Details

Autor(en) / Beteiligte

• Wirtz, Susanne
• Herzig, Stefan

Titel

Molecular mechanisms of vasoselectivity of the 1,4‐dihydropyridine lercanidipine

Ist Teil von

• British journal of pharmacology, 2004-05, Vol.142 (2), p.275-284

Ort / Verlag

Oxford, UK: Blackwell Publishing Ltd

Erscheinungsjahr

2004

Quelle

MEDLINE

Beschreibungen/Notizen

• The effects of (S)‐ and (R)‐lercanidipine on CHO cells stably expressing the cardiac (Cav1.2a) or vascular (Cav1.2b) splice variant of the L‐type calcium channel pore subunit were studied, using whole‐cell and single‐channel patch‐clamp measurements. Lercanidipine block of Cav1.2b current was enantioselective. (S)‐lercanidipine was 4.1‐fold more potent. Experiments using acidic solutions (pH 6.8) revealed a 6.4‐fold enhanced inhibitory effect of (S)‐lercanidipine compared with physiological conditions (pH 7.4) indicating that the charged form mediates inhibition. At depolarised holding potential (−40 mV), (S)‐lercanidipine exhibited a 35‐fold greater potency, compared with standard conditions (−80 mV). A comparison of the concentration‐dependent inhibition of Cav1.2a with Cav1.2b subunit currents by (S)‐lercanidipine revealed only a 1.8‐fold difference in IC50, but the slope of the dose–response curve was much steeper (nH=2.3) with Cav1.2a, compared with Cav1.2b (nH=0.8). This indicates overlap between agonistic and antagonistic effects, predominant with the cardiac Cav1.2a subunit. This idea is supported by transient stimulatory effects, and a slight leftward shift of the IV curves. These effects were more prominent for Cav1.2a than for Cav1.2b. Single‐channel experiments confirmed typical features of calcium channel agonists such as prolonged channel openings, a component of lengthened openings, and an enhanced open probability in the presence of (S)‐lercanidipine. Again, these findings were concentration‐dependent and more pronounced for Cav1.2a than for Cav1.2b. Our data indicate a splice‐variant predominant agonism as a new mechanism contributing to the vasoselectivity of lercanidipine, along with marked voltage‐dependence of action. British Journal of Pharmacology (2004) 142, 275–284. doi:10.1038/sj.bjp.0705786