P574Platelet activating factor stimulates sodiumu-hydrogen exchange in mammalian ventricular cardiomyocytes

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Abstract

Background

Sodium-hydrogen exchanger (NHE), the principal sarcolemmal acid extruder in ventricular cardiomyocytes contributes to myocardial injury and arrhythmias during ischemia/reperfusion (IR). Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent proinflammatory phospholipid that is released from various cells including platelet, neutrophil, and cardiomyocytes in response to oxidative stress and promotes myocardial IR injury. Although there are reports which described the stimulating effects of PAF on NHE in neutrophils and platelets, there is no reports about the effect of PAF on cardiac NHE (NHE1).

Methods and Results

We utilized quiescent guinea pig ventricular myocytes bathed in bicarbonate-free solutions and used epifluorescence to measure intracellular pH (pHi). Methylcarbamyl-PAF (C-PAF, 200 nM), a metabolically-stable analog of PAF, significantly increased steady-state pHi. The alkalosis was completely blocked by the NHE inhibitor, cariporide, and by sodium-free bathing solutions, indicating it was mediated by NHE activation. C-PAF also significantly increased the rate of acid extrusion induced by intracellular acidosis. The ability of C-PAF to increase steady-state pHi was completely blocked by the PAF receptor inhibitor WEB 2086 (10 µM), indicating the eefect was mediated via PAF receptor. A mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor (PD98059, 25 µM), also completely blocked the rise in pHi induced by C-PAF, suggesting participation of the MAP kinase signaling cascade downstream of the PAF receptor. Inhibition of protein kinase C (PKC) with GF109203X (1 µM) and chelerythrine (2 µM) did not significantly affect the alkalosis induced by C-PAF.

Conclutions

These results provide evidence that: a) PAF stimulates cardiac NHE1, b) the effect is mediated via the PAF receptor, and c) signal relay requires participation of the MAP kinase cascade.

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