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Molecular Pharmacology, Vol 2, 134-143, Copyright © 1966 by the American Society for Pharmacology and Experimental Therapeutics

Effects of Organic Nitrates on Mitochondrial Respiration and Swelling: Possible Correlations with the Mechanism of Pharmacologic Action

PHILIP NEEDLEMAN 1 and F. EDMUND HUNTER JR. 1

1 The Edward Mallinckrodt Department of Pharmacology, Washington University School of Medicine, St. Louis, Missouri

Several organic nitrates (e.g., mannitol hexanitrate and erythrityl tetranitrate), were found to induce swelling of rat liver mitochondria in vitro and to inhibit the mitochondrial swelling produced by inorganic phosphate and beta-hydroxybutyrate. Low concentrations of organic nitrates which are potent vasodilators stimulate oxygen consumption and cause loss of respiratory control of tightly coupled rat liver mitochondria. With organic nitrates of moderate to low pharmacologic activity high concentrations are required to produce loss of respiratory control. The organic nitrates tested which are inactive as coronary dilators do not uncouple oxidative phosphorylation even at very high concentrations. Higher concentrations of the therapeutically employed organic nitrates are required to produce loss of respiratory control with rat heart mitochondria than with liver mitochondria. There is a correlation between (a) the ability of organic nitrates to stimulate mitochondrial respiration, (b) the rate of reaction with reduced glutathione in the presence of liver organic nitrate reductase, and (c) their oil/water partition coefficients.

Note:
ACKNOWLEDGMENT This research was supported by Grants T1-GM-0096, 1-R01-HE-10107-01, and 1-R0l-CA-02284-17, The National Institutes of Health, U. S. Public Health Service.

Submitted on December 2, 1965




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