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

J Pharmacol Exp Ther. 2005 Jul;314(1):207-13. doi: 10.1124/jpet.105.083824. Epub 2005 Mar 25.

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.

MeSH terms

  • Animals
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic GMP / metabolism
  • Cyclic GMP-Dependent Protein Kinases / antagonists & inhibitors
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / pharmacology
  • Guanylate Cyclase / metabolism
  • In Vitro Techniques
  • Muscle Contraction / drug effects
  • Muscle Relaxation / drug effects
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology
  • Ouabain / pharmacology
  • Oxadiazoles / pharmacology
  • Pulmonary Artery / drug effects*
  • Pyrazoles / pharmacology*
  • Pyridines / pharmacology*
  • Quinoxalines / pharmacology
  • Rubidium Radioisotopes
  • Serotonin / pharmacology
  • Sheep
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors
  • Sodium-Potassium-Exchanging ATPase / physiology*
  • Vasoconstriction / drug effects
  • Vasodilation / drug effects*

Substances

  • 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one
  • 3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
  • Enzyme Inhibitors
  • Oxadiazoles
  • Pyrazoles
  • Pyridines
  • Quinoxalines
  • Rubidium Radioisotopes
  • Serotonin
  • Ouabain
  • Cyclic AMP-Dependent Protein Kinases
  • Cyclic GMP-Dependent Protein Kinases
  • Guanylate Cyclase
  • Sodium-Potassium-Exchanging ATPase
  • Cyclic GMP