title: Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat.
abstract: We studied the influence of soluble guanylate (sGC) on renal blood flow (RBF), glomerular filtration rate (GFR), and RBF autoregulation and its role in mediating the hemodynamic effects of endogenous nitric oxide (NO). Arterial pressure (AP), heart rate (HR), RBF, GFR, urine flow (UV), and the efficiency and mechanisms of RBF autoregulation were studied in anesthetized rats during intravenous infusion of sGC activator cinaciguat before and (except GFR) also after inhibition of NO synthase (NOS) by Nω-nitro-L-arginine methyl ester. Cinaciguat (0.1, 0.3, 1, 3, 10 μg·kg(-1)·min(-1), n=7) reduced AP and increased HR, but did not significantly alter RBF. In clearance experiments (FITC-sinistrin, n=7) GFR was not significantly altered by cinaciguat (0.1 and 1 μg·kg(-1)·min(-1)), but RBF slightly rose (+12%) and filtration fraction (FF) fell (-23%). RBF autoregulatory efficiency (67 vs. 104%) and myogenic response (33 vs. 44 units) were slightly depressed (n=9). NOS inhibition (n=7) increased AP (+38 mmHg), reduced RBF (-53%), and greatly augmented the myogenic response in RBF autoregulation (97 vs. 35 units), attenuating the other regulatory mechanisms. These changes were reversed by 77, 78, and 90% by 1 μg·kg(-1)·min(-1) cinaciguat. In vehicle controls (n=3), in which cinaciguat-induced hypotension was mimicked by aortic compression, the NOS inhibition-induced changes were not affected. We conclude that sGC activation leaves RBF and GFR well maintained despite hypotension and only slightly impairs autoregulation. The ability to largely normalize AP, RBF, RBF autoregulation, and renovascular myogenic response after NOS inhibition indicates that these hemodynamic effects of NO are predominantly mediated via sGC.
authors.affiliation: Physiologisches Institut, Albert-Ludwigs-Universität, Freiburg, Germany; and.
authors.forename: Marcel
authors.initials: M
authors.lastname: Dautzenberg
authors.affiliation: Bayer HealthCare Pharmaceuticals, Cardiology/Hematology Research, Wuppertal, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Kahnert
authors.affiliation: Bayer HealthCare Pharmaceuticals, Cardiology/Hematology Research, Wuppertal, Germany.
authors.forename: Johannes-Peter
authors.initials: JP
authors.lastname: Stasch
authors.affiliation: Physiologisches Institut, Albert-Ludwigs-Universität, Freiburg, Germany; and armin.just@physiologie.uni-freiburg.de.
authors.forename: Armin
authors.identifier: http://orcid.org/0000-0002-4897-1143
authors.initials: A
authors.lastname: Just
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006162:Guanylate Cyclase / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology*; D000071756:Soluble Guanylyl Cyclase
chemical_list: D001565:Benzoates; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; C480588:BAY 58-2667; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
keywords: cGMP; cinaciguat; glomerular filtration rate; nitric oxide; renal blood flow autoregulation; renal hemodynamics; sGC activation; soluble guanylate cyclase