TAK-044

All three members of the endothelin (ET) family of peptides, ET-1, ET-2, and ET-3, are expressed in the human kidney, with ET-1 being the predominant isoform. ET-1 and ET-2 bind to two G-protein-coupled receptors, ETA and ETB, whereas at physiological concentrations ET-3 has little affinity for the ET(A) receptor. The human kidney is unusual among the peripheral organs in expressing a high density of ET(B). The renal vascular endothelium only expresses the ET(B) subtype and ET-1 acts in an autocrine or paracrine manner to release vasodilators. Endothelial ETB in kidney, as well as liver and lungs, also has a critical role in scavenging ET-1 from the plasma. The third major function is ET-1 activation of ET(B) in in the nephron to reduce salt and water re-absorption. In contrast, ET(A) predominate on smooth muscle, causing vasoconstriction and mediating many of the pathophysiological actions of ET-1. The role of the two receptors has been delineated using highly selective ET(A) (BQ123, TAK-044) and ET(B) (BQ788) peptide antagonists. Nonpeptide antagonists, bosentan, macitentan, and ambrisentan, that are either mixed ET(A)/ET(B) antagonists or display ET(A) selectivity, have been approved for clinical use but to date are limited to pulmonary hypertension. Ambrisentan is in clinical trials in patients with type 2 diabetic nephropathy. This review summarizes ET-receptor antagonism in the human kidney, and considers the relative merits of selective versus nonselective antagonism in renal disease.

Endothelin is considered to be a key mediator of vasospasm after subarachnoid hemorrhage. A meta-analysis of randomized trials on the effectiveness of endothelin receptor antagonists in subarachnoid hemorrhage has been published previously, but since then new major trials have been published. We present the results of a systematic review and meta-analysis update.

We searched the Cochrane Library, the Cochrane Central Register of Controlled Trials, and PubMed with the following terms: subarachnoid hemorrhage AND (endothelin receptor antagonist OR clazosentan OR TAK-044 OR bosentan). All randomized, placebo-controlled trials investigating the effect of any endothelin receptor antagonists in patients with subarachnoid hemorrhage were included. Primary outcome was poor functional outcome (defined as death or dependency). Secondary outcomes were vasospasm, cerebral infarction as defined by investigators, and case fatality during follow-up. Data were pooled and effect sizes were expressed as risk ratio (RR) estimates with 95% confidence intervals (CI). We also calculated RR for several common complications.

In 5 trials with 2601 patients, endothelin receptor antagonists did not affect functional outcome (RR, 1.06: 95% CI, 0.93–1.22) despite despite a decreased incidence of angiographic vasospasm (RR, 0.58; 95% CI, 0.48–0.71). No effect was observed on vasospasm-related cerebral infarction (RR, 0.76; 95% CI, 0.53–1.11), any new cerebral infarction (RR, 1.04; 95% CI, 0.91–1.19), or case-fatality (RR, 1.04; 95% CI, 0.78–1.39). Endothelin receptor antagonists increased the risk of lung complications (RR, 1.79; 95% CI, 1.52–2.11), pulmonary edema (RR, 2.12; 95% CI, 1.32–3.39), hypotension (RR, 2.42; 95% CI, 1.78–3.29), and anemia (RR, 1.47; 95% CI,1.19–1.83).

These results argue against the use of endothelin receptor antagonists in patients with subarachnoid hemorrhage.