Nitrergic-noradrenergic interaction in penile erection: a new insight into erectile dysfunction.

Penile erection is regulated by two opposing systems: noradrenergic (anti-erectile) and nitrergic (pro-erectile) neurotransmission. Noradrenaline released from sympathetic nerves causes contraction of the blood vessels and smooth muscle of the penile corpus cavernosum, thus leading to detumescence of the penis. Nitric oxide (NO) released from nitrergic nerves causes relaxation of the smooth muscle of the corpus cavernosum, thus allowing engorgement of blood into the cavernous space and leading to erection. Nitrergic neurotransmission is known to modulate noradrenergic responses. We have recently shown that the degree of this modulation varies among species. In the human corpus cavernosum, noradrenergic responses are under nitrergic control, such that even pharmacological concentrations of noradrenaline fail to show an effect when nitrergic neurotransmission is operating. This situation is similar in the monkey and rabbit, where nitrergic neurotransmission does not merely modulate but actually controls the sympathetic responses; however it differs in the rat, mouse and dog where the sympathetic system is predominant. Our recent work has demonstrated that the interaction between the two systems occurs in the smooth muscle, suggesting a physiological antagonism. Our observations suggest that the key element in this interaction is intracellular calcium in the smooth muscle. The nitrergic pathway causes a decrease in intracellular calcium concentrations thus leading to relaxation of the smooth muscle. Noradrenergic stimulation, in contrast, elicits an increase in the intracellular calcium concentrations thus leading to a contraction. The neuronal pathway which controls the concentrations of intracellular calcium in the smooth muscle determines the dominance of that pathway over the other. Nitrergic dominance over noradrenergic system in the human corpus cavernosum also suggests a key role for this interaction in the pathophysiology of erectile dysfunction. Indeed, a nitrergic-noradrenergic imbalance in favor of the noradrenergic system has been implicated in penile tissues from patients with erectile dysfunction. However, the mechanism of this imbalance is not fully understood. In addition, since the present study has demonstrated that phosphodiesterase type V inhibitors can enhance and prolong the nitrergic control of noradrenergic responses, such compounds may have therapeutic potential in impotence, where defective nitrergic transmission is accompanied by increased noradrenergic activity.