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You are here: Home Research Groups Renal Hemodynamics Recent Activities Soluble Guanylate Cyclase in Renal Hemodynamics
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Soluble Guanylate Cyclase in Renal Hemodynamics

Dautzenberg, Kahnert, Stasch, Just

Nov 11, 2014

Soluble Guanylate Cyclase in Renal Hemodynamics

Dautzenberg et al 2014

Dautzenberg M., Kahnert A., Stasch J.P., Just A.
Role of soluble guanylate cyclase in renal hemodynamics and autoregulation in the rat.
Am J Physiol Renal Physiol 2014 Nov, 307(9): F1003-F1012

 

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Summary

Soluble guanylate cyclase (sGC) is the key enzyme of the cGMP signaling cascade and thought to be the main target for the effects of nitric oxide. We studied the effects of pharmacological activation of sGC by Cinaciguat on blood flow and filtration in the kidney and also the role of sGC in mediating the physiological effects of endogenous nitric oxide.

Despite the known reduction of arterial pressure by Cinaciguat, renal blood flow and filtration rate were well maintained, with only slight depression of filtration fraction and blood flow autoregulation. This indicates safety of systemic sGC activation with regard to renal function.

Elimination of endogenous nitric oxide elevated arterial pressure, reduced renal blood flow, and modified autoregulation. These changes were reversed by 77, 78, and 90% by cinaciguat, indicating that these hemodynamic effects of endogenous NO are mediated predominantly via sGC.

 

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 N(ω)-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.

 

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