ON THE SUBCELLULAR SITE OF DIHYDROQUINIDINE ACTION

¹ The Ohio State University College of Medicine, Department of Pharmacology, Columbus, Ohio

The ventricular surface conduction velocity (CV) was monitored throughout the Langendorff perfusion and subsequent vascular washout of guinea-pig hearts with dihydroquinidine-H³ (DH³Q) at several concentrations and for different time periods. Sucrose homogenates prepared from these hearts were then separated into nuclear, mitochondrial, microsomal and supernatant fractions with standard techniques of differential centrifugation. The control CV was 290 (±22) mm/sec. This was decreased maximally (about 80 mm/sec less than control) after 9-min perfusion with a DH³Q concentration of 5 x 10^-6 M. Uptake of DH³Q by the microsomal fraction was greater than by the other subcellular fractions at all times and perfusion concentrations. The DH³Q content of the microsomal fraction was directly related to the decrease in the CV, up to the point of maximal measurable decrease in CV. At this time the microsomal DH³Q content was 375 pmol/mg of protein. At higher perfusion concentrations, further increase in microsomal content occurred without further change in CV. The total uptake by the other particulate fractions followed a slower time course, and their final accumulation was less. A double-reciprocal plot of homogenate against fractions' content suggested that a large part of the nuclear and the mitochondrial uptake represented contamination with membrane fragments and/or uptake which was nonspecific for the effect measured. Sephadex G-25 chromatography of the supernatant revealed that the DH³Q present was not bound to macromolecular structures. The evidence presented is consistent with the concept that receptors for the effect of DH³Q on CV reside in the microsomal (light particulate) fraction of heart homogenates.