Endothelin A Receptor Antagonism and Angiotensin-Converting Enzyme Inhibition Are Synergistic via an Endothelin B Receptor–Mediated and Nitric Oxide–Dependent Mechanism

Abstract

Abstract. Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve Ϯ SEM; BQ-123, Ϫ2.3 Ϯ 1.8%; BQ-123ϩE, Ϫ5.1 Ϯ 1.1%; P Ͻ 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, Ϫ0.1 Ϯ 2.4%; BQ-123ϩE, 10.9 Ϯ 4.2%; P Ͻ 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, Ϫ1.2 Ϯ 3.1%; BQ-123ϩE, Ϫ12.8 Ϯ 3.0%; P Ͻ 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 Ϯ 12.8%; BQ-123ϩE, 25.2 Ϯ 12.6%; P Ͻ 0.05 versus BQ-123, P Ͻ 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptormediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.Endothelin-1 (ET-1) is a vasoactive peptide that is produced by the vascular endothelium (1) and acts through two receptors to regulate vascular tone. Vascular smooth muscle ETA and ETB receptors (2,3) mediate vasoconstriction, whereas endothelial ETB receptors mediate vasodilation through generation of nitric oxide (NO) and prostanoids (3). Angiotensin II (Ang II) is another powerful vasoconstrictor involved in the regulation of vascular tone, and there is considerable evidence for an interaction between the endothelin and renin-angiotensin systems (4). Ang II increases ET-1 transcription and secretion in vitro in a variety of cell types, including endothelial and vascular smooth muscle cells (5,6), and ET receptor antagonists attenuate the acute hemodynamic effects of Ang II in rats in vivo (7,8). However, this is by no means a uniform finding (9) and has not been replicated in dogs (10) or humans (11). Data in animals suggest that concomitant ET blockade and angiotensin-converting enzyme (ACE) inhibition produce changes greater than those seen with blockade of either system alone (12-15). In addition, clinical studies that demonstrated major hemodynamic effects of ET receptor antagonists have generally been per...

Selective Endothelin-A Receptor Antagonism Reduces Proteinuria, Blood Pressure, and Arterial Stiffness in Chronic Proteinuric Kidney Disease

“…[27][28][29] Furthermore, we have shown recently that acute ET A receptor antagonism can reduce proteinuria by an additional Ϸ30% on top of that achieved with optimal treatment with inhibitors of the renin-angiotensin system in subjects with proteinuric CKD. 14 The current study suggests that these effects are maintained longer term and are of a similar magnitude.…”

The Endothelin System and Its Antagonism in Chronic Kidney Disease

“…With respect to the kidneys, when ET A receptor antagonism is given in the presence of ACE inhibition in healthy subjects, contrary to a lack of effect of ET A receptor antagonism alone, an increase in RBF and natriuresis is observed, an effect that seems to be both ET B dependent and NO mediated (53). Although it is tempting to attribute the increase in sodium excretion to the activity of an unblocked tubular ET B receptor, it is possible that the natriuresis is entirely a consequence of the renal vasodilation and so essentially a hemodynamic effect.…”

“…Also, many clinical studies using ET receptor antagonists in patients with heart failure demonstrated major additional hemodynamic effects (153,154) in patients who already were receiving ACE inhibitors. Synergism with respect to acute systemic hemodynamic effects between ET A receptor antagonists and angiotensin receptor type 1 antagonists (ARB) (51) or ACE inhibitors (53) has been demonstrated in humans. More recently, the combination of ET receptor antagonism and ACE inhibition has been shown to improve endothelial function (155,156).…”

Blood Pressure–Independent Reduction in Proteinuria and Arterial Stiffness After Acute Endothelin-A Receptor Antagonism in Chronic Kidney Disease

“…Thus, based on this work, we hypothesized that, in patients with nondiabetic proteinuric CKD, selective ET A receptor antagonism would reduce proteinuria and arterial stiffness and improve endothelial dysfunction and that these effects would be greater than those achieved with BP reduction alone. Because we have previously demonstrated a synergism between ACE inhibitors and selective ET A receptor antagonism in health, 19 we anticipated that these effects might be evident on top of standard treatment with ACE inhibitors and/or angiotensin receptor blockers.…”