ARE THE CARDIOVASCULAR EFFECTS AND 5-HT SYNDROME INDUCED BY MDL-73,975 AND FLESINOXAN IN THE DOG MEDIATED BY 5-HT1A RECEPTORS

The cardiovascular effects of the 5-HT1A receptor agonists MDL 73,975 ydro-8-methoxy-1,4-benzodocxin-2-yl)methylaminol]- ethyl]-8-azaspiro[4 ,5]decane-7,9-dione hydrochloride) and flesinoxan (10-300 mu g/kg subc utaneously, s.c.) the 5-HT1A receptor antagonist NAN 190 tyl]-1H-isoin dole-1,3(2H)-dioate),1,2-ethanedioate and the alpha(1)-adrenoceptor an tagonist prazosin have been investigated in conscious normotensive and renal hypertensive dogs. In normotensive dogs the increases in heart rate and respiratory rate induced by both agonists were dose-related, as were the decreases in systolic and diastolic blood pressure induced by MDL 73,975. Both compounds caused a dose-related increase in the i ntensity of the '5-HT syndrome'. After pretreatment with NAN 190 (100 mu g/kg s.c.) the increases in heart rate, respiratory rate and sympto ms of the '5-HT syndrome' were significantly reduced but the decreases in systolic and diastolic pressure were additive. Pretreatment with p razosin (100 mu g/kg s.c.) antagonized the '5-HT syndrome' and the inc rease in respiratory rate. Similar responses were evident in renal hyp ertensive dogs. Tolerance did not develop to the increases in heart ra te, respiratory rate and manifestations of the '5-HT syndrome' in norm otensive dogs during 5 days of treatment with MDL 73,975 or flesinoxan . In conclusion, MDL 73,975 and flesinoxan induced a 5-HT1A receptor-m ediated fall in blood pressure but the changes in heart rate, respirat ory rate and the '5-HT syndrome' are probably mediated by alpha 1-adre noceptors.