Nonselective Endothelin Receptor Antagonist Initiated Soon After the Onset of Myocardial Infarction May Deteriorate 24-Hour Survival

Abstract

To investigate the effects of endothelin blockade initiated immediately after the onset of myocardial infarction on survival and left ventricular remodeling, treatment with the nonselective receptor antagonist TAK-044 (n = 22) or saline (n = 19) for 3 weeks was initiated immediately after coronary ligation in rats. The 24-h survival rate was significantly lower in the TAK-044 group than in the saline group. The systolic blood pressure 24 h after the onset of myocardial infarction was similar in the saline and TAK-044 groups, although it was significantly lower in the TAK-044 group during the 3-week protocol. Heart weight/tibial length was significantly increased in the TAK-044 group compared with the saline group. As all deaths in the TAK-044 group occurred within 24 h after myocardial infarction, we performed additional experiments using a separate group of rats 12-16 h after myocardial infarction. Plasma and myocardial endothelin-1 levels were significantly increased, and a bolus injection of TAK-044 significantly reduced left ventricular dP/dtmax in these rats that had had a myocardial infarction compared with sham-operated rats. Endothelin receptor blockade initiated immediately after the onset of myocardial infarction may deteriorate acute-phase survival and left ventricular remodeling. Inhibition of the positive inotropic action of endothlin-1 may partially explain the increased 24-h mortality.

Clinical trials of endothelin antagonists in heart failure: publication is good for the public health

“…19 Indeed, early administration of endothelin antagonists after experimental myocardial infarction may increase mortality, most likely due to a remodelling-related increase in cardiac dimensions. 20 21 …”

Cardiac myofibroblasts isolated from the site of myocardial infarction express endothelin de novo

“…Several in vivo studies using ET-receptor antagonists implicated a role for ET in modulating extracellular matrix turnover, tissue repair, and remodeling (7,8,11,16,19,21,22,27,30,39). ET-1 production in the failing heart as examined immunohistochemically revealed heavy ET-1 immunostaining that was confined to granulation tissue and proliferating fibroblasts (21).…”

“…Although several studies support the concept that administration of ET antagonists mitigates ET-mediated adverse remodeling (27,30), some reports demonstrate that antagonizing ET action may aggravate remodeling after MI (7). However, the time of treatment with these receptor antagonists and the choice of antagonist used have been shown to play important roles in alleviating the ET-induced adverse remodeling (19,22,29,39). In rats, subsequent to MI, ET was elevated in plasma and heart interstitial fluid (3,8).…”

Current concepts for the neurohormonal management of left ventricular dysfunction after myocardial infarction

“…Thus, factors such as receptor specificity of the drug or time of onset of therapy might influence the outcomes. Studies of endothelin antagonists post-MI have shown beneficial [41,42] and deleterious [43][44][45] results. However, these studies have been of nonselective and selective agents, have started the medications at various times after the infarct, and have treated for various durations.…”