title: Systemic and intratubular effects of cyclosporin-A and tacrolimus on the rat kidney.
abstract: Cyclosporin-A and tacrolimus can cause hypertension and renal failure through endothelin receptors. The importance of tubular function was never investigated. The aim of this study was to compare the effects of intratubular injection of cyclosporin-A and tacrolimus with effects observed during systemic infusion. In 20 rats, either cyclosporin-A or tacrolimus was infused, 30 and 1 mg/kg i.v., respectively, in 30 min. Before and after administration, glomerular filtration rate, single nephron filtration rate, proximal and distal absolute reabsorption and percent reabsorption were measured by clearance and micropuncture techniques. In 22 other rats, single nephron filtration rate, absolute reabsorption, percent reabsorption, were measured at the last proximal and early distal tubules before and during intraluminal microinjection of either cyclosporin-A or tacrolimus. During cyclosporin-A and tacrolimus i.v. infusion, glomerular filtration rate fell from 536+/-43 to 448+/-37 microl/min (P<0.026) and from 408+/-33 to 284+/-81 microl/min (P<0. 02), single nephron filtration rate from 26.4+/-2.0 to 20.6+/-1.9 (P<0.002) and from 21.6+/-2.2 to 17.4+/-2.0 nl/min, respectively (P<0.02). The last proximal absolute reabsorption remained unchanged with cyclosporin-A (16.8+/-2.2 vs. 15.1+/-1.7 nl/min, P>0.444), but was slightly reduced by tacrolimus (14.4+/-1.7 vs. 11.3+/-1.7 nl/min, P<0.05). During microinjection, single nephron filtration rate was increased by cyclosporin-A (20+/-1 vs. 63+/-8 nl/min, P<0.0001), and tacrolimus (from 17+/-2 to 49+/-9 nl/min, P<0.0001), and so was reabsorption, independent of the sampling site. Cyclosporin-A and tacrolimus, indeed, raise single nephron filtration rate directly when injected intraluminally. Since this effect occurs in the direction opposite to that recorded during systemic infusion, it must be mediated through different pathways. The i.v. infusion of cyclosporin-A, but not tacrolimus, impairs glomerulo-tubular balance.
authors.affiliation: DPMSC, Internal Medicine, University of Udine, Medical School, Udine, Italy. giulio.romano@dpmsc.uniud.it
authors.forename: G
authors.initials: G
authors.lastname: Romano
authors.forename: A
authors.initials: A
authors.lastname: Cavarape
authors.forename: G
authors.initials: G
authors.lastname: Favret
authors.forename: N
authors.initials: N
authors.lastname: Bortolotti
authors.forename: E
authors.initials: E
authors.lastname: Bartoli
mesh_terms: D000042:Absorption; D000818:Animals; D016572:Cyclosporine / Q000493:pharmacokinetics / Q000494:pharmacology*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D007677:Kidney Function Tests; D007684:Kidney Tubules / Q000187:drug effects*; D008297:Male; D008657:Metabolic Clearance Rate; D009399:Nephrons / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus