Influence on turnover and level of hypothalamic noradrenaline by a new antihypertensive agent (GYKI 11679).
In an attempt to delineate the possible importance of the concentration of noradrenaline at hypothalamic noradrenergic receptor sites in a hypotensive response to a drug, the action of a new antihypertensive agent, 1-(6-morpholino-3-pyridazynyl)-2-(1-[tert-butoxycarbonyl]-2-propylidene)-diazane (GYKI 11679), on the turnover rate and the endogenous level of noradrenaline (NA) in rat hypothalamus was examined. An effective, antihypertensive i.p. dose of the compound (10 mg/kg) produced a significant but relatively short-lasting reduction in the hypothalamic noradrenaline content, whereas no change was observed in the cardiac catecholamine level. The NA turnover determinations, carried out in GYKI 11679-pretreated rats by measuring the disappearance of labeled NA at 1, 2, 3, and 5 h after the injection of the radioactive amine, showed that a 10 mg/kg i.p. dose of the compound, given 1 h prior to the i.c.v. administration of the labeled NA, increased the turnover rate of noradrenaline to a great extent. The estimated half-lives of NA in the hypothalamus of the treated and of the non-treated animals were calculated as 1.72 and 3.62 h, respectively. In vitro studies showed that the spontaneous outflow of noradrenaline from hypothalamic slices was accelerated by GYKI 11679 in a dose-dependent manner in a concentration range of 10(-5) to 10(-7) M. In a 10-fold higher range, GYKI 11679 produced inhibition of both the hypothalamic and the adrenal tyrosine hydroxylase activity but did not alter DOPA-decarboxylase, dopamine-beta-hydroxylase, or monoamine oxidase activities. Direct in vivo measurements of catecholamine synthesis by determining the 3H-catecholamines (CA) formed from [3H]tyrosine in the hypothalamus after an i.c.v. administration of the labeled precursor showed a moderate increase in [3H]CA formation following a 10 mg/kg dose of the compound. When GYKI 11679 was administered in a 75 mg/kg i.p. dose to rats, the transformation was reduced by approximately 50%. Adenylate cyclase activity measurements did not show stimulatory or inhibitory actions of the drug on the NA-stimulated adenylate cyclase of the rat hypothalamus, in accordance with previous results. This suggests that the increased NA turnover (utilization) caused by an effective, antihypertensive dose of GYKI 11679 is the direct consequence of an increased outflow, which occurs primarily in the hypothalamus. The increased activity of the noradrenergic neurons in this brain region might lead to a reduced sympathetic activity in the periphery and thus to a significant decrease in blood pressure.