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(Circulation. 2000;101:142.)
© 2000 American Heart Association, Inc.

Clinical Investigation and Reports

Contrasting Inotropic Effects of Endogenous Endothelin in the Normal and Failing Human Heart

Studies With an Intracoronary ET_A Receptor Antagonist

Philip A. MacCarthy, BSc, MB, ChB, MRCP; Richard Grocott-Mason, MA, MD, MRCP; Bernard D. Prendergast, BMedSci, MD, MRCP; Ajay M. Shah, MD, FRCP, FESC

From the Department of Cardiology (P.A.M., R.G.-M., B.D.P.), University of Wales College of Medicine, Heath Park, Cardiff, UK, and GKT School of Medicine (A.M.S.), King’s College London, London, UK.

Correspondence to Professor Ajay M. Shah, Department of Cardiology, GKT School of Medicine, King’s College London, Bessemer Rd, London SE5 9PJ, United Kingdom. E-mail ajay.shah{at}kcl.ac.uk

Background—Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its physiological effects on intrinsic myocardial contractile function in humans in vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the failing human heart are also unknown.

Methods and Results—A specific ET_A receptor antagonist, BQ123, was infused (40 nmol/min, 16 minutes) into the left coronary artery in 8 patients with atypical chest pain (normal left ventricular [LV] function and coronary arteries) and 8 patients with nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic catheterization. In normal subjects, BQ123 rapidly induced a significant reduction in LV dP/dt_max (-270±71 mm Hg/s after 16 minutes; P<0.05) and in LV dP/dt at a developed pressure of 40 mm Hg (LV dP/dt₄₀) (-179±54 mm Hg/s; P<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dt_max (62±49 mm Hg/s after 16 minutes) or LV dP/dt₄₀ (83±51 mm Hg/s;P<0.05 compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation, LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either patient group.

Conclusions—Endogenous ET-1 has a tonic positive inotropic effect in normal subjects, independent of effects on the peripheral vasculature and unmasked by inhibition of ET_A receptors. However, the effect of short-term ET_A blockade in DCM patients was opposite to that in normal subjects, which suggests that ET-1 may cause negative inotropic effects in the failing heart.

Key Words: endothelin • cardiomyopathy • contractility

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