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Physiological significance of nitrergic transmission in human penile erection

P.G. Adaikan, S.C. Ng

Department of Obstetrics & Gynaecology, National University Hospital,National University of Singapore, Lower Kent Ridge Road, Singapore 119 074

Asian J Androl  2000 Mar; 2: 51-56

Keywords: erection; neurotransmission; corpus cavernosum; nitric oxide; cyclic GMP
The corpora cavernosa (CC) muscles of the human penis and their structural arrangements are essential for the physiology of erection. Contraction of this muscle causes detumescence, and relaxation, tumescence. The motor excitatory neurotransmission is adrenergic, acting through the alpha adrenoceptors. Continuous adrenergic transmitter (noradrenaline) release is necessary for the maintenance of non-erectile (contractile) state of the penis. The inhibitory neurotransmitter that relaxes CC muscle to produce erection is nitrergic i.e., the chemical messenger being nitric oxide (NO). The latter can also be released from cavernous endothelium. Presence of NO increases intracellular cGMP through activation of the enzyme guanylate cyclase. This causes relaxation of CC muscle. Phosphodiesterase type 5 (PDE5) is responsible for the degradation of cGMP and regulation of CC muscle tone. Specific PDE inhibitors such as sildenafil enhance the intracellular cGMP to improve erection. Increase in intracellular cAMP can also bring about pharmacological erection in man (eg. PGE1, papaverine and histamine). Inhibition of excessive adrenergic tone with appropriate alpha-adrenergic blocking agents (eg. phentolamine) can also contribute to the onset of pharmacological erection.

1 Mechanisms of erection

Fundamental to the understanding of autonomic neuropharmacology of human penile erection is the existence in the trabecular smooth muscle and vasculature of the corpus cavernosum (CC) of (a) cavernous nerve, (b) mediators of neurotransmission and (c) receptoral affinity for these and various endogenous autacoids.

The CC muscle is the most dominating structure of the penis, contributing to the control of tumescence and erection. Contraction of this muscle maintains detumescence and relaxation promotes tumescence and erection. The excitatory motor neurotransmission (adrenergic) elicits contraction of the CC muscle and inhibitory neurotransmission (nitrergic) produces relaxation[1-3]. Indeed, dual (contractile and relaxant) affinities were also present in the human CC muscle for adrenoceptors[4], cholinoceptors[5], histaminergic receptors[6], various prostaglandins[2,7] and others; we believe this ying yang activity plays a key role in manipulating autonomic control of penile erection in relation to detumescence and tumescence. In this interplay it is the contractile state that is considered to be dominant. The myogenic activity in the non-erect penis would be a contributory factor[8].

Continuous adrenergic transmitter release within the cavernosum is necessary to maintain the rugosity (the non-erectile state) of the penis - the state in which it is most of the time. This can be seen in experiments in vitro on CC muscle (when it is not precontracted artificially with another agent - a method very often employed by many investigators). When the CC muscle is electrically stimulated the predominant action was excitatory motor neurotransmission, which was antagonised by -adrenoceptor blocking agents such as phentolamine and prazosin. It has now been established beyond doubt by many investigators that the excitatory motor neurotransmission to the CC is adrenergic, acting on the 1 adrenoceptors[8]. In our experiments, suppression of this adrenergic transmission very often unmasked the inhibitory neurotransmission, which is non-adrenergic, non-cholinergic (NANC) neurotransmission[2] (see below). This is when we postulated that adrenergic transmitter release in the penis (as in vasomotor tone) is necessary to keep it in the flaccid, contracted state[2] and that suppression of -adrenoceptor activity in the penis might be expected to lead to penile enlargement and erection. Alpha-adrenergic blocking agents have been shown to cause erection when given intracavernously to humans[9], baboons[10] and cats[11].

Compounds such as trazodone, ketanserin, yohimbine and papaverine that are known to facilitate erection in man showed -adrenoceptor antagonism to noradrenaline (NA) induced contraction of the human CC muscle[12]. Clinical reports indicate that even by oral route of administration, agents that block the -adrenoceptor activity could induce erection or priapism in man[13-16]. Hence, it would appear that inactivation of -adrenoceptor activity in the penis may be an initial step in the erectile process. In fact, this activity may well be the change needed for erection to commence[2]; this endogenous inactivation would also have the capacity to trigger the pro-erectile receptoral affinities mentioned above and more importantly the NANC-nitrergic neurotransmission as seen in our experiments (Figure 1).

Figure 1. Autonomic control of human penile erection (Adaikan et al, 1991).

Secondly, if this mechanism were to operate physiologically, endogenous inhibitory modulators for temporal withdrawal of -adrenergic activity in the penis would be necessary before erection could commence. Naturally-occurring compounds such as prostaglandin E1 (PGE1) and vasoactive intestinal polypeptide (VIP) were shown to suppress the adrenergic motor neurotransmission[17,18]. These compounds also facilitated erection when given intracavernously[l8-20].

It is likely that endogenously the level of these modulators should reach supraphysiological levels before inactivation of adrenergic activity in the CC. In this context, central arousal state would be a contributory factor. It should be noted that apart from the endothelial NO synthase (eNOS-type III) and neuronal NO synthase (nNOS-type I), there exists abundant inducible NO synthase (iNOS-type II) in the CC muscle.

2 Nitrergic neurotransmission

The third and important step in the autonomic control of penile erection would be the NANC inhibitory neurotransmission. Acetylcholine (ACh) is the conventional neurotransmitter of parasympathetic pathway in many systems. In vitro studies in animal and human have questioned the role of ACh as the transmitter of erection[21,22].

Studies carried out in vitro on erectile tissues of animal and man also revealed that the inhibitory transmitter is non-cholinergic[1,2,23,24]. On the other hand exogenous ACh has been reported to cause either contraction or no effect on erectile tissues of several animal species[25] and it caused contraction and relaxation of human CC, these effects were atropine sensitive, indicating the presence of muscarinic excitatory and inhibitory receptors[5]. VIP was also shown not to fit in the characteristics of a NANC transmitter, although it has very often been postulated as the co-transmitter of erection[l8].

Study using specific inhibitors of enzyme involved in the synthesis of nitric oxide (NO), has indicated that the NANC neurotransmission in the human CC muscle is nitrergic (i.e. the chemical mediator being NO)[3] (Figure 2). These results are in line with the proposals for rat anococcygeus muscle[26], canine ileocolonic junction[27] and the findings in animal and human CC[28,29]. NANC nerve terminals are frequently identified in the cavernosum[30].

Figure 2. The effect of L-NG-nitro-arginine (L-NOArg) and L-arginine (L-Arg) on the response of isolated human cavernosum muscle to transmural stimulation of the NANC inhibitory nerves. The nerves were stimulated by square pulses of 70 V and l ms at the frequencies shown (from Adaikan et al, 1991).

In general, nitric oxide has been considered to be the main endothelium-derived relaxing factor (EDRF) in many systems. Endothelial cells have been reported to be lining the lacunar spaces of the CC[24,30]. However, compounds which inactivate EDRF or disrupt endothelial integrity did not block the NANC-induced relaxation[3,31]. Hence the NANC nerve-mediated response of the cavernous smooth muscle may not be via endothelium[3]. In support of this interpretation was the report that neurogenic relaxation in human CC was not affected by endothelium removal[32]. In addition, results from our laboratory indicate that the mechanism of relaxant action of ACh in the human CC muscle may also differ from that of the conventional EDRF release[3,31,33]. In addition, they indicate that the relaxant responses of PGE1, histamine and papaverine in the human CC are endothelium-independent[3,33]. Therefore, further research is needed to substantiate the role played by endothelium in penile erection. Methylene blue, which is a selective inhibitor of guanylate cyclase[34], inhibited the NANC-induced relaxation of human CC in vitro[3,31] (Figure 3) indicating that cellular cGMP accumulation is involved in the nitric oxide mediated NANC relaxation. Report on rabbit CC muscle supported this finding[28].

Figure 3. Effects of methylene blue on relaxations evoked by NANC nerve stimulation (S) and exogenous acetylcholine (ACh) and histamine (H) on human corpus cavernosum muscle strip (from Adaikan et al, 1991).

NO increases the intracellular cGMP through activation of the enzyme, soluble guanylate cyclase, producing smooth muscle relaxation in the corpus cavernosum. Relaxation of the CC muscle is necessary for the inflow of blood into the penis and for the subsequent engorgement and rigidity of the penis. Such increase of intracellular cGMP is kept at check by the phosphodiesterases type 5 (PDE5), which is responsible for the degradation of cGMP and the regulation of smooth muscle tone in the CC. Introducing phosphodiesterase inhibitors into this system would naturally offset this balance and enhance the intracellular cGMP level. An example of such a compound is sildenafil, which enhances the effect of NO by inhibiting PDE5 thereby increasing the level of intracellular cGMP resulting in smooth muscle relaxation. The successful oral use of sildenafil confirms the contribution of NO-cGMP axis in playing a physiological role in promoting penile erection. Sildenafil, a classical PDE5 inhibitor, has no direct relaxant effect on the cavernosum at submicromolar concentrations[35]. It requires the initial release of NO and subsequent cGMP through sexual stimulation. However, recent results indicate that sildenafil is capable of relaxing the CC muscle precontracted by NA. The increased magnitude and duration of neurogenic relaxation in human CC in vitro, in the presence of sildenafil seems to correlate with the significant improvements reported in the rigidity and duration of erections seen in patients who have been treated with oral sildenafil[36]. Sildenafil is more potent on PDE5 than on other commonly known phosphodiesterases (PDE2, PDE3 and PDE4 about >1000 fold). However, it is only about 10 fold as potent on PDE5 compared to PDE6, an enzyme involved in phototransduction in the retina; this is likely to be the basis for the side effect of blue colour vision. In flexible titration studies of 4 to 26 weeks, 3% of patients on sildenafil have reported visual disturbances, described as colour tinge or increased sensitivity to light or blurred vision compared to no such findings in placebo treated patients[37]. Furthermore, sildenafil may potentiate the hypotensive effects of nitrates or NO donors and is contraindicated in cardiovascular patients taking these drugs. While the ease of oral administration is an added advantage, the deleterious side effect of sildenafil on the cardiovascular system should be explored beyond the simple explanation of an additive vasodepression. In this context, the recent observation that a circulatory redistribution compromising coronary perfusion throws some light on the aetio-pathology[38]. Hence there is more scope in this area for the identification of organ specific PDE inhibitors.

3 Conclusion

Several physiopharmacological processes within the CC muscle of the human penis may be involved in the erectile process controlling penile detumescence and tumescence[3,8]. These include:
(1)    The -adrenoceptor mediated dominant motor response that maintains the nonerectile state.
(2)    Endogenous modulators of the above excitatory neurotransmission (e.g. PGE1).
(3)    Unmasking of the nitrergic inhibitory neurotransmission (NO being the chemical mediator releasing cGMP for relaxation).
(4)    Additional support coming from the endogenous autacoids (e.g. histamine, ACh and PGs) acting appropriately on the contractile (for detumescence) and relaxant receptors (for tumescence), cAMP being involved in the relaxation of some of the autacoids.

The temporal sequences, trigger and interplay of all these humoral agents, nerve-mediated responses and their central and spinal connections play a consorted role in relation to the physiology of erectile function. Pharmacologically, it is possible to create an erection with all of these approaches either individually or collectively[39] (Figure 4).

Figure 4. Physio-pharmacology of human penile erection indicating three major pathways. Each of these pathways can be exploited either independently or synergistically for the treatment of impotence (from Adaikan et al, 1999,Ref 39).

It should be noted that the cAMP pathway could also bring about a physiological erection independent of the GMP accumulation. In the last 15 years, we have been using intracavernous prostaglandin E1 very successfully at our centre in the treatment of erectile dysfunction in man.

4 Acknowledgements

The work presented here covers studies carried out in two decades in collaboration with Ms. L.C. Lau and Professors S.S. Ratnam, S. Kottegoda and S.M.M. Karim. Thanks are due to Dr. B. Srilatha for helping in the manuscript.


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[39] Adaikan PG, Srilatha B, Lau LC,  Ng  SC. Physiopharmacology of penile erection: peripheral and central mechanisms. In: Kim YC, Tan HM, editors. APSIR book on erectile dysfunction.  New Zealand: Adis International Ltd; 1999. p 27-45.


Correspondence to: Associate Professor P Ganesan Adaikan, Vice President of Singapore Society for the Study of Andrology and Sexology, Department of Obstetrics & Gynaecology, National University Hospital, National University of Singapore, Lower Kent Ridge Road, Singapore 119074.
Tel: +65-772 4128  Fax: +65-779 4753
e-mail: obgadaik@nus.edu.sg
Received 2000-03-13     Accepted 2000-03-15