Functional adenosine receptors in human corpora cavernosa

Abstract

We have demonstrated that adenosine has potent relaxant activity on the rabbit corpus cavernosum, acting through the A2a subtype receptor for adenosine. We now report studies on the identification and functional characterization of adenosine receptors in human penile vessels. To identify A2 receptors in human corpora cavernosa (HCC) we performed binding studies using the selective radioligand [125I]PAPA-APEC in membranes from HCC. We found the presence of a single class of high affinity (Kd= 0.23 +/- 0.06 nM), low capacity (Bmax=134 +/- 37 fmoles/mg protein) binding sites. Adenosine and CGS 21680 completely displaced [125I]PAPA-APEC binding (Kd= 146.7 +/- 64 microM and 51.52 +/- 27 nM, respectively). Accordingly, in functional studies adenosine relaxed phenylephrine precontracted HCC with an IC50=2.28 +/- 0.17 mM. The effect of adenosine was independent from nitric oxide (NO), and was counteracted by the A2 antagonist CGS 15943. In order to evaluate the in vivo effect of adenosine, increasing concentrations (6, 60, 600 microg) of adenosine or prostaglandin E1 (PGE1) (10 microg) were injected into the corpora cavernosa of four healthy volunteers. Blood flow and erectile response were evaluated at different times by duplex sonography and visual inspection, respectively. It was found that adenosine increased cavernosal peak blood flow velocity in a time- and dose-dependent manner. The highest concentrations of injected adenosine elicited a response that was not statistically different from that of PGE1 (10 microg). However, in contrast to PGE1, a full or partial erection was never obtained. To further investigate the lack of effect of adenosine on penile tumescence (despite the substantial increase in cavernosal blood flow), in vitro experiments were performed on human deep dorsal penile veins (DDPV) obtained from surgical ligation for impotence. Adenosine did not affect basal tone, but it induced almost complete relaxation in noradrenaline-precontracted vein strips with an IC50=1.6 +/- 0.22 mM. Conversely, PGE1 stimulated a sustained increase in basal tone. Therefore, the lack of effect of adenosine on penile tumescence could be due to a simultaneous relaxing activity on penile corpora cavernosa and veins. In conclusion, our study indicates that adenosine relaxes HCC as well as penile veins without affecting erection, at least at the concentrations we have used. Conversely, PGE1 relaxes corpora cavernosa as well as adenosine but strongly stimulates vein contraction, allowing penile tumescence.

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

“…Therefore, NO donors are not widely used in the therapy of ED. Similarly inconsistent results were obtained with the intracavernosal administration of neurotransmitters that mediate their effect through an increase in the cAMP-mediated pathway, such as CGRP (20,21), VIP (22) and adenosine (23,24). Conversely, interesting results were obtained by blocking cAMP breakdown using a nonspeci®c inhibitor of PDE, such as papaverine.…”

Corpus Cavernosum from Men with Vasculogenic Impotence Is Partially Resistant to Adenosine Relaxation due to Endothelial A2BReceptor Dysfunction

“…As far as we know, this is the first study to suggest the involvement of two subtypes of adenosine receptors, high-affinity A 2A and low-affinity A 2B , in the relaxation of cavernosal vessels of the human penis. Receptor heterogeneity might explain some controversies found in the literature concerning the efficacy profile of nonselective adenosine agonists (e.g., NECA) on erectile tissues of human and other species (Mantelli et al, 1995;Filippi et al, 2000;Andersson, 2001;Noto et al, 2001).…”

“…For example, A 2A receptors might contribute to adenosine-induced relaxation of human and rabbit corpus cavernosum (Filippi et al, 2000), but these authors failed to induce erection by intracavernous injection of adenosine in human volunteers. In this study, we aimed at characterizing the receptor subtype underlying adenosine actions on human corpus cavernosum (HCC) in control subjects (organ donors) and in patients with severe vasculogenic erectile dysfunction (ED), because this condition is the most common cause of failure to achieve erections with usual vasodilators and of patients referred for surgical treatment.…”

Medical management of ischemic stuttering priapism: a contemporary review of the literature

“…Adenosine is a signaling nucleoside that shares multiple features with NO; both are potent vasodilators, induce cyclic nucleotide second messengers and both affect penile erection. [74][75][76][77][78] Recent studies in both animals and humans have shown that intracavernous injection of adenosine results in tumescence and penile erection, providing evidence that excess adenosine may contribute to priapism. [74][75][76] Theophylline, an adenosine receptor antagonist, has consequently been shown to inhibit these adenosine-induced erections.…”

“…[74][75][76][77][78] Recent studies in both animals and humans have shown that intracavernous injection of adenosine results in tumescence and penile erection, providing evidence that excess adenosine may contribute to priapism. [74][75][76] Theophylline, an adenosine receptor antagonist, has consequently been shown to inhibit these adenosine-induced erections. 74,79 These results suggest the possibility that another signaling pathway may represent a potential target for the future prevention and treatment of priapism.…”