Korean J Physiol Pharmacol.  2016 Jan;20(1):119-127. 10.4196/kjpp.2016.20.1.119.

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

• Lee HA
• Hyun SA
• Park SG
• Kim KS
• Kim SJ

• KMID: 2150481
• DOI: http://doi.org/10.4196/kjpp.2016.20.1.119

Abstract

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (I(Ca)) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (I(Kr), I(Ks)) and voltage-gated Na+ channel current (I(Na)). The concentration-dependent inhibition of Ca2+ channel currents (I(Ca)) was examined in rat cardiomyocytes; these CCBs have similar potency on I(Ca) channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 microM whereas NIC and AML shortened APD50 but not APD90 up to 30 microM. According to ion channel studies, NIC and AML concentration-dependently inhibited I(Kr) and I(Ks) while ISR had only partial inhibitory effects (<50% at 30 microM). Inhibition of I(Na) was similarly observed in the three CCBs. Since the I(Kr) and I(Ks) mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I(Ca).

Keyword

Antihypertensives; Cardiac action potentials; Cardiac repolarization; Dihydropyridine calcium channel blockers; Ion channels

MeSH Terms

Action Potentials
Amlodipine
Animals
Antihypertensive Agents
Arrhythmias, Cardiac
Calcium Channel Blockers*
Calcium Channels*
Calcium*
Cardiovascular Diseases
Inhibitory Concentration 50
Ion Channels
Isradipine
Myocytes, Cardiac
Nicardipine
Purkinje Fibers
Rats
Amlodipine
Antihypertensive Agents
Calcium
Calcium Channel Blockers
Calcium Channels
Ion Channels
Isradipine
Nicardipine

Figure

• 

  Fig. 1 Structures of dihydropyridine class-calcium channel blockers, NIC, ISR, and AML.Dihydropyridine (DHP) calcium channel blockers including NIC, ISR, and AML, are derived from the molecule dihydropyridine (red dotted circles). DHP is a molecule based upon pyridine, and the parent of a class of molecules that have been semi-saturated with two substituents replacing one double bond.

• 

  Fig. 2 Effect of NIC, ISR, and AML on ICa in rat cardiomyocytes.(A) ICa traces of rat cardiomyocytes under before and after application of 0.01, 0.1, 1, and 10 µM of CCBs. (B) Concentration response curves for inhibition of ICa by the CCBs, providing the IC50 values of 0.142±0.03 µM for NIC, 0.227±0.28 µM for ISR, and 0.229±0.02 µM for AML (each n=3).

• 

  Fig. 3 Effect of NIC, ISR, and AML on INa in HEK293.(A) Representative INa traces under control conditions and after application of various test concentrations of NIC, ISR, and AML. (B) Statistical summary and Hill's fitting of concentration–dependent inhibitions of INa for these drugs (each n=4). It provided the IC50 values of approximately 7.08, 3.05, and 6.38 µM for NIC, ISR, AML, respectively.

• 

  Fig. 4 Concentration-dependent effects of NIC, ISR and AML on the AP in rabbit Purkinje fibers.(A~C) Representative illustrations for the effects of NIC, ISR, and AML on the cardiac AP in rabbit Purkinje fibers. (D~F) Effects of NIC, ISR, and AML on the action potential duration of rabbit Purkinje fibers at 50% (APD50, opened circles) and 90% repolarization (APD90, closed circles). Data are expressed as mean±SEM and compared by ANOVA followed by Dunnett's test (each n=4). *p<0.05; **p<0.01, compared with VC (vehicle control, 0.1% DMSO in NT).

• 

  Fig. 5 Effect of NIC, ISR and AML on IKr in HEK293 cells.(A) Representative current traces of IKr under control and after application of various concentrations ranging from 0.1~30 µM of NIC, ISR, and AML. (B) Concentration–dependent inhibitions of IKr for NIC, ISR, and AML were summarized and fitted with Hill function (each n=4). The IC50 values were 0.88±0.05 µM for NIC, 6.78±0.36 µM for AML, and >30 µM for ISR.

• 

  Fig. 6 Effect of NIC, ISR and AML on IKs expressed in HEK293 cells.(A) Representative current traces showing the effects of NIC, ISR, and AML on IKs at doses of 1, 3, 10, and 30 µM, respectively. (B) Dose-response relationships of IKs for NIC, ISR, and AML were summarized and fitted with Hill function (each n=4).

• 

  Fig. 7 Effect of NIC, ISR and AML on IK1 expressed in HEK293 cells.(A) Representative current traces demonstrating the effects of NIC, ISR, AML on IK1 at 0 (control), 1, 3, 10, 30 µM, respectively. (B) Concentration–dependent inhibitions of IK1 induced by NIC, ISR, and AML were summarized and fitted with Hill function for IC50 values (each n=4). The IC50 value of AML on the IK1 was 9.78±0.18 µM. Since the maximum inhibition rates of NIC and ISR were smaller than 50%, we could not obtain the IC50 values for these drugs.

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