The Differential Effects of Leukotriene C4 and D4 on the Pulmonary and Systemic Circulations in Newborn Lambs

Abstract

ABSTRACT. Leukotriene (LT) C4 or D4 may mediate pulmonary hypertension induced by hypoxia. LT have also been isolated from patients with persistent pulmonary hypertension of the newborn syndrome and the adult respiratory distress syndrome. To compare the effects of LTC4 and D4 on the pulmonary and systemic circulations, we performed dos4response studies on spontaneously breathing newborn lambs. To determine whether the hemodynamic effects of LT are mediated through a-adrenergic stimulation, some lambs were pretreated with the a-adrenergic antagonist phentolamine mesylate before LT injection. These results were com~ared to the effects of retreatment with the LT receptor &tagonist F~~5 7 2 3 i .To determine whether the LT-induced decrease in cardiac output was mediated by the decrease in heart rate, other lambs had their heart rate maintained by left atrial pacing. We found that LTC4 and D4 increased systemic arterial pressure and decreased cardiac output and heart rate. However, LTD,, but not LTC4, increased pulmonary arterial pressure. The hemodynamic effects of LTC4 and LTD4 were completely blocked by FPL57231 but not by phentolamine mesylate. Maintenance of heart rate by left atrial pacing did not alter the LT-induced decrease in cardiac output. We conclude that LTC4 and D4 have similar effects on the systemic circulation. However, LTD4 produces more pulmonary vasoconstriction. Because FPL57231 did block the pulmonary vasoconstriction caused by LT, LT antagonists may be useful in treating patients with pulmonary hypertension. (Pediatr Res 21: 176-182, 1987 animal species (13,14,17). Clinically, LT have been isolated from the lung lavage fluid of patients with either the persistent pulmonary hypertension of the newborn syndrome (19) or the adult respiratory distress syndrome (20, 2 1).The specific LT that cause pulmonary vasoconstriction and other types of smooth muscle contraction are L T C and LTD4, both C-6 peptide derivatives of LTA4. L T C is converted to LTD4 through peptidolysis (6). Several previous studies have shown LTD4 to be a potent in vivo pulmonary vasoconstrictor (1 2, 18,22,23). Evidence suggests that LTC4 is also a pulmonary vasoconstrictor (3, 1 1, 16, 24). If LT do mediate the pulmonary vasoconstriction seen in some disease states, then LTC4 and LTD4 may play equal roles, or one may predominate.In this study, we first wanted to determine whether L T C and LTD4 produce equal pulmonary and systemic circulatory effects. We therefore performed dose-response studies of L T C and LTD4 on spontaneously breathing newborn lambs.It is possible that the pulmonary and systemic vasoconstriction produced by LT are mediated through other substances. To investigate whether the hemodynamic effects of LT are mediated through LT receptor stimulation or a-adrenergic stimulation (25), we treated some lambs with FPL57231, a LT receptor antagonist, or phentolamine mesylate, an a-adrenergic antagonist, before injecting LT.Although previous studies had suggested that LT decrease cardiac output without affecting hear...

Three Different Strains of Heat-Killed Group B β-Hemolytic Streptococcus Cause Different Pulmonary and Systemic Hemodynamic Responses in Conscious Neonatal Lambs

“…A similar biohasic resvonse of R, to leukotriene D4 injection in neonatal iambs was'observed by both Yokochi et al (36) and, inconsistently, by Schreiber et a/. (37). In spontaneously hypertensive rats, very high dose leukotriene D4 injection (20 pg/kg intraarterially) has produced a similar systemic vasodepressor effect followed by a pressor response; however, this initial depressor effect was not observed in normotensive rats (38).…”

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

“…The effects of these mediators on liver metabolism has been overlooked but an investigation has demonstrated that both LTD 4 and LTC 4 are equipotent in altering glucose and lactate output, and this modification is blocked by CGP 35949, a CysLT 1 antagonist Jungermann, 1988, 1989). In addition, investigations on the actions of the cys-LTs on renal function (Chapnick, 1984;Filep et al, 1985;Piper et al, 1985;Petric and FordHutchinson, 1995), the pulmonary circulation (Smedegard et al, 1982;Kadowitz and Hyman, 1984;Jones and Masson, 1985;Malik et al, 1985;Garcia et al, 1987;Ohtaka et al, 1987;Schreiber et al, 1987), systemic circulation (Pfeffer et al, 1983), and on the microcirculation (Dahlén et al, 1981;Bisgaard et al, 1982Bisgaard et al, , 1985Bisgaard et al, , 1986Soter et al, 1983;Chan and Ford-Hutchinson, 1985;Hua et al, 1985) to established specific CysLT receptors have not been pursued.…”

Leukotriene Antagonists Attenuate Thromboxane-Inducible Pulmonary Hypertension

“…Therefore, FPL57231 is not a thromboxane receptor antagonist. In some studies, FPL5723 1 has decreased vascular pressures and tended to increase cardiac output (43,44), but not in others (5,17). In pump-perfused fetal goat lungs, very large bolus doses of FPL57231 (to 10 mg/kg) prevented the pulmonary pressor response to leukotriene D4 and lowered normal pulmonary vascular resistance (45).…”

“…To determine the role of leukotrienes in producing the hemodynamic effects of U46619, either the putative leukotriene receptor antagonist, FPL57231, or the putative leukotriene synthesis inhibitor, U60257, was given before infusing U466 19. The doses used were based on previous studies from our and other laboratories (1-3, 5, 6,16,17). First, with the lamb spontaneously breathing and resting in a sling, baseline measurements of the hemodynamic variables and systemic arterial pH and blood gases were made (baseline 1).…”