Sildenafil Nitric oxide

At clinical trials, sildenafil did not work well as a treatment for angina. Instead, it was observed that it overcomes erectile dysfunction. Later, it was found that cyclic GMP also increases the level of nitric oxide, which is needed in penile erections. 

Sildenafil is a selective inhibitor of cGMP-specific PD-5 and therefore inhibits the degradation of cGMP PD-5, the predominant type in the corpus cavernosum, also is present in other tissues (e.g., lungs, platelets, and eye). TTie selective inhibition of this enzyme facilitates the release of nitric oxide and smooth muscle relaxation of the corpus cavernosa. Sildenafil enhances erection by augmenting nitric oxide-mediated relaxation pathways. It has been suggested that sildenafil s mechanism of action is due to cross-talk between cGMP- and cAMP-dependent transduction pathways within the cavernous muscles. 

Figure 1. Role of nitric oxide, cGMP, phosphodiesterase and sildenafil in erectile function.

FIGURE 60.1 Mechanism of action of sildenafil in corpus cavernosal smooth muscle cells. NANC Non-adrenergic, noncholinergic NO nitric oxide PDE5 Phosphodiesterase Type 5. 

Sildenafil increases the release of nitric oxide and increases the levels of cyclic guanosine monophosphate (cGMP), a smooth muscle relaxant. Sildenafil enhances the effects of nitric oxide by inhibiting phosphodiesterase 5, an enzyme found primarily in the penis that degrades cGMP. As a result, increased levels of cGMP in the corpus cavemosum enhance smooth muscle relaxation, the inflow of blood, and erection. Sildenafil has no effect in the absence of sexual stimulation (see Figure 60.1). 

Pulmonary hypertension is a devastating, potentially fatal disorder. Recent years have witnessed a great expansion in our understanding of the molecular pathophysiology of this condition. Options for therapy have just become available in recent years, focused either on the prostacyclin pathway or the nitric oxide pathway for pulmonary arteriolar relaxation. Continuous infusion of prostacyclin has been successful, demonstrating the relevance of the former pathway. The efficacy of both inhaled nitric oxide and systemic sildenafil support the latter. In the future, gene transfer could be used for sustained delivery of either of these agents, by means of... 

Sildenafil is a potent inhibitor of phosphodiesterase tjrpe V, and therefore of the breakdown of cyclic guanosine monophosphate (cGMP) in the corpora cavernosa. The increased concentration of cGMP leads to nitric oxide-mediated relaxation of the smooth muscle cells and vasodilatation in the corpus cavernosum, which is essential for... 

The authors suggested that in this case the effect of sildenafil may have been reduced by impaired gastrointestinal absorption. They speculated that exogenous nitric oxide inhibits nitric oxide sjmthase activity, with a consequent reduction in pulmonary vascular smooth muscle cGMP concentration. Phosphodiesterase type V inhibitors, such as sildenafil, increase cGMP concentration and ameliorate the rebound effect... 

Atz AM, Wessel DL. Sildenafil amehorates effects of inhaled nitric oxide withdrawal. Anesthesiology 1999 91(1) 307-10. 

The type V inhibitor sildenafil citrate is a selective cGMP-specific inhibitor, which acts as a SMOOTH MUSCLE RELAXANT and VASOoaATOR, probably through enhancing the action of nitric oxide (NO). It relaxes blood vessels of the corpus cavernosum of the penis, and is used in oral therapy for... 

Webb DJ, Muirhead GJ, Wulfif M, Sutton JA, Levi R, Dinsmore WW. 2000. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J. Am. Coll. Cardiol. 36 25-31... 

Lepore JJ, Maroo A, Bigatello LM, et al. Elemodynamic effects of sildenafil in patients with congestive heart failure and pulmonary hypertension combined administration with inhaled nitric oxide. Chest 2005 127 1647-53. 

Sildenafil citrate is a phosphodiesterase type 5 inhibitor that enhances the effect of nitric oxide by inhibiting phosphodiesterase type 5 in the corpus cavernosum of the penis. This results in vasodilation, increased inflow of blood into the corpora cavernosa, and ensuing penile erection npon sexnal stimulation. It is indicated in the treatment of impotence related to erectile dysfunction of the penis. 

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