Attenuation of myocardial reperfusion injury by reducing intracellular calcium overloading with dihydropyridines.
The effects of three different dihydropyridine (DHP) calcium channel antagonists, nisoldipine, nimodipine, and nifedipine, on myocardial ischemic and reperfusion injury were studied using isolated rat hearts subjected to ischemia and reperfusion. Hearts were perfused with Krebs-Henseleit bicarbonate buffer containing 0, 4, 16, 64 and 100 nM concentrations of the above dihydropyridines for 15 min. Global ischemia was then induced by terminating the aortic flow for 30 min at 37 degrees, followed by 30 min of reperfusion. Left ventricular (LV) functional (LV developed pressure, its first derivative and coronary flow) and biochemical parameters (creatine kinase release) were monitored prior to ischemia and during reperfusion. In separate group of hearts, intracellular free Ca2+ ([Ca2+]i) was monitored with an intracellular calcium analyzer using a fluorescent Ca2+ indicator (Fura-2 AM). Tissue Ca2+ was also measured by atomic absorption spectroscopy after perfusing the hearts with ion-free cold buffer to wash out extracellular Ca2+. Significant recovery of the coronary flow was observed in all hearts treated with a high concentration (100 nM) of DHPs compared with the control group (P < 0.05), while a lower dose of nisoldipine (16 nM) and nifedipine (64 nM) also improved the coronary flow effectively. Reduction of myocardial creatine kinase release and improvement of the recovery of LV developed pressure, dp/dtmax, were achieved by DHPs in a concentration-dependent manner. A higher concentration of DHPs also decreased the formation of myocardial thiobarbituric acid reactive substances, although these compounds did not possess direct free radical scavenging effects in vitro. Tissue Ca2+ content was reduced significantly in treated groups. The rise of [Ca2+]i during ischemia and reperfusion appeared to be attenuated by these DHPs. The concentration-response study of the three DHPs showed the effective concentrations for reducing [Ca2+]i to be 16, 64 and 100 nM nisoldipine, nifedipine and nimodipine, respectively, in this experimental setting. The above results indicate that pretreatment with DHPs can attenuate the myocardial reperfusion injury by modulating Ca2+ overloading and decreasing the susceptibility of the membrane to free radical attack.
Liu
X
X
Department of Surgery, University of Connecticut School of Medicine, Farmington 06030.
Engelman
R M
RM
Wei
Z
Z
Bagchi
D
D
Rousou
J A
JA
Nath
D
D
Das
D K
DK
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003326:Coronary Circulation / Q000187:drug effects; D003402:Creatine Kinase / Q000032:analysis; D004095:Dihydropyridines / Q000494:pharmacology*; D016166:Free Radical Scavengers; D015227:Lipid Peroxidation; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D009543:Nifedipine / Q000494:pharmacology; D009553:Nimodipine / Q000494:pharmacology; D015737:Nisoldipine / Q000494:pharmacology; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D016277:Ventricular Function, Left / Q000187:drug effects
D004095:Dihydropyridines; D016166:Free Radical Scavengers; D015737:Nisoldipine; D009553:Nimodipine; D003402:Creatine Kinase; D009543:Nifedipine; D002118:Calcium