Gene transfer of prepro-calcitonin gene-related peptide restores erectile function in the aged rat. Prog Urol 1997 7: 24–33.īivalacqua TJ et al. Guiliano F, Rampin O, Benoit G, Jardin A. Modulation of vascoactive intestinal polypeptide (VIP)-mediated relaxation by nitric oxide and prostanoids in the rabbit corpus cavernosum. The role of nitric oxide in penile erection. Nitric oxide: a physiological mediator of penile erection. Enzyme activities of the nitric oxide–cGMP pathway in corpus cavernosum isolated from middle-aged rats. Akt-dependent phosphorylation of endothelial nitric-oxide synthase mediates penile erection. NIH Consensus Development Panel on Impotence. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. Soluble guanylate cyclase: the forgotten sibling. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Proc Natl Acad Sci USA 1985 82: 7738–7742.įurchgott RF, Zawadzki JV. Mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Development of pharmacologic agents with this effect has closely paralleled the emerging science. Inhibition of PDE5 is expected to enhance penile erection by preventing cGMP degradation. Phosphodiesterase 5 (PDE5) inactivates cGMP, which terminates NO-cGMP-mediated smooth muscle relaxation. Based on the increasing knowledge of intracellular signal propagation in cavernous smooth muscle tone regulation, selective PDE inhibitors have recently been introduced in the treatment of ED. Numerous systemic vasculature diseases that cause erectile dysfunction (ED) are highly associated with endothelial dysfunction, which has been shown to contribute to decreased erectile function in men and a number of animal models of penile erection. Thus, cGMP effect depends on the expression of a cell-specific cGMP-receptor protein in a given cell type. The effects of cGMP are mediated by cGMP dependent protein kinases, cGMP-gated ion channels, and cGMP-regulated phosphodiesterases (PDE). NO is released from nerve endings and endothelial cells and stimulates the activity of soluble guanylate cyclase (sGC), leading to an increase in cyclic guanosine-3′,5′-monophosphate (cGMP) and, finally, to calcium depletion from the cytosolic space and cavernous smooth muscle relaxation. nNOS is expressed in penile neurons innervating the corpus cavernosum, and eNOS protein expression has been identified primarily in both cavernosal smooth muscle and endothelium. Thus, PGI(2) analogs potently inhibit proliferation of human pulmonary artery, probably via a cAMP-dependent pathway, although cAMP elevation in itself is not a good predictor of antiproliferative potency.Nitric oxide (NO) is formed from the conversion of L-arginine by nitric oxide synthase (NOS), which exists in three isoforms: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). UT-15 produced a significantly larger and more sustained increase in cAMP compared with other analogs, with iloprost being the weakest elevator. Intracellular cyclic AMP (cAMP) was elevated by all analogs and inhibited by DDA, although SQ22536 was a highly variable inhibitor, suggesting that different pathways might mediate cAMP generation. Effects were reversed by the adenylyl cyclase inhibitor, 2,5'dideoxyadenosine (DDA) but not SQ22536. Serum-induced proliferation, as assessed by thymidine incorporation (30 h) or cell number (48 h), was significantly inhibited with a 10-fold difference in potency, ranking in effectiveness UT-15 > iloprost > cicaprost > beraprost. We therefore investigated the antiproliferative activity of several prostacyclin (PGI(2)) analogs on human pulmonary arterial smooth muscle cells, including UT-15 and iloprost, analogs that have recently completed successful clinical trials. Stable analogs are increasingly being used to treat this disease, although no data exists comparing their effects on proliferation. Primary pulmonary hypertension is characterized by increased pulmonary vascular resistance and smooth muscle proliferation.
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