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Heme oxygenase-mediated vasodilation involves vascular smooth muscle cell hyperpolarization

Vascular Physiology Group, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87131-5218

Submitted 23 December 2002 ; accepted in final form 10 March 2003

Chronic hypoxia is associated with both blunted agonist-induced and myogenic vascular reactivity and is possibly due to an enhanced production of heme oxygenase (HO)-derived carbon monoxide (CO). However, the mechanism of endogenous CO-meditated vasodilation remains unclear. Isolated pressurized mesenteric arterioles from chronically hypoxic rats were administered the HO substrate heme-L-lysinate (HLL) in the presence or absence of iberiotoxin, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), ryanodine, or free radical spin traps (N-tert-butyl--phenylnitrone and 4,5-dihydroxy-1,3-benzenedisulfonic acid disodium salt). The effects of HLL administration on vascular smooth muscle (VSM) membrane potential were assessed in superior mesenteric artery strips in the presence and absence of zinc protoporphyrin IX or iberiotoxin. The vasodilatory responses to exogenous CO were assessed in the presence and absence of ODQ or iberiotoxin. HLL administration produced a dose-dependent vasodilatory response that was nearly eliminated in the presence of iberiotoxin. Neither ODQ, spin traps, nor ryanodine altered the vasodilatory response to HLL, although ODQ abolished the vasodilatory response to S-nitroso-N-acetyl-penicillamine. HLL administration produced a zinc protoporphyrin IX- and iberiotoxin-sensitive VSM cell hyperpolarization. Iberiotoxin and ODQ inhibited the vasodilatory response to exogenous CO. Thus the vasodilatory response to endogenous CO involves cGMP-independent activation of VSM large-conductance Ca²⁺-activated K⁺ channels and does not likely involve the formation of Ca²⁺ sparks emanating from ryanodine-sensitive stores.

carbon monoxide; Ca²⁺-activated K⁺ channels; mesenteric; isolated vessel; soluble guanylyl cyclase; hypoxia

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