Involvement of L-Type Calcium Channels in Hypoxic Relaxation of Vascular Smooth Muscle

Abstract

In the systemic vasculature, hypoxia elicits a local vasodilator response that may be partially mediated by ionic channels on vascular smooth muscle, such as adenosine triphosphate sensitive K⁺ channels. Recent electrophysiological studies suggest that hypoxia may also inhibit voltage-dependent Ca²⁺ channels (L type) on peripheral vascular smooth muscle cells. We hypothesized that hypoxia elicits relaxation of vascular smooth muscle by inhibiting L-type Ca²⁺ channels. In endothelium-denuded rat thoracic aortic rings contracted with phenylephrine, mild and moderate hypoxia (PO₂ 35 and 20 mm Hg, respectively) elicited significant relaxation. Pretreatment with the L-type Ca²⁺ channel antagonist nifedipine completely inhibited mild hypoxic relaxation and diminished relaxation under moderate hypoxia, whereas glibenclamide, a blocker of adenosine triphosphate sensitive potassium channels, only attenuated the response to moderate hypoxia. In rings contracted with the L-type Ca²⁺ channel agonist (–)BAY K 8644 both mild and moderate hypoxia elicited almost complete relaxation. Furthermore, in rings contracted with hyperkalemic solutions (85 mM K⁺ or 120 mM K), mild and moderate hypoxia elicited significant relaxations. Thus, we conclude that hypoxia acts directly on vascular smooth muscle to cause relaxation in part by inhibiting L-type Ca²⁺ channels.