Contribution of Cav1.2 Channels to Coronary Microvascular Dysfunction in Metabolic Syndrome

Abstract

Previous investigations by our group indicate that diminished functional expression of KV channels impairs control of coronary blood flow in obesity/metabolic syndrome (MetS). The goal of this investigation was to test the hypothesis that coronary microvascular dysfunction in MetS is also related to subsequent increases in CaV1.2 channel activity. Initial studies revealed that inhibition of KV channels with 4‐aminopyridine (4AP, 0.3 mM) increased intracellular [Ca2+], contracted isolated coronary arterioles, and decreased coronary reactive hyperemia, and that these effects were reversed by blockade of CaV1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of CaV1.2 channels with nifedipine (10 μg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, blockade of CaV1.2 channels significantly elevated coronary blood flow, conductance, and the balance between flow and metabolism in swine with the MetS (P < 0.05). These changes were associated with a ~50% increase in inward CaV1.2 current and elevations in α1c and α2δ1 channel subunit expression in coronary smooth muscle cells from MetS swine. Taken together, these data indicate that increased functional expression of coronary CaV1.2 channels contributes to coronary microvascular dysfunction in the MetS.