Effects of ANG II, ETA, and TxA2 receptor antagonists on cyclosporin A renal vasoconstriction.
The renin-angiotensin system, endothelin (ET), and vasoconstrictor prostaglandins have been reported in separate studies to mediate the renal vasoconstrictor effect of cyclosporin A (CsA). However, direct comparison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable agonist-inhibiting doses of receptor antagonists for angiotensin II (ANG II), DuP-753 at 2.5 mg/kg, for ETA, BQ-123 at 0.5 mg/kg, and for thromboxane A2 (TxA2), SQ-29,548 at 1.6 mg.kg-1.h-1, or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared in anesthetized Sprague-Dawley rats. All three receptor antagonists significantly limited the CsA-induced increase in renal vascular resistance; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Because all three receptor antagonists demonstrated at least some attenuation of CsA-induced renal vasoconstriction, the potential role of acute CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonists were determined to exclude the possibilities that there was a general increased agonist sensitivity and that detection of a single or primary constrictor mediator was obscured by "crossover" receptor antagonist 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 nonspecific effects. It is concluded that CsA-induced renal vasoconstriction is complex and involves activation of multiple constrictor agonists independently or sequentially.
Conger
J D
JD
Department of Medicine, University of Colorado Health Sciences Center, Denver.
Kim
G E
GE
Robinette
J B
JB
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D016232:Endothelins / Q000037:antagonists & inhibitors*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012079:Renal Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D057911:Angiotensin Receptor Antagonists; D016232:Endothelins; D017482:Receptors, Thromboxane; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D019331:NG-Nitroarginine Methyl Ester