Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation.

Abstract

The role of the endothelium in hypoxic constriction of the intact pulmonary vascular bed has not been clearly elucidated.To test for a possible role for endothelium-derived relaxing factor(s) (EDRF) in the hypoxic pressor response, isolated, whole blood-perfused rat lungs from male Sprague-Dawley rats treated with meclofenamate were prepared. Three protocols were performed, including: (a) normal saline (control); (b) the putative EDRF inhibitors, eicosatetraynoic acid (ETYA, 1 X 10-4 M) or nordihydroguaiaretic acid (NDGA, 1 X 10-4 M) versus vehicle DMSO; and (c) the putative EDRF inhibitor hydroquinone (HQ, 1 X 10-4 M) versus vehicle ethyl alcohol (ETOH). The pulmonary pressor response to angiotensin II (Ang II, 0.25 Mg) injections alternated with 6-min periods of hypoxic ventilation (3% 02,5% C02) was measured before and after the administration of saline, inhibitors, or vehicles. The administration of the EDRF inhibitors ETYA, NDGA, and HQ resulted in a marked accentuation of the hypoxic pressor response that was not seen in the controls (P < 0.05). In separate experiments, lungs precontracted with norepinephrine (1 X 10-6 M) were pretreated with edrophonium (1 X 10-4 M) and then observed for endothelium-dependent vasodilator responses to acetylcholine at increasing doses (1 X 10-7 X 10-4 M). Administration of ETYA, NDGA, or HQ abrogated the observed vasodilatation to acetylcholine, which was not seen with vehicles alone (P < 0.01). These studies suggest an important role for the endothelium in pulmonary vascular responsiveness to alveolar hypoxia through possible release of a relaxing factor(s) that attenuates the degree of pulmonary arterial constriction.

Exercise-induced pulmonary vasoconstriction during combined blockade of nitric oxide synthase and beta adrenergic receptors.

“…All catheters were flushed with heparinized saline and were sewn to the skin. Sheep were allowed to recover in pens for [4][5][6][7] d after surgery with free access to water and feed.…”

Changes in Pulmonary Hemodynamics during Normoxia and Hypoxia in Awake Rats Treated with Intratracheal Bleomycin.

“…In this model, a lung endothelial dysfunction, as well as structural damage, is produced (Catravas et al 1983;Fasske and Morgenroth 1983). An essential role for endotheliumderived relaxing factor in pulmonary circulation during normoxic and hypoxic states has been suggested (DeMey and Vanhoutte 1982; Holden and McCall 1984;Brashers et al 1988). Contractile interstitial cells, which have the potential of playing an important role in control of local blood flow, are increased (Kapanci et al 1974; Adler et al 1986).…”

Pulmonary vascular response to acetylcholine in isolated rat lungs treated with intratracheal bleomycin.

“…Antagonists of EDRF augment HPVC in isolated perfused rat rung which is the same experimental system used in our study (Brashers et al 1988). The authors suggested an important role for endothelium in pulmonary vascular response to alveolar hypoxic.…”

“…Then the release of an endothelium-derived relaxing factor(s) (EDRF) (De Mey and Vanhoutte 1982) may be altered. An important role for EDRF in pulmonary vascular response to acute alveolar hypoxia has been recently suggested (De Mey and Vanhoutte 1982; Holden and McCall 1984;Brashers et al 1988). The present study was designed to test the hypothesis that during alveolar hypoxia the dilator response to acetylcholine (ACh) (Furchgott and Zawadzki 1980) is altered in the model of interstitial pulmonary fibrosis produced by bleomycin.…”