Structure determination of a sildenafil analogue contained in commercial herb drinks.

Shin C, Hong M, Kim D, Lim Y.

Bio/Molecular Informatics Center, Konkuk University, Hwayang-Dong 1, Kwangjin-Ku, Seoul 143-701, Korea.

It was found from HPLC analysis that a commercial herb drink contains a putative sildenafil analog. In order to identify the sildenafil-like compound, separation and purification were carried out. The structure determination was performed based on routine 1D and 2D NMR experiments. Unlike sildenafil, the compound contains an ethylpiperazine instead of a methylpiperazine group. In addition, the piperazine and phenyl groups are connected through an acetyl group instead of the sulfonyl group of sildenafil. Copyright 2004 John Wiley & Sons, Ltd.

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Synergistic effects of ANP and sildenafil on cGMP levels and amelioration of acute hypoxic pulmonary hypertension.

Preston IR, Hill NS, Gambardella LS, Warburton RR, Klinger JR.

Department of Pulmonary, Critical Care and Sleep Medicine, Tufts-New England Medical Center, 750 Washington Street, Box #257, Boston, MA 02111, USA.

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.

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Sildenafil citrate alleviates pulmonary hypertension after hypoxia and reoxygenation with cardiopulmonary bypass.

Lyons JM, Duffy JY, Wagner CJ, Pearl JM.

Division of Cardiothoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

BACKGROUND: Sudden reoxygenation of hypoxic neonates undergoing cardiac operation exacerbates the systemic inflammatory response to cardiopulmonary bypass secondary to reoxygenation injury, worsening cardiopulmonary dysfunction. Reports suggest sildenafil decreases pulmonary hypertension and may affect myocardial function. Sildenafil's efficacy for treating postbypass cardiopulmonary dysfunction remains unknown. STUDY DESIGN: Fourteen neonatal piglets (5 to 7 kg) underwent 90 minutes of hypoxia, 60 minutes of reoxygenation with cardiopulmonary bypass, and 120 minutes of recovery. Six animals received 50 mg oral sildenafil and eight received saline at hypoxia. Data are presented as mean +/- SD. RESULTS: Sildenafil prevented the high pulmonary vascular resistance observed in controls (controls baseline 81 +/- 37 dynes. s/cm(5) versus recovery 230 +/- 93 dynes. s/cm(5), p = 0.004; sildenafil baseline 38 +/- 17 dynes. s/cm(5) versus recovery 101 +/- 60 dynes. s/cm(5), p = 0.003). Despite lower pulmonary vascular resistance after sildenafil, arterial endothelin-1 (ET-1) was increased in both groups (control baseline 1.3 +/- 0.5 pg/mL versus recovery 4.5 +/- 3.7 pg/mL, p = 0.01; sildenafil baseline 1.3 +/- 0.3 pg/mL versus recovery 9.8 +/- 4.9 pg/mL, p = 0.003). Intravenous nitric oxide (NO) levels were preserved after sildenafil treatment (sildenafil baseline 340 +/- 77 nM versus recovery 394 +/- 85 nM). IV NO levels in controls were decreased when compared with baseline (control baseline 364 +/- 83 nM versus recovery 257 +/- 97 nM, p = 0.028). Although levels of exhaled NO decreased in both groups, the sildenafil-treated animals had higher levels of exhaled NO when compared with controls at the end of recovery (0.6 +/- 0.4 parts per billion versus 1.8 +/- 0.9 parts per billion, respectively, p = 0.029). CONCLUSIONS: Sildenafil alleviated pulmonary hypertension after reoxygenation with cardiopulmonary bypass. Despite increased ET-1 levels, pulmonary vascular resistance was lower with sildenafil treatment, suggesting sildenafil's effect on the pulmonary vasculature is capable of countering vasoconstriction by ET-1. Further study into the role of sildenafil in perioperative therapy and its interactions with ET-1 are warranted.

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Sildenafil: emerging cardiovascular indications.

Raja SG, Nayak SH.

Department of Paediatric Cardiac Surgery, Alder Hey Children's Hospital, West Derby, Liverpool, United Kingdom. drrajashahzad hotmail.com

The discovery in 1989 of sildenafil, a highly selective inhibitor of phosphodiesterase-5 (PDE-5), was the result of extensive research on chemical agents targeting PDE-5 that might potentially be useful in the treatment of coronary heart disease. Initial clinical studies on sildenafil in the early 1990s were not promising with respect to its antianginal potential. However, the incidental discovery of its antiimpotence effect led to its approval of for the treatment of erectile dysfunction. Thereafter, several reports of adverse cardiac events in patients on sildenafil raised concerns about its safety in cardiovascular disorders. Novel therapeutic indications are emerging for sildenafil with the recent discovery that PDE-5 is expressed in various other tissues such as the arterial vasculature, including pulmonary and coronary arteries, venous vasculature, skeletal muscles, platelets, and visceral and tracheobronchial muscles. In this review we briefly summarize the pharmacology of sildenafil and the current available evidence on its potential therapeutic applications in cardiovascular disorders.

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Signaling molecules in overcirculation-induced pulmonary hypertension in piglets: effects of sildenafil therapy.

Rondelet B, Kerbaul F, Van Beneden R, Motte S, Fesler P, Hubloue I, Remmelink M, Brimioulle S, Salmon I, Ketelslegers JM, Naeije R.

Laboratory of Physiology, Faculty of Medicine, Free University Brussels, Belgium.

BACKGROUND: The phosphodiesterase type-5 (PDE-5) inhibitor sildenafil has been reported to improve pulmonary arterial hypertension (PAH), but the mechanisms that account for this effect are incompletely understood. Severe pulmonary hypertension has been characterized by defects in a signaling pathway involving angiopoietin-1 and the bone morphogenetic receptor-2 (BMPR-2). We investigated the effects of sildenafil on hemodynamics and signaling molecules in a piglet overcirculation-induced model of early PAH. METHODS AND RESULTS: Thirty 3-week-old piglets were randomized to placebo or sildenafil therapy 0.75 mg/kg TID after anastomosis of the left subclavian artery to the pulmonary arterial trunk or after a sham operation. Three months later, the animals underwent a hemodynamic evaluation followed by pulmonary tissue sampling for morphometry, immunohistochemistry or radioimmunoassay, and real-time quantitative-polymerase chain reaction. Chronic systemic-to-pulmonary shunting increased pulmonary mRNA for angiopoietin-1, endothelin-1 (ET-1), angiotensin II, inducible nitric oxide synthase, vascular endothelial growth factor, and PDE-5. Pulmonary messenger RNA for BMPR-1A and BMPR-2 decreased. Pulmonary angiotensin II, ET-1, and vascular endothelial growth factor proteins increased. Pulmonary artery pressure increased from 20+/-2 to 33+/-1 mm Hg, and arteriolar medial thickness increased by 91%. The expressions of angiopoietin-1, ET-1, and angiotensin II were tightly correlated to pulmonary hypertension. Sildenafil prevented the increase in pulmonary artery pressure, limited the increase in medial thickness to 41%, and corrected associated biological perturbations except for the angiopoietin-1/BMPR-2 pathway, PDE-5, and angiotensin II. CONCLUSIONS: Sildenafil partially prevents overcirculation-induced PAH and associated changes in signaling molecules. Angiotensin II, PDE-5, and angiopoietin-1/BMPR-2 signaling may play a dominant role in the early stages of the disease.

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Absence of clinically important HERG channel blockade by three compounds that inhibit phosphodiesterase 5--sildenafil, tadalafil, and vardenafil.

Dustan Sarazan R, Crumb WJ Jr, Beasley CM Jr, Emmick JT, Ferguson KM, Strnat CA, Sausen PJ.

Lilly Research Laboratories, Eli Lilly and Company, 2001 W. Main St., Greenfield, Indianapolis, IN 46140, USA. sarazan lilly.com

Compounds that inhibit phosphodiesterase 5 (PDE5) have been developed for the treatment of erectile dysfunction. Because men with erectile dysfunction frequently have comorbid cardiovascular disease, they may have limited cardiac repolarization reserve and be at risk of arrhythmia if treated with medications that prolong ventricular repolarization. The human ether-a-go-go related gene (HERG) channel is important for repolarization in human myocardium and is a common target for drugs that prolong the QT interval. We studied the ability of three compounds that inhibit PDE5--sildenafil, tadalafil, and vardenafil--to block the HERG channel. Using a whole cell variant of the patch-clamp method, the HERG current was measured in a stably transfected human embryonic kidney cell line expressing the HERG channel. The compounds produced dose-dependent reductions in HERG current amplitude over a concentration range of 0.1 to 100 microM. The IC50 values were 12.8 microM for vardenafil and 33.3 microM for sildenafil. Because the maximum soluble concentration of tadalafil (100 microM) produced only a 50.9% inhibition of the HERG current amplitude, the IC50 value for tadalafil could not be determined with the Hill equation. Tadalafil had the weakest capacity to block the HERG channel, producing a 50.9% blockade at the maximum soluble concentration (100 microM), compared with 86.2% for vardenafil (100 microM) and 75.2% for sildenafil (100 microM). In conclusion, the concentrations of the PDE5 inhibitors required to evoke a 50% inhibition of the HERG current were well above reported therapeutic plasma concentrations of free and total compound. None of the three compounds was a potent blocker of the HERG channel.

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Selective reversal of hyperglycemia-evoked gastric myoelectric dysrhythmias by nitrergic stimulation in healthy humans.

Coleski R, Gonlachanvit S, Owyang C, Hasler WL.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA.

Acute hyperglycemia disrupts gastric myoelectric rhythm in healthy humans. Defective nitrergic function is a factor in animal models of diabetic gastropathy. We tested participation of nitrergic pathways in hyperglycemia-evoked myoelectric dysrhythmias and compared their role in preventing dysrhythmic actions of experimental motion sickness. Twelve healthy volunteers underwent electrogastrography (EGG) with and without intravenous 20% dextrose to produce plasma glucoses of 250 mg/dl. EGG continued for 2 h after oral nitroglycerin (9 mg) or the cyclic GMP-specific phosphodiesterase inhibitor sildenafil (100 mg). In separate studies, 12 volunteers underwent circular vection (60 degrees /s) without and 90 min after nitroglycerin (9 mg) or sildenafil (100 mg) with concurrent EGG. Hyperglycemia decreased recording time in normal rhythm, increased tachygastria more than 3-fold, and decreased power of the dominant frequency (P < 0.05). Nitroglycerin and sildenafil reversed effects of hyperglycemia, improving normal rhythm, decreasing tachygastria (both P < 0.05), and blunting power decreases. Neither agent affected EGG rhythm during euglycemia. Vection decreased time in normal rhythm and increased tachygastria (P < 0.05). However, nitroglycerin and sildenafil did not reverse dysrhythmic effects of vection (P = N.S.). In conclusion, administration of a nitric oxide (NO) donor or an inhibitor of cyclic GMP-selective phosphodiesterase reverses the dysrhythmic effects of hyperglycemia on gastric myoelectric activity in healthy humans. These agents have no effect on dysrhythmias during motion sickness. These findings are consistent with selective impairment of nitrergic function in this model of diabetic gastropathy and suggest that NO donors and other agents that increase NO activity may be useful for treating diabetic dysrhythmias.

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[The positive effect of sildenafil on LUTS from BPH while treating ED]

[Article in Chinese]

Ying J, Yao D, Jiang Y, Ren X, Xu M.

Department of Urology, Shanghai Ninth People's Hospital Affiliated to Shanghai Second Medical University, Shanghai 200011, China.

OBJECTIVE: To explore the possible relationship between erectile dysfunction (ED) and benign prostate hyperplasia (BPH) in men, and to assess the positive effect of Sildenafil on the lower urinary tract symptoms (LUTS) from BPH while treating ED. METHODS: Thirty-two patients with ED and BPH were offered oral Sildenafil and reviewed before and six months after the administration of Sildenafil by the International Index of Erectile Function-5 (IIEF-5) and the International Prostate Symptom Score (IPSS) questionnaires. Scores were tested by chi-square. RESULTS: IIEF-5 scores were increased by 42.36% and IPSS scores declined by 20.14%, with statistical significance (P < 0.01). CONCLUSION: Treatment of ED with Sildenafil appears to improve urinary symptom scores. A lower IPSS at baseline seems to predict a better response to Sildenafil therapy for ED.

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