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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
Published on: July 3, 2013
In vitro and in vivo effects of the atrial selective antiarrhythmic compound AVE1231
Klaus J Wirth1, Joachim Brendel, Klaus Steinmeyer
1Sanofi-Aventis Deutschland GmbH, D-65926 Frankfurt/M, Germany.
Insights
The novel compound AVE1231 effectively blocks atrial potassium channels, prolonging atrial refractoriness. This suggests AVE1231 is a promising treatment for preventing atrial fibrillation without impacting ECG intervals or ventricular function.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
- Ion Channel Research
Background:
- Atrial fibrillation (AF) is a common arrhythmia with significant health implications.
- Current treatments for AF have limitations, necessitating the development of novel therapeutic agents.
- Targeting specific ion channels in the atria offers a potential strategy for AF management.
Purpose of the Study:
- To investigate the electrophysiological effects of the novel compound AVE1231.
- To determine the potential of AVE1231 in preventing atrial fibrillation.
- To assess the selectivity of AVE1231 on cardiac ion channels and its effects on atrial and ventricular properties.
Main Methods:
- In vitro electrophysiology in CHO cells expressing hKv1.5 and hKv4.3 + KChIP2.2b channels.
- Patch-clamp studies on pig left atrial myocytes to assess effects on various ionic currents.
- In vivo studies in anesthetized pigs and conscious goats to evaluate effects on atrial refractoriness, vulnerability, and ECG parameters.
- Assessment of AVE1231's impact on electrical remodeling in goats after rapid pacing.
Main Results:
- AVE1231 selectively blocked hKv1.5 and hKv4.3 + KChIP2.2b channels (IC50 values 3.6 and 5.9 microM).
- In pig atrial myocytes, AVE1231 blocked a voltage-dependent outward current (IC50 1.1 microM) and IKACh (IC50 8.4 microM) with minimal effects on other currents.
- Oral administration in pigs dose-dependently increased left atrial refractoriness and reduced arrhythmia vulnerability without altering ECG intervals.
- In goats, AVE1231 significantly prolonged left atrial refractoriness, even under conditions of electrical remodeling, outperforming dofetilide in this context.
Conclusions:
- AVE1231 demonstrates potent blockade of key atrial potassium channels, leading to prolonged atrial refractoriness.
- The compound exhibits a favorable safety profile, with no significant effects on ECG intervals or ventricular repolarization.
- These findings suggest AVE1231 holds promise as a novel therapeutic agent for the prevention of atrial fibrillation.
Abstract:
The novel compound AVE1231 was investigated in order to elucidate its potential against atrial fibrillation. In CHO cells, the current generated by hKv1.5 or hKv4.3 + KChIP2.2b channels was blocked with IC50 values of 3.6 microM and 5.9 microM, respectively. In pig left atrial myocytes, a voltage-dependent outward current was blocked with an IC50 of 1.1 microM, mainly by accelerating the time constant of decay. Carbachol-activated IKACh was blocked by AVE1231 with an IC50 of 8.4 microM. Other ionic currents, like the IKr, IKs, IKATP, ICa, and INa were only mildly affected by 10 microM AVE1231. In guinea pig papillary muscle the APD90 and the upstroke velocity were not significantly altered by 30 microM AVE1231. In anesthetized pigs, oral doses of 0.3, 1, and 3 mg/kg AVE1231 caused a dose-dependent increase in left atrial refractoriness (LAERP), associated by inhibition of left atrial vulnerability to arrhythmia. There were no effects on the ECG intervals, ventricular monophasic action potentials, or ventricular refractory periods at 3 mg/kg AVE1231 applied intravenously. In conscious goats, both AVE1231 (3 mg/kg/h iv) and dofetilide (10 microg/kg/h iv) significantly prolonged LAERP. After 72 hours of tachypacing, when LAERP was shortened significantly (electrical remodelling), the prolongation of LAERP induced by AVE1231 was even more pronounced than in sinus rhythm. In contrast, the effect of dofetilide was strongly decreased. The present data demonstrate that AVE1231 blocks early atrial K channels and prolongs atrial refractoriness with no effects on ECG intervals and ventricular repolarisation, suggesting that it is suited for the prevention of atrial fibrillation in patients.
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