Populations resistant to PDE5 inhibitor therapy

Nitric oxide (NO), a key mediator in the initiation and maintenance of penile erection, is synthesized and released by the endothelium and the autonomic nerves of penile arteries and corpus cavernosum tissue.¹ Upon its release, NO enters the smooth muscle cell and activates soluble guanylyl cyclase, which promotes the formation of cGMP. Cellular concentrations of cGMP are regulated by phosphodiesterase (PDE) enzymes, of which PDE5, a cGMP specific hydrolyzing enzyme, is the most functionally important in human penile tissue.^2,3

Certain conditions, which include aging, vascular and metabolic diseases, and traumatic or degenerative alterations of nerves, can result in the impaired synthesis, release, or availability of NO from the endothelium, the autonomic nerves, or both. The specific patient populations considered challenging-to-treat with respect to PDE5 inhibitor therapy include patients with severe neurologic damage (eg, due to radical prostatectomy), diabetes mellitus, and severe vascular disease. The result is erectile dysfunction (ED) due to insufficient dilation of penile arteries and relaxation of trabecular smooth muscle.

PDE5 inhibitors prevent the normal hydrolysis of cGMP by PDE5 and thereby promote its accumulation, which facilitates penile smooth muscle relaxation. For this reason, PDE5 inhibitors can reverse, to a certain degree, deficiencies in the NO/cGMP pathway and are effective in the treatment of ED. The limitation in the efficacy of these agents is that a minimum or 'critical amount' of NO is necessary for these drugs to work. Nerves that are severely damaged will not be able to synthesize NO. Also, conditions in which there is a decrease in the expression or activity of neuronal or endothelial NO synthase (NOS), impairment of NO release, or destruction of NO will preclude sufficient guanylyl cyclase activation and formation of sufficient amounts of cGMP. If these alterations are severe, they cannot be compensated by PDE5 inhibition. Therapeutic strategies that promote NO synthesis, release, or availability may improve erectile function or at least enhance the efficacy of PDE5 inhibitors when applied in combination.

Possible means of increasing NO available in penile tissue include the following.

1. Facilitating NO release through -2 antagonists. In penile arteries and corpus cavernosum tissue, nitrergic relaxation is regulated by adrenergic activity. Nitrergic nerves are regulated through pre-junctional, -2 adrenergic receptors.^4,5 An -2 agonist inhibits release of NO and, conversely, an -2 antagonist such as yohimbine enhances release of NO. Furthermore, it has been demonstrated that the combination of yohimbine (an -2 receptor antagonist) or phentolamine (an -1 and -2 receptor antagonist) with a PDE5 inhibitor synergistically potentiates nitrergic nerve-mediated relaxation of corpus cavernosum tissue.
2. Enhancing NO synthesis by providing more substrate for the reaction. The enzymatic activity responsible for NO generation is NOS, which uses L-arginine as substrate, promoting its oxidation with NADPH and molecular oxygen consumption, and yielding L-citrulline and NO. Although L-arginine concentration theoretically is not a limiting step in NO formation, high doses of L-arginine can improve NO-mediated relaxation in diseases in which there is impaired endothelium-dependent relaxation, such as diabetes mellitus.⁶ Long-term administration of L-arginine enhanced endothelium-dependent relaxation of corpus cavernosum from diabetic rabbits⁷ and improved erectile responses in aged rats.⁸ In impotent men, L-arginine has been tested with encouraging results.⁹
   Hydroxy-arginine (OH-arginine) is an intermediate product in the synthesis of NO. This molecule carries an atom of oxygen bonded to the guanidine group of L-arginine. If OH-arginine is used as substrate, NOS requires a lesser amount of oxygen and NADPH to produce NO. It has been shown that OH-arginine, but not L-arginine, promotes NO-mediated relaxation and cGMP accumulation in rabbit corpus cavernosum tissue.¹⁰ Furthermore, OH-arginine potentiates NO-mediated responses induced by stimulation of endogenous NO generation in hypoxic and aged tissues. Thus, OH-arginine could be of interest in the treatment of ED, at least in ED secondary to defective NO production.
3. Inhibiting the inactivation of NO by reactive oxygen species (ROS) with the use of antioxidants. In diabetes and other vascular diseases, reactive oxygen species (ROS) are formed. These can interact with NO, thereby preventing its vasodilatory effects. In aged rat cavernosal tissue, a three-fold increase in superoxide formation is associated with impaired neurogenic relaxation and lower cGMP levels.¹¹

Several studies have reported erectile function benefits from antioxidant treatment. Gene transfer of extracellular superoxide dismutase (SOD) reduced superoxide formation and restored age-associated erectile function.¹¹ The effects of streptozotocin-induced diabetes in rats and long-term treatment with the antioxidant -lipoic acid was investigated using an in vitro corpus cavernosum preparation.¹² After 4 and 8 weeks, there was an approximately 41% reduction in endothelium-dependent NO-mediated relaxation to acetylcholine in diabetic, phenylephrine-precontracted cavernosum. -lipoic acid reversed this reduction by 65%. Endothelium-independent relaxation to the NO donor, sodium nitroprusside, was not altered by diabetes or treatment with -lipoic acid. Autonomic innervation of corpus cavernosum resulted in adrenergic-mediated contractions that were not affected by diabetes or -lipoic acid. Nonadrenergic, noncholinergic (NANC) nerve responses, which were dependent to a significant degree on NO, occurred after phenylephrine precontraction in the presence of atropine and guanethidine. NANC stimulation resulted in maximum relaxation of approximately 40%. Diabetes reduced this response by about 25%.

-lipoic acid treatment prevented the NANC relaxation deficit associated with diabetes. -Lipoic acid corrected about 52% of an established diabetic deficit. These findings suggest that ROS are responsible, in part, for diabetes-related impairment in erectile function,¹³ and that antioxidant therapy may prevent or partially reverse this deficit.

Further evidence for the role of ROS in ED and the possibilities of antioxidant therapy comes from a murine study on the effects of vitamin E and sodium selenate on the neurogenic and endothelium-dependent relaxation of isolated corpus cavernosum from streptozotocin-induced diabetes.¹⁴ Diabetes was associated with reduced responses of corpus cavernosum precontracted by phenylephrine to electrical field stimulation and to acetylcholine. Hyperglycemia did not affect the response to sodium nitroprusside or papaverine. Both vitamin E and sodium selenate partially restored diabetes-impaired endothelial function in the corpus cavernosum. Sodium selenate, but not vitamin E, partially prevented the impairment of neurogenic relaxation. In nondiabetic mice, neither vitamin E nor sodium selenate produced any effect on the relaxant response of corpus cavernosal tissue.

Important yet unanswered questions regarding therapeutic strategies for patients with ED resistant to PDE5 inhibition include:

1. Can pharmaceutical research improve the efficacy of PDE5 inhibitors in fully reversing ED by developing investigational agents to augment local synthesis, release, and/or availability of NO?
2. Is it feasible from a pharmacokinetic and pharmacodynamic point of view to combine such therapies with PDE5 inhibitors?
3. What would be the safety profile of such combinations?

References

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11. Bivalacqua TJ et al. Gene transfer of extracellular SOD to the penis reduces superoxide anion and improves erectile function in aged rats. Am J Physiol Heart Circ Physiol, [serial online] 2003, Apr [cited 2002 Dec 27] 284(4): Available from: http://ajpheart.physiology.org/cgi/content/full/284/4/H1408.
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