EFFECTS OF INDAPAMIDE ON CA2-MUSCLE CELLS( ENTRY INTO VASCULAR SMOOTH)

Part of the antihypertensive action of indapamide has been attributed to a direct inhibitory action on Ca2+ entry into vascular smooth muscl e cells. The present study has been performed to identify the possible mechanisms involved. To this end the effect of indapamide on intracel lular Ca2+ activity - [Ca2+](i) - has been tested under control condit ions and under conditions known to increase [Ca2+](i) such as osmotic cell swelling (mimicking mechanical stress), depolarization (increase of extracellular K+ concentration) and oxidative stress (H2O2) Indapam ide (10 mu mol/l) was without effect on control [Ca2+](i), but signifi cantly blunted the increase of [Ca2+](i) following potassium-induced d epolarization or following osmotic cell swelling. It did not significa ntly modify the increase of [Ca2+](i) induced by H2O2. The effects on cell membrane potential induced by increased [K+], osmotic cell swelli ng, or H2O2 were not significantly modified by indapamide (10 mu mol/l ). Voltage-gated Ca2+ currents were not significantly modified by 10 m u mol/l indapamide, but were significantly reduced by 100 mu mol/l and blunted by 1 mmol/l, Hn conclusion, indapamide at high concentrations (100 mu mol/l) inhibits voltage-gated Ca2+ channels, an effect which blunts the increase of [Ca2+](i) during depolarization of the cell mem brane at increased extracellular [K+] or osmotic stress. Whether these effects at high concentrations of indapamide are relevant to the anti hypertensive action, however, cannot be established from these in vitr o studies.