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 (8-[2-(2,3-dihydro-8-methoxy-1,4-benzodoxin-2-yl)methylaminol++ +]-ethyl]-8- azaspiro[4,5]decane-7,9-dione hydrochloride) and flesinoxan (10-300 micrograms/kg subcutaneously, s.c.), the 5-HT1A receptor antagonist NAN 190 (2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)- dione,1,2-ethanedioate), and the alpha 1-adrenoceptor antagonist 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 intensity of the '5-HT syndrome'. After pretreatment with NAN 190 (100 micrograms/kg s.c.) the increases in heart rate, respiratory rate and symptoms of the '5-HT syndrome' were significantly reduced but the decreases in systolic and diastolic pressure were additive. Pretreatment with prazosin (100 micrograms/kg s.c.) antagonized the '5-HT syndrome' and the increase in respiratory rate. Similar responses were evident in renal hypertensive dogs. Tolerance did not develop to the increases in heart rate, respiratory rate and manifestations of the '5-HT syndrome' in normotensive dogs during 5 days of treatment with MDL 73,975 or flesinoxan. In conclusion, MDL 73,975 and flesinoxan induced a 5-HT1A receptor-mediated fall in blood pressure but the changes in heart rate, respiratory rate and the '5-HT syndrome' are probably mediated by alpha 1-adrenoceptors.
Di Francesco
G F
GF
Marion Merrell Dow, Strasbourg, France.
D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006977:Hypertension, Renal / Q000188:drug therapy / Q000503:physiopathology; D007279:Injections, Subcutaneous; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology*; D011224:Prazosin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D044263:Receptors, Serotonin, 5-HT1; D012119:Respiration / Q000187:drug effects; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013618:Tachyphylaxis
D000959:Antihypertensive Agents; C091408:MDL 73975; D010879:Piperazines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C058895:1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine; C056895:flesinoxan; D011224:Prazosin