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CARDIOVASCULAR

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

Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Uttar Pradesh, India

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; E_max = 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 (E_max = 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 (E_max = 20.17 ± 4.55%; n = 6). K⁺-free solution also attenuated (E_max = 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 (E_max = 12.09 ± 3.76%, n = 6 versus vehicle control dimethyl sulfoxide; E_max = 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.

Address correspondence to: Dr. Santosh K. Mishra, Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122 (UP), India. E-mail: smishraivri{at}rediffmail.com

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