The present study was designed to determine the involvement of nitric oxide (NO) and prostaglandins (PG) in the stimulatory action of clenbuterol, a selective beta(2)-adrenergic receptor agonist on hypothalamic-pituitary-adrenal (HPA) axis under basal and social crowding stress conditions. Clenbuterol given i.c.v. (10 microg) or i.p. (0.2 mg/kg) considerably increased ACTH and corticosterone secretion. A selective beta(2)-receptor antagonist compound ICI 118551 and non-selective beta-receptor antagonist propranolol given by either route reduced the stimulatory action of clenbuterol. Crowding stress (21 rats in a cage for 7) for 3-7 days significantly reduced the i.c.v. clenbuterol-induced ACTH and corticosterone secretion and i.p. clenbuterol-elicited ACTH secretion. L-NAME, mainly endothelial nitric oxide synthase (NOS) blocker, stronger than L-NNA, a neuronal NOS blocker, reduced the clenbuterol-evoked ACTH and corticosterone secretion in control rats but did not significantly alter this secretion already reduced by crowding stress. Piroxicam, predominantly constitutive cyclooxygenase (COX-1) inhibitor, given i.p. significantly diminished the i.p. clenbuterol-induced ACTH and corticosterone secretion in control rats and tended to reverse the reduction of ACTH secretion by crowding stress. These results indicate that clenbuterol, a selective beta(2)-adrenoceptor agonist, is much stronger stimulator of the HPA axis than isoprenaline, a non-selective beta-receptor agonist. Social crowding stress reduces to a larger extent the HPA response to beta(2)-receptor stimulation. Likewise, in the HPA axis stimulation via beta(2)-adrenoceptors endogenous NO and prostaglandins are significantly involved. Beta2-adrenoceptor is a dominant functional subtype of beta-receptor in the stimulatory and modulatory signals regulating the HPA axis activity under basal and social stress conditions.