Glomerular hemodynamics and hormonal participation on cyclosporine nephrotoxicity

Abstract

The mechanism of cyclosporine A (CyA) nephrotoxicity is unclear. In order to evaluate renal microcirculation seven euvolemic Munich-Wistar (MW) rats were studied after acute CyA treatment (50 mg/kg, i.v.). Both total glomerular filtration rate (GFR, 0.96 ± 0.04 vs. 0.47 ± 0.07 ml/min) and single nephron GFR (27.90 ± 3.39 vs. 14.02 ± 3.49 nl/min) declined significantly (P < 0.001). It was observed an increase in afferent (R(A), ↑ 188%) and efferent (R(E), ↑ 360%) arteriolar resistances that caused a decrease on glomerular plasma flow rate (Q(A)) from 100.99 ± 17.09 to 44.37 ± 13.37 nl/min (P < 0.001). Mean glomerular capillary hydraulic pressure (P̄(GC)) increased from 45 ± 1 to 55 ± 4 mm Hg (P < 0.05) and the glomerular ultrafiltration coefficient (K(f)) decreased by 70% (0.096 ± 0.030 to 0.031 ± 0.010 nl/sec · mm Hg, P < 0.05). Additionally, in order to study hormonal participation in this nephrotoxicity, other three groups of MW rats were previously treated with captopril (2 mg/kg, i.v.), verapamil (20 μg/kg/min, i.v.) or indomethacin (2 mg/kg, i.v.). Both captopril and verapamil minimized the renal effects of CyA, with a decline of ~25% instead of ~50% on GFR and RPF. Moreover, two groups of Brattleboro rats were studied. Acute CyA administration in homozygote Brattleboro rats produced a decline of only ~22% and ~31%, respectively, in GFR and renal plasma flow (RPF), when compared with MW rats (P < 0.05). Similar results were observed in heterozygote Brattleboro rats when compared with MW rats, disclosing differences due to a different strain of rats. According to these data, acute CyA administration caused a reduction in SNGFR due to an increase on R(A) and R(E) with decreases on Q(A) and K(f) values. These studies suggest that, at least, the renin-angiotensin system and ADH may participate in this glomerular function impairment. Furthermore, indomethacin did not alter the effect induced by CyA, indicating that prostaglandins may be not an important factor in these alterations. The protective action of verapamil may indicate a potential use of Ca channel blockers in order to minimize CyA nephrotoxicity.