Electrophysiologic Effects of Lercanidipine on Repolarizing Potassium Currents

Abstract

Blockade of cardiac repolarizing potassium channels by drugs may result in QT-interval prolongation, eventually degenerating into "torsades de pointes," a life-threatening arrhythmia. Lercanidipine (LER) is a recently introduced lipophilic calcium antagonist with no cardiodepressant activity and long-lasting antihypertensive action. Its chemical structure is characterized by the presence of a diphenylpropylaminoalkyl group, which is present in some of the drugs that have been reported to cause QT-interval prolongation. Our previous data demonstrated that LER blocks L-type calcium channels without affecting sodium current; however, no data are available concerning its effects on cardiac potassium channels. Transient outward (I(to)), delayed rectifier (I(K)), background currents, and action potential (AP) profile were measured from patch-clamped ventricular myocytes isolated from rat, guinea pig, or human hearts using enzymatic dissociation procedures. LER did not affect I(K) (and I(Kr)) density and activation curve in guinea pig myocytes; the reversal potential of the background current (I(K1)) and its slope were not changed by the drug. Maximal diastolic potential (MDP) and duration of the AP measured at -60 mV (APD(-60)) were not significantly changed. I(to) density and activation curves measured in rat myocytes were similar in the absence and presence of 1 or 10 microM LER. Finally, the effect of LER was tested in human ventricular myocytes: superfusion with 1 microM LER did not affect MDP and APD(-60). I(to) density and the midpoint of activation and inactivation curves were similar in the absence and presence of LER. In conclusion, our data demonstrate that LER does not affect repolarizing potassium currents and action potential profile recorded from guinea pig, rat, and human ventricular myocytes. It is unlikely that LER could cause QT prolongation in vivo.

Comparative Pharmacology of Guinea Pig Cardiac Myocyte and Cloned hERG (IKr) Channel

“…Parallel studies with isolated guinea pig, dog, and human cardiac myocytes for identifying species similarities or differences would be useful. Use of dog and human myocytes to evaluate potential I Kr blockers reportedly is useful 8,32,44,45 . The human myocyte may be an alternative screening strategy to the cloned hERG and Purkinje fibers.…”

“…Use of dog and human myocytes to evaluate potential I Kr blockers reportedly is useful. 8,32,44,45 The human myocyte may be an alternative screening strategy to the cloned hERG and Purkinje fibers. Immortalized cardiac myocytes also may be a useful model cell type for some studies.…”

Influência do etilbenzeno na farmacocinética enantiosseletiva do lercanidipino em ratos

“…A atividade anti-hipertensiva reside essencialmente no enantiômero (+)-(S)- LER (HERBETTE et al, 1998;CERBAI et al, 2000;CARGNONI et al, 1997). LEONARDI et al (1997) (HERBETTE et al, 1998).…”

“…Vários estudos das propriedades farmacodinâmicas, "in vitro" e "in vivo", com animais (CERBAI et al, 2000;SABBATINI;TOMASSONI;AMENTA, 2001;CORSINI et al, 1996;GUARNERI et al, 1996;SIRONI et al, 1996. ) COMINACINI et al, 1999;AMBROSINI;CIRCO, 1997;ACANFORA et al, 2000;DE GIORGIO et al, 1999), têm sido realizados com o LER, comprovando sua eficácia como agente hipotensor e sua possível interferência nos eventos da aterogênese (BORASO et al, 1997).…”