Functional genomics could be used to identify novel modulators of ischaemia induced lethal arrhythmias, but this application has been limited by the infrequency of ventricular fibrillation (VF) in the wildtype murine heart. The aim of this study was to develop a robust mouse isolated-heart model of ischaemia/reperfusion induced VF. The initial strategy was to reintroduce catecholamines and angiotensin II (A-II), putative arrhythmogens in vivo that are ordinarily absent in perfused heart preparations. Hearts from male T/O mice were Langendorff perfused with control solution (standard Krebs modified to contain 2.4 mM Ca²⁺ and 3 mM K⁺) before being perfused with a test solution containing catecholamines (noradrenaline 313 nM, adrenaline 75 nM) and/or A-II (100 pM), or control (n = 10 per group). Hearts were then subjected to 30 min regional ischaemia by ligation of the left main coronary artery, followed by reperfusion. The ECG was monitored throughout. Catecholamine perfusion significantly increased VF incidence during ischaemia (5/10 vs 0/10 hearts, p<0.05) and during reperfusion (5/10 vs 0/10 hearts, p<0.05). Catecholamine perfusion also had typical haemodynamic effects (p<0.05 vs controls), increasing heart rate from 380±15 to 457±25 beats/min and coronary flow from 18±2 to 30±3 ml.min^-1g^-1 (values 14 min before ischaemia). A-II had no effect on VF susceptibility or on the VF priming effect of catecholamines. In conclusion, physiological catecholamine supplementation converts the VF resistant mouse perfused heart into a viable bioassay for investigating modulation of ischaemia induced VF, using functional genomics.

This work was funded by a British Heart Foundation PhD studentship.

It was discovered recently that cardiac tissues express constitutively a multicomponent NADPH oxidase which generates reactive oxygen species (ROS). The ROS thus produced serve as secondary messengers in redox signalling pathways and participate in the regulation of cardiac development and cardiovascular function. In this study, we investigated …