Recent studies demonstrate that endothelin, a potent endogenous vasoconstrictor peptide, circulates in plasma of normal animals and humans. However, the role of this peptide in pathophysiological states remains unclear. The present study was designed to test the hypothesis that circulating endothelin concentrations are increased in experimental congestive heart failure (CHF), a pathophysiological state characterized by activation of vasoconstrictor mechanisms. In anesthetized dogs with CHF produced by 8 days of rapid ventricular pacing (n =28), circulating plasma endothelin was increased compared with values for normal controls (n=28; 20.4+1.4 versus 9.7+0.9 pg/ml, respectively; p<0.0001). A plasma endothelin level of more than 14.0 was a sensitive and specific indicator of significant CHF. Moreover, within the group with experimental CHF, right atrial pressure and pulmonary capillary wedge pressure correlated independently with circulating endothelin levels. Based on recent studies demonstrating the physiological actions of twofold increases in circulating endothelin, as observed in the present study, a possible role for endothelin in the pathophysiology of CHF is advanced. (Circulation 1990;82:2226-2230 E ndothelin is a peptide hormone with potent vasoconstrictor actions that was first isolated from cultured porcine aortic endothelial cells.' The vasoconstrictive properties, modulatory actions on the renin-angiotensin-aldosterone system, and antinatriuretic effects of endothelin have been well characterized in vitro and in vivo.2 Although such peptide actions suggest an important regulatory action, a potential role of endothelin in physiological or pathophysiological states remains unclear. In this context, recent studies have demonstrated that endothelin circulates in plasma of normal animals and humans.3-7 Increases in circulating endothelin have been documented in states of severe cardiovascular stress, including cardiogenic shock.7 acute myocardial infarction,8 after major abdominal surgery,6 and after liver transplantation9; these increases are consistent with a role for endothelin as an important endogenous vasoconstrictor that appears to modu-

Background. The endothelium possesses the ability to modulate vascular tone by the release of vasodilators and vasoconstrictors, among them endothelium-derived relaxing factor (EDRF) and endothelin (ET). Abnormalities in EDRF generation have been demonstrated in various cardiovascular pathophysiological states. Moreover, a twofold increase in plasma ET concentration was reported in these disease states. Recent in vitro studies have suggested the interaction between these two endotheliumderived substances, suggesting that imbalance between the two may contribute to alternation in vascular tone characteristic of these disease states. Thus, the hypothesis of this study was that inhibition of endogenous EDRF will enhance the vasoconstrictor response to a twofold increase in plasma ET concentrations.Methods and Results. Experiments were conducted in three groups of anesthetized dogs. In group 1, ET-1 was infused intravenously to double circulating ET concentrations. Group 2 received both ET and NG-monomethyl L-arginine (L-NMMA), a competitive inhibitor of EDRF generation, and group 3 received a continuous infusion of L-NMMA alone. Twofold increase in plasma ET concentrations was characterized by an increase in systemic and renal vasoconstriction. The inhibition of EDRF markedly enhanced the vasoconstriction to ET specifically involving the systemic, pulmonary, coronary, and renal arterial circulations.Conclusions. The present study demonstrates that inhibition of endogenous EDRF augments the vasoconstrictor property of ET and supports a functional role for the balance between endotheliumderived vasodilating and vasoconstricting factors in the regulation of vascular tone.

The present studies demonstrate that endothelin at pathophysiological plasma concentrations produced by exogenous endothelin has biological action. These studies support a functional role for endogenous endothelin as a potentially pathophysiological vasoconstrictor peptide hormone in the regulation of cardiovascular, renal, and endocrine function.

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The endothelium has emerged as an important modulator of vascular tone by producing both vasodilating and vasoconstricting substances. In vitro studies have demonstrated that endothelial cells produce endothelium-derived relaxing factor (EDRF), which promotes vasodilation via the stimulation of intracellular guanosine 3',5'-cyclic monophosphate (cGMP). However, the role of EDRF in the basal regulation of cardiopulmonary and renal function is not well defined. The present study was therefore designed to assess the function of EDRF by studying two groups of normal anesthetized dogs, of which one received a competitive inhibitor to EDRF generation, NG-monomethyl-L-arginine (L-NMMA; 50 micrograms.kg-1.min-1 iv), and the other received a vehicle. The L-NMMA infusion produced no significant increase in mean arterial pressure but marked increases in systemic, pulmonary, and renal vascular resistances compared with the vehicle group. Although renal blood flow decreased with L-NMMA, no changes were observed in glomerular filtration rate or sodium excretion. Associated with the cardiopulmonary and renal responses with L-NMMA was a modest increase in plasma endothelin (7.9 +/- 1.3 to 10.2 +/- 1.8 pg/ml, P less than 0.05), an endothelium-derived vasoconstrictor. No alteration was observed in plasma or urinary cGMP with EDRF inhibition. These cardiopulmonary and renal responses with L-NMMA may be attributed not only to EDRF inhibition but to an imbalance between endothelium-derived relaxing and contracting factors.