title: BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine]-induced dilation in ovine pulmonary artery: role of sodium pump.
abstract: The mechanisms of relaxation to nitric oxide (NO)-independent soluble guanylyl cyclase (sGC) activator BAY 41-2272 [5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]pyrimidin-4-ylamine] were investigated in isolated ovine pulmonary artery. BAY 41-2272 (1 nM-10 microM) produced concentration-dependent relaxation of endothelium-denuded pulmonary artery rings (pD2 = 6.82 +/- 0.16; Emax = 92.30 +/- 2.31%; n = 8), precontracted with 1 microM 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 microM), an inhibitor of sGC, partially inhibited (Emax = 57.10 +/- 3.10%; n = 6) the relaxation response of BAY 41-2272. In comparison with ODQ, sodium pump inhibitor ouabain (1 microM) produced a greater decrease in the vasodilator response of BAY 41-2272 (Emax = 20.17 +/- 4.55%; n = 6). K+-free solution also attenuated (Emax = 39.97 +/- 3.52%; n = 6) BAY 41-2272-induced relaxation. ODQ (10 microM) plus 1 microM ouabain abolished the relaxant response of BAY 41-2272 (Emax = 12.09 +/- 3.76%, n = 6 versus vehicle control dimethyl sulfoxide; Emax = 15.83 +/- 1.72%, n = 6). KT-5823 [1-oxo-9.12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-I][1,6]benzodiazocine-10-carboxylic acid methyl ester (2 microM), a specific inhibitor of protein kinase G had no effect on 10 microM ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 microM) inhibited Ca2+-induced contractions in K+-depolarized preparations. BAY 41-2272 (10 microM) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 microM ODQ. BAY 41-2272 (0.1, 1.0, and 10 microM) significantly (P < 0.05) increased ouabain-sensitive 86Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 microM) also stimulated sarcolemmal Na+-K+-ATPase activity. However, 10 microM ODQ had no significant effect on either basal or BAY 41-2272-stimulated 86Rb uptake/Na+-K+-ATPase activities. In conclusion, this study provides the first evidence of sodium pump stimulation by BAY 41-2272 independent of cGMP as an additional mechanism to sGC activation in relaxation of ovine pulmonary artery.
authors.affiliation: Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122 (UP), India.
authors.forename: Dnyaneshwar U
authors.initials: DU
authors.lastname: Bawankule
authors.forename: K
authors.initials: K
authors.lastname: Sathishkumar
authors.forename: Kautuk K
authors.initials: KK
authors.lastname: Sardar
authors.forename: Debabrata
authors.initials: D
authors.lastname: Chanda
authors.forename: A Vamsi
authors.initials: AV
authors.lastname: Krishna
authors.forename: Vellanki Ravi
authors.initials: VR
authors.lastname: Prakash
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology; D010042:Ouabain / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D012414:Rubidium Radioisotopes; D012701:Serotonin / Q000494:pharmacology; D012756:Sheep; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011720:Pyrazoles; D011725:Pyridines; D011810:Quinoxalines; D012414:Rubidium Radioisotopes; D012701:Serotonin; D010042:Ouabain; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; D006152:Cyclic GMP