title: Inhibition of post-ischemic ventricular recovery by low concentrations of prostacyclin in isolated working rat hearts: dependency on concentration, ischemia duration, calcium and relationship to myocardial energy metabolism.
abstract: The objective of this study was to characterize the effect of prostacyclin (PGI2) on ventricular function following total global ischemia in isolated working rat hearts and to investigate the mechanism of its action. Ischemia was initiated for 10, 15, 20 or 25 min with or without treatment with PGI2. Increasing durations of ischemia resulted in a progressive decline in high energy phosphate (HEP) stores, an elevation in tissue lactate, and incomplete recovery of function with reperfusion. Prostacyclin at either 1 or 10 ng/ml had no effect on HEP levels or total adenine nucleotides, and tissue lactate was not significantly affected by PGI2 in hearts made ischemic for 10 to 20 min, but both PGI2 concentrations significantly elevated lactate levels after 25 min ischemia. Reperfusion recovery of left ventricular function was complete following 10 and 15 min ischemia, but incomplete recovery was evident following 20 min ischemia (77% of pre-ischemic function); and although PGI2 had no direct effect on the function of aerobically perfused hearts, recovery of aortic flow with 1 ng/ml PGI2 after 20 min of ischemia was reduced to approximately 20% (P less than 0.01). This depression in recovery was associated with significantly increased lactate levels during reperfusion. At a concentration of 10 ng/ml PGI2 did not depress ventricular recovery or elevate lactate content after 20 min ischemia. When hearts made ischemic for 20 min were analyzed, a significant negative correlation was found between ventricular recovery (aortic flow rate) and lactate concentration; however, no correlation existed between recovery and ATP levels. After 25 min of ischemia, five of eight (62.5%) untreated hearts demonstrated some degree of ventricular recovery, however, only two of ten hearts studied demonstrated any measurable functional recovery with either PGI2 concentration. This effect of PGI2 to reduce or prevent recovery of ventricular function following either 20 or 25 min of ischemia as well as the corresponding elevation in lactate levels was prevented by treatment with the calcium channel blocker verapamil. This study therefore shows that PGI2 at critical low concentrations can depress left ventricular recovery following total ischemia. This effect of PGI2 becomes more pronounced as ischemia duration is prolonged and is associated with elevated tissue lactate levels. The studies with verapamil suggest that PGI2 may be acting via the slow calcium channel to increase lactate levels and depress ventricular recovery following prolonged periods of ischemia.
authors.affiliation: Weis Center for Research, Geisinger Clinic, Danville, PA 17821.
authors.forename: M
authors.initials: M
authors.lastname: Karmazyn
authors.forename: J R
authors.initials: JR
authors.lastname: Neely
mesh_terms: D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003327:Coronary Disease / Q000503:physiopathology; D004734:Energy Metabolism; D011464:Epoprostenol / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
chemical_list: D000227:Adenine Nucleotides; D007773:Lactates; D019344:Lactic Acid; D011464:Epoprostenol; D002118:Calcium