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(Circulation. 2000;102:1447.)
© 2000 American Heart Association, Inc.

Basic Science Reports

Effects of Combined Angiotensin II and Endothelin Receptor Blockade With Developing Heart Failure

Effects on Left Ventricular Performance

R. Brent New, MD; Angela C. Sampson, BS; Mary K. King, DVM; Jennifer W. Hendrick, BA; Mark J. Clair, MS; James H. McElmurray, III, BS; Jeffrey Mandel, MD; Rupak Mukherjee, PhD; Marc de Gasparo, MD; Francis G. Spinale, MD, PhD

From the Division of Cardiothoracic Surgery (R.B.N., A.C.S., M.K.K., J.W.H., M.J.C., J.H.M., J.M., R.M., F.G.S.), Medical University of South Carolina, Charleston, and the Pharmaceutical Division (M.d.G.), Novartis, Basel, Switzerland.

Correspondence to Francis G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Building, 770 MUSC Complex, Medical University of South Carolina, 114 Doughty St, Charleston, SC 29425.

Background—The goal of this study was to determine the comparative effects of angiotensin II type 1 (AT₁) receptor inhibition alone, endothelin-1 (ET) receptor blockade alone, and combined receptor blockade on left ventricular (LV) function, contractility, and neurohormonal system activity in a model of congestive heart failure (CHF).

Methods and Results—Pigs were randomly assigned to each of 5 groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant AT₁ receptor blockade (valsartan, 3 mg/kg per day) and rapid pacing (n=8), (3) concomitant ET receptor blockade (bosentan, 50 mg/kg BID) and rapid pacing (n=8), (4) concomitant combined AT₁ and ET receptor inhibition and rapid pacing (n=8), and (5) sham-operated control (n=9). LV stroke volume was reduced from the control value after rapid pacing, was unchanged with either AT₁ or ET receptor blockade alone, but was improved with combination treatment. LV peak wall stress was reduced in both groups with ET receptor blockade compared with the rapid pacing group. Plasma norepinephrine levels were increased by >3-fold after rapid pacing, remained increased in the monotherapy groups, but were reduced after combination treatment. LV myocyte velocity of shortening was reduced after rapid pacing–induced CHF, remained reduced after AT₁ receptor blockade, increased after ET receptor blockade (compared with rapid pacing–induced CHF values), and returned to within control values after combined blockade.

Conclusions—Combined AT₁ and the ET receptor blockade in this model of CHF improved LV pump function, and contributory factors included the effects of LV loading conditions, neurohormonal system activity, and myocardial contractile performance. Thus, combined receptor blockade may provide a useful combinatorial therapeutic approach in CHF.

Key Words: ventricles • norepinephrine • hemodynamics • heart failure • angiotensin • endothelin

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