The role of serotonin (5HT2) receptor blockade in myocardial reperfusion injury: effects of LY53857 in a canine model of myocardial infarction.
The potential protective effects of serotonin receptor antagonism during the process of acute myocardial infarction were studied in anesthetized male dogs, which were subjected to a 90-min left circumflex coronary artery occlusion followed by 5 h of reperfusion. Either vehicle (0.9% NaCl) or the serotonin (5HT2) receptor antagonist LY53857 was infused i.v. at a dose of 0.5 mg/kg, followed by a constant infusion of 2 mg/kg/min beginning 5 min before left circumflex coronary artery occlusion and continuing throughout the duration of the ischemia and subsequent reperfusion. Verification of functional 5HT2 receptor antagonism in the circulating blood of the LY53857-treated dogs was monitored throughout the experiments by periodic assessment of ex vivo platelet reactivity to exogenous serotonin. After 5 h of reperfusion, the hearts were excised and analyzed utilizing histochemical staining with triphenyltetrazolium, which demarcates myocardial infarct size and anatomical area of myocardium at risk of infarction. There was not a significant reduction of infarct size with LY53857 treatment: control infarct/area at risk = 38.6 +/- 4.7%, n = 9 LY53857 infarct/area at risk = 33.4 +/- 3.8%, n = 6. Similarly, when myocardial infarct size was analyzed as a function of myocardial collateral blood flow, there were no significant effects of drug treatment on the relationship between collateral blood flow and infarct size. The effects of 5HT on neutrophil activation were determined by measuring the potential ability of 5HT to enhance the chemotactic peptide-induced production of superoxide. 5HT did not activate human neutrophils in vitro and LY53857 had no effect on neutrophil superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)
Simpson
P J
PJ
Department of Cardiovascular Pharmacology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
Schelm
J A
JA
Jakubowski
J A
JA
Smallwood
J K
JK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004285:Dogs; D004873:Ergolines / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D007958:Leukocyte Count / Q000187:drug effects; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D010976:Platelet Count / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014693:Ventricular Fibrillation / Q000188:drug therapy
D004873:Ergolines; D012702:Serotonin Antagonists; D013481:Superoxides; D012701:Serotonin; D009195:Peroxidase; C032663:LY 53857