Phosphodiesterase-5 Inhibition: the Molecular Biology of Erectile Function and Dysfunction

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The signaling pathway that provides for penile erection

The first step in the male erectile response involves activation of specific neurologic pathways by sexually arousing stimuli; these can be either cerebral or physical in origin. Regulation of penile erection involves precise coordination of output from parasympathetic, sympathetic, and somatosensory neural pathways that results in vasodilation of penile arteries, increased blood flow to the penis, and increased volume capacity within penile vascular structures (Fig. 1). This vasodilation is

Modulation of cellular cyclic GMP level

Cellular cGMP level is dictated by the balance between the rates of synthesis by GC and breakdown by cyclic nucleotide (cN) phosphodiesterases (PDE) [54], [55], [56], [57], [58]. PDEs cleave the cyclic phosphate ring that is required for the action of cGMP or cyclic AMP (cAMP) in the respective signaling pathways (see Fig. 3; Fig. 4). PDE activities in mammalian cells provide the primary counterpoint to cAMP and cGMP synthesis and act to dampen or terminate a cN signal such as that of cGMP in

Mechanism by which phosphodiesterase-5 inhibitors enhance erectile function

The prominence of PDE5 as a cGMP-PDE in vascular smooth muscle garnered the attention of investigators interested in developing pharmaceuticals that would block its action [64], [65]. It was predicted that inhibition of PDE5 would elevate cellular cGMP and decrease vascular tone. As a result, PDE5 was considered an excellent pharmacologic target for treatment of systemic hypertension because the cGMP-signaling pathway seems to feature prominently in regulating cGMP levels in most blood vessels

Impact of regulation of phosphodiesterase-5 on cyclic GMP signaling and inhibitor potency

PDE5 is highly regulated, and these regulatory mechanisms in part provide for negative feedback regulation of cGMP levels under normal physiologic conditions and for a feed-forward action to increase potency of pharmacologic inhibitors of PDE5 (see Fig. 6). First, by most estimates, the catalytic activity of PDE5 under basal physiologic conditions is relatively low because the cellular cGMP concentration is well below that required to saturate PDE5 and achieve the maximum hydrolytic rate (Vmax

Cessation of inhibitor effects

The three commercially marketed PDE5 inhibitors are not metabolized in the smooth muscle cell where their primary actions take place. The inhibitors must dissociate from PDE5, successfully diffuse out of the cell, escape re-entry, and be transported to the liver where they are metabolized or inactivated by cytochromes CYP3A4, CYP2C9, CYP2C19, and CYO2D6 [77]. Certain metabolites of sildenafil, although less potent, account for part of its inhibition of PDE5. The high affinity with which

Tissues affected by action of phosphodiesterase-5 inhibitors

The perception of much of the medical and lay community is that PDE5 inhibitors act only in the penis. In fact, when any of the three inhibitors is ingested, the particular inhibitor will enter cells throughout the body, including vascular smooth muscle cells of the systemic and pulmonary beds, platelets, and heart; the inhibitors will block PDE5 action potently in all tissues containing PDE5. Box 1 summarizes factors that contribute to the selective action of these inhibitors to improve

Summary

Commercially marketed PDE5 inhibitors are highly specific for PDE5, and in the face of continuing cyclic GMP synthesis, elevate cellular cGMP. This elevation results from direct competitive inhibition of PDE5 and from blocking the negative feedback regulation of the enzyme. Elevation of cGMP activates PKG, which mediates the effects of the cGMP-signaling pathway to decrease smooth muscle tone and dilate penile vascular smooth muscle. By exploiting features of PDE5 regulatory mechanisms that

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    This work was supported by National Institutes of Health grants DK40029 and 58277.

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