Stimulation of the nitric oxide-guanosine 3', 5'-cyclic monophosphate pathway by sildenafil: effect on rectal muscle tone, distensibility, and perception in health and in irritable bowel syndrome.

Fritz E, Hammer J, Schmidt B, Eherer AJ, Hammer HF.

Universitatsklinik fur Innere Medizin IV, Abteilung fur Gastroenterologie und Hepatologie, University of Vienna, Vienna, Austria.

OBJECTIVES: Nitric oxide, a neurotransmitter in the noncholinergic, nonadrenergic nervous system, is a mediator of relaxation of GI smooth muscle and of visceral nociception mainly studied in vitro. Sildenafil stimulates the nitric oxide guanosine 3', 5'-cyclic monophosphate (NO-cGMP) pathway through inhibition of phosphodiesterase 5. The aims of this study were to evaluate in vivo the effect of stimulation of the NO-cGMP pathway on rectal tone, distensibility, and perception in healthy individuals and in patients with irritable bowel syndrome (IBS). METHODS: In eight healthy subjects and four patients with IBS rectal tone, distensibility and perception thresholds were measured with an electronic barostat both before and 60 min after administration of sildenafil (50 mg p.o.). Perception was scored on a graded scale of 0-6. At the end of a distension series an anatomic questionnaire was filled out by the subjects. RESULTS: Sildenafil significantly reduced rectal tone in healthy subjects (intrabag volume predrug: 145.5 +/- 18.7 ml vs postdrug: 164.4 +/- 16.9 ml, p = 0.01) and IBS (111.3 +/- 25.2 ml vs 136.5 +/- 33.3 ml; p = 0.01) but did not alter rectal compliance (healthy subjects: 5.8 +/- 0.4 vs 6.3 +/- 0.6 ml/mm Hg, p > 0.05; IBS subjects: 6.1 +/- 0.6 vs 7.1 +/- 1.0 ml/mm Hg, p > 0.05). Intrabag pressure and rectal wall tension to reach perception thresholds for initial sensation, sensation of stool, and urgency were not altered by sildenafil. However, intrabag volumes to reach these thresholds were significantly increased by sildenafil both in healthy subjects and in patients with IBS. Viscerosomatic referral was unchanged. CONCLUSIONS: Stimulation of the NO-cGMP pathway decreases rectal tone but does not influence rectal distensibility. Relaxation of the rectum is accompanied by an increase in rectal volumes to reach perception thresholds in healthy subjects and in patients with IBS, but no direct effect on rectal perception can be demonstrated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14572576&dopt=Abstract sildenafil Viagra online



Drug combinations in the therapy of low response to phosphodiesterase 5 inhibitors in patients with erectile dysfunction.

Dunzendorfer U, Behm A, Dunzendorfer E, Dunzendorfer A.

Maingau Hospital, J.-W.-G.-University Frankfurt, D 60318 Frankfurt, Scheffelstr. 2-16, Germany.

Combinatorial drugs utilising a clinically-proven single agent approach in erectile dysfunction (ED) have led to the search for additional compounds to improve therapy and the safety profile. Selective inhibitors of Phosphodiesterase type 5, such as Sildenafil, demonstrate a defined failure rate in ED. The therapeutic concept to increase blood influx and or to decrease blood efflux in patients with ED under therapy encountered severe drawbacks. It appeared impossible to decrease the NO-content in the corpora cavernosa and associated organs followed by synchronized increase of NO by a second drug. One has to metabolically activate cAMP by the first acting compound followed by cGMP stimulation. The pharmacology of the counteractive drugs was investigated clinically and a combination of 50 mg sildenafil with 5 mg dihydro-ergotamine (DHE) was identified as of practical use in patients with low response to Sildenafil. The safety profile appeared to be improved by this combination therapy. The present study is a clinical follow-up of patients treated with different therapeutical regimens to document the effectiveness of Sildenafil in combination with DHE.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12494876&dopt=Abstract sildenafil Viagra online



[Interaction between sildenafil and calcineurin inhibitors in renal transplant recipients with erectile dysfunction]

[Article in Spanish]

Cofan F, Gutierrez R, Beardo P, Campistol JM, Oppenheimer F, Alcover J.

Unidad de Trasplante Renal, Universidad de Barcelona, Barcelona. fcofan medicina.ub.es

AIM: Hepatic metabolism of sildenafil uses the same metabolic pathway as the calcineurin inhibitors (cyclosporine/tacrolimus), through the CYP3A4 isoenzyme. The aim of this pilot study was to evaluate the potential interaction between sildenafil therapy and circulating levels of cyclosporine and tacrolimus in a group of steady-state renal transplant recipients with erectile dysfunction. MATERIAL AND METHODS: A prospective pilot study of sildenafil interactions was carried out in 9 stable male renal transplant recipients with severe erectile dysfunction (mean age 50 +/- 8 years, range 38-64). All patients were receiving therapy with calcineurin inhibitors (5 with cyclosporine and 4 with tacrolimus). Erectile dysfunction was evaluated by clinical history, physical examination, International Index of Erectile Function (IIEF) questionnaire and the nocturnal penile tumescence test (RigiScan). Each patient received a first dose of 50 mg of sildenafil, one hour before sexual activity and a second dose at 72 hours of 50 or 100 mg according to the clinical response to the first dose. We evaluated the efficacy and safety of sildenafil and the evolution of cyclosporine-tacrolimus levels. Cyclosporine and tacrolimus trough whole blood concentrations were determined in basal conditions (before starting sildenafil) and on days 1, 4 and 7 after sildenafil therapy. RESULTS: Eighty-nine percent of patients (n = 8) required a complete 100 mg dose of sildenafil. There was a positive clinical response in two-thirds of cases (6 patients). In 5 patients (55%) sildenafil administration produced a complete response, in one patient the response was incomplete, and in the remaining 3 cases (33%) no clinical response was observed. Associated side effects included self-limited tachycardia in one patient and mild visual disturbances in another. Cyclosporine and tacrolimus levels remained stable in all patients. There were no significant differences in circulating levels of cyclosporine (basal 120 +/- 47; day 1: 116 +/- 55; day 4: 123 +/- 56 and day 7: 121 +/- 56 ng/ml p = NS) or tacrolimus (basal 11.6 +/- 1.3; day 1: 11.9 +/- 1.3; day 4: 11.1 +/- 1.0 and day 7: 11.8 +/- 0.9 ng/ml p = NS) over the study period. CONCLUSIONS: Sildenafil therapy is safe and effective for the treatment of erectile dysfunction in renal transplant recipients. Recommended therapeutic doses of sildenafil did not modify cyclosporine and tacrolimus trough blood levels.

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Protection by sildenafil and theophylline of lead acetate-induced oxidative stress in rat submandibular gland and saliva.

Abdollahi M, Fooladian F, Emami B, Zafari K, Bahreini-Moghadam A.

Department of Toxicology and Pharmacology, Faculty of Pharmacy and Laboratory of Toxicology, Pharmaceutical Sciences research Centre, Tehran University of Medical Science, Tehran, Iran. mohammad.abdollahi utoronto.ca

The role of oxidative stress in lead toxicity has been proposed in many organs, however, no study has been performed in the salivary glands, which are important parts of the gastrointestinal tract with a high implication in health of the whole body. Recently, it has been proposed that increasing the levels of cGMP and cAMP in the cells may protect from the neurotoxicity of lead. The objective of this study was to determine the ability of lead acetate to produce oxidative stress in rat submandibular as the main salivary gland of the body and to study the role of pretreatment by specific phosphodiesterase inhibitors in the prevention of oxidative stress. Lead acetate (100 mg/kg), alone or in combination with theophylline (25 mg/kg) and sildenafil (5 mg/kg), was administered intraperitoneally to rats. After 2 hours and under general anaesthesia, the submandibular gland ducts were cannulated intraorally using microcannula, and pure saliva was collected for 30 min using pilocarpine (8 mg/kg) as a secretagogue. The submandibular glands were then isolated free under surgery. Oxidative stress in the gland and pure saliva were evaluated measuring lipid peroxidation (thiobarbituric acid reactive substances assay), total thiol groups content and total antioxidant capacity (the ferric reducing ability assay). Results showed significant oxidative stress in the gland and secretions as indicated by increased lipid peroxidation, decreased total antioxidant capacity and thiol group levels. The use of cAMP and cGMP phosodiesterase inhibitors, theophylline and sildenafil, prevented lead-induced increased lipid peroxidation and also protected from decreased thiol groups content and total antioxidant power of the gland and secretions. The same trend of effects was observed in gland and saliva. It is concluded that lead toxicity is mediated through oxidative stress in salivary glands, while increasing intracellular cAMP and cGMP levels may prevent lead-induced oxidative stress.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14686481&dopt=Abstract sildenafil Viagra online



Beneficial effects of phosphodiesterase 5 inhibition in pulmonary hypertension are influenced by natriuretic Peptide activity.

Zhao L, Mason NA, Strange JW, Walker H, Wilkins MR.

Section on Clinical Pharmacology, Imperial College School of Science, Technology and Medicine, Hammersmith Hospital, London, England.

BACKGROUND: Phosphodiesterase type 5 (PDE5) inhibitors (eg, sildenafil) are a novel, orally active approach to the treatment of pulmonary arterial hypertension. The role of natriuretic peptides in the response to sildenafil was examined in mice lacking NPR-A, a guanylyl cyclase-linked natriuretic peptide receptor, in which pulmonary hypertension was induced by hypoxia. METHODS AND RESULTS: Mice homozygous for NPR-A (NPR-A+/+) and null mutants (NPR-A-/-) were studied. Sildenafil inhibited the pressor response to acute hypoxia in the isolated perfused lungs of both genotypes. This effect was greater in the presence of atrial natriuretic peptide in the perfusate in NPR-A+/+ mice but not NPR-A-/- animals. In vivo, NPR-A mutants had higher basal right ventricular (RV) systolic pressures (RVSPs) than did NPR-A+/+ mice, and this was not affected by 3 weeks of treatment with sildenafil (25 mg x kg(-1) x d(-1)). Both genotypes exhibited a rise in RVSP and RV weight with chronic hypoxia (10% O2 for 21 days); RVSP and RV weight were reduced by continuous sildenafil administration in NPR-A+/+ mice, but only RVSP showed evidence of a response to the drug in NPR-A-/- mice. The effect of sildenafil on hypoxia-induced pulmonary vascular muscularization and cyclic GMP levels was also blunted in NPR-A-/- mice. CONCLUSIONS: The natriuretic peptide pathway influences the response to PDE5 inhibition in hypoxia-induced pulmonary hypertension, particularly its effects on RV hypertrophy and vascular remodeling.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12538421&dopt=Abstract sildenafil Viagra online



[Determination of sildenafil in medicines for erectile dysfunction by capillary electrophoresis]

[Article in Chinese]

Li RK, Bo T, Liu HW, Li KA.

College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.

A method has been developed for the determination of sildenafil in the medicines for erectile dysfunction by capillary electrophoresis. The samples were analyzed with 60 mmol/L NaH2PO4(pH 5.0) running buffer at 35 degrees C capillary temperature and 30 kV voltage. A linear calibration was obtained from 0.07 g/L to 1.05 g/L of sildenafil (r = 0.9985) with the RSD of 4.7% for peak area, and the average recovery was 97.4%. The results were compared with those of HPLC, showing that the method is precise, simple and cost-effective, and can be used as a complementary method to HPLC.

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Sildenafil citrate does not affect cardiac contractility in human or dog heart.

Corbin J, Rannels S, Neal D, Chang P, Grimes K, Beasley A, Francis S.

Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA. jackie.corbin vanderbilt.edu

OBJECTIVE: This study evaluated whether sildenafil citrate, an oral treatment for erectile dysfunction and a selective inhibitor of phosphodiesterase type 5 (PDE5) with modest vasodilating properties, affects cardiac contractility in vitro. Research design and methods: Slices of freshly obtained human (n = 2) or dog (n = 3) atrial appendage were suspended in organ baths containing Krebs-Ringer bicarbonate buffer (pH 7.4, 37 degrees C) bubbled continuously with 95% O2 and 5% CO2, and isometric tension was recorded using a Gould physiograph. Contractions were elicited by 1-Hz electric pacing. After 15 min of equilibration, 1 microM sildenafil was added to the bath, followed 15 min later (human and dog) by 5 microM epinephrine, an inotropic agent, and 10 min later (dog) by 88 microM 3-isobutyl-1-methylxanthine (IBMX), a nonselective PDE inhibitor. In a separate experiment, cyclic guanosine monophosphate levels and PDE, protein kinase G, and protein kinase A activities were determined. RESULTS: Addition of 1 microM sildenafil to isolated dog or human atrial tissue had no significant effect on force of cardiac contraction, whereas epinephrine produced a robust increase in contractile force in the same muscle strip. The addition of IBMX produced a marked stimulation of contractile force in dog atrial tissue. Very low amounts of PDE5 were found in extracts of human heart, consistent with its known primary location in the smooth muscle of systemic vasculature. CONCLUSIONS: Sildenafil is unlikely to directly produce inotropic effects on cardiac muscle in patients being treated for erectile dysfunction.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14687446&dopt=Abstract sildenafil Viagra online



[Sildenafil does not change coronary flow reserve in diabetics with erectile dysfunction]

[Article in German]

Dietz U, Tries HP, Merkle W, Jaursch-Hancke C, Lambertz H.

Abteilung fur Kardiologie, Deutsche Klinik fur Diagnostik, Wiesbaden. dietz.kardio dkd-wiesbaden.de

BACKGROUND AND AIM OF STUDY: Disturbance of the microvascular coronary circuit is common in diabetics with erectile dysfunction. We investigated effects of sildenafil on coronary flow reserve (CFR) of the left anterior descending branch. PATIENTS AND METHODS: 43 diabetics (aged 59 +/- 7 years) with erectile dysfunction and without symptoms of coronary artery disease were selected. Cardiac diagnosis, including stress ECG and echocardiography was performed in all. Because of the clinical suspicion of coronary artery disease coronary angiography was performed in 16 of them. Severe coronary artery disease was confirmed in 12 patients who were excluded from further analyses as well as 10 diabetics in whom coronary flow measurements were not possible. In the other 21 diabetics, adenosine-mediated CFR was calculated at baseline and 1 hour after ingestion of 50 mg sildenafil by transthoracic Doppler echocardiography. RESULTS: CFR at baseline was at the lower level of the normal range in 17/21 diabetics (median 245 %, range 210 - 490 %). CFR decreased insignificantly in 12/21 patients after sildenafil administration (Delta CFR -10 %, p = 0.3). Patients with a body mass index > 25 kg/m(2), and left ventricular hypertrophy had the highest reduction of CFR after sildenafil, but a drop of the CFR below 200 % was not observed in any patient. Systemic blood pressure dropped significantly from 130/80 mmHg to 120/72 mmHg (p < 0.002). CONCLUSION: Diabetics with erectile dysfunction often have a CFR in the lower range of normal. Sildenafil did not further reduce CFR. Asymptomatic, severe coronary artery disease often can be found in diabetics with erectile dysfunction. Cardiological screening for contraindications for sildenafil seems mandatory in diabetics with a high cardiovascular risk profile.

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