The role of
anions in the initiation of
ischemia- and reperfusion-induced arrhythmias is unknown. We examined the antiarrhythmic effects of isotonic substitution of extracellular Cl- with NO3- by using the rat Langendorff preparation (n = 12 per group). During 30 minutes of regional
ischemia, the incidence of
ventricular fibrillation (VF) was reduced from 50% in hearts perfused with control
solution (containing a Cl-:NO3- ratio of 100:0) to 25%, 0% (p less than 0.05), 0% (p less than 0.05), and 0% (p less than 0.05) by perfusion with
solution containing Cl-:NO3- ratios of 75:25, 50:50, 25:75, and 0:100, respectively. The incidence of reperfusion-induced VF was also reduced from 58% to 25%, 8% (p less than 0.05), 8% (p less than 0.05), and 0% (p less than 0.05), respectively. Similar effects were produced in hearts reperfused after briefer durations of
ischemia (10 or 15 minutes). Substitution of NO3- for Cl- also facilitated spontaneous termination of VF. Heart rate and occluded zone size were not affected by
anion manipulation. Coronary flow was affected by NO3-, but changes did not correlate with arrhythmias. During
ischemia, electrocardiographic changes indicative of class III activity (widening of the ventricular complex) were produced by
anion substitution. These changes occurred selectively in the ischemic tissue with no significant influence before
ischemia onset. However, the relation between this effect and
arrhythmia reduction was not linear and a cause-effect relation is therefore unlikely. In separate groups of hearts (n = 12 per group), switching from 100:0 to 0:100 Cl-:NO3-
solution or vice versa 10 seconds after
coronary occlusion or just before reperfusion demonstrated that 1) protection against
ischemia-induced VF resulted partly from an action in the ischemic zone and partly from an action in the nonischemic zone, and 2) protection against reperfusion-induced VF resulted principally from an action occurring during reperfusion and within the reperfused tissue. To assess whether benefit was offset by deleterious effects on contractile function in nonischemic tissue, we constructed Starling curves in isolated rate hearts. The 0:100 Cl-:NO3-
solution had no effect on compliance or contractility at physiological end-diastolic pressures but reduced the slope of the peak systolic pressure-volume relation by approximately 20% as end-diastolic pressure was increased above 10 mm Hg. In conclusion,
anions appear to play a hitherto unrecognized role in arrhythmogenesis in
ischemia and reperfusion. Manipulation of
anion homeostasis may represent a novel target for
antiarrhythmic drug development.