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.
The D/I (deletion, D, insertion, I) polymorphism of the angiotensin-converting enzyme (ACE) gene has been extensively studied for its association with a number of cardiovascular and other disease states. However, its potential association with differential clinical efficacy of ACE inhibitors (ACE-I) administered to patients who had suffered a myocardial infarction (MI), i.e. the prevention of left ventricular (LV) remodeling, has so far not been specifically studied. The aim of the study was to investigate whether the D/I polymorphism of the ACE gene is associated with the incidence of post-MI LV remodeling in patients drawn from the 'Healing and Early Afterload Reducing Therapy' (HEART) Study. The ACE D/I polymorphism was characterized by the polymerase chain reaction (PCR) in 265 subjects from the 'Healing and Early Afterload Reducing Therapy' Study, a double-blind, placebo-controlled trial with the objective of determining whether early or delayed administration of the ACE-I, ramipril, in patients with acute anterior wall MI would be optimal in reducing LV enlargement. Selected frequencies for the ACE D and I alleles were 0.59 and 0.41 (placebo-high dose group), 0.56 and 0.44 (low dose-low dose group), and, 0.60 and 0.40 (high dose-high dose group), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and outcome regarding LV size or function, nor with the initial blood pressure response after ACE-I administration (adjusted for covariates). Our data provide no evidence for an association of the ACE D/I polymorphism with the risk of LV remodeling post-MI in the presence of ACE-I therapy, and therefore do not suggest that differential clinical efficacy of ACE-inhibitors is related to this genetic marker.
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