CLINICAL RESEARCH Effects of alpha-2 blockade on sexual response: experimental studies with Delequamine (RS15385)

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1 (2000) 12, Suppl 1, S64±S69 ß 2000 Macmillan Publishers Ltd All rights reserved /00 $ CLINICAL RESEARCH : experimental studies with Delequamine (RS15385) 1 1 The Kinsey Institute, Indiana University, USA The role of alpha-2 receptors and alpha-2 antagonists in central and peripheral mechanisms of sexual response are discussed. It is concluded that the predominant role of the alpha-2 antagonist centrally is to increase arousal which in certain circumstances, is sexual. It is further concluded that the predominant role of the alpha-2 antagonist peripherally is to modulate (block) the norepinephrine (NE)-induced contractility in the smooth muscle of the penis. How the central arousal mechanisms are speci cally linked to sexual response is not understood. Experimental studies with a selective alpha-2 antagonist, delequamine, are brie y reviewed and their complex results discussed. Evidence from sleep studies was consistent with delequamine having both central excitatory and inhibitory effects, dependent on dosage. The possibility that men with psychogenic erectile dysfunction might have increased central alpha-2 tone was considered. The apparent loss of responsiveness to the alpha-2 antagonist in older dysfunctional men was discussed. More questions are raised than answered; further research is needed in this area. (2000) 12, Suppl 1, S64±S69 Keywords: alpha-2 blockade; delequamine Role of adrenergic agonists The pharmacological agent with the longest history for enhancing sexual response is yohimbine, originally available as a plant (bark) extract. 1 Yohimbine's principal pharmacological action is as an alpha-2 adrenoceptor antagonist. Activation of presynaptic alpha-2 receptors increases re-uptake of norepinephrine (NE) at the synapse, hence reducing NE transmission. Antagonism of presynaptic alpha-2 receptors will therefore have the principal effect of increasing NE transmission. Antagonism of postsynaptic alpha-2 receptors will inhibit NE action at the smooth muscle. Both central and peripheral effects of such a drug need to be considered. The role of the norepinephrine system Central effects There are good reasons for expecting an alpha-2 antagonist to have central effects. The NE system in the brain originates in two brain stem nuclei, the Correspondence: Dr, The Kinsey Institute, Morrison Hall 313, Bloomington, IN Received 2 September 1999; accepted 15 November 1999 locus coeruleus (l.c.) and the lateral tegmental nucleus (l.t.n.). 2 Each nucleus has neurons with ascending and descending projections. Of the two, the l.c. system is most likely to be relevant to sexual arousal and response; it is activated by novel sensory input to produce a state of central arousal which may be associated with aversive or rewarding situations. The ascending projections of the l.c. terminate, quite widely, in the dorsal thalamus, hypothalamus, basal forebrain, including hippocampus, and the frontal cortex. The descending projections from the l.c. go to the spinal cord (mainly ventral horn) and to sensory nuclei in the brain stem. The l.c. neurons are populated with alpha-2 receptors. 3 Davidson's group showed that yohimbine and other alpha-2 antagonists such as idazoxan, could substantially restore sexual behavior in the castrated male rat and that the sexually enhancing effect of yohimbine was independent of any direct effect on erection, leading them to conclude that the drug's principal effect was on central arousal. 4 Peripheral effects Some attention has been paid to the presence and possible function of alpha-2 receptors in the erectile tissue. Saenz de Tejada et al 5 concluded that adrenergic activity is modulated, in part, by pre-

2 synaptic alpha-2 receptors in the corpus cavernosum; in those circumstances an alpha-2 antagonist would be expected to increase NE transmission and hence smooth muscle contractility. Andersson 6 suggested that such alpha-2 receptor activity may play an important role in the cavernous artery wall, but not in the trabecular smooth muscle. However, Traish et al 7 identi ed post-synaptic alpha-2 receptors on the trabecular smooth muscle, though the function of these receptors remains unclear. 8 The very limited evidence of the effects of injecting alpha-2 antagonists into the corpus cavernosum indicates very little effect. 9 If a drug produces a predominantly presynaptic antagonistic effect on alpha-2 receptors in the erectile tissues, the consequence would be an increased release of NE and a resulting increase in contractile tone. The possibility of a post-synaptic effect of alpha-2 receptor antagonist on inhibition of NE binding on the trabecular smooth muscle has to be considered, with two such contrasting effects possibly cancelling each other out. The relationship between the central and peripheral effects of the NE system We thus have a paradox; central effects of NE on sexual response are excitatory and presynaptic peripheral effects are probably inhibitory. The rst fundamental point in tackling this paradox is to recognize that the excitatory central effects of the NE system are not con ned to sexual arousal. The upward projections of the l.c. are involved in general arousal, and in many circumstances it is entirely appropriate that elicitation of general central arousal should require localized peripheral inhibition of genital response. Thus if the NE system generates `arousal' in response to the threat of punishment, an emotional state which in those circumstances Gray 10 would call `anxiety', then inhibition of other response patterns, such as sexual response, which might interfere with an appropriate avoidance response would be adaptive. However, one of the principal mysteries of the central NE system is how it is mobilized to serve sexual function in some situations and avoidance behavior in others. 11 Testosterone may be relevant to this selective process, because of the capacity for alpha-2 antagonists to restore sexual behavior in castrated male rats (see above), though the mechanism of this hormonal effect is far from clear. Further complexity is suggested in a study by Sala et al, 12 showing a curvi-linear dose response relationship between an alpha-2 antagonist and central excitation, with middle range doses producing maximal excitatory effects and high doses inhibitory effects. The relevance of the central NE system to sexual arousal is further indicated from studies of sexual satiation or exhaustion in rats. This state, which results from repeated copulation, is characterized by a prolonged period of sexual unresponsiveness, lasting for several days before recovery. 13,14 This unresponsive state can be partially corrected with a variety of pharmacological manipulations including the opioid antagonist, naloxone (indicating that opioid inhibition is probably involved), 8-OH- DPAT, a 5HT1a agonist (indicating that serotonergic inhibition is involved), and yohimbine. However, the effects of the rst two require an intact NE system, indicating complex interactions between peptide and catecholamine systems. 15±17 Thus, in those circumstances where central arousal is elicited by an aversive situation, we should not be surprised if this NE system produces central arousal of `anxiety' type and peripheral inhibition of sexual response at the same time. Conversely, when central arousal is in response to sexual stimuli we might expect a reduced presynaptic peripheral inhibition of genital response, although there does not appear to be any evidence directly relevant to that point. The integrating component of the system is presumably the l.c., with both its upwards and downwards projections. It may be relevant that of the two sources of neuronal input to the l.c., one of them is from the nucleus paragigantocellularis (npgi) which has direct, serotonergically mediated inhibitory in uences on the erectile response. 18 In conclusion, whereas it is clear that the central NE system is of fundamental importance to sexual arousal and response, we remain largely ignorant of how it functions in that respect. Pharmacological studies in humans A series of clinical studies of the effect of yohimbine in men with erectile dysfunction have been carried out. 19±22 Most of these studies have been affected by methodological problems of various kinds, but a consistent though weak average bene cial effect on erectile function has been reported, presumably due to central effects of the drug. In experimental studies, yohimbine induces anxiety 23 and combined with naloxone, it produces both anxiety and penile erection. 24 Anxiety has not been a problem as a side effect in the treatment studies cited above, and it remains a question of some interest why anxiety has been evoked in such experimental studies, but not in treatment studies. It may be a matter of acute dosage contrasted with chronic dosage; or it may be dependent on the context in which the drug is taken. Given its theoretical importance, further research should be directed at this issue. S65

3 S66 Experimental human studies with a speci c alpha-2 antagonist, Delequamine About 10 years ago a new alpha-2 antagonist, RS15385 (delequamine) was developed by Syntex Pharmaceuticals as a potential prosexual drug (Figure 1). This compound has more speci c and selective alpha-2 antagonist action than yohimbine. 25 This provided us with the opportunity to carry out some experimental studies of the effects of a selective alpha-2 antagonist on human male sexual response. We based these studies on a theoretical model derived from the effects of testosterone on human male sexuality, and the capacity for alpha-2 antagonists to restore sexual response in testosterone de cient animals (see above). We worked on the assumption that the alpha-2 antagonist would have similar effects in eugonadal men as testosterone replacement would have in hypogonadal men. Previous research had shown that erections occurring during sleep (nocturnal penile tumescence or NPT) were very sensitive to testosterone and were markedly diminished in hypogonadal men and restored with testosterone replacement. 26±29 By contrast, erections in response to visual erotic stimuli (VES) were relatively independent of testosterone. In a series of studies, maximum erectile response to VES was not signi cantly different in hypogonadal and eugonadal men. 27,29,30 A more recent study showed that duration and to some extent rigidity of erectile response, variables which had not been measured in the earlier studies, were sensitive to testosterone withdrawal and replacement. 31 This indicated some degree of testosterone dependence, but much less clear cut than in the case of NPT. The hypotheses that we set out to test were as follows; that delequamine would: (1) Enhance spontaneous erections and spontaneous feelings of sexual arousal (i.e. NPT or spontaneous erections when awake, not in response to an external sexual stimulus); or (2) have no effect on maximum erectile response to visual erotic stimuli, but would prolong erectile responses to such stimuli. Two types of experimental procedures were therefore used, both involving intravenous infusion of the drug in two contrasting dosages (`high' and `low' dose) compared with a third placebo condition. The rst procedure assessed effects of the drug during sleep on nocturnal penile tumescence; 32 the second on subjective, erectile and cardiovascular responses to visual erotic stimuli and erotic fantasy in the waking state. 33,34 In each study, 12 `normal controls' and 24 men with psychogenic erectile dysfunction were involved (there was a small overlap of subjects in the two studies). Effects on nocturnal penile tumescence Our hypotheses were largely con rmed. 32 Erections during sleep were increased by the drug in both the controls and the dysfunctional men, and in the controls, spontaneous erections occurred with the high dose of the drug just before sleep onset. However, the effects during sleep were complex. In the normal controls, there was a curvilinear dose± response relationship; the low dose of the drug increased erections but mainly during non-rapid eye movement (non-rem) sleep. The high dose, apart from its positive effects on spontaneous erections before sleep onset, reduced erections during REM sleep (an effect which was characterized by a fragmentation of the erectile response). In analyzing the results for the dysfunctional men, we divided them into two age groups around the median split of 47 y. Although men in the older group were, as expected, more sensitive to the sleep disrupting effect of the drug (diminution of total sleep time), they showed no effect of the drug on erections at either dose level. The younger dysfunctional men, on the other hand, showed a linear doseresponse relationship; the low dose showed no signi cant effect; the high dose of the drug increased erections during non-rem sleep, mostly between stage 2 and the rst episode of REM. There was therefore an interesting contrast between the controls and the younger dysfunctional men. In the controls, the high dose of the drug only stimulated spontaneous erections during the waking state at the time when sleep onset was delayed. In the younger dysfunctional men, the positive effects of the high dose was observed shortly after sleep onset, as if in their case inhibitory tone which was high in the waking state was reduced by the onset of sleep. Effects in the waking state Figure 1 Delaquamine: Alpha 2 selective antagonist. Once again our hypotheses were broadly con- rmed. 33; 34 In this study the age groups of the dysfunctional men were formed around the median split of 45 y. In the controls, there were signi cantly higher subjective ratings of sexual arousal and an

4 increased likelihood of spontaneous erections occurring with the high dose of the drug before the presentation of visual erotic stimuli or use of erotic fantasy. Response to VES, on the other hand, showed no effect of the drug on penile circumference, but in the controls and the younger dysfunctional men there was a signi cant prolongation of erectile response to VES with the high dose of the drug. There were further interesting ndings in relation to the cardiovascular system. There was a blunting of blood pressure (BP) and heart rate (HR) response to the erotic stimuli in the younger dysfunctional men during the placebo condition, which was partially normalized by the high dose of the drug. The cardiovascular responses of the older dysfunctional subjects were not different from those of the controls, whereas their erectile responses were impaired, suggesting some form of dissociation between cardiovascular and erectile responses in older dysfunctional men. Interpretations and questions raised by these results The sleep study The evidence from the sleep study is consistent with there being a double role for NE in the central nervous system, both excitatory and inhibitory, each of which could be elicited by this alpha-2 antagonist, depending on the dose. One possible interpretation of the curvilinear dose±response relationship in the controls is the consequence of a dose related shift from predominantly excitatory to predominantly inhibitory action. However, the linear dose response relationship in the younger dysfunctional men was consistent with an increased alpha-2 inhibitory tone in those cases. According to that interpretation, higher doses of the drug than those used in this study would produce a curvilinear picture in the dysfunctional men also. 35 If there is any validity in such an interpretation it raises the possibility of central `increased alpha-2 tone' as being a causal factor in certain cases of psychogenic erectile dysfunction. But how does this shift from `excitation' to `inhibition' work? One widely accepted explanation for this type of curvi-linear dose±response curve is a shift from predominantly pre-synaptic to postsynaptic effect. But it is dif cult to see how that would explain these ndings. An important factor to take into account is the physiological signi cance of REM sleep. This has been described as a state involving virtual cessation of NE neuron activity within the l.c. 36 This offers a partial explanation for why erections occur during REM sleep; i.e., there is a `switching off' or at least reduction of the centrally derived peripheral inhibitory tone in the erectile tissues. What we found in our controls was that with the low dose of the drug there was an increase in erectile response, noticeable during both REM and non-rem sleep but only signi cant during non- REM. With the high dose of the drug, we found a signi cant reduction in erectile response, compared to the low dose during REM-sleep. In some way our lower dose was activating the NE excitatory system, producing effects which were most noticeable during non-rem sleep, presumably because during REM the drug, particularly at the higher dose level, was also activating the inhibitory system, `turning on' the `switched off' l.c. neurons. An interesting comparison is to be made with the effects of trazadone on NPT reported by Saenz de Tejada et al. 37 Trazadone increased NPT in a dose related fashion, but this effect was largely con ned to the period following REM related erections. In other words, when the centrally derived peripheral inhibition was `switched on' again following a REM related erection, the drug blocked the resulting detumescence, prolonging the erection. This was not the pattern with delequamine which increased erection during non-rem sleep predominantly in the period between sleep onset and rst REM. Nor was there any evidence of trazadone disrupting NPT during REM sleep, though there might conceivably have been with a higher dose. It is also relevant that delequamine had a marked effect in delaying sleep onset which trazadone did not. These contrasting effects are consistent with trazodone having a peripheral alpha-1 antagonist effect and delequamine a central alpha-2 antagonist effect. Trazadone has a complex pharmacological action which also includes serotonergic effects, and it remains a possibility that these effects may have been responsible or contributed to the pattern observed. At this stage we can only go so far in explaining these complex effects of delequamine during sleep. Are there l.c. cells which are responsible for the downstream peripheral inhibition and others responsible for the upstream arousal effects? Is there a change of balance of control of these systems during REM sleep which makes response to pharmacological agents unpredictable at that time or less relevant to their effects at other times? During the waking state Given that our controls and younger dysfunctional men showed an increase in the duration of erections in response to VES with delequamine, it is reasonable to conclude that, while both central and peripheral effects may have been involved, the balance was in favor of the central alpha-2 `excitatory' effects, and, at least with the doses used, with no suggestion of a curvi-linear dose-response relationship. Of particular interest are the blunted cardiovascular responses in the younger dysfunctional men. We should consider the possibility that such blunting may be part of a more generalised S67

5 S68 pattern consistent with general anxiety. Recent evidence has shown that reduced responsiveness is a characteristic of general anxiety disorder, and is at least in part due to loss of vagal control. 38 However, the partial normalization of the cardiovascular responsiveness by the alpha-2 antagonist in our study suggests that in these men with erectile dysfunction it was not solely a matter of vagal control. This does raise some interesting research possibilities, however. Younger men with psychogenic dysfunction should be compared with men with general anxiety disorder in their patterns of cardiovascular responsiveness to a variety of stimuli, including sexual. At the same time, the distinction between `increased inhibitory tone', whether alpha-2 or otherwise, and an acute inhibitory response to some threatening aspect of the sexual situation is of fundamental theoretical importance. Are we dealing, at least in some cases, with a high basal inhibitory tone, which is part of a more general personality trait, which makes the individual vulnerable to erectile dysfunction, or is it a matter of the degree of inhibitory response to some perceived external sexual threat that makes him vulnerable? In the former case pharmacological treatment may hold particular appeal. In the latter the analysis of sexual threats may lend itself to exploitation by psychological methods of treatment. The use of sleep studies, when it is assumed that the individual is not reacting to speci c threats in his environment, provides one model for studying `inhibitory tone'. But the investigation of cardiovascular (and electrodermal) responsiveness to a variety of external stimuli, including aversive, sexual and non-sexual positive, in younger men with psychogenic erectile dysfunction, may throw additional light on this issue. The age effect The impact of age on the effects of delequamine, in both the sleep and waking studies, is also of theoretical interest. It was not expected and as a consequence we did not have aged matched controls for our dysfunctional subjects. The controls were slightly younger than the younger dysfunctional men. It would be interesting to assess the effects of this drug in a group of older functional men. The results, nevertheless, suggest that there is a decline in responsiveness to central NE stimulation, at least that mediated by alpha-2 receptors, with increasing age (although no lack of interference with sleep in the older men). Lerner et al 39, on the basis of in vitro studies, concluded that there is an increase in peripheral norepinephrine inhibitory tone in the erectile tissues in older men, contributing to the age related increase in vulnerability to erectile dysfunction. Can their ndings be reconciled with our agerelated loss of response to alpha-2 antagonists? Is it possible, for example, that there is a loss of alpha-2 receptor responsiveness in the periphery as well as centrally, which would reduce or impair the normal alpha-2 modulation of NE release, resulting in increased NE tone in the smooth muscles? Conclusions Given the complex ndings with delequamine in these acute dosage studies, this paper has raised more questions than it has provided answers. However, most of the questions raised are researchable, and are of potential relevance to de ning the characteristics of the man with erectile dysfunction who is likely to bene t from this type of drug. The tendency in the pharmaceutical industry when evaluating drugs of this kind is to look for a broad therapeutic impact in large scale phase 3 studies. More consideration should be given to formulating theoretical models which may enable us to predict likely responders, who may be relatively speci c sub-groups, and to structure treatment outcome studies accordingly. 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