Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future?
Lukas E. Spieker, MDa,
Georg Noll, MDa,
Frank T. Ruschitzka, MDa and
Thomas F. Lüscher, MD, FACCa
a Cardiovascular Center, Cardiology Department, University Hospital, Zürich, Switzerland
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Figure 1 Endothelin-1 (ET-1) exerts vasoconstriction and proliferation via ETA receptors on smooth muscle cells. Endothelial ETB receptors mediate vasodilation via release of nitric oxide (NO) and prostacyclin. EndothelinB receptors in the lung clear ET-1 from plasma. AI/II = angiotensin I/II; AT = angiotensin receptor; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; COX = cyclo-oxygenase; ECE = endothelin-converting enzyme; IL = interleukin; L-Arg = L-arginine; NOS = nitric oxide synthase; oxLDL = oxidized low density lipoprotein; PGI2 = prostacyclin; SR = scavenger receptor; T = thrombin receptor; TGF = transforming growth factor; Thr = thrombin.
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Figure 2 EndothelinA (ETA) receptors in the human forearm vasculature cause vasoconstriction, whereas ETB receptors mediate vasodilation via release of nitric oxide (NO). (A) When BQ-123 (10 nmol/min), a selective ETA-receptor antagonist, is infused intra-arterially in healthy subjects, a progressive increase in forearm blood flow is noted. In contrast, intra-arterial infusion of BQ-788 (1 nmol/min), a selective ETB-receptor antagonist, decreases forearm blood flow. (B) Vasodilation induced by infusion of BQ-123 (100 nmol/min; intra-arterially) in healthy subjects is attenuated by inhibition of NO synthesis with L-NMMA (200 µg/100 ml forearm volume) and concomitant sodium nitroprusside (12 to 30 ng/min, adjusted to restore basal blood flow) infusion ("NO clamp"). Acetylsalicylic acid (600 mg orally) had no effect on BQ-123-induced vasodilation. (Modified from [63]).
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Figure 3 Circulating endothelin (ET) is a prognostic indicator of one-year mortality after acute myocardial infarction (MI). (A) The relative risk of death in patients with acute MI is determined by plasma ET-1. (B) The proportion of patients surviving after acute MI is higher in patients with low plasma ET. (Modified from [125]).
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Figure 4 Pathophysiological role of endothelin-1 (ET-1) in congestive heart failure. In the heart, ET-1 contributes to contractility. In addition to its vasoconstrictive effects in the systemic and pulmonary circulation, ET-1 leads to hypertrophy of myocardial and smooth muscle cells. The pulmonary circulation is an important source of ET-1 but is also involved in the clearance of ET-1. In the kidney, ET-1 regulates sodium and water excretion. ANP = atrial natriuretic peptide.
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Figure 5 Hemodynamic severity of congestive heart failure correlates with circulating endothelin-1 (ET-1). There is an inverse relationship between stroke volume and ET-1, whereas pulmonary vascular resistance is positively related to circulating ET-1. (Modified from [223]).
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Figure 6 Systemic infusion of BQ-788 (300 nmol/min), a selective ETB-receptor antagonist, in healthy subjects increases systemic vascular resistance (SVR) and decreases heart rate (HR), cardiac index (CI) and stroke volume index (SVI). There was no significant change in systemic arterial blood pressure (MAP). (Modified from [206]).
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Figure 7 Hemodynamic effects of the selective endothelinA (ETA)-receptor antagonist darusentan after oral administration in moderate congestive heart failure. Darusentan caused a dose-dependent decrease in systemic and pulmonary vascular resistance, whereas cardiac index increased. Plasma catecholamines and heart rate did not change. (Modified from [223]).
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