Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes

Cheng, Jianhua; Niwa, Ryoko; Kamiya, Kaichiro; Toyama, Junji; Kodama, Itsuo

doi:10.1016/s0014-2999(99)00368-4

Cited by 76 publications

(66 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…14 The activation-deactivation kinetics of I Kr (chromanol 293B-resistant component) and I Ks (chromanol 293B-sensitive component) in control rabbits were similar to those in our previous reports, 14,19 in which I Kr and I Ks were estimated as E-4031-sensitive and -insensitive components, respectively. Unlike other animal species, activation-deactivation kinetics of I Kr and I Ks in rabbits are similar (Table 2).…”

Section: Short-term Effects Of Amiodarone On I Kr and I Kssupporting

confidence: 87%

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current

et al. 2001

Self Cite

View full text Add to dashboard Cite

Background-Amiodarone is the most promising drug for the treatment of life-threatening tachyarrhythmias in patients with structural heart disease. The pharmacological effects of amiodarone on cardiac ion channels are complex and may differ for short-term and long-term administration. Methods and Results-The delayed rectifier K ϩ current (I K ) of ventricular myocytes isolated from rabbit hearts was recorded with the whole-cell voltage-clamp technique. I K was separated into 2 components by use of specific blockers for either I Ks (chromanol 293B, 30 mol/L) or I Kr (E-4031, 10 mol/L). Short-term application of amiodarone caused a concentration-dependent decrease in I Kr with an IC 50 of 2.8 mol/L (nϭ8) but only a minimal reduction in I Ks . The short-term effects of amiodarone were also determined in Xenopus oocytes expressing the cloned human channels that conduct I Kr and I Ks (HERG and KvLQT1/minK). HERG current in oocytes was reduced by amiodarone (IC 50 ϭ38 mol/L), whereas KvLQT1/minK current was unaffected by 300 mol/L amiodarone. To study the effects of long-term drug administration, rabbits were treated for 4 weeks with oral amiodarone (100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 ) before cell isolation. Long-term administration of amiodarone decreased I K to 55% (nϭ10) in control rabbits and altered the relative density of I Kr and I Ks . The majority (92%) of current was I Kr . mRNA levels of rabbit ERG, KVLQT1, and minK in left ventricular myocardium did not differ between control and long-term amiodarone. Conclusions-Amiodarone has differential effects on the 2 components of I K , depending on the application period;short-term treatment inhibits primarily I Kr , whereas long-term treatment reduces I Ks .

show abstract

Section: Short-term Effects Of Amiodarone On I Kr and I Kssupporting

confidence: 87%

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current

et al. 2001

Self Cite

View full text Add to dashboard Cite

show abstract

“…14 Carvedilol, on the other hand, demonstrates no significant reverse frequency dependence and, in its low ventricular proarrhythmic potential, more closely resembles amiodarone. 9 At concentrations of 1 and 3 µM, carvedilol prolonged the APD in rabbit papillary muscle 7-12% and 12-24%, respectively, at stimulation frequencies of 0.1-3.0 Hz. 9 This electrophysiologic effect of carvedilol appears to be due to a balanced inhibition of L-type calcium channels (more prominent at lower stimulation frequencies) as well as potassium channels, resulting in a moderately prolonged APD with minimal reverse frequency dependence compared with pure Class III agents.…”

Section: Introductionmentioning

confidence: 90%

“…9 At concentrations of 1 and 3 µM, carvedilol prolonged the APD in rabbit papillary muscle 7-12% and 12-24%, respectively, at stimulation frequencies of 0.1-3.0 Hz. 9 This electrophysiologic effect of carvedilol appears to be due to a balanced inhibition of L-type calcium channels (more prominent at lower stimulation frequencies) as well as potassium channels, resulting in a moderately prolonged APD with minimal reverse frequency dependence compared with pure Class III agents. 9,14 The inhibition of L-type calcium channels at concentrations > 0.3 µM not only protects against the potentially hazardous effects of prolonged APD, but also decreases sinus node firing that can mitigate the tachycardia-induced ischemia in myocardial infarction (MI).…”

Section: Introductionmentioning

confidence: 90%

“…9 The major impact of clinically utilized levels of carvedilol (0.1-0.6 µM) 9 on the APD in rabbit papillary muscle is due to a concentration-dependent inhibition of I Kr , the channel encoded in humans by the ether-a-go-go-related gene (HERG). 9,10 At a comparably adjusted concentration, carvedilol can similarly block cloned HERG channels expressed in Xenopus oocytes. 10 In spite of this measured activity, patients treated with carvedilol do not demonstrate a significantly prolonged QT interval on the surface electrocardiogram (ECG).…”

Section: Introductionmentioning

confidence: 99%

“…9 This electrophysiologic effect of carvedilol appears to be due to a balanced inhibition of L-type calcium channels (more prominent at lower stimulation frequencies) as well as potassium channels, resulting in a moderately prolonged APD with minimal reverse frequency dependence compared with pure Class III agents. 9,14 The inhibition of L-type calcium channels at concentrations > 0.3 µM not only protects against the potentially hazardous effects of prolonged APD, but also decreases sinus node firing that can mitigate the tachycardia-induced ischemia in myocardial infarction (MI). 9,15 Prolonged APD may be particularly proarrhythmic in the setting of a decreased sodium current in which the refractory and vulnerable periods are increased.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

Naccarelli

Lukas

2005

Clinical Cardiology

View full text Add to dashboard Cite

Summary:Carvedilol is a beta-and alpha-adrenergic-blocking drug with clinically important antiarrhythmic properties. It possesses anti-ischemic and antioxidant activity and inhibits a number of cationic channels in the cardiomyocyte, including the HERG-associated potassium channel, the L-type calcium channel, and the rapid-depolarizing sodium channel. The electrophysiologic properties of carvedilol include moderate prolongation of action potential duration and effective refractory period; slowing of atrioventricular conduction; and reducing the dispersion of refractoriness. Experimentally, carvedilol reduces complex and repetitive ventricular ectopy induced by ischemia and reperfusion.In patients, carvedilol is effective in controlling the ventricular rate response in atrial fibrillation (AF), with and without digitalis, and is useful in maintaining sinus rhythm after cardioversion, with and without amiodarone. In patients with AF and heart failure (HF), carvedilol reduces mortality risk and improves left ventricular (LV) function. Large-scale clinical trials have demonstrated that combined carvedilol and angiotensin-converting enzyme inhibitor therapy significantly reduces sudden cardiac death, mortality, and ventricular arrhythmia in patients with LV dysfunction (LVD) due to chronic HF or following myocardial infarction (MI).Despite intensive neurohormonal blockade, mortality rates remain relatively high in patients with post-MI and nonischemic LVD. Recent trials of implantable cardioverter-defibrillators added to pharmacologic therapy, especially beta blockers, have shown a further reduction in arrhythmic deaths in these patients.

show abstract

New Arrhythmia Technologies

Wang

Naccarelli

Rosen

et al. 2005

View full text Add to dashboard Cite

show abstract

Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes

Cited by 76 publications

References 42 publications

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

New Arrhythmia Technologies

Contact Info

Product

Resources

About

Carvedilol blocks the repolarizing K+ currents and the L-type Ca2+ current in rabbit ventricular myocytes

Cited by 76 publications

References 42 publications

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K + Current

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K + Current

Carvedilol's antiarrhythmic properties: Therapeutic implications in patients with left ventricular dysfunction

New Arrhythmia Technologies

Contact Info

Product

Resources

About

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current

Short- and Long-Term Effects of Amiodarone on the Two Components of Cardiac Delayed Rectifier K ⁺ Current