p38 mitogen-activated protein kinase activation is required for thromboxane- induced contraction in perfused and pressurized rat mesenteric resistance arteries.
Thromboxane A(2) (TxA2) is a potent proaggregating, vasoconstrictor agent produced in many physiological and pathological situations. Although mitogen-activated protein (MAP) kinases [MAPK (ERK1/2 and p38)] have been shown to be activated after endoperoxide/thromboxane receptor (TP) stimulation, no study has investigated their potential role in resistance arteries, especially in physiological conditions of pressure and flow in which the arteries can contract. Thus, responses to TP stimulation by the stable agonist U46619 were studied in isolated rat mesenteric resistance arteries (inner diameter 262 +/- 5 microm) mounted in an arteriograph. Changes in diameter were recorded under physiological levels of flow (90 microl/min) and pressure (50 mm Hg). TP stimulation induced a concentration-dependent contraction (EC(50) value of 1.94 +/- 0.22 x 10(-7) M), without desensitization. U46619-induced contraction was inhibited by calcium entry blockade (nifedipine) and protein kinase C inhibition (GF109203X), but it was not affected by tyrosine kinase inhibition (tyrphostin A25). MAPKK (MEK) inhibition (PD98059) did not alter U46619-dependent contraction, although ERK1/2 MAPK were activated. By contrast, p38 MAPK inhibition (SB203580) dose-dependently inhibited the contraction, and Western blot analysis showed activation of p38 MAPK in arteries contracted with U46619. Activation of p38 MAPK by U46619 was inhibited by nifedipine and in the absence of extracellular calcium. This study brings new insights in the transduction pathway involved in the contractile response of resistance arteries to TxA2/endoperoxide receptor stimulation. This contraction requires p38 MAPK activation, but did not involve ERK1/2 MAPK activation although both were activated.
INSERM, U348, IFR Circulation-Paris-Nord, Paris VII University, Hôpital Lariboisière, Paris, France.
Manlio
M
Bolla
Khalid
K
Matrougui
Laurent
L
Loufrani
Jacques
J
Maclouf
Bernard
B
Levy
Sylviane
S
Levy-Toledano
Aïda
A
Habib
Daniel
D
Henrion
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008638:Mesenteric Arteries / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009543:Nifedipine / Q000494:pharmacology; D010477:Perfusion; D011312:Pressure; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000494:pharmacology; D013928:Thromboxane A2 / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D008301:Maleimides; D011725:Pyridines; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D009543:Nifedipine; C070515:bisindolylmaleimide I; C093642:SB 203580