Effects of indapamide on Ca2+ entry into vascular smooth muscle cells.
Part of the antihypertensive action of indapamide has been attributed to a direct inhibitory action on Ca2+ entry into vascular smooth muscle cells. The present study has been performed to identify the possible mechanisms involved. To this end the effect of indapamide on intracellular Ca2+ activity - [Ca2+]i - has been tested under control conditions 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). Indapamide (10 micromol/l) was without effect on control [Ca2+]i, but significantly blunted the increase of [Ca2+]i following potassium-induced depolarization or following osmotic cell swelling. It did not significantly modify the increase of [Ca2+]i induced by H2O2. The effects on cell membrane potential induced by increased [K+], osmotic cell swelling, or H2O2 were not significantly modified by indapamide (10 micromol/l). Voltage-gated Ca2+ currents were not significantly modified by 10 micromol/l indapamide, but were significantly reduced by 100 micromol/l and blunted by 1 mmol/l. In conclusion, indapamide at high concentrations (100 micromol/l) inhibits voltage-gated Ca2+ channels, an effect which blunts the increase of [Ca2+]i during depolarization of the cell membrane at increased extracellular [K+] or osmotic stress. Whether these effects at high concentrations of indapamide are relevant to the antihypertensive action, however, cannot be established from these in vitro studies.
Zempel
G
G
Department of Physiology, University of Tübingen, Germany.
Ditlevsen
J
J
Hoch
M
M
Emerich
U
U
Heinle
H
H
Schiavi
P
P
Dubois
F
F
Lang
F
F
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001013:Aorta, Thoracic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D005456:Fluorescent Dyes; D016257:Fura-2; D007190:Indapamide / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D013050:Spectrometry, Fluorescence
D000959:Antihypertensive Agents; D015220:Calcium Channels; D005456:Fluorescent Dyes; D007190:Indapamide; D002118:Calcium; D016257:Fura-2