Alterations in dihydropyridine receptors in dystrophin-deficient cardiac muscle

Abstract

The deficiency of dystrophin, a critical membrane stabilising protein, in the mdx mouse causes an elevation in intracellular calcium in myocytes. One mechanism that could elicit increases in intracellular calcium is enhanced influx via the L-type calcium channels. This study investigated the effects of the dihydropyridines BayK 8644 and nifedipine and alterations in dihydropyridine receptors in dystrophin-deficient mdx hearts. A lower force of contraction and a reduced potency of extracellular calcium (P<0.05) was evident in mdx left atria. The dihydropyridine agonist Bay K 8644 and antagonist nifedipine had 2.7 and 1.9 fold lower potencies in contracting left atria (P<0.05). This corresponded with a 2.0 fold reduction in dihydropyridine receptor affinity evident from radioligand binding studies of mdx ventricular homogenates (P<0.05). Increased ventricular dihydropyridine receptor protein was evident from both radioligand binding studies and Western blots and was accompanied by increased mRNA levels (P<0.05). Patch clamp studies in isolated ventricular myocytes showed no change in L-type calcium current density, but revealed delayed channel inactivation (P<0.05). This study indicates that a deficiency of dystrophin leads to changes in dihydropyridine receptors and L-type calcium channel properties that may contribute to enhanced calcium influx. Increased influx is a potential mechanism for the calcium overload observed in dystrophin deficient cardiac muscle.