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Erectile Responses (erectile + response)

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Medical Sciences	100%

Selected Abstracts

Are the Inhibitory Effects of Nicotine on Erectile Response in Nonsmokers Generalizable to Long-Term Smokers?

THE JOURNAL OF SEXUAL MEDICINE, Issue 8 2008
A Reply
[source]

Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide Signaling

THE JOURNAL OF SEXUAL MEDICINE, Issue 8 2010
Javier Angulo PhD
ABSTRACT Introduction., Traditional beta-blockers have sometimes been associated with erectile dysfunction (ED). Nebivolol is a cardioselective ,1 -adrenoceptor antagonist that promotes vasodilation through a nitric oxide (NO)-dependent mechanism. Aim., We evaluated the effects of nebivolol on the NO/cyclic guanosine monophosphate (cGMP) signaling pathway, on erectile function and dysfunction, and in human penile vascular tissues. Methods., Erectile response to cavernosal nerve electrical stimulation in control and diabetes-induced ED rats were evaluated, along with serum nitrite/nitrate (NOx) concentration and plasma/tissue cGMP levels. Endothelium-dependent and sildenafil-induced relaxation of isolated human corpus cavernosum (HCC) and human penile resistance arteries (HPRA) were also determined. Main Outcome Measures., The effects of nebivolol on erectile function and dysfunction and on NO/cGMP-mediated responses. Results., Treatment with nebivolol significantly potentiated erectile response in control rats, regardless of its effects on blood pressure. Nebivolol increased NOx and plasma cGMP by 3-fold and 2.75-fold, respectively, and significantly augmented the elevation of plasma cGMP produced by sildenafil. Nebivolol enhanced endothelium-dependent and sildenafil-induced relaxations of HCC tissue, and produced endothelium-dependent vasodilation of HPRA. Nebivolol, but not atenolol, significantly improved erectile response in diabetic rats (51.6%, 53.2%, and 87.1% of response at 3 Hz in nondiabetic rats, for vehicle-treated, atenolol-treated, and nebivolol-treated diabetic rats, respectively); after sildenafil administration, ED was completely reversed in nebivolol-treated diabetic rats (69.6% and 112% for diabetic rats treated with sildenafil and nebivolol plus sildenafil, respectively). Accordingly, nebivolol restored systemic NOx levels and cGMP content in penile tissue from these animals. Conclusions., Nebivolol in vivo activated the NO/cGMP pathway, enhanced erectile response and reversed ED in diabetic rats. Moreover, nebivolol in vitro potentiated NO/cGMP-mediated relaxation of human erectile tissues. These effects may account for the low incidence of ED in nebivolol-treated hypertensive patients. Nebivolol therefore may have utility in the treatment of ED, particularly ED associated with diabetes. Angulo J, Wright HM, Cuevas P, González-Corrochano R, Fernández A, Cuevas B, La Fuente JM, Gupta S, and de Tejada IS. Nebivolol dilates human penile arteries and reverses erectile dysfunction in diabetic rats through enhancement of nitric oxide signaling. J Sex Med 2010;7:2681,2697. [source]

Putative Role of Carbon Monoxide Signaling Pathway in Penile Erectile Function

THE JOURNAL OF SEXUAL MEDICINE, Issue 1 2009
Mohamed T. Abdel Aziz MD
ABSTRACT Introduction., Erectile response depends on nitric oxide (NO) generated by NO synthase (NOS) enzyme of the nerves and vascular endothelium in the cavernous tissue. NO activates soluble guanylate cyclase (sGC), leading to the production of cyclic guanosine monophosphate (cGMP). cGMP activates cGMP-dependent protein kinase that activates Ca2+/ATPase pump that activates Ca2+/K efflux pump extruding Ca2+ across the plasma membrane with consequent smooth muscle cell relaxation. A role similar to that of NOS/NO signaling has been postulated for carbon monoxide (CO) produced in mammals from heme catabolism by heme oxygenase (HO) enzyme. Aim., To assess CO signaling pathway for erectile function by reviewing published studies. Methods., A systematic review of published studies on this affair based on Pubmed and Medical Subject Heading databases, with search for all concerned articles. Main Outcome Measures., Documentation of positive as well as negative criteria of CO/HO signaling focused on penile tissue. Results., The concept that HO-derived CO could play a role in mediating erectile function acting in synergism with, or as a potentiator for, NOS/NO signaling pathway is gaining momentum. CO/HO signaling pathway has been shown to partially mediate the actions of oral phosphodiesterase type 5 inhibitors. In addition, it was shown that the use of CO releasing molecules potentiated cavernous cGMP levels. However, increased CO production or release was reported to be associated, in some studies, with vasoconstriction. Conclusion., This review sheds a light on the significance of cavernous tissue CO signaling pathway that may pave the way for creation of therapeutic modalities based on this pathway. Abdel Aziz MT, Mostafa T, Atta H, Wassef MA, Fouad HH, Rashed LA, and Sabry D. Putative role of carbon monoxide signaling pathway in penile erectile function. J Sex Med 2009;6:49,60. [source]

Age-Related Changes in Phosphorylation of Endothelial Nitric Oxide Synthase in the Rat Penis

THE JOURNAL OF SEXUAL MEDICINE, Issue 3 2005
Biljana Musicki PhD
ABSTRACT Aim., Aging is associated with erectile dysfunction (ED) attributed to reduced nitric oxide synthase (NOS) activity and nitric oxide bioavailability. However, the mechanism for this effect has not been fully investigated. We evaluated (i) whether age-related ED involves dysregulation of endothelial NOS (eNOS) phosphorylation; and (ii) whether vascular endothelial growth factor (VEGF) exerts erectile effects and operates via eNOS phosphorylation in aged rats. Methods., Male Fischer 344 "young" (4-month-old) and "aged" (19-month-old) rats were used. Electrical stimulation of the cavernous nerve (CNS) was performed to generate penile erection. Erectile response in the presence of rhVEGF165 was evaluated by intracavernosal pressure monitoring 25 minutes after intracavernosal injection of VEGF. Penes were excised at baseline, with or without rhVEGF treatment, and after CNS for Western immunoblot of phospho-eNOS (Ser-1177 and Thr-495), phospho-Akt, and eNOS. Results., Erectile response was significantly reduced in aged rats compared with young rats. Phospho-eNOS (Ser-1177) and phospho-Akt were significantly reduced, while phospho-eNOS (Thr-495) was significantly increased, in the aged penis at baseline and after CNS. rhVEGF significantly improved erection and reversed downregulated Ser-1177, but not upregulated Thr-495 phosphorylation, on eNOS in aged penes. eNOS protein was significantly increased in aged penes. Conclusions., Age-related ED is associated with eNOS inactivation through a decrease in phosphorylation of its positive regulatory site (Ser-1177) and an increase in phosphorylation of its negative regulatory site (Thr-495) in the penis. Altered phosphorylation/constitutive activation of eNOS by fluid shear stress may be a major determinant of compromised vascular homeostasis of the aged penis. The finding that VEGF rapidly induces erection and partly corrects alterations in eNOS phosphorylation in the aged rat penis suggests impaired eNOS activation by deficient endogenous VEGF and supports the potential for growth factor therapy in the treatment of age-related ED. [source]

The Novel Antioxidant, AC3056 (2,6-di-t-butyl-4-((Dimethyl-4-Methoxyphenylsilyl)Methyloxy)Phenol), Reverses Erectile Dysfunction in Diabetic Rats and Improves NO-mediated Responses in Penile Tissue from Diabetic Men

THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2009
Javier Angulo PhD
ABSTRACT Introduction., Diabetes is associated with a high incidence of erectile dysfunction (ED) and poor response to standard treatments. Oxidative stress could be relevant in the pathophysiology of diabetic ED. Aim., To evaluate the effects of the antioxidant, AC3056 (2,6-di- t -butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), on diabetic ED. Methods., Erectile responses to cavernosal nerve electrical stimulation were determined in streptozotocin-induced diabetic rats. Relaxation of human corpus cavernosal (HCC) tissue and penile resistance arteries (HPRA) from human cavernosal specimens was evaluated in organ chambers and myographs, respectively. Main Outcome Measures., The influence of AC3056 on erectile responses, lipid peroxidation, and nitrite plus nitrate serum content, and nuclear factor-,B (NF-,B) expression in penile tissue, in diabetic rats, and on endothelium-dependent and neurogenic relaxation of HCC and HPRA from diabetic patients was determined. Results., Eight weeks of diabetes caused ED in rats that was prevented by oral AC3056 (0.3% w/w in rat chow) when given from the induction of diabetes. AC3056 also prevented the diabetes-induced elevation of serum thiobarbituric acid-reactive substances (TBARS), the reduction of serum nitric oxide (NO) derivatives, and the increase of NF-,B expression. Acute oral administration of AC3056 (450 mg/kg) partially reversed ED in 8-week diabetic rats. Complete reversion of ED was achieved after 3 days of treatment with 0.3% AC3056. This effect remained after 5 weeks of treatment, but it disappeared after withdrawing for 1 week. Erectile function in diabetic rats was inversely related to serum TBARS. AC3056- (30 µM) reversed endothelial dysfunction in diabetic HCC and enhanced endothelium-dependent relaxation in diabetic HPRA and significantly potentiated neurogenic relaxation of both tissues. The reduced cGMP content in HCC from diabetic patients after exposure to acetylcholine (10 µM) was corrected by AC3056 (30 µM). Conclusions., These results suggest that oxidative stress has a relevant role in pathophysiology of diabetic ED and provide a rationale for the use of antioxidant therapy in the treatment of ED in diabetes. Angulo J, Peiró C, Cuevas P, Gabancho S, Fernández A, González-Corrochano R, La Fuente JM, Baron AD, Chen KS, and Sáenz de Tejada I. The novel antioxidant, AC3056 (2,6-di-t-butyl-4-([dimethyl-4-methoxyphenylsilyl] methyloxy) phenol), reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men. J Sex Med 2009;6:373,387. [source]

Insulin-Like Growth Factor-1 Restores Erectile Function in Aged Rats: Modulation the Integrity of Smooth Muscle and Nitric Oxide-Cyclic Guanosine Monophosphate Signaling Activity

THE JOURNAL OF SEXUAL MEDICINE, Issue 6 2008
Xiao-Yong Pu MD
ABSTRACT Introduction., Insulin-like growth factor-1 (IGF-1) is one of the growth factors that have a wide range of biologic effects. We have confirmed that gene transfer of IGF-1 to the penis could improve erectile capacity. However, there are some limitations in gene therapies, such as toxicity or a risk of insertional mutagenesis. Protein treatment may be another choice for decreasing these risks. Aim., To investigate whether intracavernosal injection of IGF-1 protein can restore erectile function in the aging rat. Main Outcome Measures., Erectile responses, morphological changes, and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) signaling pathways-related marker were determined. Methods., Ten young (4 months) and 30 old (24 months) Sprague-Dawley male rats were enrolled in this study. The old rats were divided into three groups: vehicle-only (N = 10), IGF-1 1 µg/kg (N = 10) and IGF-1 10 µg/kg treatment group (N = 10). After 4 and 8 weeks of single IGF-1 injection treatment, intracavernous pressure (ICP) responses with electrical stimulation to the cavernous nerve were evaluated. The percent of smooth muscle in corpus cavernosum tissue, the expression of mRNA and protein of endothelial nitric oxide synthase (eNOS) were also evaluated. The activity of nitric oxide synthase (NOS) and concentration of guanosine 3,,5,-cyclic-monophosphate (cGMP) that act upon the major NO-cGMP signaling pathways in penile tissue were also analyzed. Results., After IGF-1 treatment, the ICP responses was significantly increased as the young control group in both the IGF-1 1 µg/kg and the IGF-1 10 µg/kg group compared with the vehicle-only group at 4 and 8 weeks (P < 0.05). Masson's trichrom staining showed the percentage of cavernosal smooth muscle was increased in IGF-1 treatment group. IGF-1 increased e-NOS expression. NOS activities and cGMP concentrations were also significantly increased in IGF-1 treatment rats. Conclusions., IGF-1 improved erectile function in aged rats via restoration the integrity of smooth muscle of corpus cavernosum and modulation of NO-cGMP pathways. Pu, X-Y, Wang X-H, Gao W-C, Yang Z-H, and Li S-L. Insulin-like growth factor-1 restores erectile function in aged rats: Modulation the integrity of smooth muscle and nitric oxide-cyclic guanosine monophosphate signaling activity. J Sex Med 2008;5:1345,1354. [source]

The Breakdown of Preformed Advanced Glycation End Products Reverses Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats: Preventive Versus Curative Treatment

THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2006
Mustafa F. Usta MD
ABSTRACT Objectives., Accumulation of advanced glycation end products (AGEs) has been linked to many of the complications of diabetes mellitus, including erectile dysfunction (ED). Furthermore, it has been demonstrated that inhibitors of AGE formation, such as aminoguanidine, can prevent ED in diabetic animals. However, it is unknown whether late administration of a putative cross-link breaker, ALT-711, can reverse diabetic ED. We therefore compared ALT-711 and aminoguanidine in their ability to reverse ED in diabetic rats. Materials and Methods., Male Sprague,Dawley rats were randomly divided into four groups: (i) age-matched controls; (ii) streptozotocin (STZ)-induced diabetic rats (60 mg/kg; intraperitoneal injection); (iii) STZ diabetic rats treated with ALT-711 (3 mg/kg/day, intraperitoneal injection); and (iv) STZ diabetic rats treated with aminoguanidine (1 gm/L in drinking water) during the final 6 weeks of 12 weeks of induced diabetes. At the end of 12 weeks, erectile response to cavernous nerve stimulation (CNS) was determined. Neuronal nitric oxide synthase (nNOS) contents were measured in all penises, and AGE levels were determined both in penile tissues and in serum samples. Results., Erectile responses to CNS and penile nNOS protein content were significantly reduced, while AGE levels were elevated in the penises and serum of untreated diabetic animals. Treatment with ALT-711, but not with aminoguanidine, reversed ED and nNOS depletion and reduced serum and penile tissue AGE levels. Conclusions., These results suggest that cross-link breakers, such as ALT-711, are the optimal therapeutic approach, compared with treatment with inhibitors of AGE formation, in the reversal of diabetes-related ED. Usta MF, Kendirci M, Gur S, Foxwell NA, Bivalacqua TJ, Cellek S, and Hellstrom WJG. The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: Preventive versus curative treatment. J Sex Med 2006;3:242,252. [source]

Nebivolol Dilates Human Penile Arteries and Reverses Erectile Dysfunction in Diabetic Rats through Enhancement of Nitric Oxide Signaling

Pharmacological and Functional Characterization of Novel EP and DP Receptor Agonists: DP1 Receptor Mediates Penile Erection in Multiple Species

THE JOURNAL OF SEXUAL MEDICINE, Issue 2 2008
Nadia Brugger PhD
ABSTRACT Introduction., Despite the widespread use of prostaglandin E1 as an efficacious treatment for male erectile dysfunction for more than two decades, research on prostanoid function in penile physiology has been limited. Aim., To characterize the pharmacological and physiological activity of novel subtype-selective EP and DP receptor agonists. Methods., Radioligand binding and second messenger assays were used to define receptor subtype specificity of the EP and DP agonists. Functional activity was further characterized using isolated human and rabbit penile cavernosal tissue in organ baths. In vivo activity was assessed in rabbits and rats by measuring changes in cavernous pressure after intracavernosal injection of receptor agonists. Main Outcome Measures., Receptor binding and signal transduction, smooth muscle contractile activity, erectile function. Results., In organ bath preparations of human cavernosal tissue contracted with phenylephrine, EP2- and EP4-selective agonists exhibited variable potency in causing relaxation. One of the compounds caused mild contraction, and none of the compounds was as effective as PGE1 (EC50 = 0.23 µM). There was no consistent correlation between the pharmacological profile (receptor binding and second messenger assays) of the EP agonists and their effect on cavernosal tissue tone. In contrast, the DP1-selective agonist AS702224 (EC50 =29 nM) was more effective in relaxing human cavernosal tissue than either PGE1, PGD2 (EC50 = 58 nM), or the DP agonist BW245C (EC50 =59 nM). In rabbit cavernosal tissue, PGE1 and PGD2 caused only contraction, while AS702224 and BW245C caused relaxation. Intracavernosal administration of AS702224 and BW245C also caused penile tumescence in rabbits and rats. For each compound, the erectile response improved with increasing dose and was significantly higher than vehicle alone. Conclusions., These data suggest that AS702224 is a potent DP1-selective agonist that causes penile erection. The DP1 receptor mediates relaxation in human cavernosal tissue, and stimulates pro-erectile responses in rat and rabbit. Thus, rabbits and rats can be useful models for investigating the physiological function of DP1 receptors. Brugger N, Kim NN, Araldi GL, Traish AM, and Palmer SS. Pharmacological and functional characterization of novel EP and DP receptor agonists: DP1 receptor mediates penile erection in multiple species. J Sex Med 2008;5:344,356. [source]

The Breakdown of Preformed Advanced Glycation End Products Reverses Erectile Dysfunction in Streptozotocin-Induced Diabetic Rats: Preventive Versus Curative Treatment

Genetic association study of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms and the risk to develop erectile dysfunction in a German ED population

ANDROLOGIA, Issue 4 2010
A. Eisenhardt
Summary Erectile dysfunction (ED) is often associated with cardiovascular disorders such as hypertension, coronary heart disease, hypercholesterolaemia and diabetes mellitus. The genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms have been identified as genetic risk factors for cardiovascular disorders. The association between the genotypes in these polymorphisms and the risk to develop ED was analysed. In 455 German ED patients and 111 age-matched healthy controls genotyping in the candidate polymorphisms was performed after DNA extraction from whole blood. Association studies between the genotype distribution in the control group in comparison with the ED-group and age of onset of the disease as well as erectile response to intracorporal prostaglandin injection in dependence of candidate polymorphism genotype were performed using the SPSS-Software®. Genotype distribution of the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms was similar in the ED population and the healthy control group. The age of onset of the disease as well as the erectile response to intracorporal prostaglandin injection was independent of the genotypes in the three candidate polymorphisms. In contrast to the previous studies in this analysis, the risk to develop ED is not influenced by the genotypes in the GNB3 C825T, the ACE I/D and the eNOS G894T polymorphisms. [source]

Chronic inhibition of nitric-oxide synthase induces hypertension and erectile dysfunction in the rat that is not reversed by sildenafil

BJU INTERNATIONAL, Issue 1 2010
Serap Gur
Study Type , Aetiology (case control) Level of Evidence 3b OBJECTIVE To evaluate the effect of N(G)-nitro- l -arginine methyl ester (L-NAME)-induced hypertension (HT) on erectile function in the rat and determine if the phosphodiesterase (PDE)-5 inhibitor, sildenafil, can reverse the effects of nitric oxide (NO) deficiency, as HT is a risk factor for erectile dysfunction (ED) and the NO synthase (NOS) inhibitor L-NAME induces NO-deficient HT. MATERIALS AND METHODS Thirty-six adult Sprague-Dawley male rats were divided into three groups, i.e. a control, L-NAME-HT (40 mg/rat/day in the drinking water for 4 weeks), and sildenafil-treated L-NAME-HT (1.5 mg/rat/day sildenafil, by oral gavage concomitantly with L-NAME). The erectile response expressed as a ratio of intracavernosal pressure (ICP)/mean arterial pressure (MAP), evaluated after electrical stimulation of the right cavernous nerve. The isometric tension of corpus cavernosum smooth muscle (CCSM) was measured in organ-bath experiments. NOS expression was determined immunohistochemically for neuronal (n)NOS and by Western blot analysis for endothelial (e) and inducible (i) NOS protein. cGMP levels were evaluated by enzyme-linked immunosorbent assay. RESULTS The erectile response was diminished in the HT group. Nitrergic and endothelium-dependent relaxation was reduced, while the relaxation response to sodium nitroprusside and contractile response to phenylephrine were not altered in CCSM from L-NAME-treated rats. HT rats showed decreased expression of nNOS, whereas eNOS and iNOS protein expression was increased. Sildenafil partly restored endothelial and molecular changes in CCSM from HT rats, but did not reverse the decreased erectile response, even as cGMP levels returned to normal levels. CONCLUSIONS Sildenafil treatment did not correct the ED in L-NAME-treated HT rats. Under sustained high blood pressure, up-regulation of PDE5 expression failed to reverse the depletion of neuronal NO and/or impaired nNOS activity. However, endothelium-dependent relaxation was restored. Drug targeting of neuronal dysfunction might delay the onset of ED in HT. [source]

The Novel Antioxidant, AC3056 (2,6-di-t-butyl-4-((Dimethyl-4-Methoxyphenylsilyl)Methyloxy)Phenol), Reverses Erectile Dysfunction in Diabetic Rats and Improves NO-mediated Responses in Penile Tissue from Diabetic Men

Telemetric Intracavernosal and Intraspongiosal Pressure Monitoring

THE JOURNAL OF SEXUAL MEDICINE, Issue 10 2008
Rany Shamloul MD
ABSTRACT Introduction., Despite the major breakthroughs basic research in erectile physiology experienced in the last, most of the methods used for quantitative assessment of erectile function in longitudinal studies suffer many drawbacks. Objective., This review will focus on radiotelemetric assessment of intracavernosal (ICP) and intraspongiosal (ISP) regarding the technique, data collection, interpretation, and overall benefits. Results., Telemetric recording of ICP and ISP allows for qualitative and quantitative assessment of erectile responses in experimental animals, a characteristic that is not possible using other techniques. This technique has many advantages that can collectively lead to production of high quality data regarding erection. The system suffers two drawbacks, its high cost and the need for surgical implantation of the transmitter. Conclusion., The use of telemetric monitoring of ICP and ISP carries many advantages that will, hopefully, establish this technique as the gold standard method for assessment of erectile responses in the near future. Shamloul R. Telemetric intracavernosal and intraspongiosal pressure monitoring. J Sex Med 2008;5:2246,2252. [source]

Effects of Natriuretic Peptides on Intracavernous Pressure and Blood Pressure in Conscious Rats

THE JOURNAL OF SEXUAL MEDICINE, Issue 10 2008
Naoki Aizawa PhD
ABSTRACT Introduction., Natriuretic peptides activate particulate guanylyl cyclases and have been shown to induce penile erection in rats, rabbits, and humans. Aim., We investigated the effects of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) on intracavernous pressure (ICP) and systemic blood pressure (BP) in conscious, free-moving rats. Methods., ICP and BP were measured in male Sprague,Dawley rats after catheters were inserted into the crus corpus cavernosum and carotid artery, respectively. Natriuretic peptides were given by intravenous bolus (3, 10, and 30 nmol/kg) or continuous (0.1 and 1 nmol/kg/minute) administration. Main Outcome Measures., The number of animals with increases in ICP were determined. Amplitudes and durations of ICP responses and changes in BP were also evaluated. Results., More animals had multiple transient increases of ICP in response to ANP and BNP than to CNP. The increases in ICP were transient and appeared to be an "all or none" response. ANP and BNP decreased BP more than CNP, especially with bolus administration. Conclusions., These findings show that in rats, erectile responses can be initiated by ANP, BNP, and less effectively, by CNP. ANP and BNP have a high affinity for the natriuretic peptide receptor-A, suggesting that this receptor is involved in the responses. Aizawa N, Ishizuka O, Ogawa T, Mizusawa H, Igawa Y, Nishizawa O, and Andersson K-E. Effects of natriuretic peptides on intracavernous pressure and blood pressure in conscious rats. J Sex Med 2008;5:2312,2317. [source]

ORIGINAL RESEARCH,BASIC SCIENCE: Erectile Dysfunction in Hypercholesterolemic Atherosclerotic Apolipoprotein E Knockout Mice

THE JOURNAL OF SEXUAL MEDICINE, Issue 4 2006
Delphine Behr-Roussel PharmD
ABSTRACT Introduction., Erectile dysfunction (ED) and cardiovascular diseases share the same risk factors. Although the use of hypercholesterolemic rabbit models has proven to be useful to illustrate the link between ED and hypercholesterolemia, the cost of daily maintenance of the animals and necessity for important amounts of drug have limited their use. Aim., We aimed to develop a new model of atherosclerosis-associated ED in a well-known experimental model of atherosclerosis, the apolipoprotein E knockout (ApoE KO) mouse. Methods., Erectile function was evaluated by recording frequency-dependent increases in intracavernous pressure following electrical stimulation of the cavernous nerve in 26-, 32-, and 38-week-old ApoE KO mice fed a Western-type diet and age-matched C57BL6/J anesthetized mice. Atherosclerotic lesions were evaluated by planimetry in oil red O-stained aortas. Results., We found that in contrast to C57BL6/J mice, ApoE mice displayed atherosclerotic lesions covering 22% of the aortic luminal surface at 26 weeks of age and increasing to 27% and 35% at 32 weeks and 38 weeks of age, respectively. The amplitude of erectile responses to electrical stimulation of the cavernous nerve was markedly impaired in 26-week-old ApoE KO mice as compared with age-matched C57BL6/J mice. Impairment in erectile function persisted in ApoE KO mice 32 and 38 weeks of age. Conclusions., The ApoE KO mouse, a well-characterized model to study disorders associated with hypercholesterolemia and atherosclerosis in cardiovascular research, could therefore be suitable for investigation of disease-modifying effects of new therapeutic strategies aiming to target both atherosclerosis and ED. Behr-Roussel D, Darblade B, Oudot A, Compagnie S, Bernabé J, Alexandre L, and Giuliano F. Erectile dysfunction in hypercholesterolemic atherosclerotic apolipoprotein E knockout mice. J Sex Med 2006;3:596,603. [source]

ORIGINAL RESEARCH,BASIC SCIENCE: Enhancement of Both EDHF and NO/cGMP Pathways Is Necessary to Reverse Erectile Dysfunction in Diabetic Rats

THE JOURNAL OF SEXUAL MEDICINE, Issue 3 2005
Javier Angulo PhD
ABSTRACT Aims and Methods., Phosphodiesterase 5 (PDE5) inhibitors are less effective in the treatment of erectile dysfunction (ED) in diabetic men than in nondiabetic patients. We have evaluated the effects of sildenafil, a PDE5 inhibitor that enhances the nitric oxide (NO)/cGMP pathway, calcium dobesilate (DOBE), which potentiates endothelium-derived hyperpolarizing factor (EDHF)-mediated responses and the combination of both on erectile responses elicited by cavernosal nerve electrical stimulation (CNES) in a rat model of ED after 8 weeks of streptozotocin-induced diabetes. Results., After 8 weeks of diabetes, erectile responses to CNES were significantly decreased in diabetic animals compared with nondiabetic time controls. While intravenous administration of sildenafil (0.3 mg/kg) or DOBE (10 mg/kg), individually, enhanced erectile responses in nondiabetic rats (214.7 ± 34.1% and 268.5 ± 30.1% of control response at 1 Hz, respectively), each failed to significantly enhance erectile responses in diabetic rats. Only when administered in combination did DOBE and sildenafil markedly potentiate erectile responses in these animals (380.1 ± 88.6% of control response at 1 Hz), completely restoring erectile function. Conclusions., These findings emphasize the importance of NO/cGMP and EDHF pathways for normal erectile function. They also give support to the in vitro observation that diabetes impairs NO and EDHF-dependent responses, precluding the complete recovery of erectile function with PDE5 inhibitors and explaining the relatively poor clinical response of diabetic men with ED to PDE5 inhibition. Finally, our study suggests that a pharmacological approach that combines enhancement of NO/cGMP and EDHF pathways could be necessary to treat ED in many diabetic men. [source]

A comparison of the International Index of Erectile Function and erectile dysfunction studies

BJU INTERNATIONAL, Issue 7 2003
W. Kassouf
OBJECTIVE To evaluate the ability of the five-item version of the International Index of Erectile Function (IIEF-5) to diagnose the vascular aetiology and severity of erectile dysfunction (ED), and to compare it with pharmacological testing and duplex Doppler ultrasonography, as such questionnaires are widely used by the pharmaceutical industry to categorize the severity of ED and to assess the efficacy of drug therapy. PATIENTS AND METHODS In all, 80 patients (mean age 45.2 years, sd 14.0; mean duration of ED 3.5 years) were reviewed by an examiner unaware of their IIEF scores during testing. Penile blood flow was assessed in each patient after an intracavernosal injection with prostaglandin-E1 (10 µg), with self-stimulation in privacy. The peak systolic velocity, end diastolic velocity and resistive index were measured for the vascular diagnosis. Visual ratings of erectile responses were also used for analysis. RESULTS Of the 80 patients, 30 had a normal vascular response, 38 arterial insufficiency and 12 were diagnosed with venous leakage. There was no significant difference in the IIEF scores among patients with a normal vascular response, arterial insufficiency or venous leakage. Analysis of visual ratings of erections showed no difference in IIEF scores among the different groups of patients. CONCLUSION The IIEF was designed and developed specifically for assessing and evaluating sexual function in clinical trials. However, as shown here, the IIEF cannot and should not be used as a tool to diagnose or compare specific vascular causes of ED. [source]

Calcium dobesilate potentiates endothelium-derived hyperpolarizing factor-mediated relaxation of human penile resistance arteries

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003
Javier Angulo
We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K+ (35 mM) or by blocking Ca2+ -activated K+ channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 ,M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K+ or a combination of APA and CTX. In vivo, DOBE (10 mg kg,1 i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED. British Journal of Pharmacology (2003) 139, 854,862. doi:10.1038/sj.bjp.0705293 [source]