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

Abstract

We investigated the effects of exogenous leukotriene D4, synthesis inhibitors, and a leukotriene receptor antagonist upon chloralose anesthetized, mechanically ventilated, neonatal piglets with constant left pulmonary blood flow and upon piglets with uncontrolled pulmonary blood flow. Leukotriene D4 (100-10,000 ng, intravenously) caused dose-dependent increases in peak tracheal pressure, pulmonary vascular resistance, and systemic arterial pressure. In a limited number of experiments, cardiovascular responses to exogenous leukotriene C4 were qualitatively similar but quantitatively less than those to leukotriene D4. Neither treatment with diethylcarbamazine or the lipoxygenase inhibitor nordihydroguaiaretic acid, nor with the leukotriene receptor antagonist, FPL55712, altered any baseline cardiovascular parameter measured, suggesting the absence of any influence of leukotrienes on resting hemodynamics. Hypoxia or hypoxia combined with mild hypercapnia caused pulmonary vasoconstriction. Neither treatment with diethylcarbamazine or the lipoxygenase inhibitor nordihydroguaiaretic acid, nor with the leukotriene receptor antagonist FPL55712, altered the pulmonary vasoconstrictor response to hypoxia or combined hypoxia/hypercapnia. We conclude that endogenous leukotrienes do not appear to have an influence on resting cardiovascular function, neither do they appear to be necessary for hypoxic pulmonary vasoconstriction in the neonatal piglet, although exogenous leukotrienes are capable of producing cardiovascular effects.

The role of blood vessels in the bioconversion of leukotrienes in the pig

“…The pulmonary artery of various species has been shown to contract to leukotrienes, for example in the guinea-pig (Hand et al, 1981;Berkowitz et al, 1984) but, in general, it is fairly unresponsive. Another possibility is that the leukotrienes may be transported (and metabolized) by the circulation to act on the pulmonary microvasculature, which is responsive to leukotrienes in the neonatal pig (Leffler et al, 1984) and in the adult sheep (Kadowitz & Hyman, 1984;Malik et al, 1985). As a number of the larger vessels can produce leukotrienes , it would be interesting to see if microvessels have this capacity.…”

Hypoxic Pulmonary Vasoconstriction

“…Leukotrienes C 4 , D 4 , and E 4 caused pulmonary vasoconstriction in dogs (1902), guinea pigs (26, 734), humans (736,1723,1994), pigs (1062,1476,1520), rats (504), and sheep (19,20,918,1726). Early studies appeared to support a role for leukotrienes in mediation of HPV, as hypoxia was reported to increase leukotriene synthesis in rat lungs (1320) and inhibitors of leukotriene synthesis and receptors to decrease HPV in lambs (1583,1734), pigs (1221), and rats (1319).…”

International Union of Pharmacology XXXVII. Nomenclature for Leukotriene and Lipoxin Receptors

“…Subsequent to the early investigations , which reported that partially purified SRS markedly reduced coronary blood flow, a number of other investigators have explored the cardiovascular effects of the cys-LTs in a variety of different animal models. The early studies have shown that the cys-LTs are potent vasoconstrictors of the coronary vasculature in both isolated perfused hearts (Woodman and Dusting, 1982; and in a number of species in vivo (Michelassi et al, 1982;Panzenbeck and Kaley, 1983;Fiedler et al, 1984Leffler et al, 1984;Kopia et al, 1987;Michelassi et al, 1987) including human (Marone et al, 1988). In sheep and pigs, cys-LTs induced not only coronary vasoconstriction but also ischemia and impaired left ventriclar function (Michelassi et al, 1982;Ezra et al, 1983;Fiedler et al, 1985).…”