Contribution of endothelin receptors in renal microvessels in acute cyclosporine-mediated vasoconstriction in rats

Abstract

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.

Quantitative Micro-Computed Tomography Imaging of Vascular Dysfunction in Progressive Kidney Diseases

“…[25][26][27][28] In addition, the implementation of quantitative analyses of 3D vascular networks revealed a previously unrecognized reduction of vessel branches during disease progression paralleled by increased tortuosity of the remaining vessels. Extending previous studies, [51][52][53] we found that not only post-glomerular vessels, i.e., capillaries, but all large-to-small-sized blood vessels in the kidney exhibited substantially reduced luminal diameters during disease progression. This reduced diameter of renal vessels, in particular of small-caliber vessels, may be the consequence of the pathologic deposition of ECM proteins during disease progression, leading to increased intrarenal and/or interstitial pressure.…”

Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

“…Endothelin exerts potent renal vasoconstrictor effects in vivo through activation of ET A and ET B receptors (18,22). Both ET A and ET B receptors are known to couple to several types of heterotrimeric G-proteins predominantly leading to PLC activation and intracellular Ca 2ϩ mobilization.…”

“…The animals had free access to food and water before the experiments. The technique and experimental procedures have been previously described in detail (18). Briefly, unilateral surgical hydronephrosis was induced by permanently ligating the left ureter via a flank incision during pentobarbital sodium anesthesia (Nembutal, 60 mg/Kg intraperitoneally; Ceva, Bad Segeberg, Germany).…”

CyA-Mediated Renal Interstitial and Vascular Lesions in the Rat under Low-Sodium Diet

“…These (16,19) but did not induce hypertension (35,41). Systemic hypertension has been reported to be caused by CyA treatment in rats (5,18,27,29,33). The rise of blood pressure may be influenced by differences in strains, dose of CyA, or type of vehicle used.…”