Effects of caffeine and ryanodine on delayed afterdepolarizations and sustained rhythmic activity in 1-day-old myocardial infarction in the dog.

Abstract

Caffeine and ryanodine are known to modulate oscillatory release of Ca2' from the sarcoplasmic reticulum. The effects of caffeine and ryanodine on delayed afterdepolarizations (DADs) and sustained rhythmic activity in subendocardial Purkinje fibers surviving 1-day-old myocardial infarction in the dog were studied with standard microelectrode techniques. In preparations that showed sustained rhythmic activity, a high concentration of caffeine (10 mM) and ryanodine (10`and 10-6 M) slowed and terminated the sustained rhythmic activity and markedly suppressed DADs. An increase in the temperature of the tissue bath from 370 to 390 C did not change these results. In quiescent normal and infarcted preparations, a low concentration of caffeine (0.5 mM) differentially induced DADs in ischemic but not in normal Purkinje fibers, increased the amplitude of existing DADs, and brought subthreshold DADs to threshold potential that caused triggered activity. Our results are consistent with the hypothesis that triggered activity arising from DADs characterizes the sustained rhythmic activity in endocardial preparations 1 day after infarction and indicate an important role for the sarcoplasmic reticulum in the genesis of DADs and triggered activity in this model. (Circulation 1990;81:1393-1400 Subendocardial Purkinje fibers surviving 1 day after myocardial infarction in the dog show varying degrees of partial depolarization and spontaneous rhythmic activity.1-4 Two different mechanisms, abnormal automaticity3,5-7 and triggered activity arising from a delayed afterdepolarization (DAD),4 have been proposed to account for the arrhythmia. During sustained rhythmic activity, abnormal automaticity at a reduced membrane potential will be difficult to discern from triggered activity arising from DADs. In earlier studies of 1-day-old ischemic endocardial preparations in the dog, the sustained rhythmic activity was considered the result of abnormal automaticity.1-3 However, when the initiation and termination of these rhythms were studied in detail, most were found to be caused by triggered activity arising from DADs.

Calcium-calmodulin dependent protein kinase II (CaMKII): A main signal responsible for early reperfusion arrhythmias

“…The occurrence of DADs was tightly associated with spontaneous Ca 2+ release from cardiac RyR2. Indeed, when the SR function was disabled by the application of 1 μM ryanodine, a concentration known to diminish DADs [25,26], the number of PBs upon reperfusion were reduced from 46 ± 5 to 22 ± 6 beats/3min (See Figure 1 of Supplementary Data), implicating the SR as a main contributor to the generation of reperfusion arrhythmias.…”

Massive Caffeine Overdose Requiring Vasopressin Infusion and Hemodialysis

“…Third, caffeine increases myocardial intracellular calcium. Caffeine both induces release of calcium from the sarcoplasmic reticulum and blocks calcium's re-uptake into the sarcoplasmic reticulum (13)(14)(15)(16). This resulting increase in cytosolic calcium may provoke dysrhythmias.…”

Sodium Calcium Exchange as a Target for Antiarrhythmic Therapy

“…Another important element is adrenergic stimulation, which may induce DADs with high incidence in myocytes from the failing heart, including human (Baartscheer et al 2003a;Pogwizd et al 2001;Verkerk et al 2001). In addition, Purkinje fibres may be more sensitive to the development of DADs (Boyden et al 2000), and a high incidence has been reported in the dog after myocardial infarction (Boutjdir et al 1990). …”