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A similar procedure in other experiments also inhibited ejaculation as well as penile intromission in rats, suggesting an alternative role of 5-HT in the transmission of sensory feedback information necessary for sexual responses Svensson and Hansen, Similarly, penile reflexes are inhibited by i. Many 5-HT receptor subtypes have been identified, which can rationally be divided into G-protein-coupled and ligand-gated ion channel-related subfamilies Gerhardt and van Heerikhuizen, ; Barnes and Sharp, The receptors use different effector systems in different cells, which may explain the conflicting reports on the effects of 5-HT agonists and antagonists on sexual functions.

For example agonists may either enhance or depress sexual function, which has been attributed to the involvement of multiple 5-HT receptors. In accordance with the selective use of 5-HT receptor agonists and antagonists, components of male copulatory behavior were found to be displayed variably. For example, 5-HT 1A receptor activation may have contrasting effects on sexual function, depending on the dose of administration and location of the receptor in the brain Ahlenius et al.

Based on their findings, Bancila et al. They both induce erection in rodents, but they also significantly inhibit ejaculation and sexual behavior Aloi et al. NOS inhibitors, given by i. Drugs that act through 5-HT mechanisms may affect sexual behavior.

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Thus, melatonin, which increases all aspects of sexual activity in rats, possesses 5-HT 2A antagonistic properties Drago et al. Evidence for a facilitatory role of melatonin in sexual behavior has been presented, suggesting that its mechanism of action may involve the 5-HT 2A receptor Brotto and Gorzalka, Central dopaminergic neurons comprise an incertohypothalamic system with projections to the medial preoptic area MPOA and paraventricular nucleus PVN Bjorklund et al.

Dopaminergic neurons have also been identified, traveling from the caudal hypothalamus within the diencephalospinal dopamine pathway to innervate the lumbosacral spinal cord Skagerberg et al. Thus, dopamine may be expected to participate in the central regulation of both the autonomic and somatic components of the penile reflexes.

Supporting this view, the dopamine receptor agonist apomorphine, administered systemically to male rats, was found to induce penile erection Benassi-Benelli et al. The effect of apomorphine was biphasic in the freely moving rat, with low doses facilitating and high doses inhibiting erection Pehek et al. These observations were subsequently extended to investigations involving low dose systemic administration of other dopamine agonists such as piribedil, lisuride, and quinelorane to rats and other animals for review, see Andersson and Wagner, The effects of these agonists were attenuated by centrally, but not peripherally, acting dopamine receptor antagonists.

Dopamine-receptor agonist-induced erections were abolished by castration in rodents, and testosterone replacement restored erectile function Scaletta and Hull, ; Heaton and Varrin, ; Melis et al. Interestingly, rhesus monkeys did not respond to apomorphine, suggesting that there are basic differences between rats and rhesus monkeys in the systems mediating sexual behavior Chambers and Phoenix, Whether the proerectile effects of apomorphine in humans are dependent on the androgenic state has not been clarified.

Dopamine receptors are distributed to various regions in the brain, with a high density particularly in the basal ganglia. Both the two major families of dopamine receptors, D 1 -like D 1 and D 5 and D 2 -like D 2 , D 3 , and D 4 receptors Sibley, , have been associated with central erectile functions. The D 2 receptor seems to be responsible for most of the behavioral effects of dopamine, whereas the effects of D 1 receptors are more difficult to define.

The dopamine-induced stretching, yawning, and penile erection syndrome seem to involve particularly the D 2 receptor subtype. The injection of apomorphine into the MPOA showed that low levels of dopaminergic stimulation, via D 1 receptors in particular, facilitated erections Bazzett et al. In contrast, dopaminergic antagonists injected into the MPOA decreased the number of penile reflexes Pehek et al.

In the PVN, similar experiments have established that D 2 rather than D 1 receptors primarily facilitate erections Melis et al. The erection following paraventricular D 2 receptor stimulation apparently involves oxytocinergic neurotransmission Carter, Conversely, injection of oxytocin into the PVN induced erections that were not attenuated by dopamine receptor blockade, suggesting that dopaminergic neurons activate oxytocinergic neurons in the PVN and that released oxytocin then accounts for the erectile response see Section II. Injection of apomorphine into the lumbosacral subarachnoid space was reported to impair ex copula penile reflexes, slow the rate of copulation, and decrease the number of intromissions preceding ejaculation Pehek et al.

This is in contrast to recent findings, showing that injection of apomorphine intrathecally in rats evoked erection in both normal Giuliano et al. The difference in the result is difficult to explain. However, most probably stimulation of the dopaminergic system can produce erection at both supraspinal and spinal sites. As mentioned above, systemically administered apomorphine, enhances seminal emission. Recording of intravesical pressure in the nonanesthetized rat after administration of apomorphine showed that the pressure response consisted of both smooth and striated muscle components Andersson et al.

This implies that apomorphine has effects not only on the sacral parasympathetic output, but also on somatic pathways. Systemically administered apomorphine induces both penile erection and bladder overactivity in male rats K. Thus, at least in rats, apomorphine has effects not only on erection but also on seminal emission and bladder function. Evidence for noradrenergic mechanisms involved in the supraspinal mediation of penile erection is sparse.

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Noradrenergic neurons from the A5 region and from the locus coeruleus project to the nuclei in the spinal cord involved in erection Giuliano and Rampin, b. Available data suggest that increased noradrenergic activity stimulates, whereas decreased noradrenergic activity inhibits, sexual function Bitran and Hull, Furthermore, accurate conclusions can only be drawn from work that suggests that central adrenergic receptors have been selectively stimulated.

Excitatory amino acids appear to exert a role in penile erection. Thus, microinjections of l -glutamate into the MPOA elicited an increase in intracavernous pressure Giuliano et al. NMDA, aminohydroxymethyl-isoxazolepropionic acid, or trans amino-1,3-cyclo-pentadicarboxylic acid, increased intracavernous pressures when injected into the PVN Zahran et al.

The effect of NMDA was prevented by i. The mechanism for NOS activation would conceivably involve increased calcium influx through previously described calcium channel-coupled NMDA receptors Snyder, Systemic administration or i.

Pharmacology of Penile Erection

Experiments using retrograde labeling have shown that oxytocin-containing neurons in the PVN project to spinal autonomic nuclei Swanson and Kuypers, ; Sawchenko and Swanson, This was confirmed by Tang et al. They found that oxytocinergic spinal projections from the PVN are more likely to influence the sacral autonomic rather than the somatic outflow. Plasma oxytocin concentrations are known to be elevated in humans following sexual stimulation Carmichael et al. Oxytocin was found to be a potent inducer of penile erection when injected into the lateral cerebral ventricle, the PVN, or hippocampus in laboratory animals Argiolas et al.

The erectile response was blocked by oxytocin antagonists and by electrolytic lesion of the PVN Argiolas et al. The oxytocin-induced erections were also abolished by castration, and testosterone replacement restored erectile function Melis et al. Immunoreactive oxytocin-containing spinal neurons associating with sacral preganglionic neurons, confirmed by retrograde labeling, support the role of oxytocin in the autonomic spinal circuitry that mediates penile erection Tang et al.

Oxytocin appears to exert an autoactivation mechanism involving stimulation of oxytocinergic receptors located on the cell bodies of the same oxytocinergic neurons in the PVN Argiolas et al. In support of this view, immunoreactive cell bodies of oxytocinergic synapses have been found to impinge upon the cell bodies of oxytocinergic neurons in both hypothalamic supraoptic and PVN nuclei Theodosis, Several central neurotransmitters may also converge upon the oxytocinergic system as activators e.

Evidence supports calcium as a second messenger mediating oxytocin-induced penile erection in the PVN and oxytocinergic receptor coupling with calcium channels through a pertussis toxin-sensitive G-protein Argiolas et al. The oxytocinergic system may also be influenced by the NO synthase signal transduction pathway since inhibitors of this pathway prevent penile erection and yawning in rats induced by oxytocin, dopamine, and NMDA stimulation Melis and Argiolas, ; Melis et al.

Recent studies have explored the physiologic basis for central oxytocin release. Thus, electrical stimulation of the dorsal penile nerve in rats, presumed to represent physiological tactile stimulation during copulation, produced orthodromic excitation in about half the oxytocin-containing cells in the PVN Yanagimoto et al. These effects were shown to be androgen-dependent, since they were abolished by castration and could be fully restored by treating castrated animals with testosterone Bertolini et al.

Interestingly, ACTH and the ACTH-like peptides do not enhance social interaction, since during periods of sexual stimulation the animals did not seek to copulate with partners Bertolini and Gessa, The cloning of five different subtypes of MC receptor Wikberg, ; Wikberg et al. Interestingly, the MC 3 receptor showed a high density in the hypothalamus and limbic systems Wikberg, , regions known to be important for erectile functions.

Calcium channels seem to mediate the effects of ACTH since i. Both lesions of the PVN Argiolas et al. This observation, combined with evidence that excitatory amino acids do not affect ACTH effects Melis et al. Endogenous opioid peptides have long been assumed to be involved in the regulation of male sexual responses, since sexual dysfunction has been observed clinically in men chronically using opiates Cushman, ; Crowley and Simpson, Copulatory behavior in male rats is depressed experimentally with the systemic administration of morphine or other opioids McIntosh et al.

Morphine, injected systemically or into the PVN of male rats, prevents penile erection induced by i. NO metabolite concentrations that are increased in the PVN following apomorphine, oxytocin, or NMDA local administration, become reduced following morphine administration into the PVN, indicating that the morphine effect depresses an NO-mediated erection induction mechanism at this level Melis et al.

These studies have suggested that cholinergic mechanisms operating seemingly at the hippocampus and MPOA may have a regulatory role in erectile function. The role of NO in the central neuromediation of penile erection followed observations that the injection of NOS inhibitors i.

The inhibitory effect of NOS inhibitors was not observed when these compounds were injected concomitantly with l -arginine, the substrate for NO. The PVN has been implicated as a prime site for NO interacting with the oxytocinergic mechanisms of penile erection Melis et al.

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This brain nucleus Fig. Nitric-oxide synthase within the paraventricular nucleus of the rat. Interestingly, since guanylyl cyclase GC inhibitors e. The additional finding that the NO scavenger, hemoglobin, does not prevent penile erection in spite of its ability to block NO production in the PVN, suggested that NO acts as an intracellular rather than an intercellular modulator of erectile responses involving the PVN Melis and Argiolas, In the spinal cord, the distribution of NOS-containing neurons suggests that nitric oxide plays a role in spinal cord neurotransmission including preganglionic sympathetic and parasympathetic, somatosensory, visceral sensory, and possibly motor pathways Valtschanoff et al.

At the spinal cord level, the functional role of NO for erection is not known. The different structures of the penis receive sympathetic, parasympathetic, somatic, and sensory innervation Dail, The nerves contain different transmitters, and the nerve populations have been categorized as adrenergic, cholinergic, and nonadrenergic, noncholinergic NANC. The nerves and endothelium of sinusoids and vessels in the penis produce and release transmitters and modulators, which interact in their control of the contractile state of the penile smooth muscles.

In addition, they may also have other important functions, some of which are discussed below. Penile arteries and veins, and cavernosal smooth muscle receive a rich adrenergic innervation, and it is generally accepted that the penis is kept in the flaccid state mainly via a tonic activity in these nerves. In a preliminary communication, Price et al. This was confirmed by other investigators Traish et al. However, Goepel et al. Cellek and Moncada found that human corpus cavernosum has a nitrergic innervation that does not merely modulate, but actually controls, the sympathetic responses.

They suggested that there is a balance between the nitrergic and sympathetic systems in the human corpus cavernosum, disruption of which may contribute to certain pathological conditions. On the basis of functional, autoradiographical, and immunohistochemical studies, endothelins ETs have been suggested to contribute to the maintenance of corporal smooth muscle tone Andersson and Wagner, Cultured endothelial cells from the human corpus cavernosum, but not nonendothelial cells, were found to express ET-1 mRNA Saenz de Tejada et al.

ET-like immunoreactivity was observed in the sinusoidal and also in cavernous smooth muscle Saenz de Tejada et al. Binding sites for ET-1 were demonstrated both in the vasculature and trabecular tissue of the human corpus cavernosum by autoradiography Holmquist et al. In rat corpus cavernosum, ET-1 and ET A receptor binding sites were primarily localized to the endothelium lining the cavernosal lacunar spaces Bell et al.

They confirmed their initial findings Parkkisenniemi et al. ET-1 potently induces slowly developing, long-lasting contractions in different penile smooth muscles: In bovine retractor penis muscle and penile artery, the contraction induced by ET-1 was mediated primarily by ET A receptors Parkkisenniemi and Klinge In the pithed rat, intravenously injected ET-1 had a vasodilator action increase in corporal pressure at low doses, but a vasoconstrictor action at high doses Ari et al.

ET-3 had mainly vasodilator effects, and it was suggested that the vasodilator actions were mediated by activation of ET B receptors on the endothelium and local release of NO, since these actions were inhibited by l -NAME. Blockade of the ET A or the ET B receptor had no effect on the erectile response induced by maximal ganglionic stimulation. Their results confirmed that cavernosal tissue of the rat penis is highly responsive to ET The failure of the ET-1 antagonists to affect penile erection in response to ganglionic stimulation seemed to reflect a minimal role of ET-1 in the erectile response in the rat.

However, the results do not rule out that ETs may play a role in keeping the penis in a flaccid state, nor that ETs may be associated with ED. ET-1 and ET A receptor binding was found to be increased in diabetic rat cavernosal tissue Bell et al. On the other hand, Christ et al. Negative results we also found by Kadioglu et al. The levels of ET-1 were determined in peripheral and cavernosal blood during flaccidity, tumescence, rigidity, and detumescence in healthy volunteers by Becker et al.

No significant changes were demonstrated. Even if accumulated information suggests that ETs may have a role in the mechanisms of flaccidity and detumescence, their exact role in penile physiology and pathophysiology remains to be established. ETs may function not only as a long-term regulator of corporal smooth muscle tone, but also as modulator of the contractile effect of other agents, e. During detumescence, there is an increase in the level of angiotensin II in cavernous blood compared with the levels in the flaccid state Becker et al.

Human corpus cavernosum was found to produce and secrete physiologically relevant amounts of angiotensin II Kifor et al. In vitro, angiotensin II contracted human Becker et al. In canine corpus cavernosum, the effect was increased by NOS inhibition Comiter et al. Intracavernosal injection of angiotensin II caused contraction and terminated spontaneous erections in anesthetized dogs, whereas administration of losartan, selectively blocking angiotensin II receptors subtype AT1 , resulted in smooth muscle relaxation and erection Kifor et al.

Also in the rabbit corpus cavernosum, results were obtained suggesting involvement of the renin-angiotensin system in the regulation of corpus cavernosum smooth muscle tone and that the angiotensin II receptor subtype AT1 is important for mediation of the response Park et al. Whether or not angiotensin II is an important regulator of tone in penile erectile tissues is unclear.

Studies using angiotensin II receptor antagonists, for example losartan, designed to elucidate this question, would be of interest. Penile tissues from animals and humans receive a rich cholinergic innervation as shown by histochemistry ACh esterase staining or immunohistochemistry Dail, ; Hedlund et al. ACh released from these nerves acts on muscarinic receptors located on cavernosal smooth muscle and endothelium. Four muscarinic receptor subtypes M 1 —M 4 were shown to be expressed in human corpus cavernosum tissue Traish et al.

In these cells, the nonsubtype selective muscarinic receptor agonist, carbachol, consistently produced contraction. This means that relaxation induced by ACh is indirect and can be obtained either by inhibition of release of a contractant factor, e. It is important to stress that parasympathetic activity is not equivalent with the actions of ACh; other transmitters may be released from cholinergic nerves Lundberg, Synthesis of NO and the consequences of NO binding to soluble guanylyl cyclase is essential for the erectile process.

There are several steps in the pathway Fig.

An important role for NO in the relaxation of corpus cavernosum smooth muscle and vasculature is widely accepted Andersson and Wagner, ; Burnett There seems to be no doubt about the presence of neuronal NOS nNOS in the cavernous nerves and their terminal endings within the corpora cavernosa, and in the branches of the dorsal penile nerves and nerve plexuses in the adventitia of the deep cavernous arteries Burnett et al.

It was therefore surprising to find that mice lacking nNOS Huang et al. In the rat, Dail et al. This is in contrast to findings in humans and several other species Burnett et al. They found a distinct expression of eNOS in cavernosal smooth muscle and in the small intracavernosal helicine arteries. No overall correlation between NOS expression and erectile function was observed. In human penile cavernosal smooth muscle cells in culture, Rajasekaran et al. Localization studies showed positive signals for NADPH diaphorase, eNOS, and calmodulin, and electron microscopic evaluation confirmed the localization of eNOS to the cytoplasm and small vesicles in the cells.

They found no eNOS activity in cavernous smooth muscle cells and cavernous nerves. The difference in the results concerning the occurrence of eNOS in cavernous smooth muscle cells is difficult to explain. If there are eNOS binding sites in the cavernous smooth muscle, they may represent the caveolae described in vascular endothelial tissue Feron et al. The expression of caveolins, caveolin-1 and caveolin-3, which are inhibitory proteins for NOS, were investigated in human corpus cavernosum by Tsutsui et al.

Caveolin-1, which preferentially binds to eNOS, appeared to be diffusely located within the smooth muscle of the corpus cavernosum and endothelium of the vasculature, whereas caveolin-3, which binds to nNOS, was located close to NADPH-positive nerve fibers Tsutsui et al. Functional studies support the occurrence and importance of eNOS in human cavernous tissue Andersson and Wagner, , and this also seems to be the case in rat Cartledge et al.

If the occurrence of nonendothelial eNOS in the corpus cavernosum can be confirmed, its functional significance should be established. Castration of rats and treatment with the anti-androgen, flutamide, reduced constitutive penile NOS activity Chamness et al. ED associated with for example diabetes was found to be associated by a decreased nNOS content and activity in the rat corpus cavernosum Vernet et al. In humans, the diabetic ED was suggested to be related to the effects of advanced glycation end products on NO formation Seftel et al. In rats, Cartledge et al. The GCs comprising both membrane bound particulate and soluble isoforms are expressed in nearly all cell types Lucas et al.

In addition, C-type natriuretic peptide 1—22, but not atrial natriuretic peptide 1—28 relaxed precontracted isolated preparations of rabbit corpus cavernosum. The enzyme, which catalyzes the conversion of GTP into cyclic GMP, consists of two different subunits and contains a prosthetic heme group that mediates up to fold activation by NO. Moreover, YC-1 caused a large activation in the presence of the NO donor, sodium nitroprusside, which led to a remarkable fold stimulation of the human recombinant sGC Lee et al.

In addition, YC-1 enhances the sGC-stimulating effect of carbon monoxide to fold above carbon monoxide alone; Friebe and Koesling, YC-1 caused concentration-dependent relaxant responses in NA-contracted rat corpus cavernosum preparations, and enhanced responses to electrical field stimulation. YC-1 also enhanced the relaxant response induced by carbachol. In vivo, YC-1 elicited not only dose-dependent erectile responses when administered intracavernously, but also increased the effects on intracavernous pressure produced by stimulation of the cavernous nerve H.

At present, however, the molecular targets that are activated by cGMP and finally execute the relaxation of penile smooth muscle are only partly known. Corpus cavernosum tissue from these mice has an inability or markedly reduced ability to relax in response to neuronally or endothelially released or exogenously administered NO Hedlund et al. This is in line with its presumed role in the erectile events. The total innervation PGP immunoreactivity and distribution of nerve populations containing transmitters or transmitter-forming enzymes believed to be important in the regulation of tone in corpus cavernosum tissue Andersson and Wagner, , were similar in normal and cGK I null mice.

Its absence cannot be compensated for by the cAMP signaling cascade that relaxes normal and cGK I null penile erectile tissue to a similar extent. Taken together, these findings suggest that activation of cGK I is a key step in the signal cascade leading to penile erection. In all specimens of cavernosal tissue, a distinct immunoreactivity was observed in different parts and structures, with a high expression in smooth muscle cells of vessels and in the fibromuscular stroma.

No clear immunoreactivity against cGK I was found in the endothelium. There was no distinct difference in immunoreactivity and cellular distribution between potent and impotent patients. This does not exclude the facts that dysfunction of cGK I can be a cause of ED in humans and that cGK I can be an interesting target for pharmacological intervention. The protein superfamily of cyclic nucleotide PDEs can be subdivided into at least 11 families of structurally and functionally related enzymes.

Because of their central role in smooth muscle tone regulation and the considerable variation of PDE isoenzymes with respect to species and tissues, PDEs have become an attractive target for drug development. The third isoform was novel and called PDE5A3; this isoform was confined to tissues with a smooth muscle or cardiac muscle component. PDE5A3 should be an interesting target for future drug developments. The identification of the various PDE families has been paralleled by the synthesis of selective or partially selective inhibitors.

Sildenafil is a highly selective inhibitor of PDE type 5 Boolell et al. It enhances NO-mediated relaxation of rabbit, rat, and human corpus cavernosum in vitro Ballard et al. Sildenafil increases the intracellular concentrations of cyclic GMP Chuang et al. This seems to involve a novel cellular signal transduction pathway in which force is dissociated from myosin light chain phosphorylation Chuang et al.

Several other selective PDE5 inhibitors are in different stages of development Meuleman et al. The penis of humans as well as animals is richly supplied with nerves containing VIP Dail, The majority of these nerves also contain immunoreactivity to NOS, and colocalization of NOS and VIP within nerves innervating the penis of both animals and humans has been demonstrated by many investigators Ehmke et al. It seems that most of these NO- and VIP-containing neurons are cholinergic, since they also contain vesicular acetylcholine transporter Hedlund et al.

VIP receptors types 1 and 2 , linked via a stimulatory G-protein to adenylyl cyclase, are considered to mediate the actions of the peptide Fahrenkrug, ; Harmar et al. The importance of the different subtypes of VIP receptor in penile tissues have not been clarified. In corporal tissue from humans Hedlund et al.

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In rats with experimentally induced diabetes, Maher et al. Since forskolin, which directly activates adenylyl cyclase, induced erection in both controls and diabetic rats, it was concluded that there was a defect at the level of the VIP receptor or of the associated G-protein. This is in contrast to previous findings in diabetic rats, showing that VIP-stimulated cAMP generation was significantly increased Miller et al. They are also in contrast to observations in human diabetes Gu et al.

However, the latter observation has not been confirmed by other investigators Haberman et al. Undeniably, VIP has an inhibitory and relaxation-producing effect on strips of human corpus cavernosum tissue and cavernosal vessels in vitro, but it has been difficult to convincingly show that VIP released from nerves is responsible for relaxation of penile smooth muscle in vitro or in vivo Andersson and Wagner, VIP antiserum Adaikan et al.

They concluded that VIP appeared to contribute to NANC-mediated corpus cavernosum relaxation and that its mechanism of relaxation was dependent on prostanoids and involved the generation of NO. This is in contrast to the conclusion drawn by Hayashida et al. As mentioned previously, many penile nerves contain NO, VIP, and ACh, and the possible interactions between these agents should be of particular interest.

They found nonsynergistic independent relaxant effects in both types of preparation. Peptide histidine methionine, which is derived from the same precursor as VIP Yiangou et al. Even if Hedlund et al. Thus, whether or not VIP has a role as a neurotransmitter or modulator of neurotransmission in the penis has not been established. Even if its physiological role in penile erection and in ED remains to be settled, VIP receptors in the penis are an interesting therapeutic target. Particularly, the combination of VIP and phentolamine seems to be effective in the treatment of ED see below.

Human corpus cavernosum tissue has the ability to synthesize various prostanoids and also has the ability to locally metabolize them Miller and Morgan, ; Andersson and Wagner, ; Porst, ; Minhas et al. The production of prostanoids can be modulated by oxygen tension and suppressed by hypoxia Daley et al. Corresponding to the five primary active prostanoid metabolites: The prostanoid receptors are G-protein-coupled with differing transduction systems Coleman et al.

The role of the different prostanoid receptors in penile physiology is still far from established Khan et al. PGE 1 -induced relaxation of human corporal smooth muscle was also suggested to be related to activation of K Ca channels, resulting in hyperpolarization Lee et al. Threshold forskolin doses were found to significantly increase the production of cAMP by PGE 1 , which suggested a possible synergistic effect.

Both forskolin and PGE 1 elicited concentration-dependent increases in the magnitude and duration of intracorporal pressure in dogs without systemic effects Cahn et al. These results suggest that it is possible to enhance the relaxant corporal effects of PGE 1 , and possibly other vasodilators, by forskolin and analogs Laurenza et al.

ATP and other purines were shown to decrease both basal tension and phenylephrine-stimulated tension in isolated rabbit corpus cavernosum preparations Tong et al. It was suggested that ATP is a NANC transmitter in the corpora cavernosa, and that purinergic transmission may be an important component involved in the initiation and maintenance of penile erection Tong et al. However, none of the purines tested facilitated or inhibited the response of corporal smooth muscle to electrical field stimulation, and therefore their role may be in the modulation of erection rather than as neurotransmitters Wu et al.

ATP injected intracavernously in dogs was found to produce increases in intracavernous pressure and erection Takahashi et al. This effect, which was unaffected by atropine and hexamethonium, could be obtained without changes in systemic blood pressure. In addition, adenosine produced full erection on intracavernous administration Takahashi et al.

The relaxant activity of ATP may be mediated either by its interaction with ATP receptors, or by adenosine generated through the endonucleotidase-mediated breakdown of ATP. Adenosine was suggested to act through stimulation of receptors belonging to the A 2a subtype Mantelli et al. They also showed that the ATP effect was partially attributable to the metabolic breakdown of ATP to adenosine but was also due to a direct stimulation of P2 receptors, seemingly different from the classical P2Yand P2X receptor subtypes. This relaxation was mediated by an endothelium-dependent mechanism.

They suggested that purines may be implicated in physiological erection in man. However, the roles of ATP or adenosine in the physiological mechanisms of erection still remain to be established. Adrenomedullin, which has been suggested to serve as a circulating hormone-regulating systemic arterial pressure, consists of 52 amino acids and has structural similarities to calcitonin-gene-related peptide CGRP Kitamura et al.

Injected intracavernously in cats, adrenomedullin caused increases in intracavernous pressure and in penile length Champion et al. Adrenomedullin and CGRP reduced blood pressure in the highest doses used. However, whether or not adrenomedullin can be used or whether it has any advantages over CGRP remains to be established. A limiting factor for both agents is that they have to be injected intracavernously. Nociceptin is a amino acid peptide that shares structural homology with the dynorphin family of peptides. The drug is an endogenous ligand for the orphan opioid receptor that has been identified in several species: Its function is not established; it may be involved in hyperalgesia or analgesia Henderson and McKnight, Nociceptin in doses of 0.

Whether nociceptin is involved in erectile mechanisms and whether the ORL1 receptor may be a target for drugs improving erectile function remains to be established. Although a variety of ion channels have been identified in corpus cavernosum smooth muscle cells Christ et al. However, electrical activity of the human corpus cavernosum in vivo as revealed by electromyographic studies is well synchronized, and corporal smooth muscle cells behave as a functional syncytium Andersson and Wagner, In the proximal part of the rat corpus spongiosum penile bulb , Hashitani demonstrated spontaneous action potentials in the inner muscle layer.

On the other hand, no action potentials could be detected by electrophysiological investigation of cultured human corpus cavernosum smooth muscle cells Christ et al. If this is valid for the cells in vivo, it calls for an alternative mechanism for impulse propagation. Such a mechanism may be provided by gap junctions. As underlined by Christ , signal transduction in corporal smooth muscle is more a network event than the simple activation of a physiological cascade or pathway in individual myocytes. Gap junctions constitute an ion channel gene family in corporal smooth muscle.

The pore-forming units are formed by hexamers of connexin. Connexin43 is the predominant gap junction protein found in corporal myocytes Campos de Carvalho et al. I can't even begin to fill your shoes. My last post was number If I was giving a simultaneous exhibition that would be boards with White Pawns. And my area code is I'm done for the day. It's Beer-thirty o'clock here anyway. I'm on my way. Don't drink without me. Yessir, those were the days Of course the lust of my life, Angie the Lotion Lady.

Good thing you don't play Go - the magic number would be I still have several excellent chess books by I. I first learned chess seriously from his "Chess Made Simple". Unfortunately, the title is a lie: Depends upon what your goals are. If you want to be champ, it's hard. If you want to be an expert, it's doable. In some quarters, this would be accepted as verification of the theory that having White is a disadvantage. Our readers are doubtless familiar with the basic reason underlying this theory--that White having the first move, will probably make the first blunder.

We mention this merely in passing. One of my fondest chess memories is the delight in seeing a fresh Chess Review at the local Newsstand. They only received a few copies, I made a point to check for it over the course of a week so as not to miss a single issue. I spent many happy hours reading and studying each Chess Review.

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