vardenafil-dihydrochloride and Hypoxia

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Line, Tumor; Colonic Neoplasms; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Resistance, Neoplasm; Drug Synergism; Drugs, Chinese Herbal; Humans; Hypoxia; Male; Mice, Inbred BALB C; Nitroso Compounds; Oxadiazoles; Oxazines; Phosphodiesterase 5 Inhibitors; Plant Extracts; Reactive Oxygen Species; Serum Albumin, Human; Soluble Guanylyl Cyclase; 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

In human bladder, phosphodiesterase type 5 (PDE5) is present not only in the muscular wall but also in the vascular beds, suggesting a role for PDE5 inhibitors in favoring bladder blood flow and tissue oxygenation.. To investigate whether acute administration of vardenafil could affect bladder oxygenation in spontaneously hypertensive rats (SHR), an animal model of naturally occurring overactive bladder.. The effect of vardenafil on hypoxia-induced alterations was studied in vivo in SHR by acute dosing (10 mg/kg, 90 minutes before sacrifice) and in vitro in human bladder smooth muscle cells (hBCs).. Bladder oxygenation was detected using the hypoxyprobe immunostaining. The expression of some hypoxia markers (vascular endothelial growth factor [VEGF] and endothelin-1 type B [ETB] receptor) was also evaluated by immunohistochemistry and Western blot. Gene expression in hBC was quantified by real-time reverse transcription-polymerase chain reaction.. Rat bladder PDE5 immunopositivity was detected in the muscular wall and in the endothelial and smooth muscle cells of blood vessels. In SHR bladder, a significant increase of hypoxic cells, VEGF, and ETB expression was observed when compared with their normotensive counterpart Wistar Kyoto rats (WKY). Vardenafil treatment dramatically decreased hypoxyprobe staining, as well as VEGF and ETB expression in SHR bladder up to WKY level. Accordingly, in SHR bladder, vardenafil administration significantly blunted relaxation induced by the selective ETB agonist IRL-1620. In hBCs, experimental hypoxia significantly induced gene expression of hypoxia markers (carbonic anhydrase IX and VEGF), which was not changed by simultaneous treatment with vardenafil. Conversely, the hypoxia-related induction of smooth muscle-specific genes (alphaSMA, SM22alpha, and desmin) was significantly reduced by vardenafil.. SHR showed bladder hypoxia which was significantly reduced by acute vardenafil treatment. Thus, besides relaxing muscular wall, PDE5 inhibition may positively affect urinary vesicle blood perfusion.

Topics: Animals; Cells, Cultured; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Administration Schedule; Gene Expression Regulation, Enzymologic; Hypoxia; Imidazoles; Immunoenzyme Techniques; Male; Muscle, Smooth; Oxygen Consumption; Piperazines; Prostatic Hyperplasia; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Endothelin B; RNA, Messenger; Sulfones; Triazines; Urinary Bladder; Urinary Bladder, Overactive; Vardenafil Dihydrochloride; Vascular Endothelial Growth Factor A; 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

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