Pulmonary artery vasoconstriction but not [Ca2+]i signal stimulated by thromboxane A2 is partially resistant to NO.
To characterize the thromboxane A2 (TXA2) -induced resistance to the vasodilator effects of the nitric oxide (NO)/cGMP pathway in pulmonary arteries, we have studied the effects of the NO donor sodium nitroprusside on intracellular calcium concentration ([Ca2+]i) and contractile force recorded simultaneously in isolated piglet pulmonary arteries loaded with fura-2 and contracted with norepinephrine or the TXA2 mimetic U46619 and by activation of protein kinase C (PKC) with phorbol 12-myristate 13-acetate. In the TXA2 mimetic- and phorbol 12-myristate 13-acetate plus norepinephrine-stimulated arteries, nitroprusside exhibited lower vasodilator efficacy (and lower potency in the TXA2 mimetic-stimulated arteries) but similar reductions in [Ca2+]i compared with arteries activated by norepinephrine. The nonselective serine/threonine kinase inhibitor staurosporine, but not the selective inhibitor of PKC bisindolylmaleimide, potentiated the relaxation of nitroprusside in the TXA2 mimetic-stimulated arteries. In conclusion, the resistance to NO/cGMP-induced vasodilation in arteries stimulated by TXA2 and PKC involves a reduced ability of the Ca2+-independent mechanisms for smooth muscle vasodilation. The resistance to NO in arteries stimulated by TXA2 is sensitive to staurosporine but not to bisindolylmaleimide, suggesting the involvement of an activation of a serine/threonine kinase distinct from PKC.
Pérez-Vizcaíno
F
F
Department of Pharmacology, Institute of Pharmacology and Toxicology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain. fperez@eucmax.sim.ucm.es
Cogolludo
A L
AL
Ibarra
M
M
Fajardo
S
S
Tamargo
J
J
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D013552:Swine; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013928:Thromboxane A2 / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011493:Protein Kinase C; D019311:Staurosporine; C088060:bisindolylmaleimide; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine