Response of isolated working hearts to fatty acids and carnitine palmitoyltransferase I inhibition during reduction of coronary flow in acutely and chronically diabetic rats.
The effects of palmitate on mechanical failure of ischemic hearts were studied in acutely (48-hour) and chronically (6-week) streptozotocin diabetic rats. Coronary flow was reduced by 50% in isolated working hearts perfused at a 15 cm H2O preload and 100 mm Hg afterload by the one-way ball valve model of ischemia. Peak systolic pressure (PSP) and cardiac output (CO) decreased 40% by 4 minutes in control hearts perfused with 11 mM glucose and paced at 280 beats/min, compared with 50% in hearts from acutely diabetic rats. Addition of 1.2 mM palmitate to the perfusate accelerated failure rates, with PSP and CO decreasing 65% and 80% by 4 minutes in control and acutely diabetic rat hearts, respectively. In chronically diabetic rats, mechanical function could not be maintained in palmitate-perfused hearts paced at 280 beats/min, even in the absence of ischemia. If these hearts were paced at 250 beats/min and subjected to ischemia, PSP and CO decreased 90% by 4 minutes, regardless of whether palmitate was added to the perfusate. Under these conditions, PSP decreased less than 10% by 4 minutes in both palmitate- or glucose-perfused control hearts. Etomoxir (10(-9) M), a carnitine palmitoyltransferase I inhibitor, markedly decreased the rate of mechanical failure in both acutely and chronically diabetic rat hearts, in the presence and absence of palmitate. The beneficial effect of Etomoxir on mechanical function did not occur as a result of a decrease in either myocardial long chain acyl-coenzyme A or long chain acylcarnitine levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Lopaschuk
G D
GD
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Spafford
M
M
D000208:Acute Disease; D000214:Acyl Coenzyme A / Q000378:metabolism; D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors*; D002908:Chronic Disease; D003327:Coronary Disease / Q000378:metabolism / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000378:metabolism; D004852:Epoxy Compounds / Q000494:pharmacology; D005227:Fatty Acids / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013311:Streptozocin; D013890:Thiourea / Q000378:metabolism
D000214:Acyl Coenzyme A; D004852:Epoxy Compounds; D005227:Fatty Acids; D010725:Phosphocreatine; D013311:Streptozocin; D000217:Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D013890:Thiourea; C054207:etomoxir