title: Renal vascular and biochemical responses to systemic renin inhibition in dogs at low renal perfusion pressure.
abstract: Renin is produced by the kidney and secreted into the systemic circulation. However, its biochemical and physiological role of regulating renal blood flow with changing renal perfusion pressure (RPP) is not fully understood. In this study, the function of the intrarenal renin for production of angiotensin (Ang) I and maintenance of vascular tone was evaluated in dogs under normal conditions and when the kidney was perfused at low RPP. The dog left kidney was perfused first at normal (100 mm Hg) and then at low (30 mm Hg) RPP in the presence or absence of the renin inhibitor ciprokiren (3 mg/kg, i.v.). Both hemodynamic and biochemical parameters were measured. Lowering RPP markedly reduced left renal blood flow and elevated left renal vascular resistance. These effects were prevented by ciprokiren, which blocked the intrarenal production of Ang I. Lowering RPP increased the renal venous/ arterial ratio from 1.4+/-0.1 to 3.6+/-0.3 for plasma renin activity and from 2.4+/-0.2 to 9.8+/-1.1 for Ang I, but did not change the venous/arterial ratio for Ang II. The net renal venous conversion rate of Ang I to Ang II decreased from 0.22 to 0.09 after RPP was lowered, whereas the conversion rate in arterial blood was 1.35 and did not decrease significantly. Our results demonstrated the importance of intrarenal renin-angiotensin system for Ang I production and for the maintenance of the vascular tone, especially at low RPP. Our study also shows the limited capacity for Ang I conversion in the renal vasculature in vivo.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland. jean-paul.clozel@actelion.com
authors.forename: J P
authors.initials: JP
authors.lastname: Clozel
authors.forename: M M
authors.initials: MM
authors.lastname: Véniant
authors.forename: C
authors.initials: C
authors.lastname: Qiu
authors.forename: U
authors.initials: U
authors.lastname: Sprecher
authors.forename: R
authors.initials: R
authors.lastname: Wolfgang
authors.forename: W
authors.initials: W
authors.lastname: Fischli
mesh_terms: D000803:Angiotensin I / Q000096:biosynthesis / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000098:blood supply* / Q000378:metabolism / Q000502:physiology; D008297:Male; D010477:Perfusion; D012079:Renal Circulation / Q000502:physiology*; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D000092502:Renin Inhibitors
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D012083:Renin; D000092502:Renin Inhibitors; C085570:ciprokiren