Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.     

Smaller age-associated reductions in leg venous compliance in endurance exercise-trained men

We determined the independent and interactive influences of aging and habitual endurance exercise on calf venous compliance in humans. We tested the hypotheses that calf venous compliance is 1) reduced with age in sedentary and endurance-trained men, and 2) elevated in young and older endurance-trained compared with age-matched sedentary men. We studied 8 young (28 +/- 1 yr) and 8 older (65 +/- 1) sedentary, and 8 young (27 +/- 1) and 8 older (63 +/- 2) endurance-trained men. Calf venous compliance was measured in supine subjects by inflating a venous collecting cuff, placed above the knee, to 60 mmHg for 8 min and then decreasing cuff pressure at 1 mmHg/s to 0 mmHg. Calf venous compliance was determined using the first derivative of the pressure-volume relation during cuff pressure reduction (compliance = beta(1) + 2. beta(2). cuff pressure). Calf venous compliance was reduced with age in sedentary (approximately 40%) and endurance-trained men (approximately 20%) (both P < 0.01). Furthermore, calf venous compliance was approximately 70-120% greater in endurance-trained compared with age-matched sedentary men and approximately 30% greater in older endurance-trained compared with young sedentary men (both P < 0.01). These data indicate that calf venous compliance is reduced with age in sedentary and endurance-trained men, but compliance is better preserved in endurance-trained men.     

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.     

Decline in insulin action with age in endurance-trained humans.

We tested the hypothesis that regular endurance exercise prevents the age-related decline in insulin action typically observed in healthy, sedentary adults. An index of whole body insulin sensitivity (ISI), obtained from minimal model analysis of insulin and glucose concentrations during a frequently sampled intravenous glucose tolerance test, was determined in 126 healthy adults: 25 young [27 +/- 1 (SE) yr; 13 men/12 women] and 43 older (59 +/- 1 yr; 20/13) sedentary and 25 young (29 +/- 1 yr; 12/13) and 33 older (60 +/- 1 yr; 20/13) endurance trained. ISI values were lower in the older vs. young adults in both sedentary (-53%; 3.9 +/- 0.3 vs. 7.0 +/- 0.7 x10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01) and endurance-trained (-36%; 7.9 +/- 0.6 vs. 12.4 +/- 1.0 x 10(-4) min(-1) x microU(-1) x ml(-1); P < 0.01) groups, but the value was 72-102% higher in the trained subjects at either age (P < 0.01). In subgroup analysis of sedentary and endurance-trained adults with similar body fat levels (n = 62), the age-related reduction in ISI persisted only in the endurance-trained subjects (12.9 +/- 1.9 vs. 8.7 +/- 1.2 x 10(-4) x min(-1) x microU(-1) x ml(-1); P < 0.01). The results of the present study suggest that habitual endurance exercise does not prevent the age-associated decline insulin action. Moreover, the age-related reduction in ISI in endurance-trained adults appears to be independent of adiposity.     

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.     

Influence of endurance exercise training status and gender on postexercise hypotension.

In sedentary individuals, postexercise hypotension after a single bout of aerobic exercise is due to a peripheral vasodilation. Endurance exercise training has the potential to modify this response and perhaps reduce the degree of postexercise hypotension. We tested the hypothesis that endurance exercise-trained men and women would have blunted postexercise hypotension compared with sedentary subjects but that the mechanism of hypotension would be similar (i.e., vasodilation). We studied 16 endurance-trained and 16 sedentary men and women. Arterial pressure, cardiac output, and total peripheral resistance were determined before and after a single 60-min bout of exercise at 60% peak oxygen consumption. All groups exhibited a similar degree of postexercise hypotension (approximately 4-5 mmHg; P < 0.05 vs. preexercise). In sedentary men and women, hypotension was the result of vasodilation (Deltaresistance: -8.9 +/- 2.2%). In endurance-trained women, hypotension was also the result of vasodilation (-8.1 +/- 4.1%). However, in endurance-trained men, hypotension was the result of a reduced cardiac output (-5.2 +/- 2.4%; P < 0.05 vs. all others) and vasodilation was absent (-0.7 +/- 3.3%; P < 0.05 vs. all others). Thus we conclude the magnitude of postexercise hypotension is similar in sedentary and endurance-trained men and women but that endurance-trained men and women achieve this fall in pressure via different mechanisms.     

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.     

Enhanced endothelium-dependent vasodilation in older endurance-trained men.

We hypothesized that abnormal endothelium-dependent vasodilation (EDD) found in older otherwise healthy subjects can be attenuated with long-term endurance training. Ten endurance-trained men, 68.5 +/- 2.3 yr old, and 10 healthy sedentary men, 64.7 +/- 1.4 yr old, were studied. Aerobic exercise capacity (VO(2 max)), fasting plasma cholesterol, insulin, and homocysteine concentrations were measured. Master athletes had higher VO(2 max) (42 +/- 2.3 vs. 27 +/- 1.4 ml. kg(-1). min(-1), P < 0.001), slightly higher total cholesterol (226 +/- 8 vs. 199 +/- 8 mg/dl, P = 0.05), similar insulin, and higher homocysteine (10.7 +/- 1.3 vs. 9.2 +/- 1.4 micromol/ml, p = 0.02) concentrations. Brachial arterial diameter, determined with vascular ultrasound, during the hyperemic response was greater in the master athletes than in controls (P = 0.005). Peak vasodilatory response was 109.1 +/- 2 vs. 103.6 +/- 2% (P < 0.05) in the athletes and controls, respectively. Endothelium-independent vasodilation in response to nitroglycerin was similar between the two groups. The increased arterial diameter during the hyperemic response correlated significantly with the VO(2 max) in the entire population (r = 0.66, P < 0.002). Our results suggest that long-term endurance exercise training in older men is associated with systemic enhanced EDD, which is even detectable in the conduit arteries of untrained muscle.     

Muscle protein metabolism responds similarly to exogenous amino acids in healthy younger and older adults during NO-induced hyperemia

The combination of increasing blood flow and amino acid (AA) availability provides an anabolic stimulus to the skeletal muscle of healthy young adults by optimizing both AA delivery and utilization. However, aging is associated with a blunted response to anabolic stimuli and may involve impairments in endothelial function. We investigated whether age-related differences exist in the muscle protein anabolic response to AAs between younger (30 ± 2 yr) and older (67 ± 2 yr) adults when macrovascular and microvascular leg blood flow were similarly increased with the nitric oxide (NO) donor, sodium nitroprusside (SNP). Regardless of age, SNP+AA induced similar increases above baseline (P ≤ 0.05) in macrovascular flow (4.3 vs. 4.4 ml·min(-1)·100 ml leg(-1) measured using indocyanine green dye dilution), microvascular flow (1.4 vs. 0.8 video intensity/s measured using contrast-enhanced ultrasound), phenylalanine net balance (59 vs. 68 nmol·min(-1)·100 ml·leg(-1)), fractional synthetic rate (0.02 vs. 0.02%/h), and model-derived muscle protein synthesis (62 vs. 49 nmol·min(-1)·100 ml·leg(-1)) in both younger vs. older individuals, respectively. Provision of AAs during NO-induced local skeletal muscle hyperemia stimulates skeletal muscle protein metabolism in older adults to a similar extent as in younger adults. Our results suggest that the aging vasculature is responsive to exogenous NO and that there is no age-related difference per se in AA-induced anabolism under such hyperemic conditions.     

Greater rate of decline in maximal aerobic capacity with age in endurance-trained than in sedentary men.

To determine the relation between habitual endurance exercise status and the age-associated decline in maximal aerobic capacity [i.e., maximal O(2) consumption (Vo(2 max))] in men, we performed a well-controlled cross-sectional laboratory study on 153 healthy men aged 20-75 yr: 64 sedentary and 89 endurance trained. Vo(2 max) (ml. kg(-1). min(-1)), measured by maximal treadmill exercise, was inversely related to age in the endurance-trained (r = -0.80) and sedentary (r = -0.74) men but was higher in the endurance-trained men at any age. The rate of decline in Vo(2 max) with age (ml. kg(-1). min(-1)) was greater (P < 0.001) in the endurance-trained than in the sedentary men. Whereas the relative rate of decline in Vo(2 max) (percent decrease per decade from baseline levels in young adulthood) was similar in the two groups, the absolute rate of decline in Vo(2 max) was -5.4 and -3.9 ml. kg(-1). min(-). decade(-1) in the endurance-trained and sedentary men, respectively. Vo(2 max) declined linearly across the age range in the sedentary men but was maintained in the endurance-trained men until approximately 50 yr of age. The accelerated decline in Vo(2 max) after 50 yr of age in the endurance-trained men was related to a decline in training volume (r = 0.46, P < 0.0001) and was associated with an increase in 10-km running time (r = -0.84, P < 0.0001). We conclude that the rate of decline in maximal aerobic capacity during middle and older age is greater in endurance-trained men than in their sedentary peers and is associated with a marked decline in O(2) pulse.     

Changes in maximal aerobic capacity with age in endurance-trained women: 7-yr follow-up.

On the basis of cross-sectional data, we previously reported that the absolute, but not the relative (%), rate of decline in maximal oxygen consumption (VO(2 max)) with age is greater in endurance-trained compared with healthy sedentary women. We tested this hypothesis by using a longitudinal approach. Eight sedentary (63 +/- 2 yr at follow-up) and 16 endurance-trained (57 +/- 2) women were reevaluated after a mean follow-up period of 7 yr. At baseline, VO(2 max) was ~70% higher in endurance-trained women (48.1 +/- 1.7 vs. 28.1 +/- 0.8 ml. kg(-1). min(-1). yr(-1)). At follow-up, body mass, fat-free mass, maximal respiratory exchange ratio, and maximal rating of perceived exertion were not different from baseline in either group. The absolute rate of decline in VO(2 max) was twice as great (P < 0.01) in the endurance-trained (-0.84 +/- 0.15 ml. kg(-1). min(-1). yr(-1)) vs. sedentary (-0.40 +/- 0.12 ml. kg(-1). min(-1). yr(-1)) group, but the relative rates of decline were not different (-1.8 +/- 0.3 vs. -1.5 +/- 0.4% per year). Differences in rates of decline in VO(2 max) were not related to changes in body mass or maximal heart rate. However, among endurance-trained women, the relative rate of decline in VO(2 max) was positively related to reductions in training volume (r = 0.63). Consistent with this, the age-related reduction in VO(2 max) in a subgroup of endurance-trained women who maintained or increased training volume was not different from that of sedentary women. These longitudinal data indicate that the greater decrease in maximal aerobic capacity with advancing age observed in middle-aged and older endurance-trained women in general compared with their sedentary peers is due to declines in habitual exercise in some endurance-trained women. Endurance-trained women who maintain or increase training volume demonstrated age-associated declines in maximal aerobic capacity not different from healthy sedentary women.     

Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves by assessing 1) the age-related decline and 2) the effect of aerobic fitness. Using laser-Doppler flowmetry, we measured skin blood flow (SkBF) in young (24 ± 1 yr) and older (64 ± 1 yr) endurance-trained and sedentary men (n = 7 per group) at baseline and during 35 min of local skin heating to 42°C at 1) untreated forearm sites, 2) forearm sites treated with bretylium tosylate (BT), which prevents neurotransmitter release from noradrenergic sympathetic nerves, and 3) forearm sites treated with yohimbine + propranolol (YP), which antagonizes α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC = SkBF/mean arterial pressure) and normalized to maximal CVC (%CVC(max)) achieved by skin heating to 44°C. Pharmacological agents were administered using microdialysis. In the young trained group, the rapid vasodilator response was reduced at BT and YP sites (P < 0.05); by contrast, in the young sedentary and older trained groups, YP had no effect (P > 0.05), but BT did (P > 0.05). Neither BT nor YP affected the rapid vasodilator response in the older sedentary group (P > 0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men and nonadrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system.     

Maximal vascular leg conductance in trained and untrained men

Lower leg blood flow and vascular conductance were studied and related to maximal oxygen uptake in 15 sedentary men (28.5 +/- 1.2 yr, mean +/- SE) and 11 endurance-trained men (30.5 +/- 2.0 yr). Blood flows were obtained at rest and during reactive hyperemia produced by ischemic exercise to fatigue. Vascular conductance was computed from blood flow measured by venous occlusion plethysmography, and mean arterial blood pressure was determined by auscultation of the brachial artery. Resting blood flow and mean arterial pressure were similar in both groups (combined mean, 3.0 ml X min-1 X 100 ml-1 and 88.2 mmHg). After ischemic exercise, blood flows were 29- and 19-fold higher (P less than 0.001) than rest in trained (83.3 +/- 3.8 ml X min-1 X 100 ml-1) and sedentary subjects (61.5 +/- 2.3 ml X min-1 X 100 ml-1), respectively. Blood pressure and heart rate were only slightly elevated in both groups. Maximal vascular conductance was significantly higher (P less than 0.001) in the trained compared with the sedentary subjects. The correlation coefficients for maximal oxygen uptake vs. vascular conductance were 0.81 (trained) and 0.45 (sedentary). These data suggest that physical training increases the capacity for vasodilation in active limbs and also enables the trained individual to utilize a larger fraction of maximal vascular conductance than the sedentary subject.     

Enhanced endothelin-1-mediated leg vascular tone in healthy older subjects.

Advanced age is associated with a decreased leg blood flow and reduced physical activity. Endothelin (ET-1), a powerful vasoconstrictor, may play a role in the increased leg vascular tone in older men. objectives: to assess the ET-1-mediated vascular tone in the legs of healthy sedentary older men, both before and after 8 wk of exercise training. methods: in 8 younger subjects (19-50 yr) and 8 older men (67-76 yr), bilateral leg blood flow was measured using venous occlusion plethysmography before and after antagonizing ET-1 (using selective ET(A/B)-receptor antagonists). In older men, reversibility of the observations was assessed after 8 wk of cycling. results: ET-receptor inhibition increased leg blood flow significantly more in older men compared with younger individuals (29 +/- 9% and 10 +/- 4%, respectively, P < 0.05). Eight-week cycling training increased baseline blood flow in older men. The blood flow response to ET-receptor inhibition in older men was not affected by the training program (25 +/- 8%, P > 0.05 for comparison with pretraining). The flow ratio (blood flows infused leg/noninfused leg) decreased significantly by training from 26 +/- 8% to 7+3% (P < 0.05). CONCLUSION: the increased baseline vascular tone in aging is at least in part mediated by the endothelin. Eight-weeks cycling training in older sedentary men decreased leg vascular tone and seems to partly decrease the ET-1-mediated vascular tone.     

Acute sympathetic vasoconstriction at rest and during dynamic exercise in cyclists and sedentary humans.

The impact of exercise training on sympathetic activation is not well understood, especially across untrained and trained limbs in athletes. Therefore, in eight sedentary subjects (maximal oxygen consumption = 40 +/- 2 ml x kg(-1) x min(-1)) and eight competitive cyclists (maximal oxygen consumption = 64 +/- 2 ml x kg(-1) x min(-1)), we evaluated heart rate, blood pressure, blood flow, vascular conductance, and vascular resistance in the leg and arm during acute sympathetic stimulation [cold pressor test (CPT)]. The CPT was also performed during dynamic leg (knee extensor) or arm (handgrip) exercise at 50% of maximal work rate (WRmax) with measurements in the exercising limb. At rest, the CPT decreased vascular conductance similarly in the leg and arm of sedentary subjects (-33 +/- 8% leg, -38 +/- 6% arm) and cyclists (-34 +/- 4% leg, -31 +/- 9% arm), and during exercise CPT-induced vasoconstriction was blunted (i.e., sympatholysis) in both the leg and arm of both groups. However, the magnitude of sympatholysis was significantly different between the arm and leg of the sedentary group (-47 +/- 11% arm, -25 +/- 8% leg), and it was less in the arm of cyclists (-28 +/- 11%) than sedentary controls. Taken together, these data provide evidence that sympathetically mediated vasoconstriction is expressed equally and globally at rest in both sedentary and trained individuals, with a differential pattern of vasoconstriction during acute exercise according to limb and exercise training status.     

Pulmonary vasodilation with structurally altered pulmonary vessels and pulmonary hypertension

To evaluate pulmonary vasodilation in a structurally altered pulmonary vascular bed, we gave endothelium-dependent (acetylcholine) and endothelium-independent [sodium nitroprusside, prostaglandin I2 (PGI2)] vasodilators in vivo and to isolated lobar pulmonary arteries from neonatal calves with severe pulmonary hypertension. Acetylcholine, administered by pulmonary artery infusion, decreased pulmonary arterial pressure from 120 +/- 7 to 71 +/- 6 mmHg and total pulmonary resistance from 29.4 +/- 2.6 to 10.4 +/- 0.9 mmHg.l-1.min without changing systemic arterial pressure (90 +/- 5 mmHg). Although both sodium nitroprusside and PGI2 lowered pulmonary arterial pressure to 86 +/- 4 and 96 +/- 4 mmHg, respectively, they also decreased systemic arterial pressure to 65 +/- 4 and 74 +/- 3 mmHg, respectively. Neither sodium nitroprusside nor PGI2 was as effective as acetylcholine at lowering total pulmonary resistance (18.0 +/- 3.6 and 19.1 +/- 2.2 mmHg.l-1.min, respectively). Right-to-left cardiac shunt through the foramen ovale was decreased by acetylcholine from 1.6 +/- 0.4 to 0.1 +/- 0.2 l/min but was not changed by sodium nitroprusside or PGI2. Isolated lobar pulmonary arteries from pulmonary hypertensive calves did not relax in response to acetylcholine, whereas isolated pulmonary arteries from age-matched control calves did relax in response to acetylcholine. Control and pulmonary hypertensive lobar pulmonary arteries relaxed equally well in response to sodium nitroprusside. We concluded that acetylcholine vasodilation was impaired in vitro in isolated lobar pulmonary arteries but was enhanced in vivo in resistance pulmonary arteries in neonatal calves with pulmonary hypertension.     

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.     

Enhanced endothelial vasoreactivity in endurance-trained older men.

Using external vascular ultrasound, we measured brachial artery diameter (Diam) at rest, after release of 4 min of limb ischemia, i. e., endothelium-dependent dilation (EDD), and after sublingual nitroglycerin, i.e., non-endothelium-dependent dilation (NonEDD), in 35 healthy men aged 61-83 yr: 12 endurance athletes (A) and 23 controls (C). As anticipated, treadmill exercise maximal oxygen consumption (VO(2 max)) was significantly higher in A than in C (40. 2 +/- 6.6 vs. 27.9 +/- 3.8 ml. kg(-1). min(-1); respectively, P < 0. 0001). With regard to arterial physiology, A had greater EDD (8.9 +/- 4.2 vs. 5.7 +/- 3.5%; P = 0.02) and a tendency for higher NonEDD (13.9 +/- 6.7 vs. 9.7 +/- 4.2%; P = 0.07) compared with C. By multiple linear regression analysis in the combined sample of older men, only baseline Diam (beta = -2.0, where beta is the regression coefficient; P = 0.005) and VO(2 max) (beta = 0.23; P = 0.003) were independent predictors of EDD; similarly, only Diam (beta = -4.0; P = 0.003) and VO(2 max) (beta = 0.27; P = 0.01) predicted NonEDD. Thus endurance-trained older men demonstrate both augmented EDD and NonEDD, consistent with a generalized enhanced vasodilator responsiveness, compared with their sedentary age peers.     

Sex differences in salt sensitivity to nitric oxide dependent vasodilation in healthy young adults

Dietary sodium and blood pressure regulation differs between normotensive men and women, an effect which may involve endothelial production of nitric oxide (NO). Therefore, we tested the hypothesis that differences in the NO component of endothelium-dependent vasodilation between low and high dietary sodium intake depend on sex. For 5 days prior to study, healthy adults consumed a controlled low-sodium diet (10 mmol/day, n = 30, mean age ± SE: 30 ± 1 yr, 16 men) or high-sodium diet (400 mmol/day, n = 36, age 23 ± 1 yr, 13 men). Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of acetylcholine (ACh, 4 μg·100 ml tissue(-1)·min(-1)) were measured before and after endothelial NO synthase inhibition with N(G)-monomethyl-l-arginine (l-NMMA, 50 mg bolus + 1 mg/min infusion). The NO component of endothelium-dependent dilation was calculated as the response to ACh before and after l-NMMA accounting for changes in baseline FBF: [(FBF ACh - FBF baseline) - (FBF ACh(L-NMMA) - FBF baseline(L-NMMA))]. This value was 5.7 ± 1.3 and 2.5 ± 0.8 ml·100 ml forearm tissue(-1)·min(-1) for the low- and high-sodium diets, respectively (main effect of sodium, P = 0.019). The sodium effect was larger for the men, with values of 7.9 ± 2.0 and 2.2 ± 1.4 for men vs. 3.1 ± 1.3 and 2.7 ± 1.0 ml·100 ml forearm tissue(-1)·min(-1) for the women (P = 0.034, sex-by-sodium interaction). We conclude that the NO component of endothelium-dependent vasodilation is altered by dietary sodium intake based on sex, suggesting that endothelial NO production is sensitive to dietary sodium in healthy young men but not women.     

H1 and H2 receptors mediate postexercise hyperemia in sedentary and endurance exercise-trained men and women.

In sedentary individuals, H(1) receptors mediate the early portion of postexercise skeletal muscle hyperemia, whereas H(2) receptors mediate the later portion. It is not known whether postexercise hyperemia also presents in endurance-trained individuals. We hypothesized that the postexercise skeletal muscle hyperemia would also exist in endurance-trained individuals and that combined blockade of H(1) and H(2) receptors would abolish the long-lasting postexercise hyperemia in trained and sedentary individuals. We studied 28 sedentary and endurance trained men and women before and through 90 min after a 60-min bout of cycling at 60% peak O(2) uptake on control and combined H(1)- and H(2)-receptor antagonist days (fexofenadine and ranitidine). We measured arterial pressure (brachial auscultation) and femoral blood flow (Doppler ultrasound). On the control day, femoral vascular conductance (calculated as flow/pressure) was elevated in all groups 60 min after exercise (sedentary men: Delta86 +/- 35%, trained men, Delta65 +/- 18%; sedentary women, Delta61 +/- 19%, trained women: Delta59 +/- 23%, where Delta is change; all P < 0.05 vs. preexercise). In contrast, on the histamine antagonist day, femoral vascular conductance was not elevated in any of the groups after exercise (sedentary men: Delta21 +/- 17%, trained men: Delta9 +/- 5%, sedentary women: Delta19 +/- 4%, trained women: Delta11 +/- 11%; all P > 0.16 vs. preexercise; all P < 0.05 vs. control day). These data suggest postexercise skeletal muscle hyperemia exists in endurance trained men and women. Furthermore, histaminergic mechanisms produce the long-lasting hyperemia in sedentary and endurance-trained individuals.