In dogs with healed myocardial infarctions, the intracellular calcium chelator BAPTA-AM prevented ventricular fibrillation in 8 of 12 susceptible animals during an exercise plus ischemia test.
Does modulation of intracellular calcium affect the development of ventricular fibrillation during exercise and ischemia in dogs with healed myocardial infarctions?
Elevated cytosolic calcium facilitates the development of malignant arrhythmias during ischemia and exercise in a canine model of healed myocardial infarction.
The contribution of intracellular calcium to ventricular fibrillation (VF) was investigated using chronically instrumented dogs with healed myocardial infarctions. A 2-minute coronary occlusion was initiated during the last minute of exercise. Fourteen animals developed ventricular fibrillation (susceptible) whereas the remaining 12 did not (resistant) during this exercise plus ischemia test. The test was then repeated for the susceptible animals after pretreatment with the intracellular calcium chelator BAPTA-AM (1.0 mg/kg). BAPTA-AM significantly reduced left ventricular dp/dt max and prevented VF in 8 of 12 susceptible animals. Conversely, myocardial cytosolic calcium levels were increased in resistant animals using the calcium channel agonist Bay K 8644 (30 micrograms/kg) or phenylephrine (10 micrograms.kg-1.min-1 3-5 min before occlusion). Bay K 8644 induced VF in all 5 resistant animals tested whereas phenylephrine induced VF in 8 of 12 resistant animals. BAPTA-AM pretreatment attenuated the hemodynamic effects of Bay K 8644 or phenylephrine and prevented VF in five of five Bay K 8644- and four of seven phenylephrine-treated animals. Finally, the endogenous level of calcium/calmodulin (Ca-CaM)-dependent phosphorylation of 170- and 55-kDa substrate proteins was measured (as an index of intracellular free calcium concentration). In the susceptible dog heart, the endogenous level of Ca-CaM-dependent phosphorylation was estimated to be two- to threefold higher than that observed in resistant dog heart. Treatment of resistant dog tissue with the calcium ionophore A23187 increased the level of Ca-CaM-dependent phosphorylation of these two proteins to the level observed in susceptible dog heart. These data suggest that elevated cytosolic calcium facilitates development of malignant arrhythmias and that elevated cytosolic calcium levels may be present in animals particularly susceptible to ventricular fibrillation.
Billman et al. (Thu,) conducted a other in Ventricular fibrillation and healed myocardial infarction (n=26). BAPTA-AM, Bay K 8644, and phenylephrine vs. Baseline (pre-treatment) was evaluated on Ventricular fibrillation during exercise plus ischemia test. In dogs with healed myocardial infarctions, the intracellular calcium chelator BAPTA-AM prevented ventricular fibrillation in 8 of 12 susceptible animals during an exercise plus ischemia test.