Faculty Bibliography

Delayed afterdepolarizations (DADs) may develop into triggered automaticity and ventricular arrhythmias. However, the potential role of DADs in the genesis of ischemic arrhythmias is not clear. We studied the effects of different components of severe ischemia (acidosis, hypoxia, lactate, increased potassium, and the absence of glucose) on DADs. DADs were evoked using trains of 30-60 externally applied pulses at a rate of 4-5 Hz in the presence of isoproterenol (10(-7) M) or dibutyryl cyclic 3', 5' adenosine monophosphate (dB-cAMP, 10(-3) M). Acidosis, caused by the addition of protons (pH = 6.8), increased the amplitude of DADs from 3.2 +/- 0.4 to 5.9 +/- 0.5 mV (n = 8, p less than 0.001). DADs were abolished by hypoxia (pO2 less than 35 mm Hg, n = 7, p less than 0.001) from control values of 3.4 +/- 0.3 mV. DADs were also abolished by neutral lactate (20 mM, n = 7, p less than 0.001) in the absence of glucose. Acidotic lactate (20 mM, pH0 = 6.8), however, was unable to abolish DADs. Increasing the extracellular potassium concentration to 16.2 mM decreased DAD amplitude from 3.6 +/- 0.27 mV to 1.3 +/- 0.1 mV (n = 5, p less than 0.002) with an associated reduction of membrane potential from -86.2 +/- 0.9 to -58.6 +/- 0.9 mV. The overall effect of simulated ischemia (all components tested together) was to abolish DADs (n = 8, p less than 0.001), with hypoxia as the most important factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium antagonists are able to reduce the incidence of early ischemic arrhythmias when given as pretreatment in a variety of models of acute myocardial regional ischemia. Two possible modes of action are electrophysiologic and anti-ischemic. First, a direct electrophysiologic effect of the calcium antagonist agents on the inward calcium current could inhibit four calcium-dependent phenomena, each of which has been linked to the development of ischemic arrhythmias: the slow response, delayed afterdepolarizations (DADs) and calcium-dependent automaticity, enhanced membrane depolarization and conduction slowing. The special circumstances in which each of these could occur are delineated. An anti-ischemic effect of calcium antagonists must also be considered in some models, because of the negative inotropic, negative chronotropic and coronary and peripheral vasodilator properties. Thus far a specific role for the calcium current in early ischemic arrhythmias has only been shown in a few models and not tested in man.