The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the trea... more The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.
Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the ... more Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the development of erectile dysfunction (ED). Vardenafil, a phosphodiesterase type 5 inhibitor has been used to treat ED. The aim of this study was to assess the in vitro and in vivo effects of vardenafil on diabetic rabbit CSMR. Organ bath studies were used. Sodium nitroprusside (SNP)- and electrical field stimulation (EFS)-induced CSMR in diabetic rabbits given the vehicle was significantly impaired when compared with controls. The in vitro addition of vardenafil significantly enhanced SNP-induced CSMR in diabetic animals given the vehicle. SNP-induced CSMR in diabetic animals given in vivo vardenafil was significantly increased when compared with the diabetic untreated group. The in vitro addition of vardenafil significantly enhanced SNP and EFS-induced CSMR in cavernosal tissue taken from diabetic animals given vardenafil in vivo. The present findings suggest that the combination of in v...
Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes... more Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes in autonomic receptors and alterations in detrusor structure and function. The changes in cholinergic and purinergic neurotransmission in the DM rabbit bladder were evaluated. DM was induced with alloxan in adult male New Zealand White rabbits. At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in organ baths. Transmural electrical field stimulation (EFS: supramaximal voltage, 0.1 ms duration, 10 s trains) was performed in the presence of atropine (10(-6) M) or alpha, beta-methylene ATP (10(-6) M), and after adding tetrodotoxin10(-6) M. Purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components were calculated independently and compared with those from controls. Both normal and DM detrusor and bladder neck strips contracted in a frequency-dependent fashion in response to transmural EFS. A plot of EFS vs. detrusor contract...
Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusivel... more Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusively demonstrated. Augmented cavernosal smooth muscle (CSM) contraction in the rat occurs following exposure to both ET-1 and phenylephrine (PE; alpha-1 agonist). The aim of this study was to assess the effect of ET-1 and its possible role in the alpha1-adrenergic pathway during the erectile process. Organ bath studies were performed on CSM strips of penises obtained from 12 age-matched New Zealand White rabbits. The effect of ET-1 and PE alone on CSM tone in the absence and presence of ETA (BQ123) and ETB (BQ788) antagonists was assessed. Tissue responses were measured as tension (newton, N). EC50 values are expressed as mean +/- S.E.M. PE (10(8) - 10(-4) M) and ET-1 (10(-10) - 10(-6) M) produced a concentration-dependent contraction in rabbit CSM strips. The EC50 values were 1.7 x 10(-7) M +/- 1.1 and 3.4 x 10(-9) M +/- 1.5, respectively. BQ123 10(-5) M significantly inhibited ET-1-mediat...
Diabetic nephropathy is a common cause of impaired renal function. We investigated the effect var... more Diabetic nephropathy is a common cause of impaired renal function. We investigated the effect vardenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, has on renal function in the diabetic rabbit. Blood was taken at 4 and 6 months from control and alloxan-induced diabetic animals (n=8, in each group) and biochemical variables pertaining to renal function determined. A 7-month sample was also analysed after giving control and diabetic animals (n=4 in each group) either vardenafil (3 mg/kg) or vehicle to drink for 4 weeks. Spot urine total protein/ creatinine ratio (TP/C) was determined at 4 and 6 months. At 7 months a 24 h-urine sample was collected to measure TP/C and creatinine clearance (CrCl). There was a significant increase in serum creatinine concentration after 6 months diabetes, which was significantly reduced by vardenafil. TP/C from diabetic rabbit spot urine samples at 6 months were significantly elevated compared to control animals, indicating the presence of proteinuri...
Serotonin (5-hydroxytryptamine; 5-HT) can cause contraction in cavernosal smooth muscle. We furth... more Serotonin (5-hydroxytryptamine; 5-HT) can cause contraction in cavernosal smooth muscle. We further evaluated this effect of 5-HT. Organ bath studies were used. 5-HT induced a sustained contraction occasionally accompanied by a transient relaxation (in 30% of rabbit cavernosal tissues) that preceded the contraction. Ondansetron and Y-25130 (both 5-HT3 receptor antagonists) but not SB-269970 (a 5-HT7 receptor antagonist) significantly inhibited or abolished this transient relaxation. Doxazosin (dox, an alpha1-receptor antagonist) and ketanserin (ketan, a 5-HT2A receptor antagonist) significantly inhibited or abolished the sustained contraction. The effects of dox on 5-HT-mediated contraction were concentration-dependent. Our findings further confirm that the peripheral serotonergic pathway may play a part in the erectile process via 5-HT2A receptor-mediated contractile and 5-HT3 receptor-mediated relaxant activities. Our results also support the findings of human studies, which suggest that both ketan and dox may exert beneficial effects on the erectile process.
The Journal of the Royal Society for the Promotion of Health, 2004
Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidenc... more Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidence links vascular risk factors (hypertension, diabetes mellitus, hyperlipidaemia and smoking) with ED. This association is not surprising since the corpus cavernosum is a modified vascular tissue. This review presents a brief account of the aetiology, diagnosis and treatment of ED. There is a need to raise awareness of this condition and to make appropriate treatment available to patients.
The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the trea... more The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.
Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the ... more Diabetes mellitus is associated with impaired cavernosal smooth muscle relaxation (CSMR) and the development of erectile dysfunction (ED). Vardenafil, a phosphodiesterase type 5 inhibitor has been used to treat ED. The aim of this study was to assess the in vitro and in vivo effects of vardenafil on diabetic rabbit CSMR. Organ bath studies were used. Sodium nitroprusside (SNP)- and electrical field stimulation (EFS)-induced CSMR in diabetic rabbits given the vehicle was significantly impaired when compared with controls. The in vitro addition of vardenafil significantly enhanced SNP-induced CSMR in diabetic animals given the vehicle. SNP-induced CSMR in diabetic animals given in vivo vardenafil was significantly increased when compared with the diabetic untreated group. The in vitro addition of vardenafil significantly enhanced SNP and EFS-induced CSMR in cavernosal tissue taken from diabetic animals given vardenafil in vivo. The present findings suggest that the combination of in v...
Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes... more Diabetes mellitus (DM)-associated alterations in bladder function have been attributed to changes in autonomic receptors and alterations in detrusor structure and function. The changes in cholinergic and purinergic neurotransmission in the DM rabbit bladder were evaluated. DM was induced with alloxan in adult male New Zealand White rabbits. At 6 months, detrusor and bladder neck muscle strips were obtained and mounted in organ baths. Transmural electrical field stimulation (EFS: supramaximal voltage, 0.1 ms duration, 10 s trains) was performed in the presence of atropine (10(-6) M) or alpha, beta-methylene ATP (10(-6) M), and after adding tetrodotoxin10(-6) M. Purinergic, alpha, beta-methylene ATP-sensitive, and cholinergic, atropine-sensitive, components were calculated independently and compared with those from controls. Both normal and DM detrusor and bladder neck strips contracted in a frequency-dependent fashion in response to transmural EFS. A plot of EFS vs. detrusor contract...
Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusivel... more Endothelin (ET-1) may play a role in the regulation of erection but this has not been conclusively demonstrated. Augmented cavernosal smooth muscle (CSM) contraction in the rat occurs following exposure to both ET-1 and phenylephrine (PE; alpha-1 agonist). The aim of this study was to assess the effect of ET-1 and its possible role in the alpha1-adrenergic pathway during the erectile process. Organ bath studies were performed on CSM strips of penises obtained from 12 age-matched New Zealand White rabbits. The effect of ET-1 and PE alone on CSM tone in the absence and presence of ETA (BQ123) and ETB (BQ788) antagonists was assessed. Tissue responses were measured as tension (newton, N). EC50 values are expressed as mean +/- S.E.M. PE (10(8) - 10(-4) M) and ET-1 (10(-10) - 10(-6) M) produced a concentration-dependent contraction in rabbit CSM strips. The EC50 values were 1.7 x 10(-7) M +/- 1.1 and 3.4 x 10(-9) M +/- 1.5, respectively. BQ123 10(-5) M significantly inhibited ET-1-mediat...
Diabetic nephropathy is a common cause of impaired renal function. We investigated the effect var... more Diabetic nephropathy is a common cause of impaired renal function. We investigated the effect vardenafil, a phosphodiesterase type 5 (PDE-5) inhibitor, has on renal function in the diabetic rabbit. Blood was taken at 4 and 6 months from control and alloxan-induced diabetic animals (n=8, in each group) and biochemical variables pertaining to renal function determined. A 7-month sample was also analysed after giving control and diabetic animals (n=4 in each group) either vardenafil (3 mg/kg) or vehicle to drink for 4 weeks. Spot urine total protein/ creatinine ratio (TP/C) was determined at 4 and 6 months. At 7 months a 24 h-urine sample was collected to measure TP/C and creatinine clearance (CrCl). There was a significant increase in serum creatinine concentration after 6 months diabetes, which was significantly reduced by vardenafil. TP/C from diabetic rabbit spot urine samples at 6 months were significantly elevated compared to control animals, indicating the presence of proteinuri...
Serotonin (5-hydroxytryptamine; 5-HT) can cause contraction in cavernosal smooth muscle. We furth... more Serotonin (5-hydroxytryptamine; 5-HT) can cause contraction in cavernosal smooth muscle. We further evaluated this effect of 5-HT. Organ bath studies were used. 5-HT induced a sustained contraction occasionally accompanied by a transient relaxation (in 30% of rabbit cavernosal tissues) that preceded the contraction. Ondansetron and Y-25130 (both 5-HT3 receptor antagonists) but not SB-269970 (a 5-HT7 receptor antagonist) significantly inhibited or abolished this transient relaxation. Doxazosin (dox, an alpha1-receptor antagonist) and ketanserin (ketan, a 5-HT2A receptor antagonist) significantly inhibited or abolished the sustained contraction. The effects of dox on 5-HT-mediated contraction were concentration-dependent. Our findings further confirm that the peripheral serotonergic pathway may play a part in the erectile process via 5-HT2A receptor-mediated contractile and 5-HT3 receptor-mediated relaxant activities. Our results also support the findings of human studies, which suggest that both ketan and dox may exert beneficial effects on the erectile process.
The Journal of the Royal Society for the Promotion of Health, 2004
Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidenc... more Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidence links vascular risk factors (hypertension, diabetes mellitus, hyperlipidaemia and smoking) with ED. This association is not surprising since the corpus cavernosum is a modified vascular tissue. This review presents a brief account of the aetiology, diagnosis and treatment of ED. There is a need to raise awareness of this condition and to make appropriate treatment available to patients.
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