Serotonin aggravates exercise-induced cardiac ischemia in the dog: effect of serotonin receptor antagonists.
We investigated the effects of serotonin (5-HT), SL65.0472 (7-fluoro-2-oxo-4-[2-[4-thieno[3,2-c]pyridine-4-yl)piperazin-1-yl]ethyl]-1,2-dihydroquinoline-1-acetamide, a 5-HT(1B)/5-HT(2A) receptor antagonist) and ketanserin (a 5-HT(2A) receptor antagonist) during exercise-induced cardiac ischemia in conscious dogs. Dogs were administered a hypercholesterolemic diet and an inhibitor of nitric oxide synthetase to produce chronic endothelial dysfunction. Myocardial ischemia was induced by a treadmill exercise test associated with limitation of left anterior descending coronary blood flow. Infusion of serotonin during exercise produced dose-related cardiovascular changes (after 10 microg/kg/min; heart rate +27+/-6 bpm, systolic blood pressure +18+/-3 mm Hg, left circumflex coronary blood flow +64+/-8 ml/min, myocardial segment length shortening in the ischemic zone -5.9+/-1.9%, P<0.05). SL65.0472 blocked serotonin-induced increases in blood pressure, rate pressure product and circumflex coronary artery flow (100 microg/kg i.v., P<0.05) and reduced serotonin-induced ischemic myocardial segment length shortening (300 microg/kg i.v., P<0.05). Ketanserin (30-300 microg/kg i.v.) had no significant effect on any serotonin-induced changes during exercise. Thus, SL65.0472 opposes serotonin-induced myocardial dysfunction in a dog model of exercise-induced ischemia.
Guilbert
Frédérique
F
Cardiovascular-Thrombosis Research Department, Sanofi-Synthélabo Research, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France.
Lainée
Pierre
P
Dubreuil
Brigitte
B
McCort
Gary
G
O'Connor
Stephen E
SE
Janiak
Philip
P
Herbert
Jean-Marc
JM
D000818:Animals; D004285:Dogs; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006937:Hypercholesterolemia / Q000150:complications / Q000503:physiopathology; D007262:Infusions, Intravenous; D007650:Ketanserin / Q000494:pharmacology; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology*; D010805:Physical Conditioning, Animal / Q000009:adverse effects; D010879:Piperazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012701:Serotonin / Q000008:administration & dosage / Q000494:pharmacology*; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
C416534:7-fluoro-2-oxo-4-(2-(4-(thieno(3,2-c)pyridin-4-yl)piperazin-1-yl)ethyl)-1,2-dihydroquinoline-1-acetamide; D010879:Piperazines; D011804:Quinolines; D058829:Serotonin 5-HT1 Receptor Antagonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D007650:Ketanserin