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, intermediate, or low affinity at the ETB receptor, as well as the potent ETB selective agonist sarafotoxin 6c (S6c), were characterized and compared. The effects of SB209670 (Ki ETA = 0.2 nM; Ki ETB = 12 nM), SB217242 (Ki ETA = 1.1 nM; Ki ETB = 111 nM), SB234551 (Ki ETA = 0.1 nM; Ki ETB = 500 nM), SB247083 (Ki ETA = 0.4 nM; Ki ETB = 467 nM), and S6c (Ki ETA = 950 nM; Ki 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 micrograms/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 micrograms) 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.
Willette
R N
RN
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceutics, King of Prussia, PA 19406, USA.
Sauermelch
C F
CF
Storer
B L
BL
Guiney
S
S
Luengo
J I
JI
Xiang
J N
JN
Elliott
J D
JD
Ohlstein
E H
EH
D000818:Animals; D001572:Benzofurans / Q000493:pharmacokinetics / Q000494:pharmacology; D002264:Carboxylic Acids / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007189:Indans / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011422:Propionates / Q000493:pharmacokinetics / Q000494:pharmacology; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014757:Viper Venoms / Q000494:pharmacology
D001572:Benzofurans; D002264:Carboxylic Acids; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007189:Indans; D011422:Propionates; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C113045:SB 247083; D014662:Vasoconstrictor Agents; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D019001:Nitric Oxide Synthase; C098288:enrasentan; D019331:NG-Nitroarginine Methyl Ester