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

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 (sGCβ 1 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 sGCβ 1 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 sGCβ 1 ki/ki and wild-type mice after stimulation with sGC-dependent and -independent vasorelaxant agents. Results NO-induced responses were abolished in sGCβ 1 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 sGCβ 1 ki/ki mice. In contrast, the relaxation response to the heme- and NO-independent sGC activator BAY 58-2667 was significantly enhanced in sGCβ 1 ki/ki mice. The relaxing effect of sGC-independent vasorelaxant agents was similar in wild-type and sGCβ 1 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 sGCα 1 β 1 , sGCα 2 β 1 is important for erectile function. In addition, the significant relaxation observed in sGCβ 1 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.