Does Slow-reacting Substance of Anaphylaxis Mediate Hypoxic Pulmonary Vasoconstriction?^1–3

Abstract

We have previously established a relationship between mast cell degranulation and hypoxic pulmonary vasoconstriction (HPV). In the present study, we investigated the possible role of slow-reacting substance of anaphylaxis (SRS-A) in the mediation of HPV. In 18 conscious sheep, pulmonary artery pressure, pulmonary arterial wedge pressure, and cardiac output were measured for the calculation of pulmonary vascular resistance (PVR) along with arterial oxygen tension (PaO2) while breathing room air and while breathing 13% O2 (balance, N2). Before and during 13% O2 breathing (pretreatment), Group 1 received an intravenous infusion of cromolyn sodium (3 mg/kg-1/min-1) and Group 2 was infused with FPL-57231, a SRS-A antagonist (2 mg/kg-1/min-1); Groups 3 and 4 received infusions of cromolyn sodium or FPL-57231 after induction of HPV. During 13% O2 breathing (mean PaO2, 47 mmHg), mean PVR increased to 190% of baseline. Pretreatment with cromolyn sodium prevented HPV, whereas infusion of cromolyn sodium after induction of HPV failed to reverse it; FPL-57231 both prevented HPV (pretreatment) and reversed it when infused after induction of HPV. Pretreatment with the prostaglandin synthetase inhibitor indomethacin (2 mg/kg) 1 h before the experiment failed to modify the FPL-57231-induced reversal of hypoxic vasoconstriction, thus excluding the release of inhibitory prostaglandins by this compound. We conclude that cromolyn sodium prevented HPV, presumably by inhibiting the release of SRS-A, which mediates pulmonary vasoconstriction directly or indirectly through other mechanisms.

Cardiovascular effects of leukotrienes in neonatal piglets. Role in hypoxic pulmonary vasoconstriction?

“…These results clearly are in contrast to those of Morganroth et al (1984a) and Gottlieb et al, (1984) in isolated, blood-or Ficoll-perfused adult rat and ferret lungs, and Ahmed and Oliver (1983) in adult sheep. Morganroth and colleagues found that diethylcarbamazine (2 mg/ml) and FPL55712 (1 ng/ ml) inhibited hypoxic pulmonary vasoconstriction but did not greatly decrease the response to exogenous angiotensin II.…”

“…Since leukotriene C 4 (LTC 4 ) and leukotriene D 4 (LTD 4 ) can constrict pulmonary vessels and increase pulmonary vascular resistance (Hand et al, 1981;Smedegard et al, 1982;Voelkel et al, 1982;Yokochi et al, 1982), and since synthesis of leuko-trienes might be augmented by inhibiting cyclooxygenase thereby shunting arachidonic acid to the lipoxygenase pathway [although this concept has been disputed (Kuehl et al, 1984)], increased leukotriene synthesis could, at least in part, account for the augmentation of pulmonary vasoconstriction by inhibition of prostaglandin cyclooxygenase. In support of this concept are recent reports that inhibitors of leukotriene synthesis or receptor antagonists attenuate hypoxic pulmonary vasoconstriction in isolated, perfused lungs from adult rats and ferrets (Gottlieb et al, 1984, Morganroth et al, 1984a, 1984b and in conscious adult sheep (Ahmed and Oliver, 1983).…”

Purinoceptors in the pulmonary circulation of the rat and their role in hypoxic vasoconstriction

“…In all our preparations, desensitization of the vasoconstrictor P2 receptor was confirmed by the administration of f,y-meATP, a compound which has agonist activity at the P21 and to a lesser extent P2Y receptors The mechanism underlying HPV has been the subject of much investigation in the past 20 years. A great deal of the interest has focused on potential mediators including histamine (Bergofsky, 1979), angiotensin II (Berkov, 1974), 5-hydroxytryptamine (Keith & Will, 1981) and more recently leukotrienes (Ahmed & Oliver, 1983). However, there have been inconsistencies in all of these proposed theories and to date the mechanism of HPV has remained elusive.…”

Bipyridine Derivatives Lower Arteriolar Resistance and Improve Left Ventricular Function in Newborn Lambs

“…Leukotrienes have been implicated as the mediator of hypoxic pulmonary vasoconstriction (19) and possible in the control of pulmonary blood flow in the fetus (20). We have previously demonstrated leukotriene D, to be a potent pulmonary vasoconstrictor in both lambs and piglets (2 1,22) with negative inotropic properties (22).…”