Abstract
Soluble guanylyl cyclase (sGC) is the major effector molecule for nitric oxide (NO) and as such an interesting therapeutic target for the treatment of erectile dysfunction. To assess the functional importance of the sGCalpha(1)beta(1) isoform in corpus cavernosum (CC) relaxation, CC from male sGCalpha(1)(-/-) and wild-type mice were mounted in organ baths for isometric tension recording. The relaxation to endogenous NO (from acetylcholine, bradykinin and electrical field stimulation) was nearly abolished in the sGCalpha(1)(-/-) CC. In the sGCalpha(1)(-/-) mice, the relaxing influence of exogenous NO (from sodium nitroprusside and NO gas), BAY 41-2272 (NO-independent sGC stimulator) and T-1032 (phosphodiesterase type 5 inhibitor) were also significantly decreased. The remaining exogenous NO-induced relaxation seen in the sGCalpha(1)(-/-) mice was significantly decreased by the sGC-inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. The specificity of the impairment of the sGC-related responses was demonstrated by the unaltered relaxations seen with forskolin (adenylyl cyclase activator) and 8-pCPT-cGMP (cGMP analog). In conclusion, the sGCalpha(1)beta(1) isoform is involved in corporal smooth muscle relaxation in response to NO and NO-independent sGC stimulators. The fact that there is still some effect of exogenous NO in the sGCalpha(1)(-/- mice suggests the contribution of (an) additional pathway(s).
Highlights
Penile erection is a complex, neurally regulated physiologic event that involves increased blood filling of the corporal tissue and restricted venous outflow, both resulting from corporal smooth muscle relaxation.[1]
In response to increasing concentrations of NOR (10 nmol lÀ1 to 10 mmol lÀ1), the penile tissue isolated from sGCa1À/À mice developed an equal force per mg tissue compared with the sGCa1þ / þ preparations (Figure 1)
The ability to relax NOR-contracted CC preparations through release of endothelial Nitric oxide (NO) was tested by the addition of ACh (10 mmol lÀ1) and bradykinin acetate (50 mmol lÀ1)
Summary
Penile erection is a complex, neurally regulated physiologic event that involves increased blood filling of the corporal tissue and restricted venous outflow, both resulting from corporal smooth muscle relaxation.[1]. Sinusoidal and vascular endothelial cells release NO in response to mechanical[3] and chemical stimuli,[4] neurogenic NO is generally considered as the primary source
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