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.

Direct effects of acute hypoxia on the reactivity of peripheral arteries of the chicken embryo

“…The role of the endothelium in relaxing responses to hypoxia is a subject of discussion. The different types of responses seem to depend not only on the vascular bed and the species studied, but also on the degree of hypoxia (15) and on the developmental stage of the animal studied (27).…”

“…Reduction of relaxation and augmentation of contractile responses during hypoxia/ anoxia have been mainly attributed to an inhibition of endothelium-derived relaxation factor (EDRF)/nitric oxide (NO) release (26,44). Vasorelaxation in response to a decrease in oxygen tension has been shown to involve NO (12,17), prostaglandins (12,22), K ϩ channels (19,41), Ca 2ϩ channels (15), and/or adenosine (41). The role of the endothelium in relaxing responses to hypoxia is a subject of discussion.…”

Effects of organ culture on arterial gene expression and hypoxic relaxation: role of the ryanodine receptor

“…The mechanism(s) by which systemic vascular smooth muscle (VSM) senses these changes in PO 2 remains unclear. Common theories include the modulation of ion channel function, an acute decrease in available ATP necessary for force maintenance, direct regulation of intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ), and modulation of Ca 2ϩ sensitivity (6,8,9,19). We have shown that these theories cannot completely account for the hypoxiainduced relaxation of porcine coronary arteries (20).…”

Role of Prostaglandins in Mediating Differences in Human Internal Mammary and Radial Artery Relaxation Elicited by Hypoxia

“…Some reports have proposed that opening of K ϩ channels, inhibition L-type Ca 2ϩ currents, and acceleration of Ca 2ϩ uptake by SR may be involved in modulating VSMC responses to changes in oxygen tension (Close et al, 1994;Franco-Obregon et al, 1995;Herrera and Walker, 1998;Shimizu et al, 2000). Opening of K ϩ channels did not mediate hypoxia-elicited relaxation of IMA and RA because inhibiting K ϩ channels with TEA did not attenuate relaxation.…”

“…In contrast, the primary response of isolated bovine calf and porcine coronary arteries to hypoxia-reoxygenation is independent of prostaglandins, NO, and reactive O 2 species (Close et al, 1994;Mohazzab et al, 1996). Although the mechanisms underlying hypoxic relaxation are poorly understood, studies have indicated that inhibition of L-type Ca 2ϩ channels (Franco-Obregon et al, 1995;Herrera and Walker, 1998), opening of ATP-dependent K ϩ channels (Daut et al, 1990;Kalsner, 1995), or accelerated sequestration of Ca 2ϩ by sarcoplasmic reticulum (SR) (Close et al, 1994;Shimizu et al, 2000) potentially mediate relaxation of coronary arteries to hypoxia. Hyperpolarization of VSM by activation of K ϩ channels is one of the mechanisms of dilation of RA (Hamilton et al, 2001).…”