Impaired reactivity of rat aorta to phenylephrine and KCl after prolonged hypoxia: role of the endothelium

Abstract

The hemodynamic response to reductions in systemic oxygen availability serves to redistribute blood flow and maintain vital organ function. The efficacy of this response depends on the degree to which hypoxia alters the function of the vascular tissues themselves. In this study we have evaluated these effects in rats exposed to 10% oxygen for 0 (control), 12, and 48 h and for 48 h followed by 12 h of normoxic recovery. In aortic segments from each group, the cumulative concentration response relationships were constructed for phenylephrine and KCl. Maximum tension generated during activation by these agents was reduced after both 12 and 48 h of hypoxic exposure. After 48 h of hypoxia, the maximum tension during activation by phenylephrine was 0.46 +/- 0.04 vs. 1.31 +/- 0. 09 g/mg dry wt for the control group (P < 0.05 for difference). The maximum tension during activation by KCl was similarly affected (0. 32 +/- 0.02 vs. 0.98 +/- 0.06 g/mg dry wt, 48 h of hypoxia vs. control, respectively; P < 0.05 for difference). Exposure to hypoxia did not alter the EC50 for either agent. Twelve hours of normoxic recovery did not fully restore contractility after 48 h of hypoxia. In aortic rings from control rats, endothelial removal enhanced contraction, whereas, in rings from rats exposed to hypoxia, removal of the endothelium was associated with a decrease in maximum tension. Prolonged exposure to hypoxia results in impairment of systemic arterial smooth muscle contractility. This is partly compensated by the release of vasoconstricting substances from the endothelium.

Hypoxia induces a functionally significant and translationally efficient neuronal NO synthase mRNA variant

“…The EC 50 value was lower (i.e., sensitivity was increased) after endothelial ablation in rings from both normoxic and hypoxic animals. Removal of the endothelium increased the maximum tension during PE-induced contraction in rings from normoxic rats, whereas, as noted previously (14,27), tension was greater in endothelium-intact than -denuded rings from rats exposed to hypoxia. Treatment with l-NAME increased maximum tension and decreased the EC 50 during PE-induced contraction in endothelium-intact rings from both normoxic and hypoxic animals but had no effect on the response to either PE or KCl in endothelium-denuded rings from normoxic rats.…”

“…The loss of vascular contractility, although adaptive on a regional level, may have pathophysiologic significance in cardiopulmonary diseases associated with generalized impairment of systemic oxygen delivery. Previous studies indicate that after prolonged reductions in global oxygen delivery, impairment of systemic vasoreactivity is widespread, involving both resistance (13) and conductance vessels (14,37). Our findings that hypoxia induced nNOS expression in myocytes of conductance as well as in resistance vessels provides, in part, a newer molecular mechanism for these prior physiological observations.…”

“…In contrast, when hypoxia is prolonged (12-48 hours), the reactivity of systemic arteries (13,14) and, hence, sympathetic vascular responses (15) are impaired. This will limit the ability to maintain vital organ oxygenation if substrate supply must be augmented in order to meet an increase in metabolic demand, such as may occur with a superimposed episode of hypotension or if hypoxia were to acutely become more severe.…”

“…All protocols involving live animals were in accordance with standards set by the Canadian Council on Animal Care and were approved by the institutional animal care committees of Meakins-Christie Laboratories, the University of Toronto Faculty of Medicine, and St. Michael's Hospital. As described previously (14), male Sprague-Dawley rats (200-250 g; Charles River Laboratories) were placed in a Plexiglas chamber (30 × 18 × 15 cm) into which the flow of air and nitrogen was controlled independently for 48 hours, then sacrificed by decapitation. Animals exposed to hypoxia breathed a mixture containing 8% oxygen, whereas control animals breathed room air only under otherwise identical conditions.…”

“…If oxygen deprivation is prolonged, however, systemic vascular smooth muscle contractility (13,14) and, hence, the sympathetic responses that preserve tissue oxygen supply (15) become progressively impaired. nNOS is expressed by VSMCs (16)(17)(18), and upregulation of nNOS protein by hypoxia has been demonstrated in neurons and skeletal muscle (10,19).…”