Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway

Prior studies have demonstrated that the erectile response in the rat penis is androgen dependent and is mediated by nitric oxide (NO), the neurotransmitter synthesized by the enzyme nitric oxide synthase (NOS). The present studies used L-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NOS, to determine if androgens also regulate alternative pathways leading to the erectile response but not mediated by NO. Castrated rats that were treated with L-NAME (L-NAME CASTRATE) exhibited little or no increase in intracavernosal pressure in response to stimulation of the major pelvic ganglion. This ganglion controls blood flow into the penis and, when stimulated, normally leads to erection. However, when castrated animals were treated with testosterone along with L-NAME (L-NAME TESTO), the animals responded to the ganglionic stimulation with increased intracavernosal pressure. This finding suggests that there are other androgen-dependent pathways that lead to penile erection but are not mediated by NO. Erection occurred in both L-NAME CASTRATE and L-NAME TESTO rats in response to intracavernosal injection of sodium nitroprusside (an NO donor drug), proving that the NO responsive mechanisms were unaffected by the inhibition of NOS activity. To investigate further the nature of this NO independent pathway, L-NAME CASTRATE and L-NAME TESTO rats were treated with either zaprinast (a specific phosphodiesterase 5 inhibitor), which would block the breakdown of cGMP to 5'GMP, or methylene blue (an inhibitor of guanylate cyclase) to prevent the synthesis of cGMP. Zaprinast treatment led to increased erectile response in L-NAME TESTO rats but not in L-NAME CASTRATE rats, demonstrating that androgen-sensitive alternative pathways increased guanylate cyclase activity. Methylene blue inhibited the erectile response in all treatment groups, showing that cyclic GMP is critical to the NO-independent pathway as well as the NO-dependent pathway. Taken together, these results support the hypothesis that androgens maintain the erectile response by alternate pathways, including one that is independent of NO but involves the synthesis of cyclic GMP.