Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

A.J. Workman, K.A. Kane, J.A. Russell, J. Norrie, A.C. Rankin

Research output: Contribution to journalArticle

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Abstract

Objective: Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. Methods: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca2+ current (ICaL), transient (ITO) and sustained (IKSUS) outward K+ currents, and input resistance (Ri) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. Results: In atrial cells from patients treated chronically with β-blockers, the APD90 and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (n = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in ICaL or IKSUS. The ITO blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n = 11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. Conclusion: The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade.
LanguageEnglish
Pages518-525
Number of pages7
JournalCardiovascular Research
Volume58
Issue number3
DOIs
Publication statusPublished - 1 Jun 2003

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Electrophysiology
Adrenergic Receptors
Pharmacology
Action Potentials
Cardiovascular Agents
Atrial Appendage
4-Aminopyridine
Anti-Arrhythmia Agents
Calcium Channel Blockers
Therapeutics
Angiotensin-Converting Enzyme Inhibitors
Muscle Cells
Heart Rate
Regression Analysis
Incidence
Pharmaceutical Preparations

Keywords

  • antiarrhythmic agents
  • arrhythmia (mechanisms)
  • remodeling
  • myocytes
  • ion channels

Cite this

Workman, A.J. ; Kane, K.A. ; Russell, J.A. ; Norrie, J. ; Rankin, A.C. / Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling. In: Cardiovascular Research. 2003 ; Vol. 58, No. 3. pp. 518-525.
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abstract = "Objective: Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. Methods: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca2+ current (ICaL), transient (ITO) and sustained (IKSUS) outward K+ currents, and input resistance (Ri) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. Results: In atrial cells from patients treated chronically with β-blockers, the APD90 and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (n = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in ICaL or IKSUS. The ITO blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n = 11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. Conclusion: The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade.",
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Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling. / Workman, A.J.; Kane, K.A.; Russell, J.A.; Norrie, J.; Rankin, A.C.

In: Cardiovascular Research, Vol. 58, No. 3, 01.06.2003, p. 518-525.

Research output: Contribution to journalArticle

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T1 - Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

AU - Workman, A.J.

AU - Kane, K.A.

AU - Russell, J.A.

AU - Norrie, J.

AU - Rankin, A.C.

PY - 2003/6/1

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N2 - Objective: Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. Methods: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca2+ current (ICaL), transient (ITO) and sustained (IKSUS) outward K+ currents, and input resistance (Ri) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. Results: In atrial cells from patients treated chronically with β-blockers, the APD90 and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (n = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in ICaL or IKSUS. The ITO blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n = 11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. Conclusion: The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade.

AB - Objective: Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. Methods: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca2+ current (ICaL), transient (ITO) and sustained (IKSUS) outward K+ currents, and input resistance (Ri) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. Results: In atrial cells from patients treated chronically with β-blockers, the APD90 and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (n = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in ICaL or IKSUS. The ITO blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n = 11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. Conclusion: The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade.

KW - antiarrhythmic agents

KW - arrhythmia (mechanisms)

KW - remodeling

KW - myocytes

KW - ion channels

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