CO modulates pulmonary vascular response to acute hypoxia: relation to endothelin

Abstract

Pulmonary intralobar arteries express heme oxygenase (HO)-1 and -2 and release carbon monoxide (CO) during incubation in Krebs buffer. Acute hypoxia elicits isometric tension development (0.77 +/- 0.06 mN/mm) in pulmonary vascular rings treated with 15 micromol/l chromium mesoporphyrin (CrMP), an inhibitor of HO-dependent CO synthesis, but has no effect in untreated vessels. Acute hypoxia also induces contraction of pulmonary vessels taken from rats injected with HO-2 antisense oligodeoxynucleotides (ODN), which decrease pulmonary HO-2 vascular expression and CO release. Hypoxia-induced contraction of vessels treated with CrMP is attenuated (P < 0.05) by endothelium removal, by CO (1-100 micromol/l) in the bathing buffer, and by endothelin-1 (ET-1) receptor blockade with L-754142 (10 micromol/l). CrMP increases ET-1 levels in pulmonary intralobar arteries, particularly during incubation in hypooxygenated media. CrMP also causes a leftward shift in the concentration-response curve to ET-1, which is offset by exogenous CO. In anesthetized rats, pretreatment with CrMP (40 micromol/kg iv) intensifies the elevation of pulmonary artery pressure elicited by breathing a hypoxic gas mixture. However, acute hypoxia does not elicit augmentation of pulmonary arterial pressure in rats pretreated concurrently with CrMP and the ET-1 receptor antagonist L-745142 (15 mg/kg iv). These data suggest that a product of HO activity, most likely CO, inhibits hypoxia-induced pulmonary vasoconstriction by reducing ET-1 vascular levels and sensitivity.

Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

“…The salutary effect of the enhancement of HO-1 activity has been attributed by some to the HO-1-mediated increase in GSH and extracellular superoxide dismutase levels, and the decrease in iNOS [59,62,69]. The decrease in oxidative stress has been shown to counteract vasoconstrictors, including ET-1 and PE [18,24,25,62,69].…”

“…These studies attribute the blood pressure lowering effect of HO-1 induction to various mechanisms, including decreased production of vasoconstrictor eicosanoids and increased production of CO [2,15,16]. CO has been shown to function as a vasodilator [17][18][19][20][21], a stimulator of soluble guanylate cyclase [22], an endogenous modulator of the cGMP signaling system [4], an activator of calciumactivated potassium channels (K Ca ) in vascular smooth muscle [23], and an inhibitor of endothelin-1 mediated vasoconstriction [18,24,25]. Recent reports have implicated HO in the regulation of renal salt excretion.…”

Hypoxic Pulmonary Vasoconstriction

“…IIIB1B and IVA2). Furthermore, inhibition of HO with chromium mesoporphyrin or treatment with HO-2 antisense oligodeoxynucleotides facilitated HPV in rat pulmonary arteries and intact animals (2189). Because this facilitation was prevented by ET-1 receptor blockade or removal of endothelium, it was concluded that CO suppressed ET-1 production and/or sensitivity (2189).…”

Heme oxygenase: the key to renal function regulation

“…55). The blood pressure lowering effect of HO-1 can be attributed to various mechanisms, including decreased production of vasoconstrictor eicosanoids and increased production of CO, which functions as a vasodilator, a stimulator of soluble guanylate cyclase, an endogenous modulator of the cGMP signaling system, an activator of calcium-activated potassium channels in vascular smooth muscle, and an inhibitor of endothelin-1 (60,227). Acute elevation of renal perfusion pressure (RPP) induced a rise of CO and nitric oxide (NO) concentrations accompanied in the medullary tissue by natriuresis (108).…”