Effects of sildenafil analogue UK 343-664 on a porcine model of acute pulmonary hypertension.

Bonnell MR, Urdaneta F, Kirby DS, Valdez NR, Beaver TM, Lobato EB.

Department of Surgery and Anesthesiology, University of Florida, College of Medicine, Gainesville, Florida 32610-0254, USA.

BACKGROUND: Sildenafil (Pfizer Pharmaceuticals, Sandwich, Kent, UK) has been associated with pulmonary vasorelaxation. A more potent Sildenafil analogue (UK 343-664 [Pfizer Pharmaceuticals]) has been developed, but its effects in vivo have not been studied. This study evaluated the effects of UK 343-664 (Pfizer) during acute pulmonary hypertension. METHODS: Fourteen adult swine were anesthetized with 1 minimum alveolar concentration isoflurane and were mechanically ventilated with an FIO(2) of 50%. End tidal CO(2) was maintained between 32 and 36 mm Hg. Micromanometer tipped catheters were placed in the ascending aorta, pulmonary artery, and right ventricle. Pulmonary flow was measured with a perivascular probe using transit time ultrasound. RESULTS: Pulmonary hypertension was induced with a continuous infusion of the thromboxane analogue U46619. Animals were randomized into two groups. Group 1 (n = 9) received 500 microg of UK 343-664 (Pfizer) intravenously for more than 2 minutes. Group 2 (n = 5) served as the control group. Data were recorded continuously for 60 minutes. Statistical analyses were performed with the analysis of variance and t tests. A p less than 0.05 was considered significant.Pulmonary hypertension was achieved in all animals. The administration of UK 343-664 (Pfizer) was associated with a significant decrease in pulmonary artery pressure (30.3%; p < 0.05) and pulmonary vascular resistance (42%; p < 0.05) with mild systemic vasodilatation. These effects were partially maintained at 30 minutes (a 17.3% and 39% decrease, respectively; p < 0.05). CONCLUSIONS: The administration of UK 343-664 (Pfizer) was associated with predominant pulmonary vasodilatation without systemic hypotension. This may represent a significant advance in the treatment of acute pulmonary hypertension. Potential clinical implications for this new phosphodiesterase enzyme type V (PDEV) inhibitor merit further study.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14726068&dopt=Abstract sildenafil Viagra online



Increasing intracellular cAMP and cGMP inhibits cadmium-induced oxidative stress in rat submandibular saliva.

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

Department of Toxicology and Pharmacology, Tehran University of Medical Science, Tehran 14155-6451, Iran. mohammad.abdollahi utoronto.ca

The effect of cadmium on induction of oxidative stress in rat submandibular saliva and protective role of increasing intracellular cAMP and cGMP by use of specific phosphodiesterase inhibitors, theophylline and sildenafil were investigated. Pure submandibular saliva was collected intraorally by micro polyethylene cannula from anaesthetized rats using pilocarpine as secretagogue. Acute administration of cadmium (10 mg/kg) caused significant oxidative stress by increasing lipid peroxidation by-products (thiobarbituric reactive substances, TBARS) and decreasing total thiols and total antioxidant power of the saliva. Concurrent therapy of rats by theophylline (25 mg/kg) and sildenafil (5 mg/kg) prevented cadmium-induced oxidative stress in saliva. Theophylline and sildenafil inhibited cadmium-induced increase in lipid peroxidation and decrease in total thiols and antioxidant power. It is concluded that cadmium administration results in oxidative stress in rat submandibular saliva, which can be protected by concurrent administration of specific cyclic nucleotide phosphodiesterase inhibitors.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12927907&dopt=Abstract sildenafil Viagra online



[Assessment of curative effect on erectile dysfunction of two drugs]

[Article in Chinese]

Yang DZ, Ma XN, Yu ZJ, Jiao Y.

Department of Sexual Medicine, No 402 Hospital, Ministry of Electronic Industry, Beijing 100039, China.

OBJECTIVES: To further discuss the method of evaluating curative effect on erectile dysfunction(ED). METHODS: Clinical trials(Phase II) of sildenafil and phentolamine were both 8-week-long, randomized, double-blind and placebo-controlled. Not only the curative effect between each treatment group and placebo group but also between the treatment groups were compared. The dosage of sildenafil and phentolamine was respectively 50-100 mg and 40 mg. RESULTS: Efficiency, success rate of sexual intercourse and general curative effect in sildenafil and phentolamine groups were respectively 79.17%, 75.00%, 83.33% and 52.38%, 85.71%, 52.38%. The result revealed a statistically significant (P < 0.05) improvement over placebo. But no obvious differences were shown between the two treatment groups(P > 0.05). CONCLUSIONS: Most assessments of curative effect of ED drugs come from questionnaires answered subjectively by patients. The Lack of objective assessment criteria way lead to the non-conformity between trial results and clinical practices. So the curative effect of drugs shall be assessed more accurately and from more perspectives.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12931365&dopt=Abstract sildenafil Viagra online



[Clinical study of sildenafil in the treatment of premature ejaculation complicated by erectile dysfunction]

[Article in Chinese]

Li X, Zhang SX, Cheng HM, Zhang WD.

Department of Urology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.

OBJECTIVES: To evaluate the efficacy and safety of sidenafil citrate in the treatment of premature ejaculation (PE) complicated by erectile dysfunction (ED). METHODS: Forty-five patients of PE complicated by ED received flexible doses of sildenafil from 50 to 100 mg for 1 to 3 months. Intravaginal ejaculatory latency time (IELT) and sexual satisfaction ratio (SSR) of partner were recorded to evaluate the effect of PE treatment, as well as the general efficacy and satisfaction of ED treatment. And the difference of IIEF-5 before and after the treatment were compared. RESULTS: Twenty-seven patients had their PE improved and the effective rate was 60%. Forty patients reported the improvement in erection and the percentage of erectile improvement was 88.88%. All the 27 patients with improvement of PE achieved effective erection through the administration of 50 mg sildenafil and the satisfaction rate reached 81.48%. On the other hand, only 1 case (5.56%) reported satisfaction over the treatment in the 18 patients who did not obtain improvement of PE. Between the PE improvement group and non-improvement group, there were significant differences (P < 0.001) shown in IIEF-5 scores before and after the treatment. Mild or moderate side effects were reported in 9 patients(20%), who recovered without any treatment. CONCLUSIONS: To premature ejaculation patients with ED, sildenafil can safely and effectively improve their erectile function, the satisfaction over the ED treatment outcome means that their PE symptoms could be alleviated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12931367&dopt=Abstract sildenafil Viagra online



Augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Volke V, Wegener G, Vasar E.

Department of Physiology, University of Tartu, Tartu, Estonia. vallov ut.ee

Several studies have reported the anxiolytic-like effects of various nitric oxide synthase inhibitors in distinct animal models. However, in the context of anxiety, the possible involvement of cyclic GMP, believed to be one of the main targets of NO, remains obscure. Cyclic GMP is degraded by the specific phosphodiesterases in the brain. Therefore, we studied the effect of the selective phosphodiesterase type 5 inhibitor sildenafil in the mouse elevated plus-maze test of anxiety and in the open field test of locomotion. We found that sildenafil (0.05-10 mg/kg i.p.) alone did not affect the behavior of animals in the plus-maze or open field tests, but the anxiogenic beta-carboline DMCM given in a subconvulsive dose (2 mg/kg i.p.) decreased the time spent on open arms in the elevated plus-maze. Treatment with the NO precursor L-arginine (200 mg/kg i.p.) did not modify the behavior of animals in the plus-maze, however, when sildenafil (1 mg/kg i.p.) was administered in combination with L-arginine (200 mg/kg i.p.), both the time spent on the open arms and the percentage of open arm visits were significantly decreased. We conclude that augmentation of the NO-cGMP cascade induces anxiogenic-like effect in mice.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14726618&dopt=Abstract sildenafil Viagra online



Sildenafil prevents change in RhoA expression induced by chronic hypoxia in rat pulmonary artery.

Sauzeau V, Rolli-Derkinderen M, Lehoux S, Loirand G, Pacaud P.

Inserm U-533, Faculte des Sciences, Nantes, France.

Exposure to chronic hypoxia (CH) induces a sustained pulmonary hypertension associated with structural and functional changes in the pulmonary arterial bed, including alterations of contractile properties. The small G-protein RhoA and its effector Rho kinase play a major role in the sustained rise in tension induced by vasoconstrictors. The aim of this study was to analyze the effect of CH on the RhoA/Rho kinase signaling pathway in the rat pulmonary artery. Maximal contraction of pulmonary artery rings to endothelin-1, noradrenaline, and the thromboxane A2 analog U46619 was markedly decreased in rats exposed to CH (10% O2, 2 weeks). This CH-induced decrease response to agonists was attributable to the abolition of RhoA-mediated Ca2+ sensitization of the contraction. Real-time reverse transcriptase-polymerase chain reaction and Western blot analysis revealed a decrease in RhoA mRNA (79.4+/-6.0%, n=4) and RhoA (81.1+/-8.0%, n=4) expression in the main pulmonary artery from CH rats, whereas RhoA expression was not modified in arterial smooth muscle cells and arteries exposed to hypoxia and high intraluminal pressure, respectively. Treatment of rats with sildenafil (25 mg/kg per day) throughout 2 weeks of exposure to CH prevented CH-induced downregulation of RhoA, reduction of contraction, and pulmonary artery remodeling. These findings indicate that CH-induced downregulation of RhoA expression, leading to the abolition of RhoA/Rho kinase-mediated Ca2+ sensitization of contraction, is responsible for the decreased responses to contracting agonists in the pulmonary artery of CH rats. These alterations are prevented by sildenafil, indicating a major role of the NO/cyclic GMP pathway in CH-induced altered RhoA signaling in the pulmonary artery.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12946946&dopt=Abstract sildenafil Viagra online



Coronary artery flow reserve in diabetics with erectile dysfunction using sildenafil.

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

Department of Cardiology, German Clinic for Diagnostics, Wiesbaden, Germany. dietz.kardio dkd-wiesbaden.de

BACKGROUND: Diabetics with erectile dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR). PURPOSE: We aimed to evaluate the effects of the phosphodiesterase 5 inhibitor sildenafil on CFR in diabetics with erectile dysfunction. METHODS: Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic erectile dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50-69) had known diabetes for 11 years (3-30) and a BMI of 27 kg/m2 (24-36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography. RESULTS: Baseline CFR was at the lower level of the normal range (median 245%, range 210 - 490%). After sildenafil administration, CFR decreased insignificantly (DeltaCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002). CONCLUSIONS: Diabetics with erectile dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance. Sildenafil did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications for sildenafil.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12952551&dopt=Abstract sildenafil Viagra online



Hemodynamic effects of sildenafil in patients with stable ischemic heart disease.

Manfroi WC, Caramori PR, Zago AJ, Melchior R, Zen V, Accordi M, Gutierres D, Noer C.

Unidade de Hemodinamica, Servico de Cardiologia, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. wmanfroi terra.com.br

BACKGROUND: Recently the new specific phosphodiesterase-5 inhibitor sildenafil was introduced into therapy for erectile dysfunction. The hemodynamic effects of sildenafil may be potentially hazardous for patients with cardiac disease. Sildenafil has been reported to augment the hypotensive effects of nitrates. There is sparse information regarding the systemic and pulmonary hemodynamic effects of a single oral dose of sildenafil in patients with stable angina. METHODS: Male patients referred for coronary angiography with diagnosis of chronic stable angina were enrolled in this study to assess the acute hemodynamic effects of sildenafil. Patients receiving long-acting or sublingual nitrates for the last 6 h before the study were excluded. Hemodynamic measurement were taken during right and left heart catheterization in the basal state and 60 min after 50 mg of oral sildenafil. RESULTS: Twelve patients (age 53+/-7 years) were studied. All had stable angina CCS class II or III. Four had previous myocardial infarction. By coronary angiography, seven patients had at least one coronary artery with >70% stenosis, four had at least one with 50-70% stenosis, and one had only intimal irregularities. There were no significant effects of sildenafil on systemic or pulmonary arterial pressure, left ventricle end diastolic pressure, cardiac output, and systemic or pulmonary vascular resistance (P>0.05 for all). No adverse events were observed. CONCLUSION: A single oral dose of sildenafil had no significant hemodynamic effect in supine patients with stable angina. Isolated administration of sildenafil does not appear to be associated to adverse cardiovascular effects.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12957746&dopt=Abstract sildenafil Viagra online