The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the renin-angiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.

The neurohumoral axis in congestive heart failure.

The renin-angiotensin system plays an important role in the regulation of arterial blood pressure and in the development of some forms of clinical and experimental hypertension. It is an important blood pressure control system in its own right but also interacts extensively with other blood pressure control systems, including the sympathetic nervous system and the baroreceptor reflexes. Angiotensin (ANG) II exerts several actions on the sympathetic nervous system. These include a central action to increase sympathetic outflow, stimulatory effects on sympathetic ganglia and the adrenal medulla, and actions at sympathetic nerve endings that serve to facilitate sympathetic neurotransmission. ANG II also interacts with baroreceptor reflexes. For example, it acts centrally to modulate the baroreflex control of heart rate, and this accounts for its ability to increase blood pressure without causing a reflex bradycardia. The physiological significance of these actions of ANG II is not fully understood. Most evidence indicates that the actions of ANG to enhance sympathetic activity do not contribute significantly to the pressor response to exogenous ANG II. On the other hand, there is considerable evidence that the actions of endogenous ANG II on the sympathetic nervous system enhance the cardiovascular responses elicited by activation of the sympathetic nervous system.

Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure

Abnormal relationship between sodium intake and sympathetic nervous system activity in salt-sensitive patients with essential hypertension.

Hemodynamic changes induced by laparoscopy and their endocrine correlates: effects of clonidine

Background: Hypothalamo-pituitary-adrenal (HPA) function has been demonstrated to be compromised for weeks and even months after alcoholics cease ethanol consumption. Because nonalcoholic subjects with family history-associated increased risk for alcoholism also exhibit compromised HPA function, it is not clear whether defects in the HPA axis of abstinent alcoholics reflect a preexisting condition that may be responsible for increased risk for alcohol abuse versus a persisting adaptational change in response to prolonged alcohol abuse. Consequently, we investigated whether chronic daily ethanol consumption and withdrawal by male Sprague Dawley® rats would induce persistent HPA changes consistent with those demonstrated in abstinent alcoholics.



Methods and Results: In an initial experiment in which ethanol (5%, w/v) was incrementally introduced to liquid diet over a 1 week period followed by 4 weeks of chronic ethanol consumption, not only ethanol-treated rats but also pair-fed control rats exhibited decreased (p < 0.05 vs. ad-libitum-fed controls) anterior pituitary pro-opiomelanocortin (POMC) mRNA concentrations and associated decreases in plasma corticosterone and adrenocorticotropin (ACTH) levels for at least 3 weeks after gradual withdrawal of ethanol from the diet. Pair-feeding-induced decreases (p < 0.05) in thymus and spleen weights suggested that the pair-fed controls were likely stressed in this model, probably in response to the marked and irregular suppression of liquid diet consumption immediately after introduction of ethanol. Consequently, a second model was developed in which ethanol was introduced to the liquid diet much more gradually (i.e., over 3 weeks). In contrast with the rapid ethanol-introduction model, this more prolonged ethanol introduction followed by 4 weeks of chronic daily ethanol consumption increased plasma corticosterone levels (p < 0.05), increased adrenal gland weight (p < 0.05), and decreased thymus and spleen weights (both p < 0.01) without altering any of these parameters in the pair-fed controls. Three weeks after gradual withdrawal of ethanol from the diet, anterior pituitary POMC mRNA concentrations were suppressed (p < 0.05) and thymus and spleen weights were increased (p < 0.05) versus both pair-fed and ad-libitum-fed controls, accompanied by trends for decreased basal plasma corticosterone and adrenal weights.



Conclusions: Chronic daily ethanol treatment induced changes in the HPA axis that persisted for at least 3 weeks after complete cessation of ethanol consumption. These persistent alterations in the HPA axis are similar to the aberrant HPA regulation of abstinent alcoholics, sons of alcoholics, Lewis rats, and individuals who suffer from posttraumatic stress disorder and some types of depression, that is, categories of individuals who all exhibit increased risk for high ethanol consumption. Thus, these chronic daily ethanol-induced persistent changes in the HPA axis may have significant roles in alcohol abstinence syndrome and may increase vulnerability to relapse.

Chronic Daily Ethanol and Withdrawal: 1. Long‐Term Changes in the Hypothalamo‐Pituitary‐Adrenal Axis

Plasma catecholamine and renin activity levels were measured across a range of dietary sodium intakes (10--300 mEq/day) in 20 normal male volunteers. Supine plasma norepinephrine levels presented a triphasic pattern in relation to urine sodium, whereas epinephrine levels were not significantly altered by sodium intake, and renin showed the well-known hyperbolic relationship to urine sodium excretion. Highest supine norepinephrine values occurred at low salt intakes, the lowest when sodium excretion was between 100 and 180 mEq/day, and intermediate when sodium excretion was greater than 180 mEq/day. These findings show that sodium intake is an important consideration in the interpretation of plasma norepinephrine levels.

Plasma norepinephrine variations with dietary sodium intake.

SUMMARY
The plasma ACTH response to corticotrophin releasing factor (CRF) was studied in seven normal individuals. Five subjects were restudied following 4 d of salt restriction which resulted in raised endogenous plasma angiotensin II secretion. In a third experiment six subjects were given CRF following pre-infusion of hypertonic saline which significantly increased endogenous plasma vasopressin (AVP) levels. We were unable to demonstrate that high endogenous plasma AII levels were associated with a significant change in the plasma ACTH or cortisol responses to CRF. However there was an almost three-fold increase in the ACTH response when endogenous plasma AVP was elevated by hypertonic saline. It is concluded that AVP is likely to be of physiological importance in potentiating the ACTH response to CRF and that AVP and CRF together may provide a better test of pituitary ACTH secretion than either peptide alone.

Augmentation of the response to CRF in man: relative contributions of endogenous angiotensin and vasopressin.

To evaluate the effect of changes in plasma catecholamines on the pituitary-adrenal response to ovine corticotrophin releasing factor (CRF) in normal man, the response to CRF alone (10 subjects) was compared responses after infusions of adrenaline (6 subjects), noradrenaline (6 subjects) and after oral administration of the alpha 2 agonist clonidine (10 subjects). Compared to control levels, plasma adrenaline and noradrenaline concentrations were increased three- and four-fold respectively by exogenous infusions, whereas plasma noradrenaline was significantly lowered by clonidine. Despite these changes in plasma catecholamine levels, the responses of plasma ACTH, cortisol and aldosterone to CRF did not differ significantly from control (CRF alone) in any of the three studies. Neither clonidine pretreatment nor catecholamine infusions altered basal levels of plasma ACTH, cortisol or aldosterone and no effect of CRF or catecholamine manipulations on plasma arginine vasopressin concentration was observed. These results show that modulation of peripheral plasma catecholamine levels within physiological limits does not affect CRF-stimulated release of ACTH or the adrenal response in normal man.

The effect of peripheral catecholamine concentrations on the pituitary-adrenal response to corticotrophin releasing factor in man.

Animal experiments indicate that angiotensin II can, under some circumstances stimulate the sympathetic nervous system at a number of different sites. In order to determine whether such a relationship of the renin-angiotensin and sympathetic nervous system exists in man, we increased (by intravenous infusion), or decreased (by administering the oral converting enzyme inhibitor captopril) circulating angiotensin II levels and monitored plasma adrenaline and noradrenaline responses. Angiotensin II infusions did not increase plasma catechol-amines, and lowering of angiotensin II by captopril treatment in patients with severe hypertension or congestive heart failure failed to alter plasma adrenaline or nor-adrenaline levels. Whether physiological levels of angiotensin II are capable of interacting directly with the sympathetic nervous system in man remains to be demonstrated.

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Evidence against an interaction of angiotensin ii with the sympathetic nervous system in man

SUMMARY
To determine the role of known secretagogues in the aldosterone response to dopamine blocking agents, plasma levels of ACTH, angiotensin II, potassium and plasma catecholamines were measured in five normal male subjects before and after intravenous injection of saline or 10 mg metoclopramide. There were no consistent changes in hormone levels after saline injection. After metoclopramide, plasma aldosterone increased three-fold to peak values at 20 min post-injection. A significant increase in aldosterone was observed within 10 min during which period there was no significant change in plasma ACTH, plasma renin activity All or K. Plasma levels of cortisol, noradrenaline, adrenaline and dopamine showed no significant changes after injection of metoclopramide which induced a ten-fold rise in plasma prolactin. These results provide direct evidence that factors other than the plasma concentration of ACTH, All and K—or fluctuations in plasma catecholamines—are likely to be responsible for the acute increase in plasma aldosterone after metoclopramide injection in normal man.

M. G. Nicholls

Papers

Plasma norepinephrine variations with dietary sodium intake.

Augmentation of the response to CRF in man: relative contributions of endogenous angiotensin and vasopressin.

The effect of peripheral catecholamine concentrations on the pituitary-adrenal response to corticotrophin releasing factor in man.

Evidence against an interaction of angiotensin ii with the sympathetic nervous system in man

Effect of metoclopramide on aldosterone and regulatory factors in man