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Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts

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ABSTRACT

The present study examined the ventricular arrhythmic and electrophysiological properties during hyperkalemia (6.3 mM [K+] vs. 4 mM in normokalemia) and anti-arrhythmic effects of hypercalcemia (2.2 mM [Ca2+]) in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricle during right ventricular pacing. Hyperkalemia increased the proportion of hearts showing provoked ventricular tachycardia (VT) from 0 to 6 of 7 hearts during programmed electrical stimulation (Fisher's exact test, P<0.05). It shortened the epicardial action potential durations (APDx) at 90, 70, 50 and 30% repolarization and ventricular effective refractory periods (VERPs) (analysis of variance, P<0.05) without altering activation latencies. Endocardial APDx and VERPs were unaltered. Consequently, ∆APDx (endocardial APDx-epicardial APDx) was increased, VERP/latency ratio was decreased and critical intervals for reexcitation (APD90-VERP) were unchanged. Hypercalcemia treatment exerted anti-arrhythmic effects during hyperkalemia, reducing the proportion of hearts showing VT to 1 of 7 hearts. It increased epicardial VERPs without further altering the remaining parameters, returning VERP/latency ratio to normokalemic values and also decreased the critical intervals. In conclusion, hyperkalemia exerted pro-arrhythmic effects by shortening APDs and VERPs. Hypercalcemia exerted anti-arrhythmic effects by reversing VERP changes, which scaled the VERP/latency ratio and critical intervals.

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(A-D) Critical intervals (APD90-VERP) and (E) VERP/latency ratio. * and ** indicate significant differences from control values, and † indicates significant differences from values obtained during hyperkalemia alone. Local critical intervals obtained from the (A) epicardium were not significantly affected by hyperkalemia alone but were reduced by hypercalcemia treatment (ANOVA, *,†P<0.05). The local critical interval obtained from the (B) endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the (C) epicardium was reduced (Student's t-test, *P<0.05 and **P<0.01) and not further altered by hypercalcemia treatment (P>0.05). (D) The transmural critical interval for reexcitation of the epicardium by the endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05; but there was a difference between K+ and K+ + Ca2+, †P<0.05). (E) VERP/latency was decreased by hyperkalemia from 2.8±0.2 to 1.9±0.2 mm (n=8; ANOVA, **P<0.01; K+ vs. K+ + Ca2+, ††P<0.01) and subsequently restored to 2.8±0.2 mm by hypercalcemia treatment, a value that was not statistically different when compared to the control value (ANOVA, P>0.05). APD, action potential duration; VERP, ventricular effective refractory periods; ANOVA, analysis of variance.
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f7-br-0-0-735: (A-D) Critical intervals (APD90-VERP) and (E) VERP/latency ratio. * and ** indicate significant differences from control values, and † indicates significant differences from values obtained during hyperkalemia alone. Local critical intervals obtained from the (A) epicardium were not significantly affected by hyperkalemia alone but were reduced by hypercalcemia treatment (ANOVA, *,†P<0.05). The local critical interval obtained from the (B) endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the (C) epicardium was reduced (Student's t-test, *P<0.05 and **P<0.01) and not further altered by hypercalcemia treatment (P>0.05). (D) The transmural critical interval for reexcitation of the epicardium by the endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05; but there was a difference between K+ and K+ + Ca2+, †P<0.05). (E) VERP/latency was decreased by hyperkalemia from 2.8±0.2 to 1.9±0.2 mm (n=8; ANOVA, **P<0.01; K+ vs. K+ + Ca2+, ††P<0.01) and subsequently restored to 2.8±0.2 mm by hypercalcemia treatment, a value that was not statistically different when compared to the control value (ANOVA, P>0.05). APD, action potential duration; VERP, ventricular effective refractory periods; ANOVA, analysis of variance.

Mentions: Increased critical intervals for reexcitation have previously been associated with increased arrhythmogenicity in hypokalemic mouse hearts (40). To determine their possible roles in hyperkalemia-induced arrhythmogenesis, these values were accordingly calculated for all the pharmacological conditions studied. The local critical interval for the epicardium was −7.0±4.1 msec under control conditions (n=7; Fig. 7A). The interval was not altered by hyperkalemia alone but was reduced by hypercalcemia treatment to −23.1±4.5 msec (ANOVA, P<0.05). By contrast, the local critical interval for the endocardium had a value of −1.4±3.5 msec (n=7; Fig. 7B) but this was not altered by either hyperkalemia alone or following further hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the epicardium had a value of 5.3±3.5 msec (n=7; Fig. 7C). This was reduced by hyperkalemia to −16.2±4.2 msec (Student's t-test, P<0.01) and not further altered by hypercalcemia treatment (P>0.05). By contrast, the critical interval for reexcitation of the epicardium by the endocardium had a value of −10.3±5.7 msec, and was not altered by either hyperkalemia alone or following hypercalcemia treatment (Fig. 7D; P>0.05).


Anti-arrhythmic effects of hypercalcemia in hyperkalemic, Langendorff-perfused mouse hearts
(A-D) Critical intervals (APD90-VERP) and (E) VERP/latency ratio. * and ** indicate significant differences from control values, and † indicates significant differences from values obtained during hyperkalemia alone. Local critical intervals obtained from the (A) epicardium were not significantly affected by hyperkalemia alone but were reduced by hypercalcemia treatment (ANOVA, *,†P<0.05). The local critical interval obtained from the (B) endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the (C) epicardium was reduced (Student's t-test, *P<0.05 and **P<0.01) and not further altered by hypercalcemia treatment (P>0.05). (D) The transmural critical interval for reexcitation of the epicardium by the endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05; but there was a difference between K+ and K+ + Ca2+, †P<0.05). (E) VERP/latency was decreased by hyperkalemia from 2.8±0.2 to 1.9±0.2 mm (n=8; ANOVA, **P<0.01; K+ vs. K+ + Ca2+, ††P<0.01) and subsequently restored to 2.8±0.2 mm by hypercalcemia treatment, a value that was not statistically different when compared to the control value (ANOVA, P>0.05). APD, action potential duration; VERP, ventricular effective refractory periods; ANOVA, analysis of variance.
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f7-br-0-0-735: (A-D) Critical intervals (APD90-VERP) and (E) VERP/latency ratio. * and ** indicate significant differences from control values, and † indicates significant differences from values obtained during hyperkalemia alone. Local critical intervals obtained from the (A) epicardium were not significantly affected by hyperkalemia alone but were reduced by hypercalcemia treatment (ANOVA, *,†P<0.05). The local critical interval obtained from the (B) endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the (C) epicardium was reduced (Student's t-test, *P<0.05 and **P<0.01) and not further altered by hypercalcemia treatment (P>0.05). (D) The transmural critical interval for reexcitation of the epicardium by the endocardium was not altered by either hyperkalemia alone or following hypercalcemia treatment (P>0.05; but there was a difference between K+ and K+ + Ca2+, †P<0.05). (E) VERP/latency was decreased by hyperkalemia from 2.8±0.2 to 1.9±0.2 mm (n=8; ANOVA, **P<0.01; K+ vs. K+ + Ca2+, ††P<0.01) and subsequently restored to 2.8±0.2 mm by hypercalcemia treatment, a value that was not statistically different when compared to the control value (ANOVA, P>0.05). APD, action potential duration; VERP, ventricular effective refractory periods; ANOVA, analysis of variance.
Mentions: Increased critical intervals for reexcitation have previously been associated with increased arrhythmogenicity in hypokalemic mouse hearts (40). To determine their possible roles in hyperkalemia-induced arrhythmogenesis, these values were accordingly calculated for all the pharmacological conditions studied. The local critical interval for the epicardium was −7.0±4.1 msec under control conditions (n=7; Fig. 7A). The interval was not altered by hyperkalemia alone but was reduced by hypercalcemia treatment to −23.1±4.5 msec (ANOVA, P<0.05). By contrast, the local critical interval for the endocardium had a value of −1.4±3.5 msec (n=7; Fig. 7B) but this was not altered by either hyperkalemia alone or following further hypercalcemia treatment (P>0.05). The transmural critical interval for reexcitation of the endocardium by the epicardium had a value of 5.3±3.5 msec (n=7; Fig. 7C). This was reduced by hyperkalemia to −16.2±4.2 msec (Student's t-test, P<0.01) and not further altered by hypercalcemia treatment (P>0.05). By contrast, the critical interval for reexcitation of the epicardium by the endocardium had a value of −10.3±5.7 msec, and was not altered by either hyperkalemia alone or following hypercalcemia treatment (Fig. 7D; P>0.05).

View Article: PubMed Central - PubMed

ABSTRACT

The present study examined the ventricular arrhythmic and electrophysiological properties during hyperkalemia (6.3 mM [K+] vs. 4 mM in normokalemia) and anti-arrhythmic effects of hypercalcemia (2.2 mM [Ca2+]) in Langendorff-perfused mouse hearts. Monophasic action potential recordings were obtained from the left ventricle during right ventricular pacing. Hyperkalemia increased the proportion of hearts showing provoked ventricular tachycardia (VT) from 0 to 6 of 7 hearts during programmed electrical stimulation (Fisher's exact test, P&lt;0.05). It shortened the epicardial action potential durations (APDx) at 90, 70, 50 and 30% repolarization and ventricular effective refractory periods (VERPs) (analysis of variance, P&lt;0.05) without altering activation latencies. Endocardial APDx and VERPs were unaltered. Consequently, &#8710;APDx (endocardial APDx-epicardial APDx) was increased, VERP/latency ratio was decreased and critical intervals for reexcitation (APD90-VERP) were unchanged. Hypercalcemia treatment exerted anti-arrhythmic effects during hyperkalemia, reducing the proportion of hearts showing VT to 1 of 7 hearts. It increased epicardial VERPs without further altering the remaining parameters, returning VERP/latency ratio to normokalemic values and also decreased the critical intervals. In conclusion, hyperkalemia exerted pro-arrhythmic effects by shortening APDs and VERPs. Hypercalcemia exerted anti-arrhythmic effects by reversing VERP changes, which scaled the VERP/latency ratio and critical intervals.

No MeSH data available.


Related in: MedlinePlus