Hypoxic contraction of small pulmonary arteries from normal and endotoxemic rats: fundamental role of NO

Abstract

The present study was aimed at examining the role of nitric oxide (NO) in the hypoxic contraction of isolated small pulmonary arteries (SPA) in the rat. Animals were treated with either saline (sham experiments) or Escherichia coli lipolysaccharide [LPS, to obtain expression of the inducible NO synthase (iNOS) in the lung] and killed 4 h later. SPA (300- to 600-μm outer diameter) were mounted as rings in organ chambers for the recording of isometric tension, precontracted with PGF2α, and exposed to either severe (bath [Formula: see text] 8 ± 3 mmHg) or milder (21 ± 3 mmHg) hypoxia. In SPA from sham-treated rats, contractions elicited by severe hypoxia were completely suppressed by either endothelium removal or preincubation with an NOS inhibitor [ N G-nitro-l-arginine methyl ester (l-NAME), 10−3 M]. In SPA from LPS-treated rats, contractions elicited by severe hypoxia occurred irrespective of the presence or absence of endothelium and were largely suppressed by l-NAME. The milder hypoxia elicited no increase in vascular tone. These results indicate an essential role of NO in the hypoxic contractions of precontracted rat SPA. The endothelium independence of HPV in arteries from LPS-treated animals appears related to the extraendothelial expression of iNOS. The severe degree of hypoxia required to elicit any contraction is consistent with a mechanism of reduced NO production caused by a limited availability of O2 as a substrate for NOS.

Hypoxic Pulmonary Vasoconstriction

“…These O 2 concentrations were shifted to higher values when the intensity of prestimulation was increased (1652) or when measurements were made in a rat strain more responsive to hypoxia (1691 656,799,814,900,903,935,991,1043,1045,1131,1151,1413,1430,1651,1652,1691,1896,1961,1976,2018,2089,2185). Moreover, substantial data suggested that the endothelium dependence of phase 1 was caused by an hypoxia-induced decrease in endothelial NO production, leading to smooth muscle contraction (506, 656,814,903,934,935,991,1151,1413,1430,1691,1896,1976,2018). In contrast, other studies reported that removal of endothelium did not eliminate or even enhanced phase 1 HPV (412, 413, 876,1038,1043,1151,1207,1208,1638,2190).…”

“…In rat (412), the magnitude of phase 2 HPV elicited by 6% O 2 was half of that elicited by 2% O 2 . With few exceptions (54, 139), phase 2 HPV was found to be endothelium-dependent (392,394,413,506,578,799,814,815,991,1038,1043,1044,1131,1639,1652,1896,2024). As discussed in section IVB2B, it is widely held that phase 2 HPV requires a diffusible contracting factor released by endothelium, which may act by increasing Ca 2ϩ sensitivity in pulmonary arterial smooth muscle.…”

“…Hypoxic inhibition of NO production could cause HPV by uncovering basal tone (1413,1651,1896); however, the contribution of NO to the normally low basal pulmonary vascular vasomotor tone is not sufficient for this to account for more than a small proportion of hypoxia-induced vasoconstriction (60, 752,1043). Moreover, studies on whole animals or perfused lungs almost universally demonstrate that inhibition of NO production potentiates HPV (60, 185, 752,1039,2064), as does inhibition of the NO target guanylate cyclase (546, 692) and eNOS knockdown (493, 1106).…”

Carbon Monoxide: Endogenous Production, Physiological Functions, and Pharmacological Applications

“…The potential down-regulation of HO-2 in these vascular tissues by NO would constantly reduce the production of CO, resulting in increased contractility and sensitivity to vasoconstrictors ). Under certain circumstances, such as severe hypoxia, NO production might be reduced due to a limited availability of O 2 as a substrate for NOS (Terraz et al, 1999). As a compensatory response of the vasculature during hypoxia, CO production from HO-2 would be increased to compensate for the shortage of NO.…”

Role of NO and Prostaglandins in Acute Hypoxic Vasoconstriction in Sheep Pulmonary Veins

“…Numerous groups have demonstrated that inhibition of NO results in an increase of hypoxia-induced contraction [17][18][19][20] . But other investigators [21,22] have demonstrated that NO synthase (NOS) inhibitors reduce rather than potentiate HPV. Since the lung has a high capacity for the production of PGs, these attracted attention as potential mediators of HPV [23] .…”