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

Dnyaneshwar U. Bawankule, K. Sathishkumar, Kautuk K. Sardar, Debabrata Chanda, A. Vamsi Krishna, Vellanki Ravi Prakash, Santosh K. Mishra

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 μM) 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 μM 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 μM), 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 μM) 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 μM) plus 1 μM 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 μM), a specific inhibitor of protein kinase G had no effect on 10 μM ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 μM) inhibited Ca2+-induced contractions in K +-depolarized preparations. BAY 41-2272 (10 μM) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 μM ODQ. BAY 41-2272 (0.1, 1.0, and 10 μM) significantly (P < 0.05) increased ouabain-sensitive 86Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 μM) also stimulated sarcolemmal Na+-K+-ATPase activity. However, 10 μM 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.

Original languageEnglish (US)
Pages (from-to)207-213
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume314
Issue number1
DOIs
StatePublished - Jul 2005
Externally publishedYes

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Sodium-Potassium-Exchanging ATPase
Pulmonary Artery
Dilatation
Sheep
Ouabain
KT 1
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
1H-pyrazolo(3,4-b)pyridine
Serotonin
Oxadiazoles
Cyclic GMP-Dependent Protein Kinases
Quinoxalines
Carboxylic Acids
Dimethyl Sulfoxide
Vasodilator Agents
Endothelium

ASJC Scopus subject areas

  • Pharmacology

Cite this

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. / Bawankule, Dnyaneshwar U.; Sathishkumar, K.; Sardar, Kautuk K.; Chanda, Debabrata; Krishna, A. Vamsi; Prakash, Vellanki Ravi; Mishra, Santosh K.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 314, No. 1, 07.2005, p. 207-213.

Research output: Contribution to journalArticle

Bawankule, Dnyaneshwar U. ; Sathishkumar, K. ; Sardar, Kautuk K. ; Chanda, Debabrata ; Krishna, A. Vamsi ; Prakash, Vellanki Ravi ; Mishra, Santosh K. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2005 ; Vol. 314, No. 1. pp. 207-213.
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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 μM) 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 μM 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 μM), 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 μM) 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 μM) plus 1 μM 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 μM), a specific inhibitor of protein kinase G had no effect on 10 μM ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 μM) inhibited Ca2+-induced contractions in K +-depolarized preparations. BAY 41-2272 (10 μM) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 μM ODQ. BAY 41-2272 (0.1, 1.0, and 10 μM) significantly (P < 0.05) increased ouabain-sensitive 86Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 μM) also stimulated sarcolemmal Na+-K+-ATPase activity. However, 10 μM 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.",
author = "Bawankule, {Dnyaneshwar U.} and K. Sathishkumar and Sardar, {Kautuk K.} and Debabrata Chanda and Krishna, {A. Vamsi} and Prakash, {Vellanki Ravi} and Mishra, {Santosh K.}",
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T1 - 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

T2 - Role of sodium pump

AU - Bawankule, Dnyaneshwar U.

AU - Sathishkumar, K.

AU - Sardar, Kautuk K.

AU - Chanda, Debabrata

AU - Krishna, A. Vamsi

AU - Prakash, Vellanki Ravi

AU - Mishra, Santosh K.

PY - 2005/7

Y1 - 2005/7

N2 - 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 μM) 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 μM 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 μM), 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 μM) 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 μM) plus 1 μM 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 μM), a specific inhibitor of protein kinase G had no effect on 10 μM ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 μM) inhibited Ca2+-induced contractions in K +-depolarized preparations. BAY 41-2272 (10 μM) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 μM ODQ. BAY 41-2272 (0.1, 1.0, and 10 μM) significantly (P < 0.05) increased ouabain-sensitive 86Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 μM) also stimulated sarcolemmal Na+-K+-ATPase activity. However, 10 μM 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.

AB - 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 μM) 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 μM 5-hydroxytryptamine (serotonin). 1-H-[1,2,4]Oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 10 μM), 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 μM) 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 μM) plus 1 μM 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 μM), a specific inhibitor of protein kinase G had no effect on 10 μM ODQ-insensitive relaxation evoked by BAY 41-2272. BAY 41-2272 (10 μM) inhibited Ca2+-induced contractions in K +-depolarized preparations. BAY 41-2272 (10 μM) caused about a 14-fold increase in the intracellular cGMP over the basal level, which was completely inhibited by 10 μM ODQ. BAY 41-2272 (0.1, 1.0, and 10 μM) significantly (P < 0.05) increased ouabain-sensitive 86Rb uptake in a concentration-dependent manner. BAY 41-2272 (10 μM) also stimulated sarcolemmal Na+-K+-ATPase activity. However, 10 μM 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.

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