vardenafil-dihydrochloride and Hypertension--Pulmonary

Topics: Antihypertensive Agents; Contraindications; Coronary Disease; Drug Interactions; Drug Therapy, Combination; Erectile Dysfunction; Female; Humans; Hypertension, Pulmonary; Hypotension; Imidazoles; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

The pathology of pulmonary arterial hypertension (PAH) is characterized by vascular vasoconstriction, smooth muscle cell proliferation, and thrombosis. Experimental studies have shown the beneficial effect of phosphodiesterase type 5 (PDE-5) inhibitors on pulmonary vascular remodeling and vasodilatation. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil which significantly improve clinical status, exercise capacity and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in management of PAH. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia.

Topics: Carbolines; Drug Therapy, Combination; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Vardenafil is a short-acting PDE5 inhibitor used in the treatment of male erectile dysfunction. It is the most potent and specific of the three commercially available PDE5 inhbitors, which may decrease incidence of side effects, although this has not been demonstrated clinically. Although its efficacy in the treatment of erectile dysfunction has been demonstrated in several studies, recent and continuing studies have shown vardenafil's promise as an effective agent in penile rehabilitation, decreasing lower urinary tract symptoms resulting from benign prostatic hyperplasia and management of pulmonary hypertension.

Topics: Animals; Erectile Dysfunction; Humans; Hypertension, Pulmonary; Imidazoles; Male; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Prostatic Hyperplasia; Sulfones; Triazines; Vardenafil Dihydrochloride

Pulmonary arterial hypertension (PAH) is a rare disease characterized by vascular proliferation and remodeling, resulting in a progressive increase in pulmonary arterial resistance, right heart failure, and death. The pathogenesis of PAH is multifactorial, with endothelial cell dysfunction playing an integral role. This endothelial dysfunction is characterized by an overproduction of vasoconstrictors and proliferative factors, such as endothelin-1, and a reduction of vasodilators and antiproliferative factors, such prostacyclin and nitric oxide. Phosphodiesterase type 5 (PDE-5) is implicated in this process by inactivating cyclic guanosine monophosphate, the nitric oxide pathway second messenger. PDE-5 is abundantly expressed in lung tissue, and appears to be upregulated in PAH. Three oral PDE-5 inhibitors are available (sildenafil, tadalafil, and vardenafil) and are the recommended first-line treatment for erectile dysfunction. Experimental studies have shown the beneficial effects of PDE-5 inhibitors on pulmonary vascular remodeling and vasodilatation, justifying their investigation in PAH. Randomized clinical trials in monotherapy or combination therapy have been conducted in PAH with sildenafil and tadalafil, which are therefore currently the approved PDE-5 inhibitors in PAH treatment. Sildenafil and tadalafil significantly improve clinical status, exercise capacity, and hemodynamics of PAH patients. Combination therapy of PDE-5 inhibitors with prostacyclin analogs and endothelin receptor antagonists may be helpful in the management of PAH although further studies are needed in this area. The third PDE-5 inhibitor, vardenafil, is currently being investigated in PAH. Side effects are usually mild and transient and include headache, flushing, nasal congestion, digestive disorders, and myalgia. Mild and moderate renal or hepatic failure does not significantly affect the metabolism of PDE-5 inhibitors, whereas coadministration of bosentan decreases sildenafil and tadalafil plasma levels. Due to their clinical effectiveness, tolerance profile, and their oral administration, sildenafil and tadalafil are two of the recommended first-line therapies for PAH patients in World Health Organization functional classes II or III.

Topics: Algorithms; Carbolines; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Veno-Occlusive Disease; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

The therapeutic effects of phosphodiesterase type 5 inhibitors in patients with pulmonary arterial hypertension (PAH) were reviewed. A double-blind, placebo-controlled study named SUPER-1 showed that sildenafil improved exercise capacity, WHO functional class, hemodynamics, and quality of life. Two randomized, double-blind, crossover studies, showed that sildenafil improved exercise tolerance and quality of life, and reduced estimated pulmonary artery systolic pressure. The dose independent effects of sildenafil on PAH are controversial. There are few case-reports that show vardenafil and tadalafil have benefits in PAH patients. A double-blind study of tadalafil in PAH patients is ongoing.

Topics: Carbolines; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride

Phosphodiesterase-5 inhibitors (PDE5I) are an important new class of drugs in the treatment of pulmonary artery hypertension (PHT). Sildenafil, a selective PDE5I, through its action on the NO/cGMP signal pathway, causes a selective reduction of pulmonary vascular resistance and improves symptoms and exercise capacity of patients with PHT. The phase III trial (SUPER-1) has clearly shown the efficacy and safety of sildenafil in PHT so that its use for this indication has recently been approved. Current guidelines of several large specialist societies have included sildenafil for the treatment of PHT, supported by a high degree of evidence. Sildenafil can also be combined with other drugs and has the potential of being efficacious also in other forms of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypertension, Pulmonary; Imidazoles; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Topics: Bosentan; Child; Drug Therapy, Combination; Endothelin Receptor Antagonists; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Postoperative Complications; Randomized Controlled Trials as Topic; Vardenafil Dihydrochloride

We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine.. ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min.. A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45 min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60 min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed.. Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Arginine; Atrial Function, Right; Atrial Pressure; Biomarkers; Cardiac Output; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Time Factors; Treatment Outcome; Vardenafil Dihydrochloride; Vasodilator Agents

Acute vasodilator testing is recommended in patients with pulmonary arterial hypertension to identify individuals who may benefit from long-term treatment with oral calcium channel blockers. The aim of this study was to investigate the use of vardenafil in acute vasoreactivity testing compared to adenosine.. A total of 20 patients eligible for right heart catheterisation were enrolled. Acute vasoreactivity testing was carried out with intravenous (iv) adenosine (n = 18) followed by oral vardenafil (n = 20). Haemodynamic responses were recorded at baseline and after 60 min (vardenafil). Responders were defined according to consensus guideline criteria.. Both vardenafil and adenosine significantly decreased mean pulmonary arterial pressure (mPAP, p < 0.001 and p = 0.026, respectively) and pulmonary vascular resistance (p < 0.001 and p > 0.001, respectively), and significantly increased cardiac output (p = 0.001 and p = 0.005, respectively). Vardenafil reduced mPAP more than adenosine (p = 0.044), while adenosine resulted in higher responses of cardiac index (p = 0.009) and pulmonary arterial oxygen saturation (p = 0.042). Acute adverse reactions were common with adenosine, while no side effects were observed after a single oral dose vardenafil. Vardenafil identified five responders (out of 20), while adenosine identified three responders (out of 18). During a 7-year follow-up, vardenafil responders had significantly lower NT-proBNP levels compared to non-responders.. Vardenafil may be safely used for acute vasoreactivity testing in patients with PH. A single oral dose of vardenafil is better tolerated than iv adenosine and may identify additional responders who could benefit from long-term vasodilator treatment.

Topics: Adenosine; Adult; Aged; Blood Gas Analysis; Cardiac Catheterization; Drug Administration Routes; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Vardenafil Dihydrochloride; Vasodilator Agents

To evaluate the pharmacokinetic parameters of a single oral dose of vardenafil in patients with pulmonary hypertension (PH).. Sixteen patients with PH received vardenafil in single oral doses (20, 10 or 5 mg), and repeated blood sampling for up to 9 h was performed. Vardenafil plasma concentration was determined using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were calculated using model-independent analysis.. The plasma vardenafil concentration increased rapidly and exhibited a median time to maximum plasma concentration (t(max)) of 1 h and a mean elimination half-life (t(1/2)) of 3.4 h. The geometric mean and standard deviation of (1) the peak plasma concentration (C(max)) was 21.4 ± 1.7 μg/L, (2) the normalized C(max) (C(max, norm)) 79.1 ± 1.6 g/L, (3) the area under the time-concentration curve (AUC) 71.5 ± 1.6 μg · h/L and (4) the normalized AUC (AUC(norm)) 261.6 ± 1.7 g · h/L. Patients co-medicated with bosentan reached t(max) later and had a 90% reduction of C(max), C(max, norm), AUC and AUC(norm).. The pharmacokinetic profile of vardenafil overall revealed considerable inter-individual variability in patients with PH. Co-medication with bosentan resulted in a pharmacokinetic drug interaction, leading to significantly decreased plasma concentrations of vardenafil. Therapeutic drug monitoring for individual dose optimization may be warranted.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events.. To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH.. In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks.. At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events.. Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

Topics: Adolescent; Adult; Double-Blind Method; Female; Heart; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Pressoreceptors; Pulmonary Circulation; Sulfones; Treatment Outcome; Triazines; Vardenafil Dihydrochloride; Vascular Resistance; Vasodilator Agents; Walking

We sought to compare the short-term impact of three different phosphodiesterase-5 (PDE5) inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with pulmonary arterial hypertension (PAH).. The PDE5 inhibitor sildenafil has been reported to cause pulmonary vasodilation in patients with PAH. Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for the treatment of erectile dysfunction.. Sixty consecutive PAH patients (New York Heart Association functional class II to IV) who underwent right heart catheterization received short-term nitric oxide (NO) inhalation and were subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7) or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8) tadalafil. Hemodynamics and changes in oxygenation were assessed over a subsequent 120-min observation period.. All three PDE5 inhibitors caused significant pulmonary vasorelaxation, with maximum effects being obtained after 40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil). Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in the pulmonary to systemic vascular resistance ratio. Significant improvement in arterial oxygenation (equally to NO inhalation) was only noted with sildenafil.. In PAH patients, the three PDE5 inhibitors differ markedly in their kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), and their impact on arterial oxygenation (improvement with sildenafil only). Careful evaluation of each new PDE5 inhibitor, when being considered for PAH treatment, has to be undertaken, despite common classification as PDE5 inhibitors.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Adult; Aged; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Administration Schedule; Enzyme Inhibitors; Female; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Oxygen; Phosphoric Diester Hydrolases; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Treatment Outcome; Triazines; Vardenafil Dihydrochloride; Vascular Resistance; Vasodilator Agents

Pulmonary arterial hypertension is characterized by pulmonary vascular proliferation and remodelling, leading to a progressive increase in pulmonary arterial resistance. Vasodilator properties of 3 different phosphodiesterase (PDE)-5 inhibitors alone and in combination with an endothelin (ET) receptor antagonist were compared in an ex vivo model.. Segments of human pulmonary arteries (PAs) and pulmonary veins (PVs) were harvested from lobectomy specimens. Contractile forces were determined in an organ bath. Vessels were constricted with norepinephrine (NE) to determine the effects of sildenafil, tadalafil and vardenafil and with ET-1 to assess the effects of bosentan.. All 3 PDE-5 inhibitors had no relevant effect on the basal tone of the vessels. Both sildenafil and vardenafil significantly (P < 0.0001) reduced the responses of the vessels to NE, whereas tadalafil was effective only in PA (P = 0.0009) but not in PV (P = 0.097). Sildenafil relaxed NE-preconstricted PV (P < 0.0001) but not PA (P = 0.143). Both tadalafil and vardenafil relaxed PA and PV significantly. Vardenafil appears to be the most potent of the PDE-5 inhibitors tested. Furthermore, we analysed the combination of bosentan and vardenafil in PA. Bosentan and vardenafil reduced ET-1 and NE induced vasoconstriction stronger than vardenafil alone (P ≤ 0.049).. Vardenafil caused the most consistent antihypertensive response in this ex vivo model. However, ET receptor antagonism appears to be an even more potent mechanism. A combination therapy using vardenafil and bosentan turned out to be an effective combination to lower vessel tension in PA.

Topics: Antihypertensive Agents; Bosentan; Dose-Response Relationship, Drug; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Veins; Sildenafil Citrate; Sulfonamides; Tadalafil; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Oxidative stress is implicated in the pathology of pulmonary arterial hypertension (PAH). Previously, we demonstrated that vardenafil, a phosphodiesterase-5 inhibitor, has potential as therapy for PAH, although the mechanism remained uncharacterized. Here, we aimed to determine baseline levels of oxidative stress in PAH and investigate whether vardenafil affects oxidative stress levels while improving PAH.. Sprague-Dawley rats with monocrotaline-induced PAH were administered oral vardenafil 1 mg kg⁻¹ day⁻¹ for 21 days (n = 12). Treatment-naive patients (n = 15) with PAH were treated with vardenafil 5 mg twice daily for 3 months. Haemodynamic data and plasma levels of nitrate/nitrite and products of oxidative damage were determined in rats and patients. Histopathology, immunohistochemistry, and assessments of oxidative/anti-oxidative enzyme expression were performed in rat lung tissue. Compared with baseline (patients) or untreated controls (rats), vardenafil significantly reduced pulmonary vascular resistance and increased cardiac output (CO). In rats, vardenafil suppressed proliferation and enhanced apoptosis of pulmonary artery smooth muscle cells, attenuating small pulmonary artery remodelling, and right ventricular hypertrophy. Vardenafil significantly reduced levels of oxidative stress biomarkers, such as 8-iso-prostaglandin-F2α and 3-nitrotyrosine, and significantly increased nitric oxide (NO) levels in rats and patients. Furthermore, vardenafil significantly increased endothelial NO synthase expression and superoxide dismutase activity, and down-regulated nicotinamide adenine dinucleotide phosphate oxidase expression in rat lung tissue.. Vardenafil reduces oxidative stress in rats and humans while improving PAH, warranting investigation of oxidative stress pathways as targets for PAH therapy.

Topics: Adolescent; Adult; Animals; Case-Control Studies; Cell Proliferation; Disease Models, Animal; Familial Primary Pulmonary Hypertension; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Male; Monocrotaline; Nitric Oxide; Oxidative Stress; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Sulfones; Triazines; Vardenafil Dihydrochloride; Young Adult

Vardenafil, a phosphodiesterase-5 inhibitor, is approved for the therapy of erectile dysfunction. However, in contrast to Sildenafil and Tadalafil, little is known about its effects on pulmonary hypertension. Four weeks after monocrotaline-administration rats exhibited a significant increase in right ventricular pressure (RVSP, 94mmHg vs. 25mmHg; p=0.001) right ventricular weight (right ventricle/left ventricle+septum, 59 vs. 23; p=0.001) and pulmonary vascular remodeling (medial wall area 104% vs. 66%; p<0.05) as compared to controls, with a corresponding reduction in exercise capacity (% from baseline value: 67%; p<0.05). Vardenafil treatment resulted in decreased RVSP (56mmHg vs. 95mmHg; p=0.008), right ventricular weight (41 vs. 59; p=0.013), pulmonary vascular remodeling (medial wall area 64% vs. 104%; p<0.05) and a significant better exercise capacity (% from baseline value: 84% vs. 67%; p<0.05) compared to monocrotaline only treated animals. In conclusion, Vardenafil exerts beneficial effects on monocrotaline-induced pulmonary hypertension in rats. Whether it is a treatment option for patients with pulmonary hypertension needs to be elucidated.

Topics: Animals; Disease Models, Animal; Hypertension, Pulmonary; Imidazoles; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Physical Conditioning, Animal; Piperazines; Rats; Rats, Wistar; Sulfones; Triazines; Vardenafil Dihydrochloride

To evaluate the acute haemodynamic effects of a single oral dose of vardenafil and to study the drug concentration in relation to haemodynamic effects in patients with pulmonary hypertension (PH).. Sixteen patients with PH (aged 29-85\\ years), received one single oral dose of vardenafil (5, 10 or 20 mg). The haemodynamic effect was assessed over a 60 min period. Vardenafil plasma concentrations were measured after 15, 30, 45 and 60 min using liquid chromatography-tandem mass spectrometry.. At 60 min a reduction in mPAP with a median % decrease of -20.3% (range -48.3 to 3.0; P < 0.001) and an increase in cardiac output and the cardiac index with a median % change of 10.6% (range -25.0 to 88.1; P = 0.015) and 12.1% (range -24.0 to 94.4; P = 0.01) respectively was observed. The pulmonary vascular resistance (PVR) was reduced with a median % decrease of -28.9% (range -61.5 to -5.9; P < 0.001), and pulmonary selectivity was reflected by a median percent reduction of -16.9% (range -49.0 to 16.5; P = 0.002; n = 14) in the PVR/systemic vascular resistance ratio. There was a correlation between the plasma concentrations of vardenafil and change in mPAP (r = -0.579, P = 0.019) and between vardenafil concentrations and change in PVR (r = -0.662, P = 0.005).. Vardenafil causes rapid changes in cardiopulmonary haemodynamics and there is a correlation between plasma vardenafil drug concentration and the acute changes in mPAP as well as PVR in patients with PH.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Cardiac Output; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Piperazines; Pulmonary Circulation; Statistics as Topic; Sulfones; Tandem Mass Spectrometry; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Phosphodiesterase type-5 (PDE-5) inhibitors are novel and important options for the treatment of pulmonary arterial hypertension (PAH). Therefore, we aimed to examine effects of vardenafil, a PDE-5 inhibitor, on the pulmonary arteries isolated from rats with monocrotaline- (MCT-) induced pulmonary hypertension. MCT (60 mg/kg) or its vehicle was administered by a single intraperitoneal injection to 6-week-old male Sprague Dawley rats. Rats were sacrificed 21 days after MCT injection, and the main pulmonary arteries were isolated and then mounted in 20 mL organ baths. Concentration-response curves for vardenafil (10(-10)-10(-5) M) were constructed in phenylephrine- (Phe-) precontracted rings. PAH caused marked rightward shift in the curves to vardenafil whereas maximal responses were not affected. Inhibition of NO synthase (L-NAME, 10(-4) M) or guanylyl cyclase (ODQ, 10(-5) M) caused similar attenuation in responses evoked by vardenafil. Moreover, contraction responses induced by CaCl(2) (3 × 10(-5)-3 × 10(-2) M) were significantly reduced in concentration-dependent manner by vardenafil. In conclusion, vardenafil induced pulmonary vasodilatation via inhibition of extracellular calcium entry in addition to NO-cGMP pathway activation. These results provide evidence that impaired arterial relaxation in PAH can be prevented by vardenafil. Thus, vardenafil represents a valuable therapeutic approach in PAH besides other PDE-5 inhibitors.

Topics: Animals; Hypertension, Pulmonary; Imidazoles; Male; Monocrotaline; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Artery; Rats; Sulfones; Triazines; Vardenafil Dihydrochloride

Vardenafil has been found to be potent in pulmonary hypertension; however, the underlying mechanisms remain poorly understood. To address this issue, we investigated the underlying mechanisms of vardenafil in the contribution of Ca(2+) signaling and mobilization in modifying vasoconstriction of pulmonary arteries in hypoxic mice.. Hemodynamic measurements and morphological studies were performed. Muscle tension was measured by PowerLab system. I(Ca,L) was recorded using a perforated patch-clamp technique. [Ca(2+)](i) was measured using a fluorescence imaging system.. Vardenafil greatly inhibited RVSP increases, RV hypertrophy and ameliorated pulmonary artery remodeling in response to chronic hypoxia. Membrane depolarization following 50 mM high K(+)-caused muscle contraction significantly decreased from 101.7 ± 10.1 in the hypoxia group to 81.8 ± 5.0 mg in hypoxia plus vardenafil arteries. Fifty mM high K(+)-elicited increase [Ca(2+)](i) was markedly decreased from 610.6 ± 71.8 in hypoxia cells to 400.3 ± 47.2 nM in hypoxia plus vardenafil cells. Application of vardenafil greatly inhibited the density of I(Ca,L) by 37.7% compared with that in the hypoxia group. Administration of 1 μM phenylephrine to stimulate α(1)-adrenergic receptor resulted in a smaller increase in [Ca(2+)](i) in hypoxia plus vardenafil cells than that in hypoxia cells. One hundred μM ATP-mediated increase in [Ca(2+)](i) was also inhibited in vardenafil-hypoxia group (from 625.8 ± 62.3 to 390.9 ± 38.1 nM), suggesting that internal calcium reserves contribute to neurotransmitter-induced Ca(2+) release from the SR through IP(3)Rs in PASMCs.. Vardenafil may effectively block Ca(2+) influx through L-type Ca(2+) channel and inhibit the Ca(2+) release from SR through IP(3)Rs, thus enhancing its vasorelaxation of pulmonary arteries under hypoxia conditions.

Topics: Adenosine Triphosphate; Adrenergic alpha-Agonists; Animals; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Chronic Disease; Drug Evaluation, Preclinical; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Imidazoles; Inositol 1,4,5-Trisphosphate Receptors; Ion Transport; Male; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Phenylephrine; Piperazines; Potassium; Sarcoplasmic Reticulum; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilation; Vasodilator Agents

Phosphodiesterase type 5 inhibitors such as sildenafil, vardenafil, and tadalafil are a class of drugs used primarily in the treatment of erectile dysfunction. Sildenafil and tadalafil are also approved for the treatment of pulmonary hypertension. The aim of this study was to develop and validate a procedure for the detection and quantification of these 3 drugs and some of their metabolites in human blood plasma.. After liquid-liquid extraction of 0.5 mL of blood plasma using diethyl ether-ethyl acetate (1:1), the analytes sildenafil, norsildenafil, vardenafil, norvardenafil, and tadalafil were separated using a Shimadzu Prominence High-Performance Liquid Chromatography System (C18 separation column, gradient elution, and a total flow of 0.5 mL/min). They were detected using an AB Sciex 3200 Q-Trap LC-MS-MS System (electrospray ionization and multiple reaction monitoring mode). The method was fully validated according to international guidelines.. The assay was found to be selective for the tested compounds. It was linear from 5 to 1000 ng/mL for sildenafil, from 2 to 700 ng/mL for norsildenafil, from 0.5 to 350 ng/mL for vardenafil, from 0.5 to 200 ng/mL for norvardenafil, and from 5 to 1000 ng/mL for tadalafil. The recoveries were generally more than 50%. Matrix effects were not observed. Accuracy, repeatability, and intermediate precision were within the required limits (<15% or <20% near the limit of quantification). No instability was observed after repeated freezing and thawing or in processed samples.. A liquid chromatography-tandem mass spectrometry assay for the determination of sildenafil, norsildenafil, vardenafil, norvardenafil, and tadalafil in human blood plasma was developed and validated. It has proven to be selective, linear, accurate, and precise for all studied drugs. The method has also proven to be applicable for forensic cases and for therapeutic drug monitoring.

Topics: Adult; Aged; Antihypertensive Agents; Biotransformation; Carbolines; Chromatography, High Pressure Liquid; Drug Monitoring; Familial Primary Pulmonary Hypertension; Forensic Toxicology; Humans; Hypertension, Pulmonary; Imidazoles; Limit of Detection; Male; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Reproducibility of Results; Sildenafil Citrate; Spectrometry, Mass, Electrospray Ionization; Sulfones; Tadalafil; Tandem Mass Spectrometry; Triazines; Vardenafil Dihydrochloride

Vardenafil is a new phosphodiesterase-5 inhibitor that has shown some efficacy in the treatment of pulmonary arterial hypertension (PAH).. To examine the long-term effects of vardenafil in patients with PAH.. A multicentre, open-label study of 1-year's duration was undertaken in 45 patients with PAH to determine the long-term safety and efficacy of vardenafil (5 mg once daily for the first 4 weeks, then 5 mg twice daily) and make a preliminary assessment of its monthly acquisition cost compared with other PAH-active treatments. The patients' clinical features, exercise capacity, WHO functional class and haemodynamic variables were measured at baseline and at 3 and at least 9 months after initiating vardenafil treatment.. At the 3 months and a mean (SD) of 14 (3) months (range 9-18) follow-up assessments, the 6 min walking distance was significantly increased from baseline by 70.7 (78.4) m (p<0.001) and 83.4 (91.8) m (p<0.001), respectively. Furthermore, long-term treatment with vardenafil for a mean duration of >1 year was also associated with improvements in haemodynamic parameters, WHO functional class and serum uric acid concentrations. Overall, vardenafil treatment was well tolerated. No patients were withdrawn owing to adverse events and none died during the course of the study.. Long-term treatment with vardenafil is well tolerated and has sustained beneficial effects on PAH, as measured by patients' exercise capacity, WHO functional class and haemodynamic parameters.

Topics: Adult; Blood Gas Analysis; Exercise Test; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Male; Phosphodiesterase Inhibitors; Piperazines; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Excessive hypoxic pulmonary hypertension imposes right ventricular strain by increasing afterload that may lead to right heart failure and death. Increased phosphodiesterase activity, as well as increased levels of endothelin-1, has been discussed as molecular mechanisms. We investigated the hemodynamic and intrapulmonary effects of the intravenous dual endothelin A and B receptor blocker tezosentan, and of the phosphodiesterase-5 (PDE-5) antagonist vardenafil in a pig model of acute normobaric hypoxic pulmonary hypertension. Eighteen 4-week-old ventilated white farm pigs were exposed to normobaric hypoxia (FiO2 12%) and randomly assigned to three groups (n = 6) in order to receive either intravenous tezosentan or vardenafil or to serve as control. Arterial alveolar oxygen differences were the same with both drugs. After 90 min of treatment, pulmonary artery pressure and vascular resistance were significantly lower in both treatment groups when compared to controls (p < 0.001). Cardiac index increased significantly with vardenafil alone (2.8 l x min(-1) x m2 +/- 0.7 to 4.2 l x min x m2 +/- 0.7, p = 0.0003). Intravenous tezosentan, as well as vardenafil equipotently attenuate acute hypoxic pulmonary hypertension without afflicting pulmonary gas exchange. However, cardiac index increases with vardenafil only.

Topics: Animals; Dose-Response Relationship, Drug; Female; Hemodynamics; Hypertension, Pulmonary; Hypoxia; Imidazoles; Injections, Intravenous; Male; Piperazines; Pulmonary Gas Exchange; Pyridines; Random Allocation; Sulfones; Swine; Tetrazoles; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

During the past 18 years, sildenafil has evolved from a potential anti-angina drug to an on-demand treatment for erectile dysfunction and more recently to a new orally active treatment for pulmonary hypertension. Recent studies suggest that the drug has powerful cardioprotective effect against ischemia/reperfusion injury, doxorubicin-induced cardiomyopathy and anti-hypertensive effect induced by chronic inhibition of nitric oxide synthase in animals. Based on several recent basic and clinical studies, it is clear that sildenafil and other clinically approved type-5 phosphodiesterase-5 inhibitors including vardenafil and tadalafil will eventually be developed for several cardiovascular indications including essential hypertension, endothelial dysfunction, ischemia/reperfusion injury, myocardial infarction, ventricular remodeling and heart failure.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Antihypertensive Agents; Carbolines; Cardiomyopathies; Cardiovascular Agents; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Doxorubicin; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Heart Failure; Humans; Hypertension; Hypertension, Pulmonary; Imidazoles; Male; Myocardial Infarction; Myocardial Reperfusion Injury; NG-Nitroarginine Methyl Ester; Nitric Oxide; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents; Ventricular Remodeling

We report a 66-year-old patient with refractory pulmonary hypertension secondary to ARDS who was being treated with inhaled nitric oxide. Enteral vardenafil (phosphodiesterase-5 inhibitor) was tried at two different doses (10 mg and 5 mg), in order to wean the patient from nitric oxide. The higher dose decreased pulmonary pressure but caused systemic hypotension and the drug was discontinued. Subsequently, a 5 mg dose of vardenafil decreased pulmonary pressure without hypotension. Pulmonary hypertension was controlled using vardenafil 10-15 mg divided in 2-3 daily doses. This therapy allowed nitric oxide withdrawal, weaning from mechanical ventilation and discharge from ICU Vardenafil acted in synergy with inhaled nitric oxide, permitted nitric oxide reduction and discontinuation and proved to be effective as a single, long-term treatment for pulmonary hypertension.

Topics: Administration, Inhalation; Female; Humans; Hypertension, Pulmonary; Imidazoles; Middle Aged; Nitric Oxide; Piperazines; Respiration, Artificial; Respiratory Distress Syndrome; Salvage Therapy; Sulfones; Triazines; Vardenafil Dihydrochloride; Vasodilator Agents

Perioperative pulmonary hypertension is a challenging clinical problem with numerous etiologies including hypoxia, adrenergic stimulation, and local inflammation. New oral phosphodiesterase-5 (PDE-5) inhibitors used for the treatment of erectile dysfunction may have beneficial effects on the pulmonary vasculature owing to the abundance of PDE-5 receptors in the lung. The purpose of this study was to compare the efficacy of sildenafil, vardenafil, and tadalafil in preventing acute hypoxic pulmonary vasoconstriction and hypoxia-induced pulmonary artery tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1beta) expression.. Isolated rat pulmonary arteries suspended in physiologic organ baths for measurement of isometric force transduction were treated with vehicle (dimethyl sulfoxide), sildenafil, vardenafil, or tadalafil to assess (1) pulmonary artery relaxation; (2) inhibition of phenylephrine-induced pulmonary artery contraction; (3) inhibition of hypoxic pulmonary vasoconstriction (pO2 = 30-35 mm Hg); and (4) hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression (reverse transcriptase-polymerase chain reaction).. Sildenafil, vardenafil, and tadalafil resulted in dose-dependent pulmonary artery relaxation and inhibited phenylephrine-induced pulmonary artery contraction, but only tadalafil significantly inhibited hypoxic pulmonary vasoconstriction (52.08% +/- 7.65% tadalafil versus 88.63% +/- 8.96% vehicle; 98.61% +/- 10.04% sildenafil; 68.46% +/- 15.84% vardenafil). Hypoxia-induced upregulation of TNF-alpha and IL-1beta mRNA in pulmonary artery was significantly decreased by tadalafil, but not sildenafil or vardenafil pretreatment.. We conclude that sildenafil, vardenafil, and tadalafil were equally efficacious in causing pulmonary artery relaxation, but only tadalafil inhibited hypoxic pulmonary vasoconstriction and attenuated hypoxia-induced pulmonary artery TNF-alpha and IL-1beta expression.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Evaluation, Preclinical; Gene Expression Regulation; Hypertension, Pulmonary; Hypoxia; Imidazoles; Interleukin-1; Isometric Contraction; Male; Phenylephrine; Phosphodiesterase Inhibitors; Piperazines; Pulmonary Artery; Purines; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sildenafil Citrate; Sulfones; Tadalafil; Triazines; Tumor Necrosis Factor-alpha; Vardenafil Dihydrochloride; Vasoconstriction

The phosphodiesterase-5 (PDE-5) inhibitor, sildenafil, has been reported to produce sustained pulmonary vasodilatation in patients with pulmonary hypertension (PH). Recently, vardenafil, a more potent and selective PDE-5 inhibitor than sildenafil, has been approved for the treatment of erectile dysfunction. However, the long-term effects of oral vardenafil in patients with PH are unknown. We studied five consecutive patients with PH; one with primary pulmonary hypertension, two with chronic pulmonary thromboembolism, one with Eisenmenger syndrome (ventricular septal defect) and one with secondary pulmonary hypertension after a ventricular septal defect closure operation. In an acute hemodynamic trial, vardenafil (5 mg) significantly decreased both the pulmonary vascular resistance (PVR) and systemic vascular resistance (SVR) with an increase in cardiac output. In a chronic hemodynamic trial, the maintenance dose of vardenafil (10 to 15 mg) for 3 months significantly decreased the PVR, but not the SVR, with a 20.7% reduction of the PVR/ SVR ratio. Plasma brain natriuretic peptide (BNP) levels were also significantly decreased after 3 months. This pilot study demonstrates that long-term oral vardenafil therapy may be a safe and effective treatment for patients with PH.

Topics: Adult; Aged; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Imidazoles; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Sulfones; Treatment Outcome; Triazines; Vardenafil Dihydrochloride

[3H]Vardenafil (Levitra) or [3H]tadalafil (Cialis) binding was used to quantify PDE5 in rat lung and heart tissue. Each radioligand bound to purified recombinant phosphodiesterase-5 (PDE5) or to PDE5 in crude extracts with strong affinity, high specificity, slow dissociation, and good stoichiometry. PDE5, the only 3H inhibitor-binding protein detected in extracts, was 15 times higher in lung than in heart extracts, and the level measured by PDE5 catalytic activity agreed with that determined by 3H inhibitor binding. High level of PDE5 in lung approximated that in penile corpus cavernosum, the tissue targeted by PDE5 inhibitors. PDE5 was the predominant cGMP-PDE in lung, and on a molar basis was five times higher than cGMP-dependent protein kinase (PKG), which phosphorylates PDE5 in vivo. The PDE5 level was one-half that of PKG in heart. Thus, abundance of PDE5 in lung vascular smooth muscle provides a strong molecular basis for PDE5 inhibitor treatment of pulmonary hypertension.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Carbolines; Chromatography, Gel; Cyclic AMP-Dependent Protein Kinases; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Enzyme Inhibitors; Humans; Hypertension, Pulmonary; Imidazoles; Lung; Myocardium; Piperazines; Rats; Sulfones; Tadalafil; Triazines; Tritium; Vardenafil Dihydrochloride

Interferon alpha2 is widely used in hepatitis and high-risk melanoma. Interferon-induced pulmonary arterial hypertension as a side effect is rare.. We describe a melanoma patient who developed severe pulmonary arterial hypertension 30 months after initiation of adjuvant interferon alpha2b therapy. Discontinuation of interferon did not improve pulmonary arterial hypertension. This patient could be treated successfully with phosphodiesterase-5 inhibitor therapy.. This is only the 5th case of interferon-induced pulmonary arterial hypertension and the first documented case where pulmonary arterial hypertension was not reversible after termination of interferon alpha2 therapy. If interferon alpha2 treated patients develop respiratory symptoms, pulmonary arterial hypertension should be considered in the differential diagnosis. For these patients phosphodiesterase-5 inhibitors, e.g. sildenafil or vardenafil, could be an effective therapeutic approach.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Humans; Hypertension, Pulmonary; Imidazoles; Interferon-alpha; Melanoma; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Sulfones; Time Factors; Treatment Outcome; Triazines; Vardenafil Dihydrochloride