Intracellular localization of the calcium antagonist propyl-methylenedioxyindene in cardiac tissue.
Propyl-methylenedioxyindene (pr-MDI) is a coronary dilating and antiarrhythmic calcium antagonist with an intracellular site of action in cardiac tissue, probably involving inhibition of calcium mobilization from the sarcoplasmic reticulum and preservation of mitochondrial structural and functional integrity. Perfusion of isolated guinea-pig hearts with [14C]pr-MDI resulted in negative inotropism, with the time-course of this effect paralleling the uptake of the drug in the whole heart and the time-course of its accumulation in atrial and ventricular tissue. Tissue-to-medium ratios of pr-MDI for both atria and ventricles were high, and washout of the drug from the heart was biexponential. Pr-MDI associated poorly with a cardiac subcellular fraction exhibiting the highest specific activity of sarcolemmal marker enzyme. The highest specific activity of pr-MDI occurred in the cardiac mitochondrial fraction and in a fraction enriched with a putative sarcoplasmic reticular marker, and the accumulation of drug in these fractions was temporally correlated with its negative inotropic action. The results support an intracellular site of action of pr-MDI in cardiac tissue.
D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007192:Indenes / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism*
D002121:Calcium Channel Blockers; D007192:Indenes; C027983:2-n-propyl-3-dimethylamino-5,6-methylenedioxyindene