Nitric oxide mediates the vagal protective effect on ventricular fibrillation via effects on action potential duration restitution in the rabbit heart

The focal source hypothesis of ventricular fibrillation (VF) posits that rapid activation from a focal source, rather than action potential duration (APD) restitution properties, is responsible for the maintenance of VF. We injected aconitine (100 μg) into normal isolated perfused swine right ventricles (RVs) stained with 4-{β-[2-(di- n-butylamino)-6-naphthyl]vinyl}pyridinium (di-4-ANEPPS) for optical mapping studies. Within 97 ± 163 s, aconitine induced ventricular tachycardia (VT) with a mean cycle length 268 ± 37 ms, which accelerated before converting to VF. Drugs that flatten the APD restitution slope, including diacetyl monoxime (10–20 mM, n = 6), bretylium (10–20 μg/ml, n = 3), and verapamil (2–4 μg/ml, n = 3), reversibly converted VF to VT in all cases. In two RVs, VF persisted despite of the excision of the aconitine site. Simulations in two-dimensional cardiac tissue showed that once VF was initiated, it remained sustained even after the “aconitine” site was eliminated. In this model of focal source VF, the VT-to-VF transition occurred due to a wave break outside the aconitine site, and drugs that flattened the APD restitution slope converted VF to VT despite continuous activation from aconitine site.

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Pro-fibrillatory Effects of K[ATP] Channel Opener and the Action Potential Duration Restitution Kinetics in Isolated Swine Right Ventricle

Korean Circulation Journal ◽

10.4070/kcj.2004.34.3.296 ◽

2004 ◽

Vol 34 (3) ◽

pp. 296

Author(s):

Hui Nam Pak ◽

Gyo Seung Hwang ◽

Sang Chil Lee ◽

Byung Soo Kim ◽

Soo Jin Lee ◽

...

Keyword(s):

Action Potential ◽

Right Ventricle ◽

Action Potential Duration ◽

Channel Opener ◽

Action Potential Duration Restitution

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Droperidol Inhibits Intracellular Ca2+, Myofilament Ca2+Sensitivity, and Contraction in Rat Ventricular Myocytes

Anesthesiology ◽

10.1097/00000542-200506000-00016 ◽

2005 ◽

Vol 102 (6) ◽

pp. 1165-1173 ◽

Cited By ~ 3

Author(s):

Toshiya Shiga ◽

Sandro Yong ◽

Joseph Carino ◽

Paul A. Murray ◽

Derek S. Damron

Keyword(s):

Nitric Oxide ◽

Action Potential ◽

Action Potential Duration ◽

Ventricular Myocytes ◽

Nitric Oxide Production ◽

Cellular Mechanisms ◽

Rat Ventricular Myocytes ◽

Oxide Production ◽

Perfused Hearts ◽

Ca Sensitivity

Background Droperidol has recently been associated with cardiac arrhythmias and sudden cardiac death. Changes in action potential duration seem to be the cause of the arrhythmic behavior, which can lead to alterations in intracellular free Ca concentration ([Ca]i). Because [Ca]i and myofilament Ca sensitivity are key regulators of myocardial contractility, the authors' objective was to identify whether droperidol alters [Ca]i or myofilament Ca sensitivity in rat ventricular myocytes and to identify the cellular mechanisms responsible for these effects. Methods Freshly isolated rat ventricular myocytes were obtained from adult rat hearts. Myocyte shortening, [Ca]i, nitric oxide production, intracellular pH, and action potentials were monitored in cardiomyocytes exposed to droperidol. Langendorff perfused hearts were used to assess overall cardiac function. Results Droperidol (0.03-1 mum) caused concentration-dependent decreases in peak [Ca]i and shortening. Droperidol inhibited 35 mm KCl-induced increase in [Ca]i, with little direct effect on sarcoplasmic reticulum Ca stores. Droperidol had no effect on action potential duration but caused a rightward shift in the concentration-response curve to extracellular Ca for shortening, with no concomitant effect on peak [Ca]i. Droperidol decreased pHi and increased nitric oxide production. Droperidol exerted a negative inotropic effect in Langendorff perfused hearts. Conclusion These data demonstrate that droperidol decreases cardiomyocyte function, which is mediated by a decrease in [Ca]i and a decrease in myofilament Ca sensitivity. The decrease in [Ca]i is mediated by decreased sarcolemmal Ca influx. The decrease in myofilament Ca sensitivity is likely mediated by a decrease in pHi and an increase in nitric oxide production.

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Commentary: Interventricular Differences in Action Potential Duration Restitution Contribute to Dissimilar Ventricular Rhythms in ex vivo Perfused Hearts

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2019.00058 ◽

2019 ◽

Vol 6 ◽

Author(s):

Andreas Kucher ◽

Roland X. Stroobandt

Keyword(s):

Action Potential ◽

Action Potential Duration ◽

Ex Vivo ◽

Perfused Hearts ◽

Action Potential Duration Restitution

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Intramural optical mapping of Vm and Cai2+ during long-duration ventricular fibrillation in canine hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00426.2011 ◽

2012 ◽

Vol 302 (6) ◽

pp. H1294-H1305 ◽

Cited By ~ 9

Author(s):

Wei Kong ◽

Raymond E. Ideker ◽

Vladimir G. Fast

Keyword(s):

Ventricular Fibrillation ◽

Action Potential ◽

Short Duration ◽

Action Potential Duration ◽

Cycle Length ◽

The Other ◽

Membrane Voltage ◽

Long Duration ◽

Intracellular Ca ◽

Rapid Pacing

Intramural gradients of intracellular Ca2+ (Cai2+) Cai2+ handling, Cai2+ oscillations, and Cai2+ transient (CaT) alternans may be important in long-duration ventricular fibrillation (LDVF). However, previous studies of Cai2+ handling have been limited to recordings from the heart surface during short-duration ventricular fibrillation. To examine whether abnormalities of intramural Cai2+ handling contribute to LDVF, we measured membrane voltage ( Vm) and Cai2+ during pacing and LDVF in six perfused canine hearts using five eight-fiber optrodes. Measurements were grouped into epicardial, midwall, and endocardial layers. We found that during pacing at 350-ms cycle length, CaT duration was slightly longer (by ≃10%) in endocardial layers than in epicardial layers, whereas action potential duration (APD) exhibited no difference. Rapid pacing at 150-ms cycle length caused alternans in both APD (APD-ALT) and CaT amplitude (CaA-ALT) without significant transmural differences. For 93% of optrode recordings, CaA-ALT was transmurally concordant, whereas APD-ALT was either concordant (36%) or discordant (54%), suggesting that APD-ALT was not caused by CaA-ALT. During LDVF, Vm and Cai2+ progressively desynchronized when not every action potential was followed by a CaT. Such desynchronization developed faster in the epicardium than in the other layers. In addition, CaT duration strongly increased (by ∼240% at 5 min of LDVF), whereas APD shortened (by ∼17%). CaT rises always followed Vm upstrokes during pacing and LDVF. In conclusion, the fact that Vm upstrokes always preceded CaTs indicates that spontaneous Cai2+ oscillations in the working myocardium were not likely the reason for LDVF maintenance. Strong Vm-Cai2+ desynchronization and the occurrence of long CaTs during LDVF indicate severely impaired Cai2+ handling and may potentially contribute to LDVF maintenance.

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