Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats.
Cyclosporine A (CsA), a widely used immunosuppressive agent, causes renal vasoconstriction and systemic hypertension. Recent data suggest that the renal effect of CsA is possibly mediated by endothelin (ET). We investigated the effects of CsA on renal microvessels and the efficacy of ETA or ETA/ETB receptor antagonists in ameliorating CsA effects in the hydronephrotic rat kidney. Infusion of CsA (30 mg.kg-1) induced a transient increase (20%) in mean arterial pressure (MAP) and a sustained reduction (85%) in glomerular blood flow (GBF) due to preferential constriction of the arcuate artery (39%) and the proximal segment of the interlobular artery (23%). Under basal conditions the ETA receptor antagonist BQ-123 had marginal effects consisting of reduction in MAP, rise in GBF and dilation of preglomerular vessels. The non-selective ETA/ETB receptor antagonist PD 145065 also reduced MAP, but tended to decrease GBF and constrict large preglomerular vessels. The difference in effects of the two antagonists indicated that under basal conditions ETB blockade constricts large preglomerular vessels and reduces GBF. After BQ-123 or PD 145065, the constriction of large preglomerular vessels and reduction in GBF induced by CsA was attenuated by about 50%, but the rise in MAP was not influenced. Our data indicate that a sizable part of renal vasoconstriction due to CsA is mediated via ET production in large preglomerular arteries and can be avoided by the blockade of ETA receptors. Additional blockade of ETB receptors does not attenuate the CsA effects further, possibly because ETB receptors mediate both vasoconstriction and dilation.
Cavarape
A
A
Department of Internal Medicine, University of Udine, Italy. alessandro.cavarape@dpmsc.uniud.it
Endlich
K
K
Feletto
F
F
Parekh
N
N
Bartoli
E
E
Steinhausen
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000737:chemistry / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology*; D004347:Drug Interactions; D065128:Endothelin Receptor Antagonists; D005260:Female; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply*; D010456:Peptides, Cyclic / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D007166:Immunosuppressive Agents; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; D016572:Cyclosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)