Abstract

Although adenosine has been implicated in penile erection in human males, the receptor subtype responsible for adenosine regulation of human corpus cavernosum (HCC) smooth muscle tone is still a matter of debate. Using selective adenosine agonists and antagonists, we aimed at characterizing the adenosine receptors mediating relaxation of precontracted (with 1 μM phenylephrine) HCC strips. HCC specimens were collected from control subjects (organ donors) and from patients with severe vasculogenic erectile dysfunction (ED). In control subjects, adenosine and 5′-N-ethyl-carboxamide adenosine (NECA) fully relaxed HCC. The selective A_2A receptor agonist 2-[4-(2-p-carboxy ethyl)phenylamino]-5′-N-ethylcarboxamido adenosine (CGS21680C) produced only a partial relaxation (30-50%) of HCC, which could be further enhanced by simultaneous application of 100 μM NECA. The selective A_2B receptor antagonist N-(4-acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-il)phenoxy] acetamida (MRS1706) (10 nM) attenuated NECA-induced relaxation without affecting CGS21680C action. The A_2A receptor antagonist 4-{2-[7-amino-2-(2-furyl)[1,2,4]triazolo-[2,3-a][1,3,5]triazin-5-ylamino]ethyl}phenol (ZM241385) (50 nM) consistently reduced the actions of both agonists. In contrast to CGS21680C, NECA-induced relaxation was attenuated when endothelial production of NO and prostanoids was reduced by 100 μM N^G-nitro-l-arginine and 10 μM indomethacin, respectively. HCC strips from patients with vasculogenic ED were partially resistant to NECA but kept relaxation to CGS21680C; the remaining effect was sensitive to blockade of A_2A receptors with 50 nM ZM241385. Data suggest that adenosine regulates HCC smooth muscle tone through the activation of two receptor populations, CGS21680C-sensitive (A_2A) and -insensitive (A_2B) receptors, located on smooth muscle fibers and on endothelial cells, respectively. Endothelial dysfunction may be correlated with a loss of adenosine A_2B receptor activity in penile vessels from men with vasculogenic ED.