Abstract
We investigated temporal differences in the protective action of three types of Ca2+ channel blockers in myocardial ischemia, focusing particularly on the blocking ability under depolarizing conditions. The effects of diltiazem, verapamil, and nifedipine on extracellular potassium concentration ([K+]e), acidosis, and level of metabolic markers were examined during 30-min global ischemia and postischemic left ventricular (LV) function in isolated guinea pig hearts. Diltiazem and verapamil, but not nifedipine, inhibited the late phase (15–30 min) of [K+]e elevation, whereas all three blockers delayed the onset of the early phase (0–8 min) of [K+]e elevation. Diltiazem and verapamil inhibited ischemic contracture and improved postischemic LV function to a greater extent. These differences appeared to be linked to preservation of ATP and creatine phosphate and delay of cessation of anaerobic glycolytic activity. Maneuvers to preserve energy sources during ischemia (decrease in external Ca2+concentration or pacing at a lower frequency) attenuated the late phase of [K+]e elevation. Inhibition of LV pressure was potentiated 12- and 8.2-fold by diltiazem and verapamil, respectively, at 8.9 mM K+ as compared with 2.9 mM K+, whereas that by nifedipine was unchanged. These results indicate that the differential cardioprotection of Ca2+ channel blockers in the late period of ischemia correlates with preservation of high-energy phosphates as a result of different Ca2+ channel blocking abilities under high [K+]e conditions.
Footnotes
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Send reprint requests to: Taku Nagao, Ph.D., Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033, Japan.
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↵1 This study was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports and Culture, Japan.
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↵2 Present address: Central Research Laboratory, Zeria Pharmaceutical Company Ltd., 2512-1 Oshikiri, Kohnan-machi, Osato-gun, Saitama 360-0111, Japan.
- Abbreviations:
- [K+]e
- extracellular K+ concentration
- LV
- left ventricular
- KHS
- Krebs-Henseleit solution
- LVEDP
- left ventricular end-diastoric pressure
- LVDP
- left ventricular developed pressure
- HR
- heart rate
- [H+]e
- extracellular H+concentration
- CrP
- creatine phosphate
- Received June 24, 1998.
- Accepted January 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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