Nitric oxide in the adrenergic-and CRH-induced activation of hypothalamic-pituitary-adrenal axis

In this report we investigated the effect of 7-nitroindazole (7-NI), a specific neuronal inhibitor of nitric oxide synthase (nNOS) and L-NAME, a nonselective NOS inhibitor upon the adrenergic- and CRH-induced stimulation of the hypothalamic-pituitary-adrenal axis in nonanesthetized rats. 7-NI given i.p. and L-NAME administered i.c.v. considerably reduced ACTH and corticosterone secretion induced by phenylephrine (30 microg i.c.v.), an alpha(1)-adrenergic receptor agonist. These inhibitors also diminished the HPA response to isoprenaline (20 microg i.c.v.), a nonselective beta-adrenergic receptor agonist, and i.c.v. L-NAME significantly lowered the ACTH and corticosterone response to clenbuterol (10 microg i.c.v.), a selective beta(2)-adrenergic agonist. L-NAME abolished the noradrenaline (NA), an alpha- and beta-receptor agonist-evoked ACTH and corticosterone response, which was reversed by pretreatment with i.p. L-arginine, an endogenous NO substrate. 7-NI abolished the stimulatory action of corticotropin-releasing hormone (CRH 1 microg/kg i.p.) on ACTH but not corticosterone secretion. L-NAME only moderately diminished the CRH-induced ACTH secretion, suggesting that a major part of the CRH-induced HPA axis activation is of neuronal origin. Dihydropyridine, nifedipine, a specific L-type Ca(2+) channel blocker, inhibited significantly the CRH-induced ACTH and corticosterone response in rats exposed to 3 days crowding stress but not in rats under basal conditions. This finding indicates the strategic importance of Ca(2+) influx into the pituitary corticotrops to meet increased secretory requirement under stressful conditions. Collectively, our results point to complex functional relationship between NO, adrenergic agents CRH and Ca(2+) in the regulation of HPA axis activity.