title: Effect of angiotensin II-induced changes in perfusion flow rate on chlorothiazide transport in the isolated perfused rat kidney.
abstract: Angiotensin II was used as a probe to study the effect of changes in perfusate flow rate on the renal clearance parameters of chlorothiazide in the isolated perfused rat kidney. Perfusion studies were performed in five rats with no angiotensin II present in the perfusate and in five rats with a 1-4 ng/min infusion of angiotensin II into the perfusate. Angiotensin II had a dramatic effect on the renal hemodynamics, resulting in a 43% decrease in perfusate flow, a 16% decrease in glomerular filtration rate (GFR), and a 45% increase in filtration fraction. Values for the fractional excretion of glucose were low and consistent, with or without angiotensin II. Although the unbound fraction (fu) of chlorothiazide was unchanged between treatments, the renal (CLr) and the secretion clearances were reduced by about 50% in the presence of angiotensin II; the excretion ratio [ER = CLr/(fu.GFR)] was reduced by 38% with angiotensin II present in the perfusate. Analysis of the data was complicated by the presence of a capacity-limited transport for renal tubular secretion. Transport parameters (+/- SD) were obtained and the corrected intrinsic secretory clearance [(Vmax/GFR)/Km] of chlorothiazide was 123 +/- 18 without angiotensin II vs. 72.8 +/- 30.0 with angiotensin II. These results demonstrate that alterations in organ perfusion can significantly reduce the clearance parameters of chlorothiazide in the rat IPK. These flow-induced changes in intrinsic secretory transport may reflect perturbations other than that of perfusion flow rate alone.
authors.affiliation: College of Pharmacy, University of Michigan, Ann Arbor 48109-1065.
authors.forename: D E
authors.initials: DE
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Guillard
authors.forename: C A
authors.initials: CA
authors.lastname: Rodríguez
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D002740:Chlorothiazide / Q000378:metabolism / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D008297:Male; D008954:Models, Biological; D010477:Perfusion / Q000379:methods; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D000804:Angiotensin II; D002740:Chlorothiazide