Jd. Conger et al., EFFECTS OF ANG-II, ET(A), AND TXA(2) RECEPTOR ANTAGONISTS ON CYCLOSPORINE-A RENAL VASOCONSTRICTION, The American journal of physiology, 267(3), 1994, pp. 60000443-60000449
The renin-angiotensin system, endothelin (ET), and vasoconstrictor pro
staglandins have been reported in separate studies to mediate the rena
l vasoconstrictor effect of cyclosporin A (CsA). However, direct compa
rison of the relative importance of these potential mediators has not
been performed. In this study, the attenuating effects of comparable a
gonist-inhibiting doses of receptor antagonists for angiotensin II (AN
G II), DuP-753 at 2.5 mg/kg, for ET(A), BQ-123 at 0.5 mg/kg, and for t
hromboxane A(2) (TxA(2)), SQ-29,548 at 1.6 mg.kg(-1).h(-1), or saline
vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared i
n anesthetized Sprague-Dawley rats. All three receptor antagonists sig
nificantly limited the CsA-induced increase in renal vascular resistan
ce; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Be
cause all three receptor antagonists demonstrated at least some attenu
ation of CsA-induced renal vasoconstriction, the potential role of acu
te CsA-related nitric oxide synthase (NOS) inhibition and nonspecific
heterologous effects of specific receptor antagonists on other agonist
s were determined to exclude the possibilities that there was a genera
l increased agonist sensitivity and that detection of a single or prim
ary constrictor mediator was obscured by ''crossover'' receptor antago
nist effects. CsA significantly reduced renal blood flow (39%) in the
presence of the NOS inhibitor, N-omega-nitro-L-arginine methyl ester,
and there was negligible indication that receptor antagonists had nons
pecific effects. It is concluded that CsA-induced renal vasoconstricti
on is complex and involves activation of multiple constrictor agonists
independently or sequentially.