Effects of delayed preconditioning on myocardial regional contractility during repeated episodes of low-flow ischaemia in anaesthetized dogs: possible role of nitric oxide

Abstract

The effect of cardiac pacing on repeated low-flow ischaemia-induced changes in regional myocardial segmental contractility, and the role in these changes of nitric oxide, were investigated in anaesthetized dogs. Dogs were instrumented for cardiac pacing (pacing electrode in the right ventricle). Dogs were paced (four times for 5 min; pacing rate 220 beats·min-1) 24 h prior to the repeated ischaemic insults. Controls were instrumented, but not paced. After 24 h, the dogs were re-anaesthetized with pentobarbitone and subjected to four 20 min low-flow ischaemia and reperfusion cycles, by constricting the left anterior descending coronary artery (LAD) to achieve an approx. 50% reduction in resting coronary blood flow. In some dogs (both control and paced), NG-nitro-L-arginine methyl ester (L-NAME; a non-selective inhibitor of nitric oxide synthase) was infused into a side-branch of the LAD 10 min prior to the first ischaemia/reperfusion cycle. Regional contractile function was measured by ultrasonic microcrystals in the ischaemic and normal regions of the left ventricular wall supplied from the LAD and left circumflex coronary artery respectively, and expressed as percentage changes in segmental shortening (%SS). In some dogs, myocardial tissue blood flow (coloured microspheres) and lactate production (local coronary venous sampling) were measured; samples were also taken for histological analysis. In control dogs, the regional %SS was progressively reduced within the ischaemic segment during the four repeated occlusions (by 40±6, 59±6, 68±6, 70±6% during occlusions 1–4 respectively). These reductions were more pronounced, especially during the first two cycles (68±6, 68±6, 67±6, 67±6%, respectively), when the dogs had been previously subjected to cardiac pacing. In both paced and control dogs, these changes in contractile function were L-NAME-sensitive. Thus, in the presence of L-NAME, changes in regional segmental shortening in control dogs were 37±8, 40±8, 37±8, 42±11% and in the paced dogs 46±6, 45±7, 45±8, 45±7% respectively, during the four consecutive occlusions. There were no significant differences in tissue blood flow or in lactate production between the groups, and no structural changes indicative of infarction. These results show that the myocardium rapidly adapts to re-occurring acute ischaemia by reducing contractility within the ischaemic segment and, thereby, metabolic demand. Furthermore, cardiac pacing 24 h prior to these ischaemic challenges induces a similar adaptive response, a form of ‘delayed preconditioning’. Since both the acute and delayed adaptation were L-NAME-sensitive, we suggest that this adaptation involves nitric oxide.