Inhibition of Myogenic Autoregulation in Cyclosporine Nephrotoxicity in the Rat

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Abstract
The mechanisms responsible for the impairment of renal blood flow (RBF) autoregulation in cyclosporine nephrotoxicity were investigated with clearance and micropuncture studies in anesthetized rats. Early chronic cyclosporine nephrotoxicity (CCN) was induced in male rats by daily intramuscular injection of 10 mg/kg/day cyclosporine-A in olive oil for 7 days; control (CON) rats received vehicle injections. Glomerular filtration rate and RBF were both reduced by 33% in CCN when compared to CON rats. RBF autoregulation was also significantly impaired in CCN, with an autoregulation index (AI) of 0.53 ± 0.03 vs. 0.16 ± 0.01 in CON rats. Micropuncture studies showed that the tubuloglomerular feedback (TGF) system is not impaired in CCN. Rather, in CCN there was a slight resetting such that the maximun TGF response was greater and the onset occurred at lower rates of perfusion than in CON. In contrast, further micropuncture studies demonstrated that TGF-independent autoregulation of glomerular capillar pressure was significantly impaired in CCN, with an AI of 0.86 ± 0.09 vs. 0.57 ± 0.06 in CON. These results indicate that the loss of autoregulatory ability in rats with CCN results from substantial impairment of the myogenic autoregulatory mechanism that is an intrinsic property of the preglomerular vasculature of the kidney.

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