Effects of Prostaglandin Cyclic Endoperoxides on the Lung Circulation of Unanesthetized Sheep

Abstract

A B S T R A C T Although prostaglandins E2 and F2, have been suggested as mediators of the pulmonary hypertension seen after endotoxin infusion or during alveolar hypoxia, their precursors, the endoperoxides (prostaglandins G2 and H2) are much more potent vasoconstrictors in vitro. In this study we compared the effects of prostaglandin (PG)H2, a stable 9-methylene ether analogue of PGH2 (PGH2-A), PGE2, and PGF2a on pulmonary hemodynamics in awake sheep. The animals were prepared to allow for measurement of (a) INTRODUCTIONThe agents mediating the pulmonary hypertension seen with alveolar hypoxia and gram-negative endotoxin infusion have not been identified. Because prostaglandins (PG)l E2 and F2, are released from the lungs during these reactions, they have been implicated as the mediators, but neither is an impressive vasoconstrictor in vitro (1, 2). In contrast, their precursors, the endoperoxides PGG2 and PGH2, are powerful vasoconstrictors, -100 times more potent in constricting isolated smooth muscle (3).Because the endoperoxides are unstable and difficult to synthesize in the large amounts needed for in vivo studies, we first used a stable 9-methylene ether analogue of PGH2 (PGH2-A; [15S] hydroxy-lla, 9a-[epoxymethano] prosta-5Z, 13E-dienoic acid, [4]) to assess the effects of endoperoxides on pulmonary vascular pressures, permeability of the lung microcirculation, and lung fluid balance in awake sheep. We then prepared PGH2, itself, in amounts large enough for brief steady-state infusions, and compared its effects to those of the analogue, PGE2 and PGF2a,.

Effects of Prostaglandin H2 on Perinatal Pulmonary Circulation

“…Systemic pressure was not affected by intrapulmonary injections of "inactivated" PGH2. DISCUSSION The finding that injections of PGH2 into the pulmonary circulation of ventilated fetal lambs produced increases in PVR confirms earlier reports on PGH2 and the adult lung (9,10). Over the dose range used in this study, PGH2 did not exhibit a dose-dependent relationship with PVR.…”

“…Additionally, bolus injections of PGH2 caused increases in lobar arterial and small vein pressures in pump-perfused canine lungs (9). Unanesthetized adult sheep responded to infusions of PGH2 with doserelated increases of pulmonary arterial pressure (10). In both of these studies, a stable analog of PGH2 also produced pulmonary vasoconstriction (9,10).…”

“…Unanesthetized adult sheep responded to infusions of PGH2 with doserelated increases of pulmonary arterial pressure (10). In both of these studies, a stable analog of PGH2 also produced pulmonary vasoconstriction (9,10). Endoperoxide analogs have been shown to cause dose-dependent increases in PVR and SAP in perinatal goats (I 1).…”

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

“…U46619 randomly chosen. The doses used were based on previous studies from our and other laboratories (22,(27)(28)(29)36). The hemodynamic variables were measured continuously and the systemic arterial pH and blood gases were measured after 15 rnin at the steady state maximal response (U46619).…”

“…The pur-8 pose of the present study was to investigate the other possibility: that thromboxane A2 stimulates the production or release of leukotrienes. Because of the instability of thromboxane A2 and the limited potency of its stable measurable metabolite, thromboxane Bz, we used the specific thromboxane Az-mimetic, U46619 (Upjohn Co., Kalamazoo, MI) (22)(23)(24)(25)(26)(27)(28)(29). In newborn lambs, after characterizing the pulmonary and systemic hemodynamic effects of U466 19 by performing dose-response studies, we attempted to block or attenuate the hemodynamic response to U466 19 using FPL5723 1, a putative leukotriene receptor antagonist (Fisons plc, Loughborough, England) (2,5,16) and U60257, a putative leukotriene synthesis inhibitor (Upjohn) (1, 6, 30-34).…”