Growth-hormone-releasing peptide (GH-RP-6) is a synthetic hexapeptide that selectively releases growth hormone (GH) when administered to a number of animals species. In the rat, maximal GH release occurs after intravenous administration of 100 micrograms/kg GH-RP-6. Intravenous administration of 5 mg/kg GH-RP-6 produced 100% lethality within 2-5 min of drug administration. Further investigative studies demonstrated that the lethal effect of GH-RP-6 was preceded by an initial hypertensive episode, followed by a rapid, profound hypotension and bradycardia. The rise and fall in blood pressure also were observed in pithed rats treated with GH-RP-6, suggesting that the central nervous system was not responsible for the changes in blood pressure. However, the GH-RP-6-induced bradycardia was not observed in pithed rats, indicating the fall in heart rate was mediated through a central reflex mechanism. No direct effects of GH-RP-6 were seen in the isolated rat aorta or canine saphenous vein. Pretreatment of conscious rats with naloxone (10 mg/kg, iv), an opiate receptor antagonist, did not prevent the hypertensive response to GH-RP-6, but the hypotension and lethality were attenuated. Pretreatment with cyproheptadine (2.5 mg/kg, iv), a dual serotonin/histamine antagonist, or ketanserin (3 mg/kg, iv), a selective serotonin antagonist, prevented the GH-RP-6-induced hypotension and lethality. Cyproheptadine unmasked a 40 mm Hg rise in mean arterial pressure which persisted for over 10 min. In addition, degranulation of mast cells with compound 48/80 inhibited the toxicity of GH-RP-6, suggesting that mast cell degranulation and the subsequent release of autocoids is responsible for the cardiovascular effects of GH-RP-6. In vitro, GH-RP-6 (10(-5) - 10(-3) M) produced a concentration-related release of histamine from rat peritoneal mast cells. However, the histamine release by GH-RP-6 (10(-4) M) was not inhibited by naloxone (10(-4) M) in isolated mast cells, suggesting either that peritoneal mast cells are not responsible or that the mast cell degranulation in vitro is not opiate mediated. In conclusion, it appears that GH-RP-6 degranulates mast cells releasing serotonin, which produces hypotension, bradycardia, and death. This degranulation of mast cells is apparently inhibited by naloxone in vivo, suggesting that opiate receptors are involved in the hypotension and lethality associated with the administration of GH-RP-6.