Lercanidipine and T-type calcium current

E. Cerbai, A. Mugelli

Department of Neurosciences, Psychology, Drug Research and Child’s Health (NEUROFARBA), University of Florence, Florence, Italy. alessandro.mugelli@unifi.it

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• Pharmacology

OBJECTIVE: Lercanidipine is a calcium antagonist with no cardiodepressant activity, long lasting antihypertensive action and reno-protective effect. Our previous data demonstrated that lercanidipine blocks L-type calcium channels (CaL). However, no data are available concerning its effects on T-type calcium channels (CaT). The aim of this study was to evaluate the effect on both CaL and CaT and the selectivity ratio of R-lercanidipine, S-lercanidipine and RS-lercanidipine. A comparison with other dihydropyridines (amlodipine and lacidipine) and the CaT blocker mibefradil was also performed.

MATERIALS AND METHODS: In patch-clamped guinea-pig ventricular myocytes, a voltage protocol was applied mimicking a normal action potential: HP of -90 mV, 200 ms depolarizing steps to -50/+50 mV. Lercanidipine was tested at concentrations (1-10 µM) able to block ≈ 50% CaL evoked from a HP in the range of -50 to -30 mV. Cells were superfused with a Na+ and K+ free solution pre-warmed to 35°C to abolish overlapping currents.

RESULTS: Using the described voltage protocol, all dihydropyridines at 1 µM blocked less than 20% CaL, with the exception of lacidipine, that reduced CaL >60% of control. All calcium channel blockers (CCBs) blocked a significant amount of CaT, varying from 28% (mibefradil) to 4.3% (amlodipine). Based on the ratio between CaT and CaL blockade in each cell (T/L), mibefradil, as expected, showed the highest T affinity (T/L=1.3). Lercanidipine, either racemate or enantiomers, showed a noticeable T selectivity, T/L varying from 1.05 (S-lercanidipine) to 1.15 (R-lercanidipine).

CONCLUSIONS: All CCBs examined in this study showed both T- and L-channel blocking activities and can be differentiated based on their relative affinity. Among tested dihydropyridines, lercanidipine showed the highest T/L selectivity.

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