1 While the expression and/or activity of endothelial nitric oxide synthase (eNOS) has been characterized in spontaneously hypertensive (SHR) 4 In WKY ECs, S-nitroso-N-acetyl-DL-penicillamine (SNAP) dose-dependently (10 ± 100 mM) and 0.1 mM atrial natriuretic factor (ANF) reduced the maximum and the decay time of a-thrombininduced calcium transient. The inhibitory e ects of SNAP and ANF were prevented by blocking cyclic GMP-dependent protein kinase. Non selective eNOS inhibitors prolonged the decay time of athrombin-induced calcium transient, while the selective inducible NOS inhibitor 1400 W was ine ective. SNAP (100 mM) and 0.1 mM ANF increased cyclic GMP content up to 22.9 and 42.3 fold respectively. 5 In SHR ECs, a-thrombin-induced calcium transient was not modi®ed by SNAP, ANF or eNOS inhibition. SNAP (100 mM) and 0.1 mM ANF increased cyclic GMP content up to 9.3 and 51 fold respectively. 6 In WKY ECs, SNAP dose-dependently (10 ± 100 mM) reduced also bradykinin-induced calcium transient, while in SHR ECs was ine ective. 7 We concluded that in SHR ECs, the cyclic GMP-dependent regulation of calcium transient is lost.

SummaryThe effects of NCX 4050, a drug belonging to a new class of NO donors, was investigated in isolated preparations of human and rabbit corpus cavernosum (CC) and in human foetal corpora cavernosa (hfCC) smooth muscle cells. In strips of rabbit CC, NCX 4050 (0.001-100 lM) induced a concentration-dependent relaxation which was influenced neither by Nw-nitro-L-arginine-methyl-ester (L-NAME; 100 lM) nor by endothelium deprivation. The NCX 4050-induced relaxation was significantly reduced by the guanylate cyclase inhibitor 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 lM) and enhanced by a specific phosphodiesterase 5 inhibitor, sildenafil (300 nM). Moreover, NCX 4050 (0.01-1 lM), induced a concentration-dependent potentiation of the relaxant response induced by electrical field stimulation (EFS) in rabbit preparations pre-treated with guanethidine and indomethacin. The relaxant effect of NCX 4050 was similar to that obtained by increasing concentrations (0.001-100 lM) of sodium nitroprusside (SNP) in either rabbit or human preparations. To further investigate the activity of NCX 4050 on human corpora cavernosa, we exposed cultured hfCC smooth muscle cells to increasing concentrations of NCX 4050 and SNP. We found that both compounds dose-dependently reduced cell proliferation. The antiproliferative effect of all the concentration tested of NCX 4050 was completely blocked by ODQ (1 lM). These results suggest that in rabbit and human corpora cavernosa NCX 4050 acts by activating guanylate cyclase activity, induces smooth muscle relaxation and quiescence. Our results provide a rationale for a possible future use of NCX 4050 in the pharmacotherapy of erectile dysfunction linked to an impaired release of NO from the endothelium.

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