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 language||English (US)|
|Number of pages||7|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jul 1 2005|
ASJC Scopus subject areas
- Molecular Medicine