Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh
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Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh. / Petersen, Johannes; Castro, Liesa; Bengaard, Anne K.P.; Pecha, Simon; Ismaili, Djemail; Schulz, Carl; Sahni, Jascha; Steenpass, Anna; Meier, Christian; Reichenspurner, Hermann; Jespersen, Thomas; Eschenhagen, Thomas; Christ, Torsten.
In: Journal of Cardiovascular Pharmacology, Vol. 79, No. 5, 2022, p. 678-686.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Muscarinic Receptor Activation Reduces Force and Arrhythmias in Human Atria Independent of IK,ACh
AU - Petersen, Johannes
AU - Castro, Liesa
AU - Bengaard, Anne K.P.
AU - Pecha, Simon
AU - Ismaili, Djemail
AU - Schulz, Carl
AU - Sahni, Jascha
AU - Steenpass, Anna
AU - Meier, Christian
AU - Reichenspurner, Hermann
AU - Jespersen, Thomas
AU - Eschenhagen, Thomas
AU - Christ, Torsten
N1 - Publisher Copyright: © 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022
Y1 - 2022
N2 - In human hearts, muscarinic receptors (M-R) are expressed in ventricular and atrial tissue, but the acetylcholine-activated potassium current (IK,ACh) is expressed mainly in the atrium. M-R activation decreases force and increases electrical stability in human atrium, but the impact of IK,AChto both effects remains unclear. We used a new selective blocker of IK,AChto elaborate the contribution of IK,AChto M-R activation-mediated effects in human atrium. Force and action potentials were measured in rat atria and in human right atrial trabeculae. Cumulative concentration-effect curves for norepinephrine-induced force and arrhythmias were measured in the presence of carbachol (CCh; 1 µM) or CCh together with the IK,ACh-blocker XAF-1407 (1 µM) or in time-matched controls. To investigate the vulnerability to arrhythmias, we performed some experiments also in the presence of cilostamide (0.3 µM) and rolipram (1 µM), inhibiting PDE3 and PDE4. In rat atria and human right atrial trabeculae, CCh shortened the action potential duration persistently. However, the direct negative inotropy of CCh was only transient in human, but stable in rat atria. In rat and human atria, the negative inotropic effect was insensitive to blockage of IK,AChby XAF-1407. In the presence of cilostamide and rolipram about 40% of trabeculae developed arrhythmias when exposed to norepinephrine. CCh prevented these concentration-dependent norepinephrine-induced arrhythmias, again insensitive to XAF-1407. Maximum catecholamine-induced force was not depressed by CCh. In human atrium, the direct and the indirect negative inotropic effect of CCh are independent of IK,ACh. The same applies to the CCh-mediated suppression of norepinephrine/PDE-inhibition-induced arrhythmias.
AB - In human hearts, muscarinic receptors (M-R) are expressed in ventricular and atrial tissue, but the acetylcholine-activated potassium current (IK,ACh) is expressed mainly in the atrium. M-R activation decreases force and increases electrical stability in human atrium, but the impact of IK,AChto both effects remains unclear. We used a new selective blocker of IK,AChto elaborate the contribution of IK,AChto M-R activation-mediated effects in human atrium. Force and action potentials were measured in rat atria and in human right atrial trabeculae. Cumulative concentration-effect curves for norepinephrine-induced force and arrhythmias were measured in the presence of carbachol (CCh; 1 µM) or CCh together with the IK,ACh-blocker XAF-1407 (1 µM) or in time-matched controls. To investigate the vulnerability to arrhythmias, we performed some experiments also in the presence of cilostamide (0.3 µM) and rolipram (1 µM), inhibiting PDE3 and PDE4. In rat atria and human right atrial trabeculae, CCh shortened the action potential duration persistently. However, the direct negative inotropy of CCh was only transient in human, but stable in rat atria. In rat and human atria, the negative inotropic effect was insensitive to blockage of IK,AChby XAF-1407. In the presence of cilostamide and rolipram about 40% of trabeculae developed arrhythmias when exposed to norepinephrine. CCh prevented these concentration-dependent norepinephrine-induced arrhythmias, again insensitive to XAF-1407. Maximum catecholamine-induced force was not depressed by CCh. In human atrium, the direct and the indirect negative inotropic effect of CCh are independent of IK,ACh. The same applies to the CCh-mediated suppression of norepinephrine/PDE-inhibition-induced arrhythmias.
KW - arrhythmia
KW - force
KW - human atria
KW - I
KW - muscarinic receptor
U2 - 10.1097/FJC.0000000000001237
DO - 10.1097/FJC.0000000000001237
M3 - Journal article
C2 - 35170489
AN - SCOPUS:85129999375
VL - 79
SP - 678
EP - 686
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
SN - 0160-2446
IS - 5
ER -
ID: 311334431