Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice

Kelly Decaluwé; Bart Pauwels; Charlotte Boydens; Robrecht Thoonen; Emmanuel S Buys; Peter Brouckaert; Johan Van de Voorde

doi:10.1016/j.jsxm.2016.12.007

Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice

J Sex Med. 2017 Feb;14(2):196-204. doi: 10.1016/j.jsxm.2016.12.007.

Authors

Kelly Decaluwé¹, Bart Pauwels¹, Charlotte Boydens¹, Robrecht Thoonen², Emmanuel S Buys³, Peter Brouckaert⁴, Johan Van de Voorde⁵

Affiliations

¹ Department of Pharmacology, Ghent University, Ghent, Belgium.
² Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
³ Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care and Pain Medicine, Massachusetts General Hospital Research Institute, Harvard Medical School, Boston, MA, USA.
⁴ Inflammation Research Center, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁵ Department of Pharmacology, Ghent University, Ghent, Belgium. Electronic address: johan.vandevoorde@UGent.be.

PMID: 28161078
DOI: 10.1016/j.jsxm.2016.12.007

Abstract

Introduction: The nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) pathway is the leading pathway in penile erection.

Aim: To assess erectile function in a mouse model in which sGC is deficient in heme (apo-sGC) and unresponsive to NO.

Methods: Mutant mice (sGCβ₁^ki/ki) that express an sGC enzyme that retains basal activity but fails to respond to NO because of heme deficiency (apo-sGC) were used. Isolated corpora cavernosa from sGCβ₁^ki/ki and wild-type mice were mounted in vitro for isometric tension recordings in response to sGC-dependent and -independent vasorelaxant agents. In addition, the erectile effects of some of these agents were tested in vivo at intracavernosal injection.

Main outcome measures: In vitro and in vivo recordings of erectile responses in sGCβ₁^ki/ki and wild-type mice after stimulation with sGC-dependent and -independent vasorelaxant agents.

Results: NO-induced responses were abolished in sGCβ₁^ki/ki mice in vitro and in vivo. The ability of the heme-dependent, NO-independent sGC stimulator BAY 41-2272 to relax the corpora cavernosa was markedly attenuated in sGCβ₁^ki/ki mice. In contrast, the relaxation response to the heme- and NO-independent sGC activator BAY 58-2667 was significantly enhanced in sGCβ₁^ki/ki mice. The relaxing effect of sGC-independent vasorelaxant agents was similar in wild-type and sGCβ₁^ki/ki mice, illustrating that the observed alterations in vasorelaxation are limited to NO-sGC-cGMP-mediated processes.

Conclusion: Our results suggest that sGC is the sole target of NO in erectile physiology. Furthermore, this study provides indirect evidence that, in addition to sGCα₁β₁, sGCα₂β₁ is important for erectile function. In addition, the significant relaxation observed in sGCβ₁^ki/ki mice with the cumulative addition of the sGC activator BAY 58-2667 indicates that sGC activators might offer value in treating erectile dysfunction.

Keywords: Apo-sGC; Erectile Dysfunction; Oxidative Stress; Soluble Guanylate Cyclase; Soluble Guanylate Cyclase Activators; Soluble Guanylate Cyclase Stimulators.

MeSH terms

Animals
Cyclic GMP / metabolism*
Disease Models, Animal
Erectile Dysfunction / physiopathology*
Guanylate Cyclase / metabolism
Heme / deficiency*
Humans
Male
Mice
Nitric Oxide / metabolism
Penile Erection / drug effects
Penis / physiopathology
Soluble Guanylyl Cyclase / metabolism*

Substances

Nitric Oxide
Heme
Guanylate Cyclase
Soluble Guanylyl Cyclase
Cyclic GMP