Hypoxic Exposure Results In Persistent Endothelium - Dependent Systemic Vascular Smooth Muscle Cell

Chronic hypoxia (CH) results in reduced sensitivity to vasoconstrictors in conscious rats that persists upon restoration of normoxia. We hypothesized that this effect is due to endothelium-dependent hyperpolarization of vascular smooth muscle (VSM) cells following CH. VSM cell resting membrane potential was determined for superior mesenteric artery strips isolated from CH rats (PB = 380 torr; 48 hours) and normoxic controls. VSM cells from CH rats studied under normoxia were hyperpolarized compared to controls. Resting vessel wall intracellular calcium concentration ([Ca]i), and pressureinduced vasoconstriction were reduced in vessels isolated from CH rats compared to controls. Vasoconstriction and increases in vessel wall [Ca]i in response to the α1-adrenergic agonist phenylephrine (PE) were also blunted in resistance arteries from CH rats. Removal of the endothelium normalized resting membrane potential, resting vessel wall [Ca]i, pressureinduced vasoconstrictor responses, and PE-induced constrictor and Ca responses between groups. Whereas VSM cell hyperpolarization persisted in the presence of nitric oxide synthase inhibition, heme oxygenase inhibition restored VSM cell resting membrane potential in vessels from CH rats to control levels. We conclude that endothelial-derived carbon monoxide accounts for persistent VSM cell hyperpolarization and vasoconstrictor hyporeactivity following chronic hypoxia. key words: rat, carbon monoxide, calcium imaging, vasoreactivity FINAL ACCEPTED VERSION R-001004-2002.R1