Corpus Cavernosum from Men with Vasculogenic Impotence Is Partially Resistant to Adenosine Relaxation due to Endothelial A_2BReceptor Dysfunction

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 M 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 5Ј-N-ethyl-carboxamide adenosine (NECA) fully relaxed HCC. The selective A 2A receptor agonist 2-[4-(2-p-carboxy ethyl)phenylamino]-5Ј-N-ethylcarboxamido adenosine (CGS21680C) produced only a partial relaxation (30 -50%) of HCC, which could be further enhanced by simultaneous application of 100 M 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) (ZM241385) (50 nM) consistently reduced the actions of both agonists. In contrast to CGS21680C, NECAinduced relaxation was attenuated when endothelial production of NO and prostanoids was reduced by 100 M N G -nitro-Larginine and 10 M 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.

A2B Adenosine Receptor Agonist Improves Erectile Function in Diabetic Rats

“…Additionally, excess adenosine lead to priapism in adenosine deaminase (ADA) deficient mice and sickle cell disease transgenic (Tg) mice, also via ADORA2B (Mi et al 2008;Wen et al 2010a, b). Moreover, Faria et al (2006) reported that adenosine regulates smooth muscle tone of human corpus cavernosum through the activation of A2A and A2B adenosine receptors, which are located on smooth muscle fibers and on endothelial cells, respectively. In addition, endothelial dysfunction was due to loss of ADORA2B activity in penile vessels from men with vasculogenic ED (Faria et al 2006).…”

“…Moreover, Faria et al (2006) reported that adenosine regulates smooth muscle tone of human corpus cavernosum through the activation of A2A and A2B adenosine receptors, which are located on smooth muscle fibers and on endothelial cells, respectively. In addition, endothelial dysfunction was due to loss of ADORA2B activity in penile vessels from men with vasculogenic ED (Faria et al 2006). However, the pathological role of ADORA2B in diabetic ED has not been elucidated.…”

Decreased Ecto-Ntpdase1/Cd39 Activity Leads to Desensitization of P2 Purinoceptors Regulating Tonus of Corpora Cavernosa in Impotent Men with Endothelial Dysfunction

“…Surprisingly, small amounts of ADP (<1.5 µM) were detected only after a 5-minute incubation period. This pattern of extacellular catabolism of ATP suggests the presence of ecto-NTPDase 1/CD39 enzyme converting ATP directly into AMP, which is then sequentially inactivated into adenosine and inosine by ecto-5'-nucleotidase (CD73) and ecto-adenosine deaminase, respectively (see, e.g., Faria et al [2] ). Table 1 shows that the extracellular catabolism of ATP is significantly (P < 0.05) slower in HCC from vasculogenic ED patients (t 1/2 = 26 ± 1 minute; n = 3) than in control subjects.…”

“…[6] We have demonstrated that endothelial dysfunction is correlated with a loss of adenosine A 2B receptor activity in penile vessels from men with vasculogenic ED. [2] Evidence that endothelial cell dysfunction may also be correlated with the loss of ecto-NTPDase 1/CD39 activity, [7] prompted us to investigate the pattern of extracellular catabolism of adenine nucleotides to probe its relevance to purinergic signaling in vasculogenic ED patients.…”

“…We recently demonstrated that adenosine regulates human corpus cavernosum (HCC) tone via CGS21680C-sensitive (A 2A ) and -insensitive (A 2B ) receptors located on smooth muscle and endothelial cells, respectively. [2] Because the functional significance of P2 purinoceptors in erectile tissue remains unclear, we investigated the vascular responses of HCC from control subjects and from impotent men with endothelial dysfunction to two subtype-selective P2-receptor agonists, α,β-methylene ATP (α,β-MeATP), and ATPγ S. The biological effects of adenine nucleotides may be cut-short by extracellular hydrolysis via the ecto-nucleotidase cascade. Many of the ecto-nucleotidases catalytically remove nucleotides in tandem with other ecto-enzymes to generate nucleosides at very high turnover rates.…”