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      p38 Mitogen-Activated Protein Kinase Activation Is Required for Thromboxane- Induced Contraction in Perfused and Pressurized Rat Mesenteric Resistance Arteries

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          Thromboxane A<sub>2</sub> (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 µm) mounted in an arteriograph. Changes in diameter were recorded under physiological levels of flow (90 µl/min) and pressure (50 mm Hg). TP stimulation induced a concentration-dependent contraction (EC<sub>50</sub> value of 1.94 ± 0.22 × 10<sup>–7</sup> 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.

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          PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinasein Vitroandin Vivo

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            Role for p38 mitogen-activated protein kinase in platelet aggregation caused by collagen or a thromboxane analogue.

            p38 mitogen-activated protein kinase (MAPK) was identified in platelets on the basis of (a) its reactivity with antibodies to C-terminal and N-terminal peptides, and (b) its ability to activate MAPK-activated protein kinase-2, which phosphorylates the small heat shock protein, hsp27. p38 MAPK was activated in platelets by collagen fibers, a collagen-related cross-linked peptide, thrombin, or the thromboxane analogue U46619. A highly specific inhibitor of p38 MAPK, a pyridinyl imidazole known as SB203580, inhibited the platelet enzyme in vitro (IC50 approximately 0.5 microM). At similar concentrations it also inhibited agonist-stimulated phosphorylation of hsp27 in platelets, and platelet aggregation and secretion induced by minimal aggregatory concentrations of collagen or U46619, but not thrombin. Inhibition of aggregation was overcome by increasing agonist dose. SB203580 might act by inhibiting thromboxane generation, but this was only inhibited by 10-20% at low agonist concentrations. p38 MAPK provides a crucial signal, which is necessary for aggregation caused by minimal concentrations of collagen fibers or U46619. Thrombin or high doses of these agonists generate signals that bypass the enzyme, or render the enzyme no longer rate-limiting.
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              Location of Resistance Arteries

              Thickening and narrowing of resistance arteries must, by definition, be key elements in the control of the cardiovascular system. However, the precise location of resistance arteries is difficult to establish. This is due to technical problems related to the small size of the vessels, to the measurement conditions disturbing the hemodynamics, and to the status of the animals while the measurements are being made. Furthermore, due to large data heterogeneity, previous studies do not give unequivocal information concerning the pressure profile in the vascular system, or the level of arterial diameter responsible for blood flow. Finally, and importantly, there is little evidence regarding the conscious state, which is thus a major limitation to understanding the mechanisms of blood distribution and the pathogenesis for disease processes such as genetic hypertension. This review first summarizes briefly the techniques which are available for identifying resistance arteries and the inherent technical limitations which are involved. The review then provides a critical assessment of the available data, both as regards measurement of local blood pressures and as regards control of peripheral resistance. The evidence suggests that, at least as regards rats and other small animals, feed arteries as well as more distal microvessels contribute to the maintenance and regulation of blood flow and resistance. Evidence from larger animals is however lacking, and it is thus unclear if resistance function should be based on arterial diameter or anatomic location. Furthermore, evidence concerning man is not available. We therefore conclude the review with suggestions for future research in this area.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                August 2002
                12 August 2002
                : 39
                : 4
                : 353-360
                INSERM aU348 and bU541, IFR Circulation-Paris-Nord, Paris VII University, Hôpital Lariboisière, and cDepartment of Physiology, Paris VII University, AP-HP-Hôpital Lariboisière, Paris, France
                65547 J Vasc Res 2002;39:353–360
                © 2002 S. Karger AG, Basel

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                Page count
                Figures: 4, References: 41, Pages: 8
                Research Paper


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