Although there is abundant evidence for ‘cross-talk’ between coronary vascular (and ventricular endocardial) endothelial cells and cardiac myocytes in the regulation of myocardial contractility, much less is known about the possibility that such endothelial-myocyte communication leads also to cardiac protection, for example in the suppression of life-threatening ventricular arrhythmias. The evidence for this concept comes from studies involving the mechanical removal of endothelial cells from isolated perfused hearts (a procedure which greatly accentuates coronary artery occlusion-induced arrhythmia severity) and from studies in a canine model of ischaemic preconditioning. These studies suggest that the antiarrhythmic effect of ischaemic preconditioning results from the release of nitric oxide (and prostacyclin) from endothelial cells and that this is ‘triggered’ by early bradykinin generation, perhaps also from endothelial cells. The protective effects of nitric oxide under these conditions are mediated through elevations of myocyte cGMP. The evidence for such endothelial bradykinin-nitric oxide-cGMP protection of cardiac myocytes comes from pharmacological studies (using methylene blue, inhibitors of the L-arginine-nitric oxide pathway, selective bradykinin B2 receptor blockade) and, more recently, from direct estimates of bradykinin and nitric oxide release. The concept suggests that endothelial dysfunction, for example in atherosclerosis and hypertension, leads to enhanced sensitivity of the myocardium to ischaemia and that this is due, in part, to the reduced formation of ‘endogenous myocardial protective substances’ derived from endothelial cells.