Cyclosporine nephrotoxicity: sodium excretion, autoregulation, and angiotensin II.
Cyclosporine-induced nephrotoxicity (CIN) was studied in rats treated for 7 days with cyclosporine (10 mg x kg-1 x day-1 im) or vehicle (CON). CIN rats displayed characteristic reductions in glomerular filtration (GFR) and renal blood blood flow (RBF), and electron microscopy showed injury to proximal cells. Metabolic studies (7 day) showed significantly lower renal sodium excretion in conscious CIN rats compared with CON. In anesthetized rats at similar blood pressures, nephron GFR (SNGFR) was lower in CIN than CON, but fractional Na reabsorption was similar. In CIN, SNGFR, measured proximally to block flow to the sensing site of tubuloglomerular feedback (TGF) at the macula densa, was not significantly different than distal SNGFR. The rate of distal fluid delivery was significantly lower in CIN than in CON. Inhibition of the renin-angiotensin system (RAS) with captopril (CAP, 10 mg/kg iv), or saralasin (SAR, 0.3 mg x kg-1 x h-1 iv) caused marked arterial hypotension in CIN and a fall in renal vascular resistance (RVR). With arterial pressure controlled, CAP or SAR increased GFR and RBF, and reduced RVR in CIN, but did not reverse the renal deficits compared with similarly treated CON. RBF autoregulation in CIN was impaired between 90 and 140 mmHg but was partially restored by CAP. We conclude that both the filtered load and excretion rate of sodium in CIN are significantly reduced compared with controls, that SNGFR in CIN is not depressed by TGF in response to elevated distal fluid delivery, and that the RAS is not a primarily mediator of the renal vasoconstriction in CIN.
D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology; D000818:Animals; D001794:Blood Pressure; D002216:Captopril / Q000494:pharmacology; D003524:Cyclosporins / Q000633:toxicity*; D005919:Glomerular Filtration Rate; D006439:Hemodynamics; D006706:Homeostasis; D007668:Kidney / Q000098:blood supply; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D007684:Kidney Tubules / Q000503:physiopathology; D008297:Male; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012083:Renin / Q000502:physiology; D012504:Saralasin / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism; D013997:Time Factors; D000092502:Renin Inhibitors
D000804:Angiotensin II; D002216:Captopril; D003524:Cyclosporins; D012083:Renin; D012504:Saralasin; D012964:Sodium; D000092502:Renin Inhibitors