NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs

Abstract

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation but may also result in chronic pulmonary hypertension. It has not been clarified whether acute HPV and the response to prolonged alveolar hypoxia are triggered by identical mechanisms. We characterized the vascular response to sustained hypoxic ventilation (3% O(2) for 120-180 min) in isolated rabbit lungs. Hypoxia provoked a biphasic increase in pulmonary arterial pressure (PAP). Persistent PAP elevation was observed after termination of hypoxia. Total blockage of lung nitric oxide (NO) formation by N(G)-monomethyl-L-arginine caused a two- to threefold amplification of acute HPV, the sustained pressor response, and the loss of posthypoxic relaxation. This amplification was only moderate when NO formation was partially blocked by the inducible NO synthase inhibitor S-methylisothiourea. The superoxide scavenger nitro blue tetrazolium and the superoxide dismutase inhibitor triethylenetetramine reduced the initial vasoconstrictor response, the prolonged PAP increase, and the loss of posthypoxic vasorelaxation to a similar extent. The NAD(P)H oxidase inhibitor diphenyleneiodonium nearly fully blocked the late vascular responses to hypoxia in a dose that effected a decrease to half of the acute HPV. In conclusion, as similarly suggested for acute HPV, lung NO synthesis and the superoxide-hydrogen peroxide axis appear to be implicated in the prolonged pressor response and the posthypoxic loss of vasorelaxation in perfused rabbit lungs undergoing 2-3 h of hypoxic ventilation.

Inhibition of hypoxic pulmonary vasoconstriction by antagonists of store-operated Ca2+ and nonselective cation channels

“…Similar temporal characteristics have been described for HPV in isolated lungs (65)(66)(67). Because the mechanisms responsible for the early and late phases of HPV might be different (55), we determined whether Ca 2ϩ -free perfusate, nifedipine, and SOCC/NSCC antagonists could inhibit sustained HPV.…”

Classical transient receptor potential channel 6 (TRPC6) is essential for hypoxic pulmonary vasoconstriction and alveolar gas exchange

“…The signaling mechanisms underlying the acute, prolonged and chronic effects of alveolar hypoxia on the pulmonary vasculature are still largely unknown (16)(17)(18)(19)(20). At present it is not clear whether the very acute hypoxic vasoconstrictor response (occurring within seconds), the prolonged response (occurring within hours), and the initiation of the structural vascular remodeling process in chronic hypoxia are regulated by identical or different mechanisms (3). Recently, TRPC6 was found to be up-regulated in hypoxia-induced, as well as idiopathic chronic pulmonary hypertension (8,15).…”

Pivotal Role for Endothelial Tetrahydrobiopterin in Pulmonary Hypertension

“…Both NO and superoxide can modulate HPV. 27,28 To evaluate the functional importance of NO compared with superoxide production by eNOS in relation to endothelial BH4 availability, we quantified HPV in perfused lung preparations from WT, hph-1 ϩ/Ϫ , hph, hph/GCH, and GCH mice. In WT lungs, inhibition of NO production with L-NAME increased HPV, reflecting the vasodilatory effect of eNOS-derived NO (Figure 7).…”