Hyperinsulinemia may contribute to hypertension by increasing sympathetic activity and vascular resistance. We sought to determine if insulin increases central sympathetic neural outflow and vascular resistance in humans. We recorded muscle sympathetic nerve activity (MSNA; microneurography, peroneal nerve), forearm blood flow (plethysmography), heart rate, and blood pressure in 14 normotensive males during 1-h infusions of low (38 mU/m2/min) and high (76 mU/m2/min) doses of insulin while holding blood glucose constant. Plasma insulin rose from 8±1 uU/ml during control, to 72±8 and 144±13 MtU/ml during the low and high insulin doses, respectively, and fell to 15±6 gU/ml 1 h after insulin infusion was stopped.MSNA, which averaged 21.5±1.5 bursts/min in control, increased significantly (P < 0.001) during both the low and high doses of insulin (±5.4 and ±9.3 bursts/min, respectively) and further increased during 1-h recovery (+15.2 bursts/min). Plasma norepinephrine levels (119±19 pg/ml during control) rose during both low (258±25; P < 0.02) and high (285±95; P < 0.01) doses of insulin and recovery (316±23; P < 0.01). Plasma epinephrine levels did not change during insulin infusion. Despite the increased MSNA and plasma norepinephrine, there were significant (P < 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during both doses of insulin. Systolic pressure did not change significantly during infusion of insulin and diastolic pressure fell -4-5 mmHg (P < 0.01). This study suggests that acute increases in plasma insulin within the physiological range elevate sympathetic neural outflow but produce forearm vasodilation and do not elevate arterial pressure in normal humans. (J. Clin. Invest.

Reports of elevated plasma catecholamine levels and augmented responses to autonomic blockade suggest increased sympathetic tone in borderline hypertension. It is not known if this reflects greater sympathetic neural outflow. We directly recorded muscle sympathetic nerve activity (microneurography) in 15 normotensive and 12 borderline hypertensive age-matched men to determine whether borderline hypertensive individuals have elevated sympathetic nerve activity. Supine heart rate, blood pressure, plasma norepinephrine, and efferent muscle sympathetic nerve activity (peroneal nerve) were measured after 6 days of both low and high dietary sodium intake (10 and 400 meq sodium/24 hr). Sympathetic nerve activity was elevated significantly in borderline hypertensive individuals on both low (37 ±1 in borderline hypertensive individuals vs. 29±1 bursts/min in normotensive individuals; p<0.01) and high (25+1 in borderline hypertensive individuals vs. 16±1 bursts/min in normotensive individuals; p<0.01) sodium diets. The borderline hypertensive group had higher systolic (p<0.01) and diastolic (/?<0.05) blood pressures independent of sodium intake. Across both groups, high sodium intake reduced muscle sympathetic nerve activity (p<0.001), plasma norepinephrine (/»<0.001), diastolic blood pressure (p<0.02), heart rate (/?< 0.002), and increased weight (p<0.005). A significant (p<0.05) group-by-diet interaction was observed for plasma norepinephrine levels. Specifically, compared with the normotensive group, plasma norepinephrine levels in the borderline hypertensive group tended to be higher on low sodium diet (p=0.08) and lower on high sodium diet (/?=0.23). High sodium intake increased diastolic pressure by over 5 mm Hg in six of 27 subjects (four borderline hypertensive and two normotensive). Sympathetic activity in sodium-sensitive subjects was not elevated compared with sodium-resistant subjects and also declined during high sodium intake. This study supports the hypothesis of elevated central sympathetic neural outflow in borderline hypertension. (Hypertension 1989;14:177-183) I ncreasing evidence suggests that mild or borderline hypertension is characterized by augmented sympathetic activity both at rest and in response to physical and psychological stressors.1 -5 For example, Esler et al 6 found elevated plasma norepinephrine levels (compared with This manuscript from the University of Iowa was sent to Randall M. Zusman, Consulting Editor, for review by expert referees, for editorial decision, and final disposition.Address for correspondence: Dr. Erling A. Anderson, Department of Anesthesia, University of Iowa, College of Medicine, Iowa City, IA 52242.Received August 12, 1988; accepted March 22, 1989. normotensive persons) in younger, but not older, hypertensive humans. Goldstein 7 reviewed studies of plasma catecholamine levels in hypertension and noted that significant elevations were reported in 11 of 16 studies comparing young (less than 40 years) hypertensive individuals with normotensive individuals but in...

Background-Moderate elevations in plasma homocyst(e)ine concentrations are associated with atherosclerosis and hypertension. We tested the hypothesis that experimental perturbation of homocysteine levels produces resistance and conduit vessel endothelial dysfunction and that this occurs through increased oxidant stress. Methods and Results-Oral administration of L-methionine (100 mg/kg) was used to induce moderate hyperhomocyst(e)inemia (Ϸ25 mol/L) in healthy human subjects. Endothelial function of forearm resistance vessels was assessed by use of forearm vasodilatation to brachial artery administration of the endothelium-dependent dilator acetylcholine. Conduit vessel endothelial function was assessed with flow-mediated dilatation of the brachial artery. Forearm resistance vessel dilatation to acetylcholine was significantly impaired 7 hours after methionine (methionine, 477Ϯ82%; placebo, 673Ϯ110%; Pϭ0.016). Methionine did not alter vasodilatation to nitroprusside and verapamil. Flow-mediated dilatation was significantly impaired 8 hours after methionine loading (0.3Ϯ2.7%) compared with placebo (8.2Ϯ1.6%, Pϭ0.01). Oral administration of the antioxidant ascorbic acid (2 g) prevented methionine-induced endothelial dysfunction in both conduit and resistance vessels (Pϭ0.03). Conclusions-Experimentally increasing plasma homocyst(e)ine concentrations by methionine loading rapidly impairs both conduit and resistance vessel endothelial function in healthy humans. Endothelial dysfunction in conduit and resistance vessels may underlie the reported associations between homocysteine and atherosclerosis and hypertension.Increased oxidant stress appears to play a pathophysiological role in the deleterious endothelial effects of homocysteine.

To determine if there would be a decrease in blood pressure after exercise in patients with borderline hypertension and if this decrease would be accompanied by a decrease in sympathetic nerve activity to muscle, we recorded multifiber postganglionic muscle sympathetic activity from the peroneal nerve at rest in nine men with borderline hypertension (age 25 ±1 years, mean±SEM) before and 60 minutes after 45 minutes of submaximal treadmill exercise. In addition, responses to a cold pressor test, handgrip, and the Valsalva maneuver were recorded before and after exercise. Four subjects were also studied before and after "sham" exercise. Sham exercise had no effect on blood pressure or sympathetic nerve activity whereas resting systolic blood pressure was lower after treadmill exercise in seven subjects (from 136±4 before to 123±2 mm Hg 60 minutes after exercise;p<0.01). Sixty minutes after exercise, sympathetic nerve activity was lower in all seven subjects (from 19±2 to 11±2 bursts/min,p<0.015; or from 27±3 to 14±2 bursts/100 heartbeats, p<0.005) but was slightly increased in the two subjects without postexercise hypotension. Heart rate and pressor and sympathoneural responses to the cold pressor test, handgrip, and the Valsalva maneuver were not altered by prior exercise. When nitropmsside was infused in five subjects to produce a reduction in systolic blood pressure similar to that seen 60 minutes after exercise, this drug increased sympathetic discharge from 37 ±6 to 57 ±4 bursts/100 heartbeats (/?< 0.001). These observations demonstrate 1) that rhythmic exercise can lower blood pressure in men with borderline hypertension and 2) that postexercise hypotension is associated with a decrease, rather than a reflex increase, in sympathetic discharge to muscle. Postexercise hypotension may be mediated in part by inhibition of sympathetic nerve activity. (Hypertension 1989;14:28-35) A fter a single bout of prolonged muscular exercise, systolic and diastolic blood pressure decrease, sometimes for several hours.1 -4 The depressor response to exercise is greater in magnitude and duration in hypertensive than in normotensive subjects and is also elicited after shorter periods of exercise in hypertensive individuals. 3Indeed, even brief (10 minutes) exercise can reduce the blood pressure of hypertensive subjects.Proposed mechanisms for postexercise decreases in blood pressure include decreased blood volume,

Background-Cigarette smoking causes endothelial dysfunction, possibly through increased oxidant stress. The enzyme xanthine oxidase produces oxidative free radicals. We tested the hypothesis that xanthine oxidase contributes to endothelial dysfunction in cigarette smokers by administering the inhibitor allopurinol. Methods and Results-Fourteen cigarette smokers (31Ϯ4 pack years) and 14 age-and sex-matched healthy non-smoking control subjects participated in a single-blinded, randomized, 2-phase crossover study. All subjects had no other risk factors for atherosclerosis. Inhibition of xanthine oxidase was achieved by a single oral dose of 600 mg of allopurinol on the day of the study. Stimulated nitric oxide endothelial responses were assessed by forearm blood flow responses to intraarterial administration of acetylcholine and bradykinin 4 to 7 hours later; basal nitric oxide was assessed using the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA); and nitroprusside was used to assess sensitivity to nitric oxide. Dilatation produced by acetylcholine was significantly less in smokers (254Ϯ57%) than healthy controls (390Ϯ55%) (Pϭ0.009). Allopurinol reversed endothelial dysfunction in smokers (acetylcholine, 463Ϯ78%, Pϭ0.001) without affecting responses in non-smokers (401Ϯ80%). Bradykinin responses were also impaired in smokers (Pϭ0.003), and improved with allopurinol, though not significantly (Pϭ0.06). Responses to nitroprusside and L-NMMA were not significantly different between smokers and controls and were not altered by allopurinol. Conclusions-Smoking-induced endothelial dysfunction of resistance vessels is rapidly reversed with oral allopurinol.These data suggest that xanthine oxidase contributes importantly to endothelial dysfunction caused by cigarette smoking.