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LevEndothelin Receptor AntagonistsKW Tim Park, MD
Endothelins (ET) are a family of 3 distinct peptides, ET-1, ET-2, and ET-3.1 Prepro-ET is initially cleaved by an endopeptidase and a carboxypeptidase to an inactive intermediate called "big ET", which is then further processed by endothelin-converting enzyme (ECE) to generate the active peptide. Multiple factors including insulin, thrombin, angiotensin II, vasopressin, low shear stress, and ET-1 itself can stimulate ET production. ET-1 is the major isopeptide produced and released abluminally (i.e., toward the subjacent smooth muscle cells) by the endothelial cells. There are two distinct G-protein coupled ET receptor subtypes, ETA and ETB. ETA receptors, localized mainly on vascular smooth muscle cells, are stimulated by ET-1 and lead to vasoconstriction and smooth muscle hypertrophy. ETB receptors are located both on the endothelial cells, where they mediate the release of endothelium-derived relaxing factor, and on the smooth muscle cells, where they mediate vasoconstriction. In the kidneys, ET-1 produces constriction of afferent arterioles via ETA receptors and constriction of efferent arterioles via ETB receptors and inhibits sodium and water reabsorption via ETB receptors in the distal tubule. In humans, ET has been implicated in development of essential hypertension, especially in African Americans who have high levels of ET-1 and a decrease in ETB ratio of endothelial to smooth muscle cells; myocardial hypertrophy; heart failure; pulmonary hypertension; and atherogenesis.2 Currently available medications in investigations to manipulate the endothelin system include nonselective endothelin receptor antagonists, bosentan and tezosentan, and the selective ETA receptor antagonist, darusentan. The affinity of darusentan for ETA receptors is about 130 times that for ETB receptors.3 Bosentan and tezosentan are available both in oral and intravenous forms, while darusentan is available orally only. In heart failure patients, plasma levels of big ET are elevated4 and correlated with hemodynamic alterations,4 prognosis,5 and functional capacity.6 Several trials have examined the effectiveness of ET receptor antagonists in ameliorating heart failure. Torre-Amione et al. examined the effect of acute intravenous administration of tezosentan in 61 patients with NYHA class III or IV heart failure.7 Tezosentan caused a dose-dependent increase in cardiac index ranging from 24.4 to 49.9 % (P < 0.05 vs. placebo), while reducing pulmonary capillary wedge pressure, pulmonary and systemic vascular resistances, with no change in heart rate. No significant systemic hypotension was noted. Similarly, Sutsch et al. performed a placebo-controlled study of oral bosentan in 36 patients with NYHA class III heart failure (left ventricular ejection fraction 22.4 ± 4.5 %) despite treatment with diuretics, digoxin, and ACE inhibitors8 and found a sustained increase in cardiac output with reduction in systemic and vascular resistances and no change in heart rate. A similar result was obtained with darusentan, the selective ETA receptor antagonist, but there was a trend toward greater mortality with higher doses (≥ 100 mg/d).9 No study has reported on the long-term effects of these medications and further studies are needed to delineate the benefits and adverse effects of these medications in heart failure patients. Other clinical applications of endothelin receptor antagonists may include treatment of systemic hypertension and of pulmonary hypertension (PHTN). Darusentan may be effective in lowering both systolic and diastolic blood pressures in essential hypertension, especially salt-sensitive hypertension prevalent in African Americans.1, 2 In a rat model of salt-sensitive hypertension, darusentan also reduced proteinuria and may be nephroprotective.10 Williamson et al. tried intravenous infusions (50 - 300 mg) of bosentan in 7 patients with primary PHTN or isolated PHTN with limited scleroderma, which was resistant to inhaled nitric oxide.11 There was a dose-dependent decrease in pulmonary vascular resistance (about 20 %) and pulmonary artery pressure (about 10 mmHg). But systemic pressures also decreased and the effect of bosentan was nonselective, indicating that its application in PHTN is likely to be limited. Thus far, there have not been any reports of using intravenous endothelin receptor antagonists in the perioperative setting and it remains to be seen whether they will have an application as a secondary or tertiary line medication in cardiovascular surgical patients with refractory heart failure. References
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