[back]

[request information]

Vasoconstrictive mechanisms

NO, that is generated both by both nerves and the endothelial cells that cover the trabeculae of the corpus cavernosum and through stimulation of sGC and the generation of cyclic GMP, is thought to play a dominant role in relaxation of smooth muscle in this tissue. The pathophysiological relevance of the cyclic GMP pathway is evidenced by the successful use of PDE5 inhibitors, as described above. Other signaling pathways involving VIP/cAMP are also accepted as being operative in relaxation of the corpus cavernosum, but as mentioned above, activation of this pathway is insufficient on its own to produce erection, with inhibition of contractile signals also being required. In severe cases of ED, intervention may be required both to stimulate inhibitory pathways and to block excitatory pathways. The contracted (resting) state of the corpus cavernosum smooth muscle is considered to be mediated by release of NE, ET, and angiotensin (see below). Inhibition of these agonists at the receptor level or in their downstream signaling pathways should, like NO stimulation, also lead to a decrease in myosin regulatory light chain phosphorylation and consequent relaxation through decreased cytoplasmic calcium.

a-Adrenoceptors: The adrenoceptor family was first divided into two subtypes, the a- and b-adrenoceptors, as determined by pharmacological studies in isolated tissue (Ahlquist, 1948). A quarter of a century later, the a-adrenoceptors were further subdivided based on their anatomical location, with the a-adrenoceptors located on peripheral sympathetic nerve terminals designated a2-adrenoceptors, and those located post-synaptically designated a1-adrenoceptors (Langer, 1974). This anatomical classification rapidly gave way to the identification of pharmacological differences between the a-adrenoceptors, notably the ability of yohimbine and rauwolscine to act as a2-adrenoceptor antagonists. Subsequent studies using pharmacological and molecular biology techniques have further subdivided the a-adrenoceptor family; three subtypes within each group have now been cloned and pharmacologically characterised. The a1-adrenoceptor subtypes have been classified as the a1A-, a1B- and a1D-adrenoceptors and the a2-adrenoceptors have been classified as the a2A- (a2D- species variation of the human a2A-), a2B- and a2C-adrenoceptors.

The importance of the a-adrenergic neuroeffector system in erectile function has long been recognized (see Andersson & Stief, 2001). Evidence from in vitro and in vivo studies has indicated that adrenergic nerves, a major source of physiologically active NE, innervate the corpus cavernosum. NE is an important neurotransmitter in the control of penile detumescence (Andersson & Wagner, 1995; Christ et al, 1990; Saenz de Tejada et al, 1991) and acts on post-junctional a1- and a2-adrenoceptors, inducing contraction in trabecular smooth muscle and penile vessels. When administered systemically, a-adrenoceptor antagonists facilitate penile erection and produce prolonged erection or priapism (Andersson & Wagner, 1995; Diederichs et al, 1990;Traish et al, 1995). Traish et al (1997) identified a1- and a2-adrenoceptor subtypes in corpus cavernosum smooth muscle using a variety of techniques, including mRNA expression, receptor binding studies and organ bath methodologies. The same authors demonstrated that corpus cavernosum contractility to NE or phenylephrine is dependent on the contributions of more than one a1-adrenoceptors subtype, and, of note, Veronneau-Longueville et al (1998) have reported expression of a1A-, a1B- and a1D-adrenoceptor expression by the rat corpus cavernosum. Furthermore, Traish et al (1997) have also demonstrated expression of post-junctional a2-adrenoceptors in the corpus cavernosum and showed that these receptors are physiologically functional (Traish et al, 1997; Gupta et al, 1998). NE released from adrenergic nerves binds to a1-adrenoceptors, localized on the corpus cavernosum smooth muscle, releasing Ca2+ from intracellular stores and increasing DAG levels. The mechanisms of action of a2-adrenoceptor in the corpus cavernosum are yet to be fully understood. Studies in other vascular systems have shown that a2-adrenoceptor activation inhibits adenylyl cyclase; however, a2-adrenoceptor activation has also been shown to modulate Ca2+ influx and to activate phospholipase C and phospholipase D (MacKinnon et al, 1994). Based on the current state of knowledge, the following consensus model has been proposed regarding presynaptic modulation by NE: NE release from adrenergic nerves binds to the pre-junctional a-2 adrenoceptor on NANC fibers thus inhibiting NO synthesis and release. Blockade by selective a2-adrenoceptor antagonists (e.g. yohimbine or delequamine) enhances NO release, facilitating erection. In addition, NE release from adrenergic nerves binds to the pre-junctional a2-adrenoceptor on the adrenergic nerves and negatively regulates NE release. Blockade of this reaction by selective a2-adrenoceptor antagonists (e.g. yohimbine or delequamine) enhances NE release, limiting the efficacy of such molecules. Based on these concepts for pre-junctional and post-junctional regulation of smooth muscle tone, the most efficacious strategy to reduce adrenergic activity and facilitate penile erection is to combine a1 and a2 adrenergic receptor antagonists. In this case, any enhancement of NE release by presynaptic receptor blockade is of little importance because the a1 receptor antagonist will impede this vasoconstrictor response. This will also enhance the release of NO, which increases smooth muscle relaxation and decreases contraction, resulting in penile erection. Although the majority of information regarding the influence of a-adrenoceptors on erectile function concerns peripheral effects, a body of data does exist supporting the involvement of central adrenoceptors. Chang et al (2001) suggested that a1A/D-, a2B-, and a2C-adrenoceptors in the hippocampus are involved in a negative feedback loop that inhibits erectile activity. The adrenoceptor profile which is optimal for ED remains unknown although the available information has been reviewed by Saenz de Tejada (2000).

Supported by this body of preclinical data, the mixed a1/2-adrenoceptor antagonist phentolamine has been evaluated in a number of clinical trials (see Goldstein, 2001 for a review). In summary, at oral doses of 40 mg and 80 mg respectively, 55% and 59% of men were able to achieve vaginal penetration, with 51% and 53% achieving penetration on 75% of attempts. The correction of ED or improvement to a less severe category of dysfunction was experienced by 53% of men with the 80 mg dose and 40% with the 40 mg dose of phentolamine. Phentolamine is thus generally accepted as being efficacious for the treatment of ED. When taken orally on a regular basis before sleep, it may be able to prevent ED in men at risk, protecting also minimally and moderately impotent patients from becoming moderately and severely impotent respectively (Hatzichristou et al, 2001). Offering further support to the concept that mixed a1/2-adrenoceptor antagonists may offer a better approach to ED than through the use of more selective antagonists is the relatively limited therapeutic efficacy of yohimbine (a selective a2-adrenoceptor antagonist; for review see Tam et al, 2001) and Ro70-0004 (a selective a1A adrenoceptor antagonist; see Choppin et al, 2001). In summary therefore mixed a1/2-adrenoceptor antagonist are of benefit in the treatment of ED. The mutual interaction between nitrergic and adrenergic innervation is of particular interest. NO is known to reduce the excitatory pro-erectile effects of NE (see above); likewise NE is known to prevent NO release. Thus a combination of a mixed a1/2-adrenoceptor antagonist and molecules such as sildenafil may offer excellent therapeutic opportunities, although the risk of priapism should be evaluated. Furthermore, human penile circumflex veins have been shown to express functional a1- and a2-adrenoceptor subtypes which mediate the contractile response to NE (Kirkeby et al, 1989). There is therefore a risk that blocking these receptors may increase venous leak, and this possibility should thus be assessed.

A small pilot study conducted to determine the effects of oral phentolamine in menopausal women with FSD was reported in 1999 (Rosen et al). Six postmenopausal women with a lack of lubrication and with sexual arousal difficulties received a single dose of oral phentolamine (40 mg) and placebo in a single-blind, dose-escalation design. Phentolamine increased lubrication and pleasurable sensations in the vagina. The drug was well tolerated, overall, with few reports of adverse side effects. Likewise, Rubio-Aurioles et al (2002) demonstrated efficacy, although this was restricted to those women receiving HRT. Consistent with these studies are reports that the a2 adrenergic agonist clonidine reduces vaginal blood flow (Meston et al, 1997). Thus phentolamine represents one of the most promising targets for the treatment of FAD to date and parallels the situation for PDE5 inhibitors described above.

Endothelin: ET-1, a peptide of 21 amino acids, was originally isolated from porcine aortic endothelial cells in 1988 and is the most potent vasoconstrictive peptide known to date. There are in fact three known ETs, ET-1, ET-2, and ET-3, which have diverse pharmacologic activities and different potencies, suggesting the existence of ET receptor subtypes. These related peptides differ from ET-1 at the two- and six-amino-acid-residue positions, respectively. A fourth peptide, vasoactive intestinal contractor (VIC), is sometimes classified as rat ET-2. All members of the ET family contain two essential disulfide bridges and six conserved amino acid residues at the C-terminus. In addition, all of the ET family members are synthesized initially as prepropolypeptides of approximately 200 amino acids encoded by separate genes (Inoue et al, 1989). These are proteolytically cleaved (Seidah et al, 1993) to produce biologically-inactive propolypeptides of approximately 40 amino acids, termed "big ETs". Big ET-1 is cleaved by the proteolytic action of a membrane-bound metalloprotease, ECE-1 (ET-converting enzyme), producing the 21-amino-acid active peptide (Yanagisawa et al, 1994). The biochemistry and biology of the ETs has been the subject of several recent reviews (Inoue et al, 1989, Yanagisawa et al, 1994). Takayanagi et al (1991) described two distinct subclasses of ET receptors, namely ET-1-specific and ET-non-selective. Vane (1990) recommended that the ET1-specific type be called ETA and the non-selective type ETB. The ETA receptor shows a higher affinity for ET-1 than for ET-2, and the lowest affinity for ET-3. The ETB receptor shows approximately equal affinity for each of the three ETs (Miller et al, 1993, Sakurai et al, 1994). Both receptors are expressed in a wide variety of tissue types, in some cases with distinct expression and in some cases showing some degree of overlapping expression (Yanagisawa et al, 1994). Both the ETA and the ETB receptors play varying roles in mediation of vasopressor actions, depending on the species and vasculature involved (Yanagisawa et al, 1994). In contrast to the ETA receptor, ETB binding is able to mediate endothelium-dependent relaxation (Yanagisawa et al, 1994). The ET family is accepted as a key player in atherosclerosis and most cardiovascular conditions associated with increased vascular tone and remodeling.