モノクロタリン誘発肺高血圧症ラットにおける肺動脈平滑筋細胞の膜イオン電流の変化に関する実験的検討

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  • Experimental Study on Alteration of Membrane Ionic Currents in Pulmonary Arterial Myocytes from Monocrotaline-induced Pulmonary Hypertensive Rat

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Pulmonary hypertension （PH） caused by an idiopathic process or various cardiopulmonary disorders is well known to be a fatal disease which is correlated with increased patient mortality. Despite its severity and difficulties in treatment or management, the physiological basis of PH has not been understood completely. The present study was undertaken to examine the changes in ionic currents of pulmonary artery smooth muscle cell （PASMC）, under the pathological condition of PH. As an animal model of PH, monocrotaline-induced pulmonary hypertensive rats were produced by single subcutaneous injection of 60mg/kg monocrotaline （MCT）. To confirm that PH developed successfully on the experimental days （18-21 days） after the treatment with MCT, right ventricular systolic pressure was measured as a indicator of pulmonary artery pressure. The whole cell patch clamp method was applied to single PASMC freshly isolated from the main pulmonary artery along with some intrapulmonary branches of MCT injected rats （MCT rats） and saline injected control rats （Saline rats）. Resting membrane potential of PASMC was not different between the two groups in the current-clamp mode. Outward currents elicited by depolarizing test pulse from a holding potential of -43mV were remarkably smaller in MCT rats than in Saline rats, using patch pipettes with 0.1mM EGTA. On the other hand, when the pipette contained 10mM EGTA, the outward currents were almost similar between the two groups. To identify the component responsible for the reduction of outward currents, the effect of inhibitors of K+ currents were examined. Nisoldipine （1μM）, which indirectly inhibits Ca2+-activated K+ channel by blocking L-type Ca2+ channels, was less effective in MCT rats than in Saline rats. Tetraethylammonium （5mM）, selectiveCa2+-activated K+ channel inhibitor, was also less effective in MCT rats than in Saline rats. In contrast, 4-aminopyridine （4mM）, selective voltage gated K+ channel inhibitor, was almost equally effective on both. The current density of L-type Ca2+ channel current in MCT and Saline rats was also investigated using 1μM nisoldipine. Ca2+ currents were small in MCT rats. Because elevation of cytoplasmic Ca2+ concentration of PASMC is expected under the pathological condition of PH, all these results suggest that elevation of cytoplasmic Ca2+ leads to a reduction of Ca2+-activated K+ currents and Ca2+ currents in PASMC.

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