Endothelin receptor subtypes in the pathogenesis of angioplasty-induced neointima formation in the rat: a comparison of selective ETA receptor antagonism and dual ETA/ETB receptor antagonism using BQ-123 and SB 209670.
The present study compared the vasculoprotective efficacy of acute and chronic endothelin (ET) ETA or dual ETA/B receptor antagonism in the rat common carotid artery (RCCA) model using BQ-123 and SB 209670. Acute intra-arterial infusion (0.1 mg/kg/min) for 2 h at the time of angioplasty of either BQ-123 or SB 209670 did not attenuate the neointima lesion formation observed 2 weeks after angioplasty (neointima:media ratios of 137% and 116% of control, respectively). In contrast, chronic administration of SB 209670 (bolus i.p. injection, 2.5 mg/kg b.i.d.) attenuated lesion formation (neointima:media ratio inhibited by 52% relative to vehicle control; p < 0.05). An identical dosage regimen of BQ-123 did not exhibit significant vasculoprotection (neointima:media ratio of 128% vehicle control). However, this dosage regimen of BQ-123 was associated with significant and selective ETA receptor antagonism. The systemic pressor response to exogenous ET-1 administration was inhibited by 91% (p < 0.05), whereas the associated depressor response was not different from that observed in vehicle-treated rats. Therefore, since chronic administration of pharmacologic doses of the ETA-selective antagonist BQ-123 does not prevent lesion formation in the RCCA model, whereas the ETA/B receptor antagonist SB 209670 is vasculoprotective, the data implicate a significant role for the ETB receptor subtype, either exclusively or in concert with ETA receptor activation, in the pathogenesis of neointima formation in the rat.
Douglas
S A
SA
Department of Cardiovascular Pharmacology, Smithkline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939, USA.
Vickery-Clark
L M
LM
Louden
C
C
Elliott
J D
JD
Ohlstein
E H
EH
D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D003619:Dansyl Compounds / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D007189:Indans / Q000494:pharmacology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology*; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000502:physiology*
D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D007189:Indans; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; 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)-; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; C072247:cyclo(Trp-Asp-Pro-Val-Leu)