Erectile Dysfunction in Heme-Deficient Nitric Oxide-Unresponsive Soluble Guanylate Cyclase Knock-In Mice.
The nitric oxide (NO), soluble guanylate cyclase (sGC), and cyclic guanosine monophosphate (cGMP) pathway is the leading pathway in penile erection.



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



Mutant mice (sGCβ1ki/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 sGCβ1ki/kiand 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.



In vitro and in vivo recordings of erectile responses in sGCβ1ki/kiand wild-type mice after stimulation with sGC-dependent and -independent vasorelaxant agents.



NO-induced responses were abolished in sGCβ1ki/kimice 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 sGCβ1ki/kimice. In contrast, the relaxation response to the heme- and NO-independent sGC activator BAY 58-2667 was significantly enhanced in sGCβ1ki/kimice. The relaxing effect of sGC-independent vasorelaxant agents was similar in wild-type and sGCβ1ki/kimice, illustrating that the observed alterations in vasorelaxation are limited to NO-sGC-cGMP-mediated processes.



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, sGCα2β1is important for erectile function. In addition, the significant relaxation observed in sGCβ1ki/kimice with the cumulative addition of the sGC activator BAY 58-2667 indicates that sGC activators might offer value in treating erectile dysfunction.
Department of Pharmacology, Ghent University, Ghent, Belgium.
Kelly
K
Decaluwé
Department of Pharmacology, Ghent University, Ghent, Belgium.
Bart
B
Pauwels
Department of Pharmacology, Ghent University, Ghent, Belgium.
Charlotte
C
Boydens
Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Robrecht
R
Thoonen
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.
Emmanuel S
ES
Buys
Inflammation Research Center, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent, Belgium; Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Peter
P
Brouckaert
Department of Pharmacology, Ghent University, Ghent, Belgium. Electronic address: johan.vandevoorde@UGent.be.
Johan
J
Van de Voorde
D000818:Animals; D006152:Cyclic GMP / Q000378:metabolism*; D004195:Disease Models, Animal; D007172:Erectile Dysfunction / Q000503:physiopathology*; D006162:Guanylate Cyclase / Q000378:metabolism; D006418:Heme / Q000172:deficiency*; D006801:Humans; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000503:physiopathology; D000071756:Soluble Guanylyl Cyclase / Q000378:metabolism*
D009569:Nitric Oxide; D006418:Heme; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D006152:Cyclic GMP
Apo-sGC; Erectile Dysfunction; Oxidative Stress; Soluble Guanylate Cyclase; Soluble Guanylate Cyclase Activators; Soluble Guanylate Cyclase Stimulators