Verapamil attenuates ATP depletion during hypoxia: 31P NMR studies of the isolated rat heart.
To test whether verapamil protects myocardial high-energy phosphate content during hypoxia by reducing pre-hypoxic cardiac work or secondary to metabolic events that occur during hypoxia, we compared the relation between myocardial performance and high-energy phosphate content during normoxia, hypoxia and reoxygenation using 31P NMR spectroscopy in isolated, isovolumic buffer-perfused rat hearts. Function was reduced either by supplying verapamil or by altering work mechanically. During normoxia, supplying verapamil (10(-6.5) to 10(-5) M) decreased cardiac performance, increased both creatine phosphate content and intracellular pH, but had no effect on ATP content. During hypoxia, supplying verapamil attenuated ATP and creatine phosphate depletion, and during reoxygenation, ATP content was higher in verapamil-supplied hearts. In hearts in which pre-hypoxic performance was reduced mechanically, high-energy phosphate content during hypoxia and reoxygenation was preserved to the same extent as in hearts treated with 10(-6.5) M verapamil. During reoxygenation, neither verapamil-pretreatment nor mechanical reduction of pre-hypoxic performance affected the creatine phosphate content or indices of cardiac performance, expressed as percentage of pre-hypoxic values. Since reducing pre-hypoxic workload, either by supplying 10(-6.5) M verapamil or mechanically, produced indistinguishable effects on ATP and creatine phosphate contents during hypoxia and reoxygenation, we conclude that the primary mechanism of action of verapamil in hypoxic injury in the buffer-perfused rat heart is the reduction of pre-hypoxic energy demand.
Neubauer
S
S
Department of Medicine, Brigham and Women's Hospital, Boston, MA.
Ingwall
J S
JS
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D006321:Heart / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D000860:Hypoxia / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010100:Oxygen / Q000494:pharmacology; D010725:Phosphocreatine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014700:Verapamil / Q000494:pharmacology*
D010725:Phosphocreatine; D000255:Adenosine Triphosphate; D014700:Verapamil; D010100:Oxygen