Effect of chronic central endothelin-1 on hemodynamics and plasma vasopressin in conscious rats.

OBJECTIVES: These studies were designed to test whether chronic central administration of endothelin-1 induces changes in systemic hemodynamics and plasma vasopressin similar to those observed with acute microinjections of endothelin-1. METHODS: Sprague Dawley rats underwent sham denervation or sinoaortic denervation. Three days later, baseline mean arterial blood pressure, heart rate, and vasopressin were assessed in conscious rats. Then, a cannula was stereotaxically inserted into the lateral ventricle and attached to an osmotic minipump that delivered one of the following: (i) artificial cerebrospinal fluid; (ii) endothelin-1, 10 pmol/hour; (iii) BQ-123, 400 pmol/hour; or (iv) endothelin-1+BQ-123. Mean arterial blood pressure and heart rate were monitored daily and blood was obtained for plasma vasopressin on days 3 and 9. On day 10, the rats were euthanized, the hypothalami were removed, and vasopressin messenger ribonucleic acid content was assessed. RESULTS: The pressor effect of intracerebroventricular endothelin-1 was similar in intact and sinoaortic denervation rats and was prevented by endothelin receptor A antagonism with BQ-123. Administration of BQ-123 alone resulted in a depressor and bradycardia in sinoaortically denervated rats. Chronic endothelin-1 administration did not change plasma vasopressin but resulted in a significant decrease in hypothalamic vasopressin messenger ribonucleic acid levels, which was reversed by endothelin receptor A inhibition. DISCUSSION: Although the pressor effect of chronic central endothelin-1 is similar to that reported with acute endothelin-1, plasma vasopressin levels do not increase, at least in part, due to downregulation of hypothalamic vasopressin gene expression. Sinoaortic denervation increases endogenous central endothelin receptor A tone. Furthermore, these observations confirm that the pressor effect of central endothelin-1 is not mediated by plasma vasopressin.

Regulation of vasopressin secretion by ETA and ETB receptors in compartmentalized rat hypothalamo-neurohypophysial explants.

The endothelins (ET) have been implicated in vasopressin (AVP) release in vivo and in vitro. The effects of ET in this system are complex, and the net AVP secretory response likely depends on a unique combination of ET isoform, ET receptor subtype, and neural locus. The purpose of these studies was to examine the role of ET receptor subtypes at hypothalamic vs. neurohypophysial sites on somatodendritic and neurohypophysial AVP secretion. Experiments were done in cultured explants of the hypothalamo-neurohypophysial system of Long Evans rats. Either the whole explant (standard) or only the hypothalamus or posterior pituitary (compartmentalized) was exposed to log dose increases (0.01-10 nM) of the agonists ET-1 (ET(A) selective), ET-3 (nonselective), or IRL-1620 (ET(B) selective) with or without selective ET(A) (BQ-123, 2-200 nM) or ET(B) (IRL-1038, 6-600 nM) receptor antagonism. In standard explants, ET-1 and ET-3 dose-dependently increased, whereas IRL-1620 decreased net AVP release. Hypothalamic ET(B) receptor activation increased both somatodendritic and neurohypophysial AVP release. At least one intervening synapse was involved, as tetrodotoxin blocked the response. Activation of ET(A) receptors at the hypothalamic level inhibited, whereas ET(A) receptor activation at the posterior pituitary stimulated, neurohypophysial AVP secretion. Antagonism of hypothalamic ET(A) receptors potentiated the stimulatory effect of ET-1 and ET-3 on neurohypophysial secretion, an effect not observed with ET(B) receptor-induced somatodendritic release of AVP. Thus the response of whole explants reflects the net result of both stimulatory and inhibitory inputs. The integration of these excitatory and inhibitory inputs endows the vasopressinergic system with greater plasticity in its response to physiological and pathophysiological states.

Modulation of ET(B) receptor-induced arginine-vasopressin secretion by N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)-dependent mechanisms in hypothalamo-neurohypophysial explants.

The endothelins (ETs) stimulate the secretion of arginine-vasopressin (AVP) in vivo and in vitro. The activation of hypothalamic ET(B) receptors increases AVP release, but the neurotransmitters mediating these responses are not known. In the compartmentalized hypothalamo-neurohypophysial explant model, the overall basal release of AVP was 53+/-17 pg x h(-1) x PP(-1) (where PP is posterior pituitary). ET(B) receptor activation in hypothalamic sites by 1 nM IRL1620 dose-dependently increased AVP secretion, with a maximal response of 340+/-70% of basal x h(-1) x PP(-1), whereas 1 nM ET-1, the ET(A) receptor-selective agonist, inhibited AVP release to 44+/-8% x h(-1) x PP(-1). Addition of MK801 along with IRL1620 inhibited AVP release to a value no different from basal (122+/-41% x h(-1) x PP(-1)). In contrast, 10 microM DNQX [6,7-dinitroquinozaline-2,3-(1H,4H)-dione] did not block ET(B) receptor-induced AVP release (326+/-73% x h(-1) x PP(-1)), and nor did non-selective alpha-adrenergic receptor antagonism. The GABA(A) (where GABA is gamma-aminobutyric acid) receptor agonist muscimol (10 microM) inhibited AVP release in response to IRL1620 (127+/-30% x h(-1) x explant(-1)). These data suggest that AVP release induced by activation of hypothalamic ET(B) receptors is mediated by a hypothalamic N-methyl-D-aspartate (NMDA) receptor-mediated mechanism. In turn, the local release of GABA associated with NMDA activation may exert an inhibitory influence and dampen the AVP secretory response.