vs. 35 +/- 15% after indinavir; P < 0.05). However, there was no significant change in insulin-mediated glucose disposal at the level of the whole body (8.9 +/- 0.5 before indinavir vs. 8.5 +/- 0.6 mgxkg(-1)xmin(-1) after indinavir; P = 0.4), or skeletal muscle. Furthermore, in a separate group of four HIV-negative healthy nonobese subjects, we found that 4 wk of indinavir has no sustained effect on insulin-stimulated glucose uptake in adipose tissue. Thus our findings indicate that 1) endothelial dysfunction alone is insufficient to impair insulin-mediated glucose disposal, and 2) indinavir-induced endothelial dysfunction is likely due to a direct effect of the drug on the endothelium and is not coupled to the induction of insulin resistance.     

ATP production and efficiency of human skeletal muscle during intense exercise: effect of previous exercise

The aim of the present study was to examine whether ATP production increases and mechanical efficiency decreases during intense exercise and to evaluate how previous exercise affects ATP turnover during intense exercise. Six subjects performed two (EX1 and EX2) 3-min one-legged knee-extensor exercise bouts [66.2 +/- 3.9 and 66.1 +/- 3.9 (+/-SE) W] separated by a 6-min rest period. Anaerobic ATP production, estimated from net changes in and release of metabolites from the active muscle, was 3.5 +/- 1.2, 2.4 +/- 0.6, and 1.4 +/- 0.2 mmol ATP x kg dry wt(-1) x s(-1) during the first 5, next 10, and remaining 165 s of EX1, respectively. The corresponding aerobic ATP production, determined from muscle oxygen uptake, was 0.7 +/- 0.1, 1.4 +/- 0.2, and 4.7 +/- 0.4 mmol ATP x kg dry wt(-1) x s(-1), respectively. The mean rate of ATP production during the first 5 s and next 10 s was lower (P < 0.05) than during the rest of the exercise (4.2 +/- 1.2 and 3.8 +/- 0.7 vs. 6.1 +/- 0.3 mmol ATP x kg dry wt(-1) x s(-1)). Thus mechanical efficiency, expressed as work per ATP produced, was lowered (P < 0.05) in the last phase of exercise (39.6 +/- 6.1 and 40.7 +/- 5.8 vs. 25.0 +/- 1.3 J/mmol ATP). The anaerobic ATP production was lower (P < 0.05) in EX2 than in EX1, but the aerobic ATP turnover was higher (P < 0.05) in EX2 than in EX1, resulting in the same muscle ATP production in EX1 and EX2. The present data suggest that the rate of ATP turnover increases during intense exercise at a constant work rate. Thus mechanical efficiency declines as intense exercise is continued. Furthermore, when intense exercise is repeated, there is a shift toward greater aerobic energy contribution, but the total ATP turnover is not significantly altered.     

Previous exercise attenuates muscle sympathetic activity and increases blood flow during acute euglycemic hyperinsulinemia.

Insulin infusion causes muscle vasodilation, despite the increase in sympathetic nerve activity. In contrast, a single bout of exercise decreases sympathetic activity and increases muscle blood flow during the postexercise period. We tested the hypothesis that muscle sympathetic activity would be lower and muscle vasodilation would be higher during hyperinsulinemia performed after a single bout of dynamic exercise. Twenty-one healthy young men randomly underwent two hyperinsulinemic euglycemic clamps performed after 45 min of seated rest (control) or bicycle exercise (50% of peak oxygen uptake). Muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow (FBF, plethysmography), blood pressure (BP, oscillometric method), and heart rate (HR, ECG) were measured at baseline (90 min after exercise or seated rest) and during hyperinsulinemic euglycemic clamps. Baseline glucose and insulin concentrations were similar in the exercise and control sessions. Insulin sensitivity was unchanged by previous exercise. During the clamp, insulin levels increased similarly in both sessions. As expected, insulin infusion increased MSNA, FBF, BP, and HR in both sessions (23 +/- 1 vs. 36 +/- 2 bursts/min, 1.8 +/- 0.1 vs. 2.2 +/- 0.2 ml.min(-1).100 ml(-1), 89 +/- 2 vs. 92 +/- 2 mmHg, and 58 +/- 1 vs. 62 +/- 1 beats/min, respectively, P < 0.05). BP and HR were similar between sessions. However, MSNA was significantly lower (27 +/- 2 vs. 31 +/- 2 bursts/min), and FBF was significantly higher (2.2 +/- 0.2 vs. 1.8 +/- 0.1 ml.min(-1).100 ml(-1), P < 0.05) in the exercise session compared with the control session. In conclusion, in healthy men, a prolonged bout of dynamic exercise decreases MSNA and increases FBF. These effects persist during acute hyperinsulinemia performed after exercise.     

Long-term bed rest-induced reductions in stroke volume during rest and exercise: cardiac dysfunction vs. volume depletion.

Long-term head-down-tilt bed rest (HDT) causes cardiovascular deconditioning, attributed to reflex dysfunctions, plasma volume reduction, or cardiac impairments. Our objective with the present study was to evaluate the functional importance and relative contribution of these during rest and exercise in supine and upright postures. We studied six subjects before (baseline), during [days 60 (D60) and 113 (D113)], and after [recovery days 0 (R0), 3 (R3), and 15 (R15)] 120 days of -6 degrees HDT. We determined cardiac output, stroke volume (SV), mean arterial pressure, and heart rate during rest and exercise in supine and upright postures. Cardiac output and SV decreased significantly in all four conditions, but the time courses differed for rest and exercise. Upright resting SV was decreased by 24 +/- 9% at D60 compared with baseline but had recovered already at R3. Supine exercise SV decreased more slowly (by 5 +/- 8% at D60 and by 18 +/- 4% at D113) and recovered more slowly after HDT termination. Steady-state mean arterial pressure showed no changes. Heart rate had increased by 18 +/- 4% at D60 and had recovered partially at R3. Our data indicate that long-term HDT causes both a rapid, preload-dependent reduction in SV, most evident during rest in the upright position, and a more slowly developing cardiac dysfunction, most evident during supine exercise. However, the ability to maintain blood pressure and to perform sustained low levels of dynamic exercise is not influenced by HDT.     

Enhanced sympathoinhibitory response to volume expansion in conscious hindlimb-unloaded rats.

Prolonged exposure to microgravity or bed rest produces cardiovascular deconditioning, which is characterized by reductions in plasma volume, alterations in autonomic function, and a predisposition toward orthostatic intolerance. Although the precise mechanisms have not been fully elucidated, it is possible that augmented cardiopulmonary reflexes contribute to some of these effects. The purpose of the present study was to test the hypothesis that sympathoinhibitory responses to volume expansion are enhanced in the hindlimb-unloaded (HU) rat, a model of cardiovascular deconditioning. Mean arterial blood pressure, heart rate, and renal sympathetic nerve activity (RSNA) responses to isotonic volume expansion (0.9% saline iv, 15% of plasma volume over 5 min) were examined in conscious HU (14 days) and control animals. Volume expansion produced decreases in RSNA in both groups; however, this effect was significantly greater in HU rats (-46 +/- 7 vs. -25 +/- 4% in controls). Animals instrumented for central venous pressure (CVP) did not exhibit differences in CVP responses to volume expansion. These data suggest that enhanced cardiopulmonary reflexes may be involved in the maintenance of reduced plasma volume and contribute to attenuated baroreflex-mediated sympathoexcitation after spaceflight or bed rest.     

Endothelial function across an oral contraceptive cycle in women using levonorgestrel and ethinyl estradiol

Oral contraceptive pills (OCPs) are a popular contraception method. Currently, lower-dose ethinyl estradiol formulations are most commonly prescribed, although they have been linked to increased arterial vascular risk. The aim of this study was to investigate endothelial function in healthy young women using lower-dose ethinyl estradiol OCPs. We examined flow-mediated, endothelium-dependent and nitroglycerin-mediated, endothelium-independent vasodilation of the brachial artery, comparing two doses of ethinyl estradiol/levonorgestrel OCPs in 15 healthy young women on two study days: once during the active phase and once during the placebo phase of an OCP cycle. Group low dose (LD) (n=7) active pills contained 150 microg levonorgestrel/30 microg ethinyl estradiol versus Group very low dose (VLD) (n=8) with 100 microg levonorgestrel/20 microg ethinyl estradiol. Endothelium-dependent vasodilation was lower during the active phase in Group VLD (5.33 +/- 1.77% vs. 7.23 +/- 2.60%; P=0.024). This phase difference was not observed in Group LD (8.00 +/- 0.970% vs. 7.61 +/- 1.07%; P=0.647). Endothelium-independent vasodilation did not differ between phases in either group. Finally, we measured endothelium-dependent vasodilation in two additional women who received 10 microg of unopposed ethinyl estradiol. Endothelium-dependent vasodilation was increased by unopposed ethinyl estradiol compared with the placebo phase (10.88 +/- 2.34% vs. 6.97 +/- 1.83%). These results suggest that levonorgestrel may antagonize the activity of ethinyl estradiol. Thus both the progestin type and estradiol dose need to be considered when assessing arterial vascular risk of OCP use in women.     

Statins as coronary vasodilators in isolated bovine coronary arteries--involvement of PGI2 and NO

Here we studied direct vasodilation induced by statins in isolated bovine coronary arteries. In rings of coronary bovine arteries preconstricted with prostaglandin F(2 alpha) (3 x 10(-8) - 10(-5)), lovastatin, simvastatin, atorvastatin and cerivastatin (3-30 microM) but not pravastatin induced concentration-dependent vasodilation. Removal of endothelium diminished response to simvastatin, cerivastatin and atorvastatin (30 microM) (67.4+/-4.56 vs. 22.7+/-8.14%, 96.9+/-2.27% vs. 54.5+/-6.86%, 67.4+/-4.01% vs. 34.6+/-5.66%, respectively). In presence of L-NAME (300 microM) or indomethacin (5 microM) responses to simvastatin, atorvastatin and cerivastatin, were also partially diminished. In contrast, lovastatin-induced vasorelaxation was not significantly affected by removal of endothelium (35.6+/-4.19% vs. 28.8+/-5.24%) or by pretreatment with L-NAME or indomethacin. In summary, with the exception of pravastatin, statins act as coronary vasodilators. Simvastatin, cerivastatin and atorvastatin but not lovastatin induced vasodilation displayed endothelium dependent- and endothelium-independent components. The endothelium-dependent effect of statins was mediated by NO and PGI(2), while the mechanism of smooth muscle cells-dependent component remains to be determined.