Therapeutic Strategies for Optimizing PDE-5 Inhibitor Therapy in Patients with Erectile Dysfunction Considered Difficult Or Challenging to Treat

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Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat

ISa´enz de Tejada*

Fundacion para la Investigacion y el Desarrollo en Andrologia (FI þ DA) Madrid, Spain

Phosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30–40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using a-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species. International Journal of Impotence Research (2004) 16, S40–S42. doi:10.1038/sj.ijir.3901215

Keywords: impotence; penis; nitric-oxide; nitric-oxide synthase; nitroprusside; adrenergic a-antagonists

Populations resistant to PDE5 inhibitor specific patient populations considered challen- therapy ging-to-treat with respect to PDE5 inhibitor therapy include patients with severe neurologic damage (eg, due to radical prostatectomy), diabetes mellitus, and Nitric oxide (NO), a key mediator in the initiation severe vascular disease. The result is erectile dys- and maintenance of penile erection, is synthesized function (ED) due to insufficient dilation of penile and released by the endothelium and the autonomic arteries and relaxation of trabecular smooth muscle. nerves of penile arteries and corpus cavernosum PDE5 inhibitors prevent the normal hydrolysis of tissue.1 Upon its release, NO enters the smooth cGMP by PDE5 and thereby promote its accumula- muscle cell and activates soluble guanylyl cyclase, tion, which facilitates penile smooth muscle relaxa- which promotes the formation of cGMP. Cellular tion. For this reason, PDE5 inhibitors can reverse, concentrations of cGMP are regulated by phospho- to a certain degree, deficiencies in the NO/cGMP diesterase (PDE) enzymes, of which PDE5, a cGMP pathway and are effective in the treatment of ED. specific hydrolyzing enzyme, is the most function- The limitation in the efficacy of these agents is that ally important in human penile tissue.2,3 a minimum or ‘critical amount’ of NO is necessary Certain conditions, which include aging, vascular for these drugs to work. Nerves that are severely and metabolic diseases, and traumatic or degenera- damaged will not be able to synthesize NO. Also, tive alterations of nerves, can result in the impaired conditions in which there is a decrease in the synthesis, release, or availability of NO from the expression or activity of neuronal or endothelial NO endothelium, the autonomic nerves, or both. The synthase (NOS), impairment of NO release, or destruction of NO will preclude sufficient guanylyl cyclase activation and formation of sufficient *Correspondence: I Sa´enz de Tejada, MD, Fundacion Para amounts of cGMP. If these alterations are severe, La Investigacion Y El Desarrollo En Andrologia (FI þ DA), they cannot be compensated by PDE5 inhibition. Antonio Robles 4, Madrid 9 C-28034, Spain. Therapeutic strategies that promote NO synthesis, E-mail: [email protected] release, or availability may improve erectile Drug-resistant erectile dysfunction ISa´enz de Tejada S41 function or at least enhance the efficacy of PDE5 formation is associated with impaired neuro- inhibitors when applied in combination. genic relaxation and lower cGMP levels.11 Possible means of increasing NO available in penile tissue include the following. Several studies have reported erectile function benefits from antioxidant treatment. Gene transfer of (1) Facilitating NO release through a-2 antagonists. extracellular superoxide dismutase (SOD) reduced superoxide formation and restored age-associated In penile arteries and corpus cavernosum tissue, 11 nitrergic relaxation is regulated by adrenergic erectile function. The effects of streptozotocin- activity. Nitrergic nerves are regulated through induced diabetes in rats and long-term treatment 4,5 with the antioxidant a-lipoic acid was investigated pre-junctional, a-2 adrenergic receptors. An a-2 12 agonist inhibits release of NO and, conversely, an using an in vitro corpus cavernosum preparation. a-2 antagonist such as yohimbine enhances After 4 and 8 weeks, there was an approximately release of NO. Furthermore, it has been demon- 41% reduction in endothelium-dependent NO- strated that the combination of yohimbine (an a-2 mediated relaxation to acetylcholine in diabetic, receptor antagonist) or phentolamine (an a-1 and phenylephrine-precontracted cavernosum. a-lipoic a-2 receptor antagonist) with a PDE5 inhibitor acid reversed this reduction by 65%. Endothelium- synergistically potentiates nitrergic nerve- independent relaxation to the NO donor, sodium mediated relaxation of corpus cavernosum tissue. nitroprusside, was not altered by diabetes or treat- (2) Enhancing NO synthesis by providing more ment with a-lipoic acid. Autonomic innervation of substrate for the reaction. The enzymatic corpus cavernosum resulted in adrenergic-mediated activity responsible for NO generation is NOS, contractions that were not affected by diabetes which uses L-arginine as substrate, promoting or a-lipoic acid. Nonadrenergic, noncholinergic its oxidation with NADPH and molecular (NANC) nerve responses, which were dependent to oxygen consumption, and yielding L-citrulline a significant degree on NO, occurred after pheny- and NO. Although L-arginine concentration lephrine precontraction in the presence of atropine theoretically is not a limiting step in NO and guanethidine. NANC stimulation resulted in formation, high doses of L-arginine can improve maximum relaxation of approximately 40%. Dia- NO-mediated relaxation in diseases in which betes reduced this response by about 25%. there is impaired endothelium-dependent relax- a-lipoic acid treatment prevented the NANC ation, such as diabetes mellitus.6 Long-term relaxation deficit associated with diabetes. a-Lipoic administration of L-arginine enhanced endothe- acid corrected about 52% of an established diabetic lium-dependent relaxation of corpus caverno- deficit. These findings suggest that ROS are respon- 7 sible, in part, for diabetes-related impairment in sum from diabetic rabbits and improved 13 erectile responses in aged rats.8 In impotent erectile function, and that antioxidant therapy men, L-arginine has been tested with encoura- may prevent or partially reverse this deficit. ging results.9 Further evidence for the role of ROS in ED and the possibilities of antioxidant therapy comes from a Hydroxy-arginine (OH-arginine) is an intermedi- murine study on the effects of vitamin E and sodium ate product in the synthesis of NO. This molecule selenate on the neurogenic and endothelium-depen- carries an atom of oxygen bonded to the guanidine dent relaxation of isolated corpus cavernosum from streptozotocin-induced diabetes.14 Diabetes was group of L-arginine. If OH-arginine is used as substrate, NOS requires a lesser amount of oxygen associated with reduced responses of corpus caver- and NADPH to produce NO. It has been shown nosum precontracted by phenylephrine to electrical field stimulation and to acetylcholine. Hyperglyce- that OH-arginine, but not L-arginine, promotes NO-mediated relaxation and cGMP accumula- mia did not affect the response to sodium nitroprus- tion in rabbit corpus cavernosum tissue.10 Further- side or papaverine. Both vitamin E and sodium more, OH-arginine potentiates NO-mediated responses selenate partially restored diabetes-impaired en- induced by stimulation of endogenous NO gene- dothelial function in the corpus cavernosum. ration in hypoxic and aged tissues. Thus, OH- Sodium selenate, but not vitamin E, partially arginine could be of interest in the treatment of prevented the impairment of neurogenic relaxation. ED, at least in ED secondary to defective NO In nondiabetic mice, neither vitamin E nor sodium production. selenate produced any effect on the relaxant response of corpus cavernosal tissue. Important yet unanswered questions regarding (3) Inhibiting the inactivation of NO by reactive therapeutic strategies for patients with ED resistant oxygen species (ROS) with the use of antiox- to PDE5 inhibition include: idants. In diabetes and other vascular diseases, reactive oxygen species (ROS) are formed. These can interact with NO, thereby preventing (1) Can pharmaceutical research improve the effi- its vasodilatory effects. In aged rat cavernosal cacy of PDE5 inhibitors in fully reversing ED by tissue, a three-fold increase in superoxide developing investigational agents to augment

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