Abstract 5843: Arginase II Deletion Increases Corpora Cavernosal Relaxation in Diabetic Mice
Erectile dysfunction in diabetes is associated with neuropathy and endothelial dysfunction. Nitric oxide (NO), synthesized from L-arginine by NO synthase (NOS), is of critical importance in the physiological regulation of penile erection. Arginase II (Arg-II), which is upregulated in diabetic cavernosal tissue, can inhibit the NO effects by reducing the substrate available for NO biosynthesis, thus decreasing formation of NO in the cavernosal muscle. Considering that NOS and arginase are colocalized in the male genitalia, we hypothesized that Arg-II inhibition enhances corpora cavernosal (CC) smooth muscle relaxation in diabetic model. In vitro organ bath studies were used to measure cavernosal reactivity in wild type (WT), WT diabetic (WT-D), Arg-II knockout (Arg-II KO) and Arg-II KO diabetic (Arg-II KO-D) mice. Concentration-response curves to acetylcholine (ACH), sodium nitroprusside (SNP), and phenylephrine (PE) as well as relaxant response induced by electrical-field stimulator (EFS; 1–32 Hz) were obtained in all groups. CC strips from Arg-II KO mice exhibited increased NO endothelium-dependent relaxation to ACH (84±4 %) compared to WT mice (70±3 %; P<0.05). WT-D mice showed a significant reduction of endothelium-dependent relaxation (44±8 %), but this impairment was significantly reverted in Arg-II KO-D mice (69±4 %; P<0.05). No differences in the NO-independent relaxation induced by SNP were observed in any group. CC strips from Arg-II KO mice exhibited decreased responses to PE, both in the absence and in the presence of L-NAME (100 μM), compared to WT mice. Nitrergic relaxation induced by EFS was also significantly enhanced in Arg-II KO mice (at 2, 4, 8, 16 and 32 Hz) in comparison to WT mice. We show for the first time that deletion of Arg-II prevents the impairment in cavernosal relaxation caused by diabetes (increasing relaxation by 55%, 48%, 37% and 38% at 4, 8, 16 and 32 Hz). Thus, our findings indicate that Arg-II plays a detrimental role in erectile function and that Arg-II KO mice display alterations that favor penile tumescence in diabetic mice.
(Supported by NIH grant HL70215)