Plasma- and cerebrospinal fluid-immunoreactive endothelin-1: Effects of nonpeptide endothelin receptor antagonists with diverse affinity profiles for endothelin-A and endothelin-B receptors

Some endothelin (ET) receptor antagonists have been reported to elevate plasma immunoreactive endothelin-1 (irET-1). However, there is no information regarding the effects of ET receptor antagonists on cerebrospinal fluid (CSF) levels. To better understand the regulation of circulating and CSF ET-1, the effects of several nonpeptide antagonists with high, inter-mediate, or low affinity at the ETB receptor, as well as the potent ET, selective agonist sarafotoxin 6c (S6c), were characterized and compared. The effects of SB209670 (K-i ET, = 0.2 nM; K-i ETB = 12 nM), SB217242 (K-i ETA = 1.1 nM; K-i ETB = 111 nM), SB234551 (K-i ETA = 0.1 nM; K-i ETB = 500 nM), SB247083 (K-i ETA = 0.4 nM; K-i ETB = 467 nM), and S6c (K-i ETA = 950 nM; K-i ETB = 1 nM) on plasma irET-1 were determined by ELISA in the anesthetized dog after i.v. administration. Systemic administration of equivalent doses of the nonpeptide ET receptor antagonists produced dose-related elevations in plasma irET-1 which were correlated (p = 0.019) with affinity at the ETB receptor. There was no significant correlation with affinity at the ETA receptor. In addition, the plasma irET-1 and ET antagonist concentrations were linearly correlated (r = 0.98) throughout the time course after antagonist administration. There was no evidence of densensitization after three bolus administrations performed at 2-h intervals (SB209670, 1 and 3 mg/kg i.v.). Elevations in plasma irET-1 (four- to fivefold) were also observed after systemic administration of S6c (1 nmoL/kg i.v.). The administration of L-NAME (200 mug/kg/min for 30 min), an inhibitor of nitric oxide (NO) synthase, increased blood pressure (33%) but did not alter plasma irET-1. In contrast, systemic administration of the ET receptor antagonists had little or no effect on the on irET-1 in the CSF. However, intracerebroventricular (i.c.v.) administration of SB209670 produced a dose-related (3-100 mug) increase in cisternal CSF levels of irET-1 without altering plasma irET-1. Systemic administration of ETB receptor antagonists and agonists rapidly increased plasma irET-1. These ETB receptor antagonist effects correlate linearly with affinity at the cloned human ETB receptor, do not exhibit desensitization, and do not appear to reflect inhibition of ETB-mediated NO production. The endothelial ETB receptor may represent a high-capacity storage/clearance site for circulating ET-1. ET receptor antagonists may also act extravascularly/abluminally to increase irET-1 in the CNS.