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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month = "7",
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TY - JOUR

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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DO - 10.1124/jpet.105.083824

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