Nicardipine prevents calcium loading and "oxygen paradox" in anoxic single rat myocytes by a mechanism independent of calcium channel blockade.
The protective effect of nicardipine (1 and 4 microM) against reoxygenation injury was studied in an unstimulated rat single myocyte oxygen paradox model in comparison with control (no drug) or nifedipine (1 microM). Either concentration of nicardipine was strongly protective, approximately doubling the duration of ATP depletion (rigor) that cells could withstand without undergoing hypercontracture when reoxygenated. Nifedipine (1 microM), which matched the negative inotropic effect of nicardipine (4 microM) (as measured by extent of shortening when stimulated), had no protective effect against reoxygenation injury. Neither drug affected the time to rigor, which is a measure of the rate at which the resting cell consumes its endogenous glycogen stores during anaerobic metabolism. Intracellular calcium, measured with the fluorescent probe indo-1, which partitions into both cytosol and mitochondria, rose progressively throughout the rigor period. This rise in calcium was almost totally suppressed by nicardipine (1 microM) but was unaffected by nifedipine. We conclude that nicardipine possesses a direct protective effect on the myocardium not shared by all dihydropyridines. This effect is associated with the prevention of intracellular, and probably mitochondrial, calcium loading but is probably not due to blockade of the L-type calcium channel or reduction of metabolic rate.
Hano
O
O
Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md.
Silverman
H S
HS
Blank
P S
PS
Mellits
E D
ED
Baumgardner
R
R
Lakatta
E G
EG
Stern
M D
MD
D000818:Animals; D002118:Calcium / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D000860:Hypoxia / Q000378:metabolism*; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009529:Nicardipine / Q000494:pharmacology*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control
D009529:Nicardipine; D002118:Calcium