Effects of BQ-123 on renal function and acute cyclosporine-induced renal dysfunction

Abstract

Cyclosporin A (CsA) is widely used to suppress graft rejection following transplantation and in the treatment of a variety of autoimmune diseases. Therapy with CsA is often accompanied by adverse effects which include hepatotoxicity, hypertension, and nephrotoxicity. The role of endothelin (Et) in CsA-induced nephrotoxicity has been the subject of recent investigations. BQ-123 is a recently discovered Et receptor antagonist which is selective for the EtA receptor. In the present study, BQ-123 was used to further characterize the role of Et in CsA-induced nephrotoxicity. All experiments were performed in Inactin (100 mg/kg, i.p.) anesthetized male Munich-Wistar rats (250 to 350 g). Animals were prepared for the recording of blood pressure (MAP) and heart rate (HR) as well as the measurement of urine volume (UV), UNaV, UKV, GFR and effective renal plasma flow (ERPF). GFR and ERPF were estimated from the clearance of 14C-inulin and 3H-PAH, respectively. On the day of the experiment, animals were randomly assigned to one of three groups and treated according to the following protocols: Group 1, pretreatment with BQ-123 (1 mg/kg, i.v. bolus with 0.1 mg/kg/hr i.v. infusion) followed by treatment with vehicle (cremophor; 0.15 ml, i.v.); Group 2, pretreatment with normal saline (1.0 ml/kg; plus 25 microliters/min infusion) followed by treatment with CsA (20 mg/kg, i.v.); and Group 3, pretreatment with BQ-123 (same as group 1) followed by CsA (20 mg/kg, i.v.). BQ-123 administration alone produced transient changes in several of the measured parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous endothelins mediate increased distal tubule acidification induced by dietary acid in rats.

“…To distinguish endothelin A -from endothelin B -mediated effects, we infused a comparison animal group with BQ-123 (Bachem California, Torrence, CA), a selective endothelin A receptor antagonist (11), 1 mg/kg i.v. followed by 0.1 mg/kg per h. This BQ-123 dose inhibited pressor responses to both stimulated endogenous endothelins and infused ET-1 (12).…”

Nephroprotection of an ET A -Receptor Blocker (LU 135252) in Salt-Loaded Uninephrectomized Stroke-Prone Spontaneously Hypertensive Rats

“…32 In hypertensive rats, the specific ET A receptor antagonist BQ123 reduces glomerular filtration rate by increasing arteriolar resistance. 22,33 Consequently, ET A receptor blockade may affect both renal hemodynamics and growth processes. LU 135252 also prevented tubulointerstitial damage in the salt-loaded UNX-SHRsp.…”

Unique endothelin receptor binding in kidneys of ETBreceptor deficient rats

“…affinity to each of the ET isopeptides, location, and their biological function (18). Endothelin A (ET A ) receptors bind ET-1 with higher affinity than ET-2 or ET-3, are localized to vascular smooth muscle cells, and cause vasoconstriction.…”

“…ET B receptors in the renal vasculature couple to nitric oxide and prostaglandin synthesis, leading to vasorelaxation (6), whereas ET B receptors on renal tubular cells promote natriuresis and diuresis (8,20). ET A receptors localized in arterioles and proximal tubules mediate vasoconstrictor (5, 20) and antinatriuretic effects (18,26).Elevated plasma levels of ET-1 have been implicated in the pathogenesis of many disease models, including pulmonary hypertension (2) and DOCA salt hypertension (27). Although plasma ET-1 levels are high in these disease models, there is still conflicting evidence as to the regulation of ET receptors.…”

“…ET B receptors in the renal vasculature couple to nitric oxide and prostaglandin synthesis, leading to vasorelaxation (6), whereas ET B receptors on renal tubular cells promote natriuresis and diuresis (8,20). ET A receptors localized in arterioles and proximal tubules mediate vasoconstrictor (5, 20) and antinatriuretic effects (18,26).…”