ReviewCentral neuropharmacological agents and mechanisms in erectile dysfunction: the role of dopamine
Introduction
At the present state of knowledge, it is a daunting task to pursue any single central anatomical pathway with a high degree of functional detail [67]. In a similar vein, penile erection is but one discrete outcome of a complex cascade of neural events, a large part of which occurs within the central nervous system. We are able to identify some of the essential neurochemical and anatomical properties of the central pathways that support erection. However, the potential interactions are highly complex, so that deciphering a single pathway in isolation can lead to difficulties in integration, interpretation and application in a clinical context. This is not to diminish the recent progress that has occurred in understanding brain mechanisms, but to acknowledge the challenge of:
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identifying specific “erecto-motor” areas in a biological “central processor” in the absence of circuit diagrams or an operator manual, so to speak;
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dissecting out (literally and figuratively) a neural system that has been “hardwired” into the core of the processor as fundamental to species propagation and survival; and,
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conducting comparative research in an area in which species differences are profoundly subtle and important.
In studying CNS drugs for human erection, there is limited opportunity to capture more than the final output of central mechanisms that harness many actuator pathways (see the paper by Sachs in this issue). The actual neural signals generated by a CNS drug for erections have not been investigated directly, and the end point (penile erection) is confounded by non-hemodynamic or “phallodynamic” effects, such that response evaluation is difficult. Animal models have the advantage of greater simplicity, but at the same time present a threat of decreased relevance. In particular, there are some specific caveats in extrapolating from studies of penile erection in non-human species. Penile erections in man are known to be under the influence of adrenergic, cholinergic and non-adrenergic non-cholinergic (NANC) local regulation [3]. In fact, there are many effector systems with specific contributions to the function of the penis [1]. There are also important species differences and similarities in some of these systems. For example, rats make no effective use of adenylyl cyclase mechanisms in their erectile response [45], whereas this is a well-described and clinically important mechanism in man [4] and guanylyl cyclase mechanisms are extensively used in both species. Clearly, there are some fundamental differences in final common pathways between species that likely have central correlates. Furthermore, an erection in man is first a neurovascular event with a secondary component of muscular action [35] (as in primates [31]), whereas in rats, for example, there is a simultaneous interaction of neuromuscular and neurovascular events that determine the type of erectile response observed [9]. The equivalencies in the sexual response cycles between rat and man are also complex (see paper by Sachs in this issue).
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Clinical considerations
Multiple potential sites have been identified in the CNS for centrally active erectogenic drugs, based on the mechanisms of neuro-chemical synaptic transmission (e.g. axonal, neuronal membrane, precursor availability, synthesis, storage, intracellular organelles, release, receptors, post-receptor mechanisms and inactivation) (see Fig. 1).
To conduct the business of targeted neural function, the brain employs one of two broad anatomical strategies, i.e. hierarchical or diffuse distribution of
The role of dopamine receptors
Dopamine receptors have been divided into D1 and D2 subclasses, based on radioreceptor and cloning studies. Additional sub-types include D5, which are similar to D1, and D3 and D4, which are similar to the D2 sub-type. They are typical 7-transmembrane region receptors, and are G-protein coupled. Recombinant dopamine (DA) receptors differ with respect to their ability to stimulate cAMP, inositol triphosphate and arachidonate, and their effects on DA release, mitogenesis, and acidification [68].
Clinical trials
Relatively few well-controlled, clinical trials of centrally acting ED agents have been reported to date. In fact, the overall field of clinical trials in ED was given a major “jump-start” by the advent and approval of sildenafil. Clinical trials of apomorphine have contributed significantly to our understanding of the potential role of centrally acting agents in this rapidly-evolving new field of therapeutics. Combinations of agents are also likely to be evaluated in the near future.
Early
Conclusion: the matrix of treatment strategies (MATS)
In addition to oral sildenafil and apomorphine SL, a number of other treatment interventions are available for the management of ED. Although a detailed review of these treatments is beyond the scope of the present paper, some concluding comments are offered regarding a new classification schema for these approaches and the implications for future drug development. By classifying treatments according to the putative site and mechanism of action, it is hoped that a more rational approach to
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