Abstract
1. We have previously shown that tetrandrine (TTD), a bisbenzyltetrahydroiosquinoline isolated from the Chinese herb Stephania tetrandra, inhibits neutrophil adhesion, Mac-1 expression, and reactive oxygen species (ROS) production. To examine whether inhibition of neutrophil function may confer upon TTD the ability to prevent myocardial ischaemia-reperfusion (MI/R) injury, experiments were performed on rats subjected to coronary ligation followed by reperfusion for induction of MI/R injury. 2. Intravenous administration of TTD (0.1 and 1.0 mg kg-1) 15 min prior to coronary ligation completely prevented MI/R-associated mortality. TTD pretreatment also significantly reduced MI/R-induced ventricular tachyarrhythmia, myocardial infarct size, and neutrophil infiltration. 3. However, TTD pretreatment did not influence mean arterial blood pressure, heart rate, or product of pressure-rate, indicating that TTD extenuated MI/R through mechanisms independent of modulating haemodynamics or myocardial oxygen demand. 4. Peripheral blood neutrophils were isolated for ex vivo examination of shape change and Mac-1 upregulation of neutrophils, two sensitive indicators of proinflammatory priming, as well as N-formyl-methionyl-leucyl-phenylalanine (fMLP)-induced adhesion and ROS production, parameters commonly used for the assessment of neutrophil activation. 5. Neutrophils from MI/R animals showed significant shape change and Mac-1 upregulation, both of which were prevented by TTD-pretreatments. On the other hand, fMLP-induced adhesion and ROS production of neutrophils were markedly enhanced by MI/R but diminished in TTD-pretreated animals. 6. These data suggest that the protective effect of TTD against MI/R injury can be accounted for by inhibition of neutrophil priming and activation, thereby abolishing subsequent infiltration and ROS production that cause MI/R injury.