Effect of the cardioselective, sarcolemmal KATP channel blocker HMR 1098 on atrial electrical remodeling during pacing-induced atrial fibrillation in dogs

András Vereckei, Heinz Gögelein, Klaus J. Wirth, Douglas P. Zipes

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Purpose: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. Methods and results: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (IV) infusion at 17 μg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving IV saline. Pharmacological autonomic blockade was induced by IV administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous IV infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 ± 21 msec at baseline to 161 ± 23 msec at 360 min at 400 msec CL) (p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP (p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. Conclusions: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.

Original languageEnglish
Pages (from-to)23-30
Number of pages8
JournalCardiovascular Drugs and Therapy
Volume18
Issue number1
DOIs
StatePublished - Jan 2004

Fingerprint

Atrial Remodeling
KATP Channels
Atrial Fibrillation
Dogs
Sinoatrial Node
Coronary Sinus
Atropine
Intravenous Infusions
Propranolol
HMR 1098
Intravenous Administration
Therapeutics
Pharmacology
Control Groups
Injections

Keywords

  • Atrial electrical remodeling
  • Atrial fibrillation
  • Channels
  • HMR 1098
  • K

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Effect of the cardioselective, sarcolemmal KATP channel blocker HMR 1098 on atrial electrical remodeling during pacing-induced atrial fibrillation in dogs. / Vereckei, András; Gögelein, Heinz; Wirth, Klaus J.; Zipes, Douglas P.

In: Cardiovascular Drugs and Therapy, Vol. 18, No. 1, 01.2004, p. 23-30.

Research output: Contribution to journalArticle

@article{af26671e2fc544298ad13070bba5aa21,
title = "Effect of the cardioselective, sarcolemmal KATP channel blocker HMR 1098 on atrial electrical remodeling during pacing-induced atrial fibrillation in dogs",
abstract = "Purpose: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. Methods and results: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (IV) infusion at 17 μg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving IV saline. Pharmacological autonomic blockade was induced by IV administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous IV infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 ± 21 msec at baseline to 161 ± 23 msec at 360 min at 400 msec CL) (p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP (p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. Conclusions: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.",
keywords = "Atrial electrical remodeling, Atrial fibrillation, Channels, HMR 1098, K",
author = "Andr{\'a}s Vereckei and Heinz G{\"o}gelein and Wirth, {Klaus J.} and Zipes, {Douglas P.}",
year = "2004",
month = "1",
doi = "10.1023/B:CARD.0000025752.63337.b2",
language = "English",
volume = "18",
pages = "23--30",
journal = "Cardiovascular Drugs and Therapy",
issn = "0920-3206",
publisher = "Kluwer Academic Publishers",
number = "1",

}

TY - JOUR

T1 - Effect of the cardioselective, sarcolemmal KATP channel blocker HMR 1098 on atrial electrical remodeling during pacing-induced atrial fibrillation in dogs

AU - Vereckei, András

AU - Gögelein, Heinz

AU - Wirth, Klaus J.

AU - Zipes, Douglas P.

PY - 2004/1

Y1 - 2004/1

N2 - Purpose: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. Methods and results: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (IV) infusion at 17 μg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving IV saline. Pharmacological autonomic blockade was induced by IV administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous IV infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 ± 21 msec at baseline to 161 ± 23 msec at 360 min at 400 msec CL) (p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP (p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. Conclusions: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.

AB - Purpose: The progressive shortening of the atrial effective refractory period (ERP) during atrial fibrillation (AF) might be due to the activation of the KATP channels by rapid atrial rates. We tested the hypothesis that the cardioselective, sarcolemmal KATP channel blocker HMR 1098 would prevent atrial ERP shortening during AF. Methods and results: Nine dogs were treated with HMR 1098 (3 mg/kg bolus injection followed by a continuous intravenous (IV) infusion at 17 μg/kg/min rate maintained throughout the study) and 7 dogs served as controls receiving IV saline. Pharmacological autonomic blockade was induced by IV administration of atropine (0.04 mg/kg) and propranolol (0.2 mg/kg) and maintained throughout the study by continuous IV infusion of atropine (0.007 mg/kg/h) and propranolol (0.04 mg/kg/h). Rapid right atrial pacing at 50 msec cycle length (CL) was initiated and maintained for 6 hours. High right atrial ERP (HRA-ERP) and corrected sinus node recovery time (HRA-cSNRT), coronary sinus ERP (CS-ERP) and corrected SNRT (CS-cSNRT) at three (400, 300, 200 msec) CLs were measured before and after pacing at different time points. Baseline values were not different between control and treated dogs. In the control group the HRA-ERP progressively shortened (from 179 ± 21 msec at baseline to 161 ± 23 msec at 360 min at 400 msec CL) (p = 0.002), with a gradual decrease, loss or inversion of ERP rate adaptation at shorter (300, 200 msec) CLs. HMR 1098 treatment did not prevent the shortening of HRA-ERP during the first 2 to 3 hours of rapid atrial pacing. However, beginning at 180-240 min, HMR 1098 increased the HRA-ERP (p = 0.01) to baseline by 360 min. HMR 1098 treatment did not prevent another feature of atrial electrical remodeling, the flattening or inversion of ERP rate adaptation. In neither group did CS-ERP shortening occur. The maximum cSNRT at 360 min prolonged significantly in both groups during HRA and CS pacing as well compared with baseline. Conclusions: HMR 1098 treatment did not prevent the shortening of HRA-ERP, the salient feature of atrial electrical remodeling in the first 2 to 3 hours of rapid atrial rates, but did prevent it thereafter. Another characteristic feature of atrial electrical remodeling, the flattening or inversion of physiological ERP rate adaptation was not prevented by HMR 1098 treatment. Sinus node depression was detectable after short-term (6 hours) rapid atrial pacing and was not affected by HMR 1098.

KW - Atrial electrical remodeling

KW - Atrial fibrillation

KW - Channels

KW - HMR 1098

KW - K

UR - http://www.scopus.com/inward/record.url?scp=3342998508&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3342998508&partnerID=8YFLogxK

U2 - 10.1023/B:CARD.0000025752.63337.b2

DO - 10.1023/B:CARD.0000025752.63337.b2

M3 - Article

VL - 18

SP - 23

EP - 30

JO - Cardiovascular Drugs and Therapy

JF - Cardiovascular Drugs and Therapy

SN - 0920-3206

IS - 1

ER -