Mechanism of the negative inotropic action of leukotrienes C4 and D4 on isolated rat heart

Abstract

Leukotrienes C4 and D4 (LTC4 and LTD4), possible mediators of cardiac dysfunction during inflammatory injury, may depress cardiac function by reducing coronary flow or by exerting a negative effect directly on the myocardium. We used an isovolumic rat heart preparation perfused at constant pressure and measured left ventricular developed pressure (mmHg), coronary flow (ml.min-1), oxygen extraction, and myocardial oxygen consumption and delivery (mumol O2.[gramme dry weight]-1.min-1) during infusion of five doses of angiotensin II, LTC4, LTD4 (approximately 10 to approximately 300 pmol.min-1), and noradrenaline (400 to 2000 pmol.min-1), or perfusion with medium which contained calcium at half-concentration. LTC4 and LTD4 were equipotent with angiotensin. At low effective doses, increased oxygen extraction offset the decrease in oxygen delivery, maintaining a stable level of oxygen consumption and left ventricular developed pressure. At the highest doses, angiotensin, LTC4 and LTD4 reduced coronary flow from 21 to 15, 21 to 13, and 21 to 13 ml.min-1, respectively. And, despite greater oxygen extraction of 59%, 58% and 65% for angiotensin, LTC4 and LTD4, left ventricular developed pressure fell from a baseline of 120 mmHg to 113, 106 and 92, respectively. In contrast, low calcium perfusion reduced left ventricular developed pressure (126 to 92) and oxygen extraction (46 to 30%) without changing coronary flow or oxygen delivery. These results suggest that LTC4 and LTD4 are potent coronary vasoconstricting agents which depress cardiac function by limiting oxygen delivery.

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

“…Although LXA 4 and LXB 4 are similar in structure, these mediators display biological activities that are quite distinct. LXA 4 interactions with neutrophils involves binding sites that are not rec- Dihydroxy-leukotrienes (LTB 4 ) Leukocyte activation Bray et al, 1980;Ford-Hutchinson et al, 1980;Goetzl and Picket, 1980;Serhan et al, 1982 Cytokine secretion Luscinskas et al, 1990;Rola-Pleszczynski et al, 1993 Nuclear transcription (PPAR␣) Devchand et al, 1996IgE synthesis Odlander et al, 1988Yamaoki et al, 1994 Cysteinyl-leukotrienes (LTC 4 , LTD 4 , LTE 4 ) Bronchospasm Drazen et al, 1980;Weiss et al, 1982;Barnes et al, 1984;Jones et al, 1985;Davidson et al, 1987;Smith et al, 1993Plasma exudation Woodward et al, 1983Evans et al, 1985;Obata et al, 1992Vasoconstriction Smedegard et al, 1982Filep et al, 1985;Garcia et al, 1987;Evans et al, 1989Vasodilation Secrest et al, 1985Sakuma and Levi, 1988;Lawson et al, 1989;Pawloski and Chapwick, 1993b;Ortiz et al, 1995 Eosinophil recruitment Foster andChan, 1991;Laitinen et al, 1993;Smith et al, 1993;Spada et al, 1994;Underwood et al, 1996Cardiodepression Levi et al, 1980Burke et al, 1982;Bittl et al, 1985;Roth et al, 1985 Smooth muscle proliferation Wang et al, 1993;…”

“…In isolated perfused guinea pig heart preparations (Terashita et al, 1982;Roth et al, 1985), LTC 4 and LTD 4 caused a reduction in myocardial contractility concommitant with the vasoconstriction. In perfused rat hearts (Bittl et al, 1985), LTD 4 caused not only a reduction in flow but also reduced the spontaneous heart rate to a greater extent than contractility, suggesting an action on conductivity in this species (Feuerstein et al, 1981;Zukowska-Grojec et al, 1982;Zukowska-Grojec et al, 1984;Tomoike et al, 1987). Burke et al (1982) also showed that FPL 55712 antagonized the cardiodepressant effects of the cys-LTs suggesting that these effects were via activation of a specific receptor and noted that the potency of FPL 55712 was greater against ventricular contraction induced by LTD 4 compared with those of LTC 4 , suggesting that there may be two receptors present in the guinea pig heart.…”

Effects of 5-Lipoxygenase Inhibition on Cardiac Anaphylaxis in Isolated Guinea Pig Hearts

“…Where dissociation between effects of exoge nous LTD4 on flow and developed pressure was observed, LTD4 still produced a fall in flow but reductions in developed pressure were no longer statistically significant. Bittl et al [4] have shown that angiotensin II, LTC4 and LTD4 all reduced flow and devel oped pressure dose-dependently in a compa rable fashion in the isolated heart. Low doses increased cardiac 0 2 extraction so that changes in flow occurred without a fall in left ventricular developed pressure (LVDP).…”

Role of a nonsteroidal anti-inflammatory agent, ibuprofen, in coronary revascularization after acute myocardial infarction

“…These leukotrienes are well known mediators for vasoconstriction (6) and can secondarily decrease myocardial contractility (22). Previous studies demonstrated that intracoronary administration of leukotrienes caused a decrease in both coronary blood flow and global myocardial contractility (19).…”