Lercanidipine is a new dihydropyridine (DHP) derivative with calcium antagonistic properties. In vitro and in vivo experiments have shown that it relaxes vascular musculature without exerting negative inotropic effects. The two ester groups present in positions 3 and 5 of the DHP ring lead to the existence of two enantiomers. We studied the electrophysiologic properties of lercanidipine and its enantiomers in multicellular preparations (i.e., rabbit and guinea pig papillary muscles) and patch-clamped isolated guinea pig ventricular myocytes. Lercanidipine (1 μM) affected neither action potential characteristics nor contraction amplitude of papillary muscles. It did not reduce sodium current or L-type calcium current (ICa) recorded from cells kept at a normal polarized membrane potential (-80 mV), both at low (0.2 Hz) and high stimulation frequency (1 Hz). (R)-Lercanidipine decreased (10.6 ± 1.6 vs. 12.1 ± 1.2 pA/pF; p < 0.05) and (S)-lercanidipine increased ICa (17.1 ± 1.0 vs. 12 8 ± 0.9 pA/pF;p<0.05). However, blocking activity on the calcium current by lercanidipine or its enantiomers was apparent when the cells were kept at a depolarized holding potential (HP = -40 mV). With long conditioning pulses (5 s), a marked shift of the steady-state inactivation curve for ICa was observed. Voltage of halfmaximal activation was shifted from -34 mV (control) to -43.1 mV, -45.0, and -43.8 mV in the presence of lercanidipine, (S)-lercanidipine, and (R)-lercanidipine, respectively. ICa blockade and recovery from blockade developed slowly with both enantiomers and the racemate, being markedly slower than that observed with nimodipine under the same experimental conditions. At HP = -40 mV, block of ICa by either (S)- or (R)-lercanidipine was markedly usedependent. At the tenth pulse, current amplitude was reduced to 11.5 ± 3.2% (n = 4) and 20.5 ± 4.9% (n = 5) of the value recorded during the first pulse by (R)-lercanidipine and (S)-lercanidipine, respectively. In conclusion, lercanidipine and its enantiomers have selective calcium antagonistic properties, which develop only at low membrane potentials.
Electrophysiologic study of Lercanidipine and its enantiomers.
BARBIERI, Mario;
1997
Abstract
Lercanidipine is a new dihydropyridine (DHP) derivative with calcium antagonistic properties. In vitro and in vivo experiments have shown that it relaxes vascular musculature without exerting negative inotropic effects. The two ester groups present in positions 3 and 5 of the DHP ring lead to the existence of two enantiomers. We studied the electrophysiologic properties of lercanidipine and its enantiomers in multicellular preparations (i.e., rabbit and guinea pig papillary muscles) and patch-clamped isolated guinea pig ventricular myocytes. Lercanidipine (1 μM) affected neither action potential characteristics nor contraction amplitude of papillary muscles. It did not reduce sodium current or L-type calcium current (ICa) recorded from cells kept at a normal polarized membrane potential (-80 mV), both at low (0.2 Hz) and high stimulation frequency (1 Hz). (R)-Lercanidipine decreased (10.6 ± 1.6 vs. 12.1 ± 1.2 pA/pF; p < 0.05) and (S)-lercanidipine increased ICa (17.1 ± 1.0 vs. 12 8 ± 0.9 pA/pF;p<0.05). However, blocking activity on the calcium current by lercanidipine or its enantiomers was apparent when the cells were kept at a depolarized holding potential (HP = -40 mV). With long conditioning pulses (5 s), a marked shift of the steady-state inactivation curve for ICa was observed. Voltage of halfmaximal activation was shifted from -34 mV (control) to -43.1 mV, -45.0, and -43.8 mV in the presence of lercanidipine, (S)-lercanidipine, and (R)-lercanidipine, respectively. ICa blockade and recovery from blockade developed slowly with both enantiomers and the racemate, being markedly slower than that observed with nimodipine under the same experimental conditions. At HP = -40 mV, block of ICa by either (S)- or (R)-lercanidipine was markedly usedependent. At the tenth pulse, current amplitude was reduced to 11.5 ± 3.2% (n = 4) and 20.5 ± 4.9% (n = 5) of the value recorded during the first pulse by (R)-lercanidipine and (S)-lercanidipine, respectively. In conclusion, lercanidipine and its enantiomers have selective calcium antagonistic properties, which develop only at low membrane potentials.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
