Relaxation Of Corpus Cavernosum Research Articles

THE ORAL EFFICACY OF VARDENAFIL HYDROCHLORIDE FOR INDUCING PENILE ERECTION IN A CONSCIOUS RABBIT MODEL

Inhibiting cyclic guanosine monophosphate metabolism may induce penile erection during concomitant nitric oxide production. Vardenafil hydrochloride is a new, highly selective, potent cyclic guanosine monophosphate phosphodiesterase 5 inhibitor. We determined the oral effectiveness of vardenafil in a simple and quantitative conscious rabbit model. Vardenafil was given orally to conscious rabbits. Erection was assessed in a time dependent manner by measuring the length of the uncovered penile mucosa. Erection was evaluated in the absence and presence of intravenous sodium nitroprusside, a nitric oxide donor. Vardenafil induced dose dependent penile erection in conscious rabbits after the oral administration of 1 to 30 mg./kg. The efficacy of vardenafil was potentiated and effective doses were significantly reduced by the simultaneous administration of sodium nitroprusside. The effect of vardenafil on penile erection after oral administration was clearly demonstrated in the conscious rabbit model. The time course and early onset of activity indicate that it may be useful for treating erectile dysfunction. Potentiation of the effect by the nitric oxide donor sodium nitroprusside implies that it would have enhanced activity during sexual arousal, when nitric oxide is produced endogenously. The clinical development of this product for erectile dysfunction is proceeding.

Combination of phentolamine and l-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle

Objectives. To analyze the effects of combining an alpha-adrenergic receptor antagonist, phentolamine, with an enhancer of the nitric oxide/cyclic guanosine monophosphate pathway ( l-arginine or sildenafil) on neurogenic relaxations of rabbit corpus cavernosum (RCC). Methods. Studies were performed on isolated RCC tissue in organ chambers. Transmural electrical stimulation (TES) was applied at increasing frequencies (0.5 to 6 Hz) on endothelin-contracted RCC strips, and the responses were evaluated. Results. The activation of alpha 2-adrenergic receptors with UK 14304 (0.3 μM) significantly inhibited the relaxation induced by TES in RCC strips in which adrenergic neurotransmission was blocked with guanethidine (10 μM). The relaxant responses produced by TES application on RCC strips without guanethidine were not significantly affected by the treatment with l-arginine or sildenafil but were significantly augmented by phentolamine (2.7-fold increase in maximum relaxation). Furthermore, the combinations of phentolamine with l-arginine or sildenafil markedly increased the relaxations evoked by the application of TES in RCC tissue, significantly more than those obtained in the presence of phentolamine alone (4.5 or 4.7-fold increase of maximum relaxation, respectively). Conclusions. Our results demonstrated a synergistic interaction between the alpha-adrenergic blockade and the potentiation of the nitric oxide/cyclic guanosine monophosphate pathway to increase neurogenic relaxation of trabecular smooth muscle relaxation. This fact suggests that the combination of alpha-adrenergic receptor blockade with l-arginine or sildenafil could represent a therapeutic advantage in the treatment of erectile dysfunction.

Nitric oxide-mediated corpus cavernosal smooth muscle relaxation is impaired in ageing and diabetes.

To examine nitric-oxide (NO)-mediated relaxation in cavernosal smooth muscle in a rat model of diabetes, as previous experiments showed that HbA1c (an isoform of glycosylated haemoglobin and a marker of long-term diabetic control) impaired NO-mediated relaxation of normal corpus cavernosal tissue through the generation of superoxide anions. Eight weeks after the induction of diabetes, male Wistar rats were killed and cavernosal tissue obtained. Strips were contracted with 1 micromol/L noradrenaline before applying acetylcholine or electrical field stimulation (EFS) or sodium nitroprusside (SNP). Relaxation responses were repeated in the presence of L-arginine (100 micromol/L), indomethacin (10 micromol/L) or superoxide dismutase (SOD, 120 IU/mL). Young and age-matched control animals were examined in the same way. Eight weeks of uncontrolled diabetes caused a significant impairment in mean relaxation responses to acetylcholine (P < 0.05) and to EFS (P < 0.05), but not to SNP, compared with young and age-matched controls, respectively. L-arginine, indomethacin and SOD had no significant effect on this impairment. Ageing caused a lesser but significant impairment in EFS-mediated cavernosal smooth muscle relaxation (P < 0.05). Diabetes impairs endothelial and neuronal NO-mediated cavernosal smooth muscle relaxation in rats in vitro. This effect is not mediated by an alteration in the intracellular action of NO, the availability of NO, superoxide anion inactivation of NO or the generation of constrictor prostanoids. It is possible that cholesterol or advanced glycation end products are responsible for the effect of diabetes on penile smooth function.

Advanced glycation end-products are responsible for the impairment of corpus cavernosal smooth muscle relaxation seen in diabetes.

To determine if advanced glycation end-products (AGEs) are responsible for the lower neuronal and endothelial-derived nitric oxide (NO)-mediated relaxation of corpus cavernosum in tissue in diabetic rats than in control rats. Diabetes was induced in male Wistar rats by an intraperitoneal injection with streptozotocin (60 mg/kg). One group of diabetic rats was given free access to water and standard diet. A second group was given standard diet and aminoguanidine with their water (50 mg/100 mL) from the initiation of diabetes. Two groups of rats that were not diabetic acted as age-matched controls. After 8 weeks animals were killed by cervical dislocation, corpus cavernosal tissue strips harvested and mounted in an organ bath to measure isometric tension. After 90 min of equilibration at optimal resting tension and contraction with 1 micromol/L noradrenaline, the response to either acetylcholine or electrical field stimulation (EFS) after adding guanethidine (5 micromol/L) and atropine (1 micromol/L) was determined for each group. There was no difference between the baseline characteristics of all the experimental groups. After 8 weeks the mean body mass and glycosylated haemoglobin (HbA1c) were significantly greater in the diabetic than in control animals. Aminoguanidine had no effect on the recorded body mass or HbA1c. The in vitro relaxation response to the application of acetylcholine or EFS of tissue strips from age-matched control animals fed a standard diet and those supplemented with aminoguanidine were the same. The administration of aminoguanidine to diabetic animals for 8 weeks reversed the expected impaired relaxation response to acetylcholine; the response to EFS was similar. AGEs are more prevalent in erectile tissue from diabetic than in control animals. Aminoguanidine reversed the impairment in neuronal and endothelial NO-mediated penile smooth muscle relaxation seen in diabetes. As aminoguanidine prevents AGE formation, erectile dysfunction in diabetes is probably caused partly by the generation of AGEs.

Phentolamine mesylate relaxes rabbit corpus cavernosum by a nonadrenergic, noncholinergic mechanism.

The contribution of NO-cGMP dependent pathway to phentolamine mesylate-evoked nonadrenergic, noncholinergic relaxation of rabbit corpus cavernosum was investigated in vitro. Stimulation of nonadrenergic, noncholinergic neurons of the rabbit corpus cavernosum elicited frequency-related relaxation that was significantly attenuated by L-NAME (NO synthase inhibitor) or ODQ (an inhibitor of guanylate cyclase). Moreover, tetrodotoxin, a sodium channel blocker, abolished the electrical field stimulation-induced relaxation of rabbit corpus cavernosum, suggesting that neuronal release of NO mediates relaxation to electrical field stimulation. Phentolamine mesylate (30 and 100 nM) dose-dependently enhanced electrical field stimulation-induced relaxation of the rabbit corpus cavernosum. Prazosin (30 microM) and yohimbine (30 microM) failed to affect phentolamine mesylate-mediated nonadrenergic, noncholinergic rabbit penile smooth muscle relaxation, suggesting that phentolamine relaxes rabbit corpus cavernosum independent of alpha-adrenergic receptor blockade. In contrast, pretreatment of the rabbit cavernosal strips with L-NAME significantly-attenuated electrical field stimulation produced relaxations to phentolamine mesylate, suggesting that phentolamine mesylate relaxes rabbit corpus cavernosum by activating NO synthase. The data suggest that phentolamine mesylate relaxes nonadrenergic noncholinergic neurons of the rabbit corpus cavernosum by activating NO synthase and is independent of alpha-adrenergic receptor blockade.

The role of nitric oxide on the relaxations of rabbit corpus cavernosum induced by Androctonus australis and Buthotus judaicus scorpion venoms

In this study, we have investigated the relaxing effects of both Androctonus australis venom (AAV) and Buthotus judaicus venom (BJV) on the rabbit corpus cavernosum (RbCC) smooth muscle strips. The RbCC strips were mounted in a cascade system and superfused with warmed and gassed Krebs solution. The nitric oxide (NO) synthesis inhibitor Nω-nitro-l-arginine methyl ester (l-NAME, 10μM), but not d-NAME (10μM), significantly inhibited the RbCC relaxations induced by acetylcholine (ACh, 0.6nmol), AAV (30μg) and BJV (30μg). Subsequent infusion of l-arginine (300μM), but not of d-arginine (300μM), partially restored the relaxations evoked by these agents. The brain NO synthase inhibitor 7-nitroindazole (7-NI, 10μM) also inhibited the relaxant responses elicited by the scorpion venoms. The guanylyl cyclase inhibitors methylene blue (MB, 30μM) and 1H-[1,2,4] oxadiazolo [4,3,-alquinoxalin-1-one] (ODQ, 10μM) virtually abolished the relaxations induced by either AAV or BJV. The infusion of muscarinic receptor antagonists such as scopolamine and atropine (1μM, each) completely abolished the ACh-induced relaxations but had no effect on those evoked by the scorpion venoms. The Na+ channel blocker tetrodotoxin (1μM) prevented the relaxations evoked by both AAV and BJV. Thus, NO released from nitrergic nerve fibres mediates the relaxations elicited by AAV and BJV in the rabbit cavernosal tissue.

Neurotransmitters: central and peripheral mechanisms.

Reflexive erection initiated by recruitment of penile afferents, involves both autonomic and somatic efferents. The reflex is mediated at the spinal cord level, modulated by supraspinal influences, and may use several transmitters. Dopamine, acetylcholine, nitric oxide, and peptides, such as oxytocin and ACTH/alpha-MSH, seem to have a facilitatory role, whereas serotonin may be either facilitatory or inhibitory, and enkephalins are inhibitory. Peripherally, the balance between contractant and relaxant factors controls the degree of contraction of the smooth muscle of the corpora cavernosa, and determines the functional state of the penis. Noradrenaline contracts both corpus cavernosum and penile vessels via stimulation of alpha1-adrenoceptors. The role of endothelins in the control of penile smooth muscle tone is presently unclear. Neurogenic nitric oxide (NO) is considered the most important factor for relaxation of penile vessels and corpus cavernosum. The role of other mediators, released from nerves or endothelium has not been definitely established. International Journal of Impotence Research (2000) 12, Suppl 4, S26-S33.

Effect of neocuproine, a selective Cu(I) chelator, on nitrergic relaxations in the mouse corpus cavernosum

The effects of neocuproine and bathocuproine, Cu(I) and Cu(II) chelators, respectively, were studied on relaxations in response to electrical field stimulation, acetylcholine, S-nitrosoglutathione, acidified sodium nitrite and sodium nitroprusside in the mouse corpus cavernosum precontracted with phenylephrine. Neocuproine significantly inhibited relaxations induced by electrical field stimulation, acetylcholine and S-nitrosoglutathione, but not by acidified sodium nitrite and sodium nitroprusside. The pre-prepared neocuproine–Cu(I) complex was ineffective on the responses. The discrepancy between the shape of relaxations in response to electrical field stimulation or to acetylcholine and S-nitrosoglutathione was abolished by adding CuCl 2 into the bathing medium. The copper action was blocked by neocuproine but not by bathocuproine. However, the pre-prepared bathocuproine–Cu(II) complex did not accelerate the relaxations affected by CuCl 2. These findings suggest that a Cu(I)-dependent mechanism may play a role in the relaxation induced by the endogenous relaxant factor as well as by S-nitrosoglutathione in mouse cavernosal tissue.

Mechanisms underlying endothelium-dependent, nitric oxide/prostacyclin-independent, acetylcholine-induced relaxation in canine corpus cavernosum.

The mechanisms underlying endothelium-dependent and nitric oxide (NO)/prostacyclin-independent, acetylcholine-induced relaxation in isolated canine corpus cavernosum were investigated. In isolated canine corpus cavernous strips treated with indomethacin (10(-6) M) and N(G)-nitro-L-arginine (10(-4) M), acetylcholine produced relaxations in a concentration-dependent manner. The relaxations were not affected by treatment with 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl 3-oxide, sodium salt (carboxy PTIO, 3 x 10(-4) M), glibenclamide (10(-6) M), iberiotoxin (10(-7) M) or charybdotoxin (10(-7) M), but were abolished or reversed to contractions by treatment with apamin (10(-8) M) or scyllatoxin (10(-8) M). Levcromakalim (10(-7)-10(-6) M) induced a concentration-dependent relaxation which was abolished by treatment with glibenclamide (10(-6) M), but was not affected by treatment with apamin (10(-8) M) or scyllatoxin (10(-8) M). These findings indicate that endothelial cells of canine corpus cavernosum have an ability to produce a relaxing substance(s) other than NO or prostacyclin in response to acetylcholine. The substance(s) may open solely small conductance Ca2+-dependent K+ channels.

Effects of vitamin E and sodium selenate on neurogenic and endothelial relaxation of corpus cavernosum in the diabetic mouse

We studied the effect of vitamin E and sodium selenate treatment on the neurogenic and endothelium-dependent relaxation of isolated corpus cavernosum obtained from streptozotocin-induced diabetic mice. Relaxant responses of corpus cavernosum precontracted by phenylephrine to electrical field stimulation and to acetylcholine were significantly decreased in diabetic mice. There was no significant difference between diabetic and non-diabetic groups for the relaxant response of corpus cavernosum to sodium nitroprusside and papaverine. Treatment with sodium selenate, but not vitamin E, partially prevented the impairment of the neurogenic relaxation, whereas both had a significant, partial restorative action on endothelial dysfunction in corpus cavernosum obtained from diabetic groups. Neither agent exhibited a significant action on the relaxant responses of corpus cavernosum obtained from non-diabetic mice. A decrease in the sensitivity of the neurogenic impairment to antioxidant action may develop more rapidly than that of endothelial dysfunction in streptozotocin-induced diabetic mice.

EFFECT OF THE PLANT-EXTRACT OSTHOLE ON THE RELAXATION OF RABBIT CORPUS CAVERNOSUM TISSUE IN VITRO

We investigated the cavernosal relaxant effect of osthole, a coumarin isolated from Cnidium monnier (L.) Cusson which has been long used in China as a herbal medicine to improve male sexual dysfunction. Strips of rabbit corpus cavernosum were precontracted with phenylephrine. Corporal relaxation evoked by osthole was then determined in the absence and presence of nitric oxide synthase inhibitor (L-NAME), soluble guanylate cyclase inhibitor (ODQ), cyclooxygenase inhibitor (indomethacin), tetradotoxin, and after endothelium deprivation. Corpus cavernosal strips showed relaxation in response to osthole (0.1 approximately 30 microM) in a dose-dependent manner. These effects were reduced partially but significantly by pretreatment with L-NAME, ODQ and by endothelial disruption. However, they were not affected by indomethacin and tetradotoxin treatment. Osthole pretreatment (from 1 to 30 microM) enhanced the sodium nitroprusside (0.3 microM)-induced relaxation of corpus cavernosum in a dose-dependent manner to a maximum of 3 times the pretreatment level at 30 microM osthole. However, this effect was abolished in the presence of zaprinast. Additionally, a higher concentration of osthole (30 microM) also enhanced forskolin-induced relaxation. The data suggested that osthole possesses a relaxant effect on rabbit corpus cavernosal tissues which is attributable to the release of NO from sinusoidal endothelium and to the potentiation of the cGMP and/or cAMP signal mediating relaxation of cavernosal smooth muscle by inhibiting phosphodiesterase.

Impairment of corpus cavernosal smooth muscle relaxation by glycosylated human haemoglobin.

To examine the effect of HbA1c, an isoform of glycosylated haemoglobin (GHb, a product of non-enzymatic reactions between elevated blood glucose and haemoglobin), on nitric oxide-mediated corpus cavernosal smooth muscle relaxation, and to categorize the mechanisms involved. Corpus cavernosal tissue from Wistar rats (300-350 g body weight) was prepared for the measurement of isometric tension. After equilibration in Krebs solution gassed with 95% O2/5% CO2 at 37 degrees C for 90 min, optimal resting tension was applied. Tissue was precontracted with 1 micromol/L noradrenaline (NAd) and either relaxed with incremental doses of acetylcholine (ACh) or sodium nitroprusside (SNP). After washout, strips were again precontracted with NAd and then incubated with pyrogallol (100 micromol/L), 100 microL of haemoglobin or 100 microL of GHb in the presence of either L-arginine (100 micromol/L), indomethacin (10 micromol/L), allopurinol (100 micromol/L), deferoxamine (100 micromol/L), catalase (600 IU/mL), or superoxide dismutase (SOD) (120 IU/mL) before ACh- or SNP-induced relaxation responses were repeated. Haemoglobin and GHb significantly impaired the relaxation of rat corpus cavernosum to ACh in a dose-dependent manner. L-arginine reversed the impairment caused by Hb, but not GHb. A donor of superoxide anions, pyrogallol, mimicked this impairment to ACh when added to control strips. Catalase, deferoxamine, indomethacin and allopurinol had no significant effect on the impaired relaxation response to ACh, whilst L-arginine partially reversed it. SOD completely reversed the GHb-induced impaired relaxation; GHb did not alter the relaxation response to SNP. GHb significantly impairs endothelial NO-mediated corpus cavernosal relaxation in the rat, in vitro. This effect is caused partly by the generation of superoxide anions and the extracellular inactivation of NO.

Effects of aldose reductase inhibition on responses of the corpus cavernosum and mesenteric vascular bed of diabetic rats.

We examined the effects of 2 months of streptozotocin-induced diabetes mellitus in rats on relaxation and contraction of corpus cavernosum and the mesenteric vascular bed in vitro. A further diabetic group was treated from diabetes induction with 10 mg/kg/day of the aldose reductase inhibitor, WAY121509. For corpus cavernosum, maximal acetylcholine-induced relaxation was 35.5% reduced (p < 0.001) by diabetes, and this deficit was completely prevented by WAY121509 treatment. Neither diabetes nor treatment affected contractile responses to field stimulation of noradrenergic nerves; however, nonadrenergic noncholinergic nerve relaxation responses were 32.9% decreased by diabetes and WAY 121509 attenuated this by 84% (p < 0.001). For the mesenteric vascular bed, diabetes depressed maximal endothelium-dependent vasodilation to acetylcholine by 25.2% (p < 0.001), and this was partially (50.6%; p < 0.01) prevented by WAY121509. Nitric oxide synthase blockade revealed endothelium-derived hyperpolarising factor-mediated vasodilation to acetylcholine that was 73.5% (p < 0.001) depressed by diabetes; WAY121509 provided partial (43.4%; p < 0.001) protection. Neither diabetes nor treatment affected endothelium-independent vasorelaxation to the nitric oxide donor, sodium nitroprusside, in corpus cavernosum or mesenteric vessels. Thus the data show protective effects of WAY121509 on nitric oxide-mediated cavernosal vasorelaxation responses and on mesenteric endothelium-derived hyperpolarising factor responses. Together these findings could account for the beneficial effects of aldose reductase inhibition on diabetic complications in experimental models.

Sympathetic pathways and adrenergic innervation of the penis

The sympathetic nervous system is important for penile function: it mediates detumescence and may contribute to the maintenance of the penis in a non-erect state. The sympathetic preganglionic neurons are found in the intermediolateral gray matter of the spinal cord. Postganglionic neurons are located to the sympathetic chain ganglia, the inferior mesenteric, hypogastric and pelvic ganglia, and possibly to ganglia near the target organ. Sympathetic fibres can be found in the pelvic, cavernous, and pudendal nerves. Stimulation of the sympathetic pathways to the penis may, however, also produce erection. It has been suggested that the suprasacral vasodilator pathway is a sympathetic cholinergic pathway, operating through cholinergic neurons in the pelvic plexus. In the penis, there is a rich sympathetic, adrenergic innervation of the corpus cavernosum (CC) and the vasculature, and in particular of the helicine arteries. Sympathetic, adrenergic nerves also contain neuropeptide Y. Parasympathetic cholinergic nerves, which mediate CC relaxation and erection, contain not only acetylcholine, but also vasoactive intestinal polypeptide, nitric oxide synthase, and probably other mediators and/or mediator-synthesizing enzymes. Activation of sympathetic adrenergic nerves causes release of noradrenaline, acting on alpha-adrenoceptors in the trabecular smooth muscle of the CC and in penile vessels. The role of interactions between different transmitters and mediators, released from nerves or generated locally, in the regulation of contraction and relaxation of CC and penile vessels, needs further study.

Erectile dysfunction in cyclic GMP-dependent kinase I-deficient mice.

The generation of nitric oxide (NO) in penile erectile tissue and the subsequent elevation of cyclic GMP (cGMP) levels are important for normal penile erection. Current treatments of erectile dysfunction elevate either cGMP levels by blocking cGMP degrading phosphodiesterase 5 or cyclic AMP (cAMP) levels by intrapenile injection of prostaglandin E1. The molecular target or targets of cGMP in erectile tissue and the role of cAMP for normal penile erection are not known. Herein, we report that mice lacking cGMP-dependent kinase I (cGKI) have a very low ability to reproduce and that their corpora cavernosa fail to relax on activation of the NO/cGMP signaling cascade. Elevation of cAMP by forskolin, however, induces similar relaxation in normal and cGKI-null corpus cavernosum. In addition, sperm derived from cGKI-null mice is normal, can undergo acrosomal reactions, and can efficiently fertilize eggs. Altogether, these data identify cGKI as the downstream target of cGMP in erectile tissue and provide evidence that cAMP signaling cannot compensate for the absence of the cGMP/cGKI signaling cascade in vivo.

Impaired endothelium-dependent and neurogenic relaxation of corpus cavernosum from diabetic rats: improvement with L-arginine.

This study describes the relaxant response to acetylcholine, electrical field stimulation and sodium nitroprusside after contraction by phenylephrine (10(-5) M) in corpus cavernosum from control and diabetic rats. The response to acetylcholine (10(-9)-10(-3) M) and electrical field stimulation (0.5-64 Hz) is decreased and can be restored by the addition of nitric oxide synthetase substrate, L-arginine(10(-5) M). The response to sodium nitroprusside is not changed in diabetic rats compared to control rats. NADPH-diaphorase staining was enhanced in a diabetic preparation compared to control preparations. The findings suggest a role for the depletion of L-arginine in diabetes mellitus. The enhanced NADPH-diaphorase staining may be due to a deficiency of NOS substrate L-arginine in the endothelium and nerves of diabetic tissues.

P2y and P2x purinoceptors are respectively implicated in endothelium- dependent relaxation and endothelium independent contraction in human corpus cavernosum.

The erectile function of the corpus cavernosum is a balance between smooth muscle contraction and relaxation modulated by nerve terminals and endothelial cells1. It is clearly demonstrated that the mechanisms of erection and detumescence are not exclusively modulated by cholinergic and adrenergic nerves but also by non-adrenergic, non-cholinergic (NANC) neuromodulators2. Purines (particularly ATP, ADP) are present in the environment of endothelial cells and smooth muscle cells of the corpus cavernosum. Nevertheless, the implication of P2y and P2x purinoceptors respectively in tumescence and detumescence have not studied before in man.

Restorative effects of zinc and selenium on nitrergic relaxations impaired by cadmium in the mouse corpus cavernosum

We investigated whether Cd 2+ intake (in drinking water, 15 ppm) for 30 days can affect the nitrergic relaxations of the mouse corpus cavernosum (CC) and whether Zn 2+ (25 mg kg −1 via a stomach tube at 48-h intervals) or sodium selenate (8 μg kg −1 day −1 intraperitoneally) has a restorative action on the impairment in the response. Relaxant responses of the CC obtained from Cd 2+-treated mice to electrical field stimulation (neurogenic) or acetylcholine (endothelium dependent) were significantly inhibited. A partial restoration was observed in the nitrergic relaxation of the CC obtained from Zn 2+- or sodium selenate-co-treated animals. Neither agent exhibited any significant action on the responses of the tissue from control mice. There was no significant difference between Cd 2+-treated and control mice in respect of the relaxation amplitude induced by sodium nitroprusside or papaverine. These results suggest that Cd 2+ intake may impair the nitrergic relaxation of the mouse CC, and, co-treatment with Zn 2+ or sodium selenate may partially improve the nitrergic mechanisms in the tissue.

The interaction of homocysteine and copper markedly inhibits the relaxation of rabbit corpus cavernosum: new risk factors for angiopathic erectile dysfunction?

To explore whether homocysteine (HCy), an independent risk factor for atherosclerosis (the angiopathic effect of which occurs through the generation of superoxide anions and hydrogen peroxide, augmented by copper, the superoxide anions reacting with nitric oxide, NO, to produce peroxynitrite, a highly angiopathic free radical) and copper contribute to erectile dysfunction (ED) through similar mechanisms, by assessing their interactive effects on the relaxation of corpus cavernosum using organ-bath techniques. Cavernosal smooth muscle strips were obtained from adult New Zealand White rabbits and mounted in organ baths. After precontraction with phenylephrine (100 micromol/L), relaxation responses to carbachol or sodium nitroprusside (SNP) were assessed in the presence or absence of HCy and copper. The effects of HCy and copper in the presence of superoxide dismutase or catalase were also investigated. HCy alone inhibited carbachol-stimulated (NO-dependent) but not SNP-stimulated relaxations (NO-independent). This effect of HCy was significantly augmented by copper, which alone had no effect. The combined effect of HCy and copper was significantly (P<0.05) reversed by superoxide dismutase or catalase. HCy inhibited NO-mediated cavernosal smooth muscle relaxation, an effect that was potentiated by copper and reversed by superoxide dismutase or catalase. It is therefore proposed that the effect of HCy on cavernosal smooth muscle relaxation is mediated by an interaction between NO and superoxide anions. Moreover, HCy may constitute a new risk factor for angiopathic ED.

IN VITRO AND IN VIVO EXPERIMENTAL EFFECT OF KOREAN RED GINSENG ON ERECTION

To elucidate the efficacy of Korean red ginseng (KRG) on penile erectile tissue and erectile response, the effect of ginseng was evaluated in both in vivo and in vitro experiments in laboratory animals. Fifty milligrams of KRG per kilogram in weight was mixed in physiologic saline and given by mouth for 3 months to both rabbits and rats. In vitro experiments were performed by observing the responses to acetylcholine (ACh) and KRG of strips of rabbit corpus cavernosum. In vivo experiments were performed by measuring the cavernosal pressures after the stimulation of pelvic nerves innervating rat corpus cavernosum. On rabbit cavernosal muscle strips precontracted with phenylephrine (5x10(-6) M), increasing concentrations of ACh (10(-7), 10(-6), 10(-5), 10(-4) M) showed dose dependent relaxation in the control group (10(-7) M: 15.32%, 10(-6) M: 35.44%, 10(-5) M: 59.45%, 10(-4) M: 76.54%)(p<0.01). After 3 months of KRG administration, the relaxation responses to ACh were increased significantly (10(-7) M: 34.18%, 10(-6) M: 56.35%, 10(-5) M: 75.33%, 10(-4) M: 89.86%)(p<0.01). Relaxation effects of KRG were significantly increased after administering KRG for 3 months, as evident by the intracavernousal pressure to electrostimulation being 107.52 cm. water in the control group and significantly increased to 138.34 cm. water after 3 months administration of KRG (p<0.01). We confirmed that the long-term administration of KRG enhances erectile capacity and that its action is mediated by endothelium-derived relaxing factor and peripheral neurophysiologic enhancement.