Reduction of Ca2+ channel activity by hypoxia in human and porcine coronary myocytes

Objective: Oxygen (O-2) tension is a major regulator of blood flow in the coronary circulation, Hypoxia can produce vasodilation through activation of ATP regulated K+ (K-ATP) channels in the myocyte membrane, which leads to hyperpolarization and closure of voltage-gated Ca2+ channels. However, there are other O-2-sensitive mechanisms intrinsic to the vascular smooth muscle since hypoxia can relax vessels precontracted with high extracellular K+, a condition that prevents hyperpolarization following opening of K+ channels. The objective of the present study was to determine whether inhibition of Ca2+ influx through voltage-dependent channels participates in the response of coronary myocytes to hypoxia. Methods: Experiments were performed on porcine anterior descendent coronary arterial rings and on enzymatically dispersed human and porcine myocytes of the same artery. Cytosolic [Ca2+] was measured by microfluorimetry and whole-cell Currents were recorded with the patch clamp technique. Results: Hypoxia (O-2 tensionapproximate to20 mmHg) dilated endotlielium-denuded porcine coronary arterial rings precontracted with high K+ in the presence of glibenclamide (5 muM), a block-or of K-ATP channels. In dispersed human and porcine myocytes, low O-2 tension decreased basal cytosolic [Ca2+] and transmembranc Ca2+ influx independently of K+ channel activation. In patch clamped cells, hypoxia reversibly inhibited L-type Ca2+ channels. RT-PCR indicated that rHT is the predominant mRNA variant of the alpha(1C) Ca2+ channel subunit in human coronary myocytes. Conclusion: Our study demonstrates, for the first time in a human preparation, that voltage-gated Ca2+ channels in coronary myocytes are under control of O-2 tension. (C) 2002 Elsevier Science BY All rights reserved.