Chronic Sildenafil Improves Erectile Function and Endothelium-dependent Cavernosal Relaxations in Rats: Lack of Tachyphylaxis

Behr‐Roussel, Delphine; Gorny, Diane; Mevel, Katell; Caisey, Stéphanie; Bernabé, Jacques; Burgess, Gillian M.; Wayman, Chris; Alexandre, L; Giuliano, François

doi:10.1016/j.eururo.2004.09.005

Cited by 112 publications

(69 citation statements)

References 19 publications

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“…12 This 20 mg kg À1 day À1 dose of sildenafil in the rat is about 10-fold higher than the one we used for vardenafil in our BCNR rat model and is within the dosages that have been tested in continuous administration in experimental animals and even in patients for conditions such as pulmonary hypertension. 33,[42][43][44] With the exception of the anti-apoptotic effect that we found with sildenafil in the current study which we did not see with vardenafil in our previous report, both drugs elicited the same effects despite the difference in dosage. 33 Therefore, it is likely that a lower dose of sildenafil would also be as effective.…”

Section: Discussioncontrasting

confidence: 75%

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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It was recently reported in the rat that vardenafil given in a continuous long-term manner was successful in preventing smooth muscle fibrosis in the penile corpora cavernosa and corporal venoocclusive dysfunction (CVOD) that occur following bilateral cavernosal nerve resection (BCNR), a model for human erectile dysfunction after radical prostatectomy. To expand on this finding and to determine whether this effect was common to other PDE5 inhibitors, and occurred in part by stimulation of the spontaneous induction of inducible nitric oxide synthase (iNOS, also known as NOS2), male Fischer 344 rats (N ¼ 10/group) were subjected to either BCNR or unilateral cavernosal nerve resection (UCNR) and treated with sildenafil (20 mg kg À1 day À1 ) in the drinking water daily for 45 days. Additional BCNR groups received L-NIL (6.7 mg kg À1 day À1 ) as inhibitor of iNOS activity, with or without concurrent sildenafil administration. It was determined that sildenafil, like vardenafil, (1) prevented the 30% decrease in the smooth muscle cell/collagen ratio, and the 3-4-fold increase in apoptosis and reduction in cell proliferation, and partially counteracted the increase in collagen, seen with both UCNR and BCNR; and (2) normalized the CVOD, measured by dynamic infusion cavernosometry, induced by both BCNR and UCNR. The long-term inhibition of iNOS activity exacerbated corporal fibrosis and CVOD in the BCNR rats, but sildenafil functional effects were not affected by L-NIL. These data suggest that the salutary effects of continuous long-term PDE5 inhibitors on erectile function post-cavernosal nerve resection involve their ability to prevent the alterations in corporal histology induced by cavernosal nerve damage, in a process apparently independent from endogenous iNOS induction.

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Section: Discussioncontrasting

confidence: 75%

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

et al. 2007

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“…For instance, sildenafil reduces malondialdehyde levels and potentiates the total antioxidant capacity of plasma in STZ-induced diabetic rats [29], induces symptomatic improvement in pulmonary hypertension [30] and prevents myocyte hypertrophy [31]. Moreover, erectile function, protein expression of phosphorylated eNOS and NOS enzymatic activity are improved in normal rats by sildenafil treatment [32][33][34]. Chronic treatment with tadalafil in patients with increased cardiovascular risk improved brachial artery flow-mediated dilation, and resulted in a net increase in nitrite/nitrate levels and a decrease in the plasma endothelin-1 level [35].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical diabetogenesis

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et al. 2009

Asian J Androl

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Erectile dysfunction (ED) is a major complication of diabetes mellitus (DM). This study investigates the relationship between ED and the downregulation of constitutive nitric oxide synthase (cNOS) in the corpus cavernosum (CC) of diabetic rats. It also examines the effects of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on ED and cNOS expression levels. After 16 weeks of daily oral treatment with udenafil in diabetic rats, the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio was recorded to measure erectile function, and cNOS expression was measured using reverse transcriptase (RT)-PCR and immunoblots. Although the ICP/ MAP ratio and the expression levels of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the CC were markedly decreased in diabetic rats, long-term udenafil treatment improved the erectile function and increased cNOS expression compared with diabetic controls. These findings suggest that ED in DM is closely related to decreased cNOS expression in the CC and that udenafil has the ability to compensate for this pathological change by modulating cNOS expression. Udenafil also has an inhibitory role in cyclic guanosine monophosphate (cGMP) degradation.

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“…Recent pre-clinical evidence suggests that PDE5 inhibitor therapy can improve endothelial cell function in the penis via phosphorylation of eNOS [27,28]. Importantly, daily PDE5 inhibitor therapy improves erectile function in a select group of ED patients potentially through an endothelial-dependent manner [29][30][31][32].…”

Section: Discussionmentioning

confidence: 99%

Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

et al. 2007

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Objectives: We sought to evaluate the regulatory influence of endothelial nitric oxide (NO) on the basal functional states of the NO and RhoA/Rho-kinase signaling pathways in the penis employing endothelial NO synthase (eNOS) mutant mice and eNOS gene transfer technology.Methods: Four groups of mice were utilized: 1) wild type (WT), 2) eNOS gene deleted (eNOS −/−), 3) eNOS and neuronal NOS gene deleted (dNOS −/−), and 4) eNOS −/− mutant mice transfected intracavernosally with eNOS. Cyclic guanosine monophosphate (cGMP) concentration, protein kinase G (PKG) activity, activated RhoA, and Rho-kinase activity were determined in penes of WT and both mutant mouse groups. Constitutive NOS and PKG activities, RhoA, Rho-kinase-α and-β isoforms, and phosphorylated myosin light chain phosphatase target subunit (p-MYPT-1) expressions as well as Rho-kinase activity were determined in penes of eNOS−/− mice after eNOS gene transfer. Results:When compared with results in the WT penis, eNOS−/− and dNOS−/− mutant mouse penes had significant reductions in NOS activity, cGMP concentration, PKG activity, Rho-kinase activity and p-MYPT-1 expression (p<0.05) with no significant changes in activated RhoA or in RhoA and Rho-kinase-α and-β protein expressions. After eNOS gene transfer to penes of eNOS−/ − mice, Rho-kinase-β and p-MYPT-1 expressions and total Rho-kinase activity were significantly increased from baseline levels (p<0.05). Conclusions:These data suggest that endothelial NO serves a role in the penis as a regulator of the basal signaling functions of the NO and RhoA/Rho-kinase erection mediatory pathways. These data offer new insight into the homeostasis of erection regulatory biology.

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Chronic Sildenafil Improves Erectile Function and Endothelium-dependent Cavernosal Relaxations in Rats: Lack of Tachyphylaxis

Cited by 112 publications

References 19 publications

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Long-term continuous sildenafil treatment ameliorates corporal veno-occlusive dysfunction (CVOD) induced by cavernosal nerve resection in rats

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical diabetogenesis

Endothelial Nitric Oxide Synthase Keeps Erection Regulatory Function Balance in the Penis

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