Reverse use dependence of calcium sensitizer levosimendan on action potential duration shortening prevents ventricular arrhythmia during therapeutic hypothermia

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
Y.C Hsieh ◽  
C.H Li ◽  
J.C Lin ◽  
C.J Weng ◽  
Y.S Chien ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Action Potential ◽  
Therapeutic Hypothermia ◽  
Action Potential Duration ◽  
Heart Failure Treatment ◽  
Novel Approach ◽  
Mapping System ◽  
Diastolic Interval ◽  
K Current ◽  
Calcium Sensitizer

Abstract Background Therapeutic hypothermia (TH) increases the risk of ventricular arrhythmia (VA) by prolonging action potential duration (APD) and steepening the APD restitution (APDR). The calcium sensitizer levosimendan, a medication for heart failure treatment, has been reported to shorten APD by enhancing ATP-sensitive K current and affect the APDR. Purpose We hypothesized that levosimendan might shorten the already prolonged APD particularly at long pacing cycle length (PCL), thus decreases the maximal slope of APDR, and prevent VA during TH. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, APD was evaluated by S1 pacing and APDR curve was plotted using APD70 versus diastolic interval. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s at the shortest PCL that achieved 1:1 ventricular capture. Results The APD was shortened from 259±8 ms at TH to 241±18 ms after levosimendan infusion at long PCL of 400 ms (p=0.024). However, at short PCL of 280 ms, the APD was not changed before (194±19) and after (188±23) levosimendan during TH (p=0.61). Levosimendan decreases the maximal slope of APDR curve from 1.99±0.65 at TH to 1.41±0.32 after adding levosimendan (p=0.034). The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% with levosimendan (p=0.023). In control hearts, the maximal slope of APDR (p=0.75) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusion Levosimendan might protect the hearts against VA during TH by shortening APD at long PCL and flattening the APDR. Enhancing ATP-sensitive K current with levosimendan during TH might be a novel approach to prevent VA during TH. Funding Acknowledgement Type of funding source: None

P2564Levosimendan shortens action potential duration, decreases alternans threshold and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
Y C Hsieh ◽  
C H Li ◽  
Y C Liao ◽  
J C Lin ◽  
C J Weng ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Action Potential ◽  
Therapeutic Hypothermia ◽  
Action Potential Duration ◽  
Ventricular Arrhythmias ◽  
Cycle Length ◽  
Novel Approach ◽  
Mapping System ◽  
K Current ◽  
Calcium Sensitizer

Abstract Background Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VA) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). The calcium sensitizer levosimendan has been reported to shorten APD by enhancing ATP-sensitive K current. We hypothesize that levosimendan might shorten the already prolonged APD during TH, decreasing SDA threshold, and prevent the occurrence of VA. Methods Langendorff-perfused isolated rabbit hearts were subjected to 15-min TH (30°C) followed by 30-min treatment with levosimendan (0.5 μM, n=9) or vehicle (n=8). Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induced SDA phenomenon. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 s using the shortest PCL that achieved 1:1 ventricular capture. Results Levosimendan shortened the ventricular APD (at PCL 300 ms, from 229±9 ms to 211±18 ms, p=0.02) and decrease the SDA threshold (from 327±88 ms to 311±68 ms, p=0.001) during TH. The VF inducibility was decreased by levosimendan from 39±30% at 30°C to 14±12% after levosimendan infusion. In control hearts, the APD (p=0.75), SDA threshold (p=ns) and VF inducibility (p=0.12) were not changed by vehicle during TH. Conclusions Levosimendan protects the hearts against VA during TH by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to prevent VA during TH.

Dual effects of external magnesium on action potential duration in guinea pig ventricular myocytes

1995 ◽  
Vol 268 (6) ◽  
pp. H2321-H2328 ◽  
Author(s):  
S. Zhang ◽  
T. Sawanobori ◽  
H. Adaniya ◽  
Y. Hirano ◽  
M. Hiraoka
Keyword(s):  
Guinea Pig ◽  
Action Potential ◽  
Decay Time ◽  
Action Potential Duration ◽  
Time Course ◽  
Ventricular Myocytes ◽  
Membrane Surface ◽  
Surface Charges ◽  
Whole Cell Patch Clamp ◽  
K Current

Effects of extracellular magnesium (Mg2+) on action potential duration (APD) and underlying membrane currents in guinea pig ventricular myocytes were studied by using the whole cell patch-clamp method. Increasing external Mg2+ concentration [Mg2+]o) from 0.5 to 3 mM produced a prolongation of APD at 90% repolarization (APD90), whereas 5 and 10 mM Mg2+ shortened it. [Mg2+]o, at 3 mM or higher, suppressed the delayed outward K+ current and the inward rectifier K+ current. Increases in [Mg2+]o depressed the peak amplitude and delayed the decay time course of the Ca2+ current (ICa), the latter effect is probably due to the decrease in Ca(2+)-induced inactivation. Thus 3 mM Mg2+ suppressed the peak ICa but increased the late ICa amplitude at the end of a 200-ms depolarization pulse, whereas 10 mM Mg2+ suppressed both components. Application of 10 mM Mg2+ shifted the voltage-dependent activation and inactivation by approximately 10 mV to more positive voltage due to screening the membrane surface charges. Application of manganese (1-5 mM) also caused dual effects on APD90, similar to those of Mg2+, and suppressed the peak ICa with slowed decay. These results suggest that the dual effects of Mg2+ on APD in guinea pig ventricular myocytes can be, at least in part, explained by its action on ICa with slowed decay time course in addition to suppressive effects on K+ currents.

Larger transient outward K+ current and shorter action potential duration in Gα11 mutant mice

2009 ◽  
Vol 459 (4) ◽  
pp. 607-618 ◽  
Author(s):  
Michael Wagner ◽  
Elena Rudakova ◽  
Vera Schütz ◽  
Magdalena Frank ◽  
Heimo Ehmke ◽  
...  
Keyword(s):  
Action Potential ◽  
Action Potential Duration ◽  
Mutant Mice ◽  
K Current

Concurrent increases in post-pacing action potential duration and contractility predict occurrence of ventricular arrhythmia

2020 ◽  
Vol 472 (12) ◽  
pp. 1783-1791
Author(s):  
Chih-Min Liu ◽  
Feng-Zhi Lin ◽  
Yao-Chang Chen ◽  
Yung-Kuo Lin ◽  
Yen-Yu Lu ◽  
...  
Keyword(s):  
Ventricular Arrhythmia ◽  
Action Potential ◽  
Action Potential Duration

scholarly journals Myocardial Depressant Effects of Sevoflurane

1996 ◽  
Vol 84 (5) ◽  
pp. 1166-1176 ◽  
Author(s):  
Wyun Kon Park ◽  
Joseph J. Pancrazio ◽  
Chang Kook Suh ◽  
Carl III Lynch
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Guinea Pig ◽  
Action Potential ◽  
Papillary Muscle ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Peak Force ◽  
Rapid Cooling ◽  
K Current ◽  
Slow Action Potentials

Background The effects of anesthetic concentrations of sevoflurane were studied in isolated myocardial tissue to delineate the mechanisms by which cardiac function is altered. Methods Isometric force of isolated guinea pig ventricular papillary muscle was studied at 37 degrees C in normal and 26 mM K+ Tyrode's solution at various stimulation rates. Normal and slow action potentials were evaluated using conventional microelectrodes. Effects of sevoflurane on sarcoplasmic reticulum function in situ were also evaluated by its effect on rapid cooling contractures, which are known to activate Ca2+ release from the sarcoplasmic reticulum, and on concentrations of rat papillary muscle. Finally, Ca2+ and K+ currents of isolated guinea pig ventricular myocytes were examined using the whole-cell patch clamp technique. Results Sevoflurane equivalent to 1.4% and 2.8% depressed guinea pig myocardial contractions to approximately 85 and approximately 65% of control, respectively, although the maximum rate of force development at 2 or 3 Hz and force in rat myocardium after rest showed less depression. In the partially depolarized, beta-adrenergically stimulated myocardium, sevoflurane selectively depressed late peak force without changing early peak force, whereas it virtually abolished rapid cooling contractures. Sevoflurane did not alter the peak amplitude or maximum depolarization rate of normal and slow action potentials, but action potential duration was significantly prolonged. In isolated guinea pig myocytes at room temperature, 0.7 mM sevoflurane (equivalent to 3.4%) depressed peak Ca2+ current by approximately 25% and increased the apparent rate of inactivation. The delayed outward K+ current was markedly depressed, but the inwardly rectifying K+ current was only slightly affected by 0.35 mM sevoflurane. Conclusions These results suggest that the direct myocardial depressant effects of sevoflurane are similar to those previously described for isoflurane. The rapid initial release of Ca2+ from the sarcoplasmic reticulum is not markedly decreased, although certain release pathway, specifically those induced by rapid cooling, appear to be depressed. Contractile depression may be partly related to the depression of Ca2+ influx through the cardiac membrane. The major electrophysiologic effect of sevoflurane seems to be a depression of the delayed outward K+ current, which appears to underlie the increased action potential duration.

Halothane Inhibits Contraction and Action Potential Duration to a Greater Extent in Subendocardial than Subepicardial Myocytes from the Rat Left Ventricle

2001 ◽  
Vol 95 (5) ◽  
pp. 1213-1219 ◽  
Author(s):  
Amber Rithalia ◽  
Clare N. Gibson ◽  
Philip M. Hopkins ◽  
Simon M. Harrison
Keyword(s):  
Left Ventricle ◽  
Action Potential ◽  
Action Potential Duration ◽  
Action Potentials ◽  
Minimum Alveolar Concentration ◽  
Negative Inotropic Effect ◽  
Inotropic Effect ◽  
Control Action ◽  
Differential Effects ◽  
K Current

Background Halothane inhibits the 4-aminopyridine-sensitive transient outward K(+) current (I(to)) which in many species, including humans, plays an important role in determining action potential duration. As I(to) is greater in the ventricular subepicardium than subendocardium, halothane may have differential effects on action potential duration and, therefore, contraction in cells isolated from these two regions. Methods Myocytes were isolated from the subendocardium and subepicardium of the rat left ventricle. Myocytes from each region were electrically stimulated at 1 Hz to measure contractions and action potentials and exposed to 0.6 mm halothane (approximately 2 x minimum alveolar concentration(50) for the rat) for 1 min. The time from the peak of the action potential to repolarization at 0 and -50 mV was measured to assess the effects of halothane on action potential duration. Results Halothane inhibited contraction to a significantly (P = 0.002) greater extent in subendocardial myocytes than in subepicardial myocytes: the amplitude of contraction during control conditions was 3.6 +/- 0.4 microm and 3.2 +/- 0.7 microm in subendocardial and subepicardial cells, respectively, and this was reduced to 1.1 +/- 0.2 microm (29 +/- 2% of control, P < 0.0001, n = 10) and 1.4 +/- 0.3 microm (46 +/- 3% of control, P = 0.007, n = 7), respectively, after a 1-min exposure to 0.6 mm halothane. Control action potential duration (at -50 mV) was 67 +/- 10 and 28 +/- 4 ms in subendocardial and subepicardial myocytes, respectively, and these values were reduced to 39 +/- 6 ms (58 +/- 3% of control, P < 0.001) and 20 +/- 3 ms (73 +/- 5% of control, P = 0.009) by halothane, respectively. Conclusions Action potential duration was reduced to a greater extent in subendocardial than subepicardial myocytes, which would contribute to the greater negative inotropic effect of halothane in the subendocardium. Furthermore, the transmural difference in action potential duration was reduced by halothane, which could contribute to its arrhythmogenic properties.

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