Associate editor: M. Kimura
Nitric oxide and penile erectile function

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Abstract

The discovery of nitric oxide (NO) as an intercellular messenger or neurotransmitter opened a new era for identifying the important mechanisms underlying physiological and pathophysiological events in autonomically innervated organs and tissues; it also provided the way for development of new therapeutics based on a novel concept of molecule and cell interaction. Endothelium-derived relaxing factor (EDRF) discovered by Furchgott and Zawadzki has been proved to be NO, a labile gaseous molecule, that modulates vascular tone, platelet aggregation and adhesion, and vascular smooth muscle proliferation. Later, NO was determined to act as a non-adrenergic, non-cholinergic (NANC) neurotransmitter of postganglionic parasympathetic nerve fibers, innervating a variety of smooth muscles including the penile corpus cavernosum (CC). The nerve is called “nitrergic” or “nitroxidergic”. Although CC sinusoidal endothelial cells also produce and liberate NO in response to chemical and possibly physical stimuli, roles of neurogenic NO in penile erection appear to be more attractive and convincing. NO is formed from l-arginine via catalysis by NO synthase (NOS) isoforms, neuronal (nNOS), endothelial (eNOS), and inducible NOS. NO from nerves and possibly endothelia plays a crucial role in initiating and maintaining intracavernous pressure increase, penile vasodilatation, and penile erection that are dependent on cyclic GMP synthesized with activation of soluble guanylyl cyclase by NO in smooth muscle cells. Erectile dysfunction (ED) is caused by a variety of pathogenic factors, particularly impaired formation and action of NO. Thus, replenishment of this molecule or intracellular cyclic GMP is expected so far to be the most promising therapeutic measures for patients with ED. This article includes recent advances in research on physiological roles and pathophysiological implications of NO in penile erection and on novel therapy for ED in reference to NO.

Introduction

Autonomically innervated organs and tissues are functionally regulated by efferent sympathetic and parasympathetic nerves, and the major neurotransmitters in postganglionic fibers are norepinephrine and acetylcholine, respectively. However, many investigators have provided evidence for functional roles of non-adrenergic, non-cholinergic (NANC) inhibitory and excitatory nerves. Various polypeptides, such as vasoactive intestinal polypeptide (VIP), substance P, and calcitonin gene-related polypeptide (CGRP), and ATP have been regarded for a number of decades as inhibitory neurotransmitters (Burnstock, 1975, Owman, 1990, Lundberg, 1996). Although some of these molecules are still considered to be neurotransmitters, a break-through was brought by the discovery of nitric oxide (NO) that functions not only as a mediator synthesized in and released from the vascular endothelium (Ignarro et al., 1987, Furchgott, 1988) but also acts as a neurotransmitter in inhibitory nerves innervating the vascular wall (Toda & Okamura, 1990a, Toda & Okamura, 1990b) and smooth muscles in the gastrointestinal tract (Bult et al., 1990, Toda et al., 1990), anococcygeus (Gillespie et al., 1989, Li & Rand, 1989), retractor penis (Gillespie & Seng, 1990), respiratory tract (Tucker et al., 1990), and urinary tract (Andersson et al., 1991, Dokita et al., 1991). Identification of NO to be a neurotransmitter has been achieved by the use of NO synthase (NOS) inhibitors, first introduced by Palmer et al. (1988), in these tissues and also in the corpus cavernosum (CC) of the penis (Ignarro et al., 1990). NO, an inorganic, labile, and gaseous molecule, would not be stored in vesicles of the nerve terminal, but is liberated immediately upon synthesis by neuronal NOS (nNOS) from substrate l-arginine. NO has a specific target, soluble guanylyl cyclase, as a binding protein intracellularly located in smooth muscles but not outside muscle cell membranes, where receptors for classical neurotransmitters locate. This novel, unprecedented discovery would lead us to reconsider the concept for neurotransmitters that have been established on the basis of constructive investigations for many decades.

Crucial roles of NO derived from NANC nerves and possibly from the CC sinusoidal endothelium in penile erection are widely accepted. The phosphodiesterase-5 (PDE-5) inhibitor sildenafil that interferes with the degradation of cyclic GMP, an intracellular messenger mediating cavernous smooth muscle relaxation, has been introduced as an effective and safe therapeutic for patients with erectile dysfunction (ED) (Goldstein et al., 1998). This review article describes recent advances of research on the physiology, pharmacology, histology, pathophysiology, and therapy concerning interesting topics on NO, including our novel idea, in reference to possible contribution of neurogenic and endothelial NO in the CC and penile vasculature to penile erection.

Section snippets

Discovery of nitrergic nerve

Ignarro et al. (1990) reported that NG-nitro-l-arginine (l-NA), NG-amino-l-arginine, NOS inhibitors, oxyhemoglobin, an NO scavenger, and methylene blue, a soluble guanylyl cyclase inhibitor, abolish electrical field stimulation-induced relaxations of the isolated rabbit CC, and the inhibitory effect of NOS inhibitors are reversed by l-arginine. They hypothesized that penile erection may be mediated by NO generated from NANC inhibitory nerves. Susceptibility of the neurogenic response to

Pre- and postjunctional regulation of nitrergic nerve functions

Evidences for the regulation of nitrergic nerve function by neurotransmitters liberated from this and other efferent nerves have been obtained in blood vessels (Toda & Okamura, 2003) and gastrointestinal tracts (Boeckxstaens et al., 1995, Hebeiss & Kilbinger, 1999). Sympathetic outflow via the cavernous and pudendal nerve to the penis participates in detumescence. Immunohistochemical studies have provided evidence for adrenergic innervation in the penis of various animal species (Baumgarten et

Endothelium-derived nitric oxide

Isolated human CC strips contracted with norepinephrine responded to acetylcholine (Saenz de Tejada et al., 1988) or bradykinin (Kimoto et al., 1990) with relaxations that were abolished in the strips lacking the endothelium (Fig. 2). Atropine abolished the acetylcholine-induced relaxation. Kimoto et al. (1990) demonstrated the release of EDRF from human CC by a sandwich mount (Furchgott & Zawadzki, 1980) and suggested that the endothelium lining lacunar spaces within the CC is required for the

Involvement of nitric oxide derived from nerves and endothelia in the penile erection

There is a consensus that NO is a prerequisite for the generation and maintenance of intracavernous pressure increment and penile erection. NO liberated from NANC inhibitory nerves was first reported to primarily contribute to the responses (Ignarro et al., 1990). Recent findings have suggested that NO derived from the endothelium is also involved in the regulation of erectile function. As indicated in Section 4, exogenously applied acetylcholine or peptides liberate NO from the endothelium and

Nitrergic innervation in the penile artery and vein

The vascular tone is regulated by adrenergic vasoconstrictor and nitrergic vasodilator nerves in primate and subprimate mammals (Toda & Okamura, 2003). In isolated penile arteries from the human (Simonsen et al., 1997b, Medina et al., 2000), monkey (Kakiailatu, 2000), cow (Liu et al., 1991), horse (Simonsen et al., 1995), and dog (Hayashida et al., 1996) and penile veins from the human (Kirkeby et al., 1993, Segarra et al., 1998, Medina et al., 2000) and dog (Hayashida et al., 1996) when

Aging and endogenous nitric oxide

Electrical field stimulation of the cavernous nerve showed that the maximal intracavernous pressure increased declined in the old (20-month-old) and senescent rat (30-month-old) compared to adult rats (5-month-old); l-NAME partially reduced the pressor response in the adult rats, but markedly decreased it in the old and senescent rats (Garban et al., 1995a). Penile soluble NOS activity sensitive to l-NAME decreased in the senescent rats, but was elevated in the old rats. Therefore, they

Pathophysiological implications

High prevalence of ED has been demonstrated in patients with diabetes mellitus irrespective of type, the prevalence being dependent on patient age, duration of diabetes, and disease severity (Rubin & Babbott, 1958, Kolodny et al., 1974, McCulloch et al., 1980, Klein et al., 1996). Neurogenic relaxation of CC strips was impaired in diabetic men with impotence (Saenz de Tejada et al., 1989) and in rabbits (Azadzoi & Saenz de Tejada, 1992) and rats (Elabbady et al., 1995, Vernet et al., 1995,

Sildenafil

The main PDE activity in the human CC is due to type 5 cyclic GMP PDE (PDE-5), with PDE-2 and -3 also identified (Boolell et al., 1996a). The selective inhibitor of PDE-5 zaprinast augments the NO-mediated relaxant response in isolated human and rabbit CC strips (Bush et al., 1992a, Rajfer et al., 1992, Gibson, 2001). Sildenafil (Viagra) is a highly selective inhibitor of PDE-5; it is 4000, 70, and 10 times more selective for PDE-5 than PDE-3, PDE-4, and PDE-6, respectively (Ballard et al., 1998

Summary and conclusion

There is a widely accepted hypothesis that nitric oxide (NO) synthesized from l-arginine via neuronal NO synthase (nNOS) acts as a neurotransmitter of non-adrenergic, non-cholinergic (NANC) inhibitory nerves innervating smooth muscles including the penile corpus cavernosum (CC) and plays a crucial role in the initiation and maintenance of increased intracavernous pressure and penile erection. In addition to cavernosal smooth muscle relaxation, penile vasodilatation and blood flow increase

Acknowledgment

We thank Prof. K-E. Andersson, Department of Clinical Pharmacology, Lund University, Sweden, for his critical review of this article.

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