Mevinolin, an inhibitor of cholesterol biosynthesis, drastically depresses Ca2+ channel activity and uncouples excitation from contraction in cardiac cells in culture.

Abstract

Mevinolin (MK803), a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) (Ki, 30 X 10(-9) M), depressed de novo synthesis of cholesterol in 11-day chicken embryonic cardiac cells cultured in lipoprotein-deficient serum (LPDS). Cardiac cells exposed to different concentrations of mevinolin for 1-3 days presented different electrophysiological and mechanical properties: The resting membrane potential, the rate of increase, and the shape of the action potential and contractile properties were changed at concentrations as low as 0.1 microM mevinolin. At a concentration of 1 microM mevinolin, the cardiac cells became quiescent and electrical stimulation induced action potentials of short duration without contraction. Isoproterenol and Bay K8644 were unable to restore excitability and contraction. Although the number of receptors for the tritiated Ca2+ channel blocker nitrendipine was the same in control and in mevinolin-treated cells, voltage-clamp data on isolated cardiac cells and 45Ca2+ flux experiments on monolayers showed that most of the slow Ca2+ channel activity was lost in mevinolin-treated cells. These results suggest that the disappearance of Ca2+ channel activity is most probably at the origin of the loss of cardiac contractility.