Mibefradil is more effective than verapamil for restoring post-ischemic function of isolated hearts of guinea pigs with acute renal failure.
The deleterious intracellular Ca(2+) overload in the ischemic-reperfusion injury of the heart can be even more expressed in subjects with acute renal failure in whom maintenance of intracellular Ca(2+) has already been disturbed in normoxia. To study the influence of acute renal failure in ischemic-reperfusion injury on the heart, we used isolated Langendorff's hearts of guinea pigs with gentamicin-induced acute renal failure. We examined arrhythmias, heart contractility and myocardial cell damage during reperfusion. Two specific Ca(2+) channel antagonists, mibefradil (0.1 and 1 microM) and verapamil (0.1 microM), were used to test the possible involvement of T-type and L-type Ca(2+) channels in these processes. We exposed hearts to 50 min of zero-flow global ischemia and 60 min of reperfusion. During reperfusion, unrecoverable ventricular fibrillation appeared more often in hearts of animals with acute renal failure than in control hearts (80% vs. 0%, respectively). Mibefradil, but not verapamil, applied either pre- or post-ischemically, terminated ventricular fibrillation in all hearts of animals with acute renal failure. Mibefradil (0.1 microM only) improved contractility in hearts of animals with acute renal failure during reperfusion by 30%. During reperfusion, lactate dehydrogenase (LDH) release rate increased less in hearts of guinea pigs with acute renal failure than in control hearts and only verapamil decreased it additionally. Thus, our results suggest a more important role of T- than of L-type Ca(2+) channels in ischemic-reperfusion injury in isolated guinea pig hearts with acute renal failure.
Grasic Kuhar
Cvetka
C
Department of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Korytkova 2, SI-1000 Ljubljana, Slovenia.
Budihna
Metka V
MV
Pleskovic
Ruda Zorc
RZ
D058186:Acute Kidney Injury / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects; D020747:Calcium Channels, T-Type / Q000187:drug effects; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D020748:Mibefradil / Q000494:pharmacology*; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D017180:Tachycardia, Ventricular / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D020748:Mibefradil; D014700:Verapamil; D007770:L-Lactate Dehydrogenase