Inhibition of hypoxic pulmonary vasoconstriction by calcium antagonists in isolated rat lungs.

Abstract

SUMMARY The role of a transmembrane calcium influx in hypoxic pulmonary vasoconstriction was studied in isolated, bloodperfused, rat lungs. We reasoned that, if the influx of extracellular calcium mediated the hypoxic mechanism, pressor responses to alveolar hypoxia (2.5% O 3 ) would be susceptible to inhibition by the calcium antagonists verapamil (2 x 10 5 to 2 x 10 ' HIM) and SKF 525 A (2.6 to 260 IDM). Susceptibility of hypoxic pressor responses to inhibition by these calcium antagonists was contrasted to that of pressor responses elicited by the humoral vasoconstrictors angiotensin II (1 or 0.5 fig) and prostaglandin F to (10 jig). Since neither saralasin (0.5 JJM), a competitive antagonist of angiotensin II, nor meclofenamate (6.8 HM), an inhibitor of prostaglandin synthesis, depressed hypoxic pressor responses, it was concluded that these humoral transmitters were not directly involved in the hypoxic mechanism, and therefore served as independent reference agonists. The order of susceptibility of pulmonary pressor responses to inhibition by verapamil was hypoxia > angiotensin II > prostaglandin F^. SKF 525A also reduced pressor responses to hypoxia more readily than those to angiotensin II. The greater inhibition of hypoxic pulmonary vasoconstriction by both calcium antagonists suggested that the hypoxic mechanism was critically dependent on the transmembrane influx of extracellular calcium. Mediation of the hypoxic response by this type of excitation-contraction coupling is consistent with the idea that hypoxia has a direct depolarizing effect on the vascular smooth muscle. It also provides a unifying explanation for inhibition of the hypoxic mechanism by various agents that have depressant or stabilizing actions on membranes in addition to other pharmacological effects.

Role of NO pathway, calcium and potassium channels in the peripheral pulmonary vascular tone in dogs

“…During acute HPV, various studies have reported effective vasodilating actions of calcium channel inhibitors. During hypoxia, verapamil inhibited HPV in isolated rat lungs [12] but not in human pulmonary artery rings [22]. Although verapamil did not induce any signi®cant change in the pulmonary vascular tone in anaesthetized dogs, nifedipine decreased pulmonary vascular resistance [13].…”

“…It has been proposed that hypoxia might inhibit outward potassium current in pulmonary smooth muscle cells, causing membrane depolarization and thus permitting calcium entry through the voltagedependent calcium channels sensitive to dihydropyridine [11]. Calcium channel blockers like verapamil, a phenylalkylamine, have been shown to inhibit HPV [12], but Young et al [13] did not observe this inhibition with verapamil whereas nifedipine, a dihydropiridine, appeared to be a more effective pulmonary vasodilator. …”

Communications

“…McMurtry, Davidson, Reeves & Grover (1976) abolished hypoxic but not A II induced vasoconstriction in rat lungs with Verapamil which inhibits transmembrane calcium transport. We confirmed this in six rats and also found Verapamil to be a selective inhibitor of hypoxic vasoconstriction in six ferret lungs.…”

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

“…Lungs were isolated and perfused according to the technique described by Hauge (1968) and modified by McMurtry et al (1976). A tracheostomy was followed by positive-pressure ventilation with air using a rodent respirator (Model 683, Harvard Equipment, Boston, MA, USA) at 80 breaths mm.…”

“…In experiment 3, the vascular response to angiotensin II and potassium chloride (KC1) were estimated. Angiotensin II was used as a reference vasoconstrictor (McMurtry et al 1976). In experiment 4, excised lung pressure-volume curves were obtained to functionally demonstrate induction of pulmonary fibrosis.…”