Erling A. Anderson

Elevated sympathetic nerve activity in borderline hypertensive humans. Evidence from direct intraneural recordings.

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 (p < 0.05) blood pressures independent of sodium intake. Across both groups, high sodium intake reduced muscle sympathetic nerve activity (p < 0.001), plasma norepinephrine (p < 0.001), diastolic blood pressure (p < 0.02), heart rate (p < 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 (p = 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.

Flow-mediated and reflex changes in large peripheral artery tone in humans.

Studies of peripheral blood vessels in humans have focused primarily on regulation of blood flow and vascular resistance, which are thought to reflect small vessel caliber. Recent studies in animals have identified flow-mediated and neurogenic changes in large artery diameter. This study tested for flow-mediated dilatation and reflex constriction of the brachial artery in humans. A dual-crystal pulsed Doppler system was used to measure brachial artery diameter and blood flow proximal to the antecubital fossa. To test for flow-mediated dilatation, flow through the brachial artery was altered by an occluding cuff placed on the forearm distal to the site of brachial artery flow and diameter measurement. Control blood flow was 123 +/- 20 ml/min, and brachial artery diameter was 4.74 +/- 0.17 mm (mean +/- SEM). By inflating the distal occluding cuff (distal circulatory arrest), flow was reduced through the brachial artery to 21 +/- 5 ml/min (p less than 0.005), and brachial artery diameter was reduced to 4.35 +/- 0.20 mm (p less than 0.001). By deflating the distal occluding cuff after 10 minutes (reactive hyperemia), brachial artery flow was increased to 358 +/- 55 ml/min (p less than 0.001), and diameter was increased to 5.6 +/- 0.19 mm (p less than 0.001). These interventions did not change systemic arterial pressure and, as measured in three subjects, caused only small changes in local brachial artery distending pressure. Thus, both increased and decreased brachial artery blood flow produced significant changes in brachial artery diameter without altering arterial distending pressure. These data provide evidence for flow-mediated dilatation in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin increases sympathetic activity but not blood pressure in borderline hypertensive humans.

We have previously demonstrated that physiological hyperinsulinemia in normotensive humans increases sympathetic nerve activity but not arterial pressure since it also causes skeletal muscle vasodilation. However, in the presence of insulin resistance and/or hypertension, insulin may cause exaggerated sympathetic activation or impaired vasodilation and thus elevate arterial pressure. This study sought to determine if insulin causes a pressor response in borderline hypertensive humans by producing exaggerated increases in sympathetic neural outflow or impaired vasodilation. We recorded muscle sympathetic nerve activity (microneurography, peroneal nerve), forearm blood flow, heart rate, and blood pressure in 13 borderline hypertensive subjects during a 1-hour insulin infusion (38 microunits/m2/min) while holding blood glucose constant. Plasma insulin rose from 12 ±3 microunits/ml (mean±SEM) during control to 73±7 microunits/ml during insulin infusion and fell to 9±2 microunits/ml 2 hours after insulin infusion was stopped. Muscle sympathetic nerve activity, which averaged 25±2 bursts per minute in control, increased significantly during insulin infusion (+9 bursts per minute) and remained elevated 1.5 hours into recovery (+7 bursts per minute, p < 0.001). Despite increased muscle sympathetic nerve activity, there were significant (p < 0.001) increases in forearm blood flow and decreases in forearm vascular resistance during insulin infusion. Further, systolic and diastolic pressures fell approximately 3 and 6 mm Hg, respectively, during insulin infusion (p < 0.01). This study suggests that acute physiological increases in plasma insulin elevate sympathetic neural outflow in borderline hypertensive humans but produce vasodilation and do not elevate arterial pressure.

Effect of Cheyne-Stokes Respiration on Muscle Sympathetic Nerve Activity in Severe Congestive Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy☆

Severe congestive heart failure (CHF) is associated with Cheyne-Stokes (C-S) respiration, which may be an index of poorer prognosis. The mechanisms linking C-S respiration to poorer functional status and prognosis in patients with CHF are unknown. We tested the hypothesis that C-S respiration increases muscle sympathetic nerve activity (MSNA) in 9 patients with CHF. Oxygen saturation was 96 +/- 1% during normal breathing and 91 +/- 1% after the apneic episodes (p < 0.05). Mean blood pressure was 79 +/- 8 mm Hg during normal breathing and 85 +/- 8 mm Hg during C-S respiration (p = 0.001). C-S respiration increased MSNA burst frequency (from 45 +/- 5 bursts/min during normal breathing to 50 +/- 5 bursts/min during C-S respiration; p < 0.05) and total integrated nerve activity (to 117 +/- 7%; p < 0.05). We also studied an additional 5 patients in whom C-S breathing was constant, without any periods of spontaneous normal breathing. In these patients, MSNA was higher (65 +/- 5 bursts/min) than MSNA in patients in whom C-S breathing was only intermittent (45 +/- 5 bursts/min; p < 0.05). In all 14 patients, the effects of different phases of C-S respiration were examined. MSNA was highest during the second half of each apnea (increasing to 152 +/- 14%; p < 0.01) and blood pressure was highest during mild hyperventilation occurring after termination of apnea (p < 0.0001). We conclude that C-S respiration decreases oxygen saturation, increases MSNA, and induces transient elevations in blood pressure in patients with CHF.

Mechanisms of insulin action on sympathetic nerve activity.

Insulin resistance and hyperinsulinemia may contribute to the development of arterial hypertension. Although insulin may elevate arterial pressure, in part, through activation of the sympathetic nervous system, the sites and mechanisms of insulin-induced sympathetic excitation remain uncertain. While sympathoexcitation during insulin may be mediated by the baroreflex, or by modulation of norepinephrine release from sympathetic nerve endings, it has been shown repeatedly that insulin increases sympathetic outflow by actions on the central nervous system. Previous studies employing norepinephrine turnover have suggested that insulin causes sympathoexcitation by acting in the hypothalamus. Recent experiments from our laboratory involving direct measurements of regional sympathetic nerve activity have provided further evidence that insulin acts in the central nervous system. For example, administration of insulin into the third cerebralventricle increased lumbar but not renal or adrenal sympathetic nerve activity in normotensive rats. Interestingly, this pattern of regional sympathetic nerve responses to central neural administration of insulin is similar to that seen with systemic administration of insulin. Further, lesions of the anteroventral third ventricle hypothalamic (AV3V) region abolished increases in sympathetic activity to systemic administration of insulin with euglycemic clamp, suggesting that AV3V-related structures are critical for insulin-induced elevations in sympathetic outflow.

Renal Sympathetic Nerve Activity Is Increased in Obese Zucker Rats

A low level of sympathetic nerve activity (SNA) to brown adipose tissue has been found in genetically obese Zucker rats and may promote obesity through decreased thermogenesis. In contrast, acquired obesity is reportedly associated with increased SNA. To determine whether low SNA levels in obese Zucker rats extend to the kidney, we compared baseline levels of renal SNA in obese and lean conscious unrestrained Zucker rats fed for 2 weeks on low salt (0.4% NaCl) and high salt (8.0% NaCl) diets. Baseline renal SNA was calculated from multifiber recordings obtained before death under conscious, resting conditions and after death. Body weight averaged 490 +/- 12 g (mean +/- SEM) in obese rats (n = 17) and 339 +/- 7 g in lean rats (n = 19). Mean arterial pressure did not differ in obese and lean Zucker rats fed the low salt diet. However, on the high salt diet, mean arterial pressure was significantly higher in obese rats (n = 8) than in lean rats (n = 9) (113 +/- 3 and 101 +/- 3 mm Hg, respectively; P < .05). Baseline renal SNA was approximately 2 to 2.5 times higher (P < .05) in obese rats than in lean rats in all groups. These studies suggest that obese Zucker rats have heightened levels of SNA to the kidney in contrast to reduced SNA to brown adipose tissue.

Hyperinsulinemia produces cardiac vagal withdrawal and nonuniform sympathetic activation in normal subjects

The exact mechanisms for the decrease in R-R interval (RRI) during acute physiological hyperinsulinemia with euglycemia are unknown. Power spectral analysis of RRI and microneurographic recordings of muscle sympathetic nerve activity (MSNA) in 16 normal subjects provided markers of autonomic control during 90-min hyperinsulinemic/euglycemic clamps. By infusing propranolol and insulin ( n = 6 subjects), we also explored the contribution of heightened cardiac sympathetic activity to the insulin-induced decrease in RRI. Slight decreases in RRI ( P < 0.001) induced by sevenfold increases in plasma insulin could not be suppressed by propranolol. Insulin increased MSNA by more than twofold ( P < 0.001), decreased the high-frequency variability of RRI ( P< 0.01), but did not affect the absolute low-frequency variability of RRI. These results suggest that reductions in cardiac vagal tone and modulation contribute at least in part to the reduction in RRI during hyperinsulinemia. Moreover, more than twofold increases in MSNA occurring concurrently with a slight and not purely sympathetically mediated tachycardia suggest regionally nonuniform increases in sympathetic activity during hyperinsulinemia in humans.

Dissociation of sympathoexcitatory and vasodilator actions of modestly elevated plasma insulin levels

Objective: To determine sympathetic and vascular responses to modest increases in plasma insulin level. Background: Most studies of sympathetic and vascular actions of insulin have evaluated high plasma insulin levels (>50µU/ml). Those levels increase sympathetic nerve activity but also cause vasodilation. Hypertension and obesity are associated with only modestly elevated fasting insulin levels. Methods: We investigated the effects of a 90min low-dose hyperinsulinemic euglycemic clamp on muscle sympathetic nerve activity (microneurography), forearm vascular resistance (plethysmography), heart rate, blood pressure and central venous pressure. Insulin and vehicle sessions were performed in 12 normal subjects. Results: Plasma insulin levels were elevated from values of 10±2 in the fasting state to 25±3µU/ml during insulin infusion. Insulin levels did not change during vehicle administration. Muscle sympathetic nerve activity increased from 16±2 to 25±3 bursts/min during the insulin session and did not change during vehicle administration. In contrast to muscle sympathetic nerve activity, forearm vascular resistance did not change during insulin administration (from 50±3 to 51±4U). Forearm vascular resistance tended to fall during vehicle administration (from 45±2 to 37 ±3 U). There were no changes in heart rate, blood pressure and central venous pressure that could be attributed to insulin. Conclusion: Modest elevations of plasma insulin levels produce sympathetic activation similar to that caused by high levels, but, in contrast to high levels, modest elevations in plasma insulin level do not decrease forearm vascular resistance. The present findings suggest a dissociation between sympathoexcitatory and vascular actions of insulin at low plasma levels.

Interpersonal skill and depression in college students: An analysis of the timing of self-disclosures*

The present study compared the timing of self-disclosures in depressed and nondepressed college students during conversations with confederates. It was predicted that depressed subjects would be more likely than nondepressed subjects to emit self-disclosures at times when such remarks were not directly solicited by confederate inquiries. To investigate the specificity of this tendency to depression, subjects expressing tendencies toward social avoidance and distress were also examined. The experimental situation consisted of a 10-min waitingroom interaction where subjects were surreptitiously audiotaped while conversing with a confederate. Confederates were carefully trained according to a standardized script. Depressed and nondepressed subjects did not differe substantially in the frequency of various categories of verbal behavior, with the exception of negative self-statements, which were significantly more frequent for depressed subjects. Sequential analyses comparing depressed and nondepressed subjects in the timing of self-disclosures revealed that depressed subjects were more inclined to self-disclose following confederate remarks that did not directly solicit selfdisclosures. Thus, the major hypothesis was confirmed.

Contrasting Autonomic and Hemodynamic Effects of Insulin in Healthy Elderly Versus Young Subjects

Acute increases in plasma insulin produce both sympathoexcitation and vasodilation in normal young adults. Aging is associated with insulin resistance and may alter the sympathetic or the vascular responses to insulin. Therefore, we assessed sympathetic and vascular responses to acute physiological increases in plasma insulin levels in 10 healthy, normotensive elderly (65+/-2 years) and 12 normal young (27+/-1 years) subjects matched for body mass index (25+/-1 kg/m2 in both groups). We measured muscle sympathetic nerve activity (microneurography), FBF (plethysmography), heart rate, and blood pressure and calculated forearm vascular resistance and insulin sensitivity (M value) during a 90-minute hyperinsulinemic/euglycemic clamp. M values were 4.3+/-0.4 mg x kg(-1) x min(-1) in the elderly and 8.4+/-1.4 mg x kg(-1) x min(-1) in the young subjects (P<.05). Baseline muscle sympathetic nerve activity was higher in the elderly subjects (33+/-3 versus 15+/-2 bursts per minute, P<.05); however, the absolute and percent increases in muscle sympathetic nerve activity were smaller in the elderly than in the young subjects (+10+/-1 versus +15+/-1 bursts per minute, or +37+/-11% versus +110+/-16%, P<.05). Forearm vascular resistance decreased with insulin from 46+/-2 to 31+/-3 units in the young but increased with insulin in the elderly subjects from 37+/-3 to 47+/-7 units (P<.05). Heart rate increased in young but not in elderly subjects. Insulin did not change blood pressure in either group. In conclusion, as opposed to vasodilation in young adults, insulin caused vasoconstriction in healthy elderly individuals. The failure of the vasodilator action of insulin in the elderly may permit even modest insulin-induced sympathoexcitation to elicit vasoconstriction. We speculate that the vasoconstrictor response to insulin may further potentiate insulin resistance in the elderly.