The role of reactive metabolites of
oxygen,
oxygen radicals (O-Rs), as mediators of potentially arrhythmogenic alterations in cellular electrical properties and contractile dysfunction of cardiac muscle during reperfusion after
ischemia was investigated. Electrical and mechanical activities of arterially perfused guinea pig right ventricular walls were recorded simultaneously with intracellular
microelectrodes and a force transducer. Preparations were maintained in
Krebs-Henseleit solution (perfusion rate, 1.5 mL/min) and subjected to 30 minutes of no-flow
ischemia followed by 60 minutes of reperfusion or pretreated with O-R scavengers (
superoxide dismutase, 50 U/mL;
catalase, 600 U/mL; and
mannitol, 2 mmol/L) for 10 to 20 minutes, followed by 30 minutes of
ischemia and 60 minutes of reperfusion. Reperfusion in untreated preparations caused (1) depolarization of resting membrane potential by 8 to 10 mV and slow recovery of action potential duration requiring 60 minutes to attain the preischemic duration, (2)
tachyarrhythmias and premature action potentials, (3) postischemic contractile dysfunction, and (4) increased coronary perfusion pressure in untreated preparations. Pretreatment with scavenger cocktail affected neither electrical nor contractile activity before or during no-flow
ischemia, but it (1) accelerated recovery of resting membrane potential and action potential duration, (2) reduced the incidence of
tachyarrhythmia, (3) improved contractile function, and (4) inhibited the rise in perfusion pressure on reflow. Reperfusion with an exogenous O-R-generating system containing
xanthine/
xanthine oxidase (X/XO, 2 mmol/L:10 mU/mL) inhibited recovery of action potential duration and contractility. Treatment of normoxic arterially perfused right ventricular walls with X/XO caused a decline in action potential duration by approximately 20% within 30 minutes. In contrast, X/XO caused a 30% increase in the duration of action potentials in superfused papillary muscles or small strips of right ventricular walls over the same time period. Pretreatment with
sodium nitroprusside (10 mumol/L) inhibited the decline in duration induced by X/XO in normoxic right ventricular walls but was without effect on prolongation due to X/XO in papillary muscles. Reperfusion with
nitroprusside after no-flow
ischemia caused (1) accelerated recovery of preischemic action potential configuration, (2) a significant decline in the incidence of reperfusion arrhythmias, (3) improved postischemic contractile performance, and (4) inhibition of the increase in perfusion pressure associated with reflow. The data indicate that slow recovery of the action potential duration caused by O-Rs in reperfusion cannot be explained by the direct effects of O-Rs on cardiac myocytes.(ABSTRACT TRUNCATED AT 400 WORDS)