Brief ischemia in "remote" organs protects myocardium against infarction as effectively as myocardial preconditioning. The mechanism of protection by MAO differs from that of CAO, because ganglion blockade abolished protection by MAO but not by CAO. The neurogenic pathway is activated during reperfusion after 15-minute MAO, because sustained MAO failed to produce cardioprotection.

Mild hypothermia limited IA/AR modestly but markedly enhanced the cardioprotection afforded by ischaemic preconditioning in the in situ rat heart so that irreversible damage produced by even prolonged coronary artery occlusions was limited.

Rapid ventricular pacing protects the myocardium against infarction via nonischemic KATP+ channel activation. Continued activation of KATP+ channels does not appear mandatory for the protection that is still present 15 minutes after cessation of pacing.

Heme oxygenase (HO) isozymes, HO-1 and HO-2 catalyze the cleavage of heme b to form the antioxidant biliverdin IXa, iron and the putative cellular messenger carbon monoxide (CO). Heat and stress have been reported to induce the expression of HO-1, in analogy to ubiquitin, a protein of 8 kDa involved in ATP dependent proteolysis. Earlier, we have shown in anesthetized pigs that brief periods of coronary artery occlusion followed by reperfusion produce prolonged regional cardiac dysfunction (stunning) associated with altered expression of a number of genes. In the present study, we report on a coordinated expression pattern of HO-1 and ubiquitin in the same porcine model in which the left anterior descending coronary artery (LAD) was occluded for 10 min and reperfused for 30 min (group I) and after a second occlusion of 10 min, reperfused for either 30 min (group II) or 90 min (group III) or 210 min (group IV). Myocardial tissue from LAD (stunned) and left circumflex coronary artery (LCx, control) perfused regions were collected in liquid nitrogen and analysed by Northern and dot blot hybridization techniques. We demonstrated a basal myocardial expression of multiple mRNAs (monomer and polymers) encoding ubiquitin and a single mRNA species (1.8 kb) encoding HO-1. However, the expression of both genes was drastically enhanced in the stunned myocardium as compared to the control in groups II and III with maximum mRNAs levels in group II. These results suggest that the myocardial adaptive response to ischemia involves the coordinated induction of HO-1 and ubiquitin, which may be indicative for the existence of a pathophysiologically important defense mechanism whereby, both degradation of denatured cellular proteins and generation of biologically active products of heme metabolism are accelerated.

Ischemic preconditioning studies employ one or more brief total coronary artery occlusions separated by complete reperfusion to limit infarct size during a subsequent prolonged coronary artery occlusion. We now present evidence that in anesthetized pigs a partial coronary artery occlusion without intervening reperfusion between the partial and prolonged total occlusions can also precondition the myocardium provided that the reduction in coronary blood flow is sufficiently severe. Thus infarct size was reduced after a 60 min total coronary artery occlusion when the total occlusion was preceded by a partial coronary occlusion that reduced coronary blood flow by 70% but not when the flow reduction was only 30%. In this two-stage coronary occlusion model the degree of protection appears greater in the epicardial than in the endocardial half. In view of evidence that brief occlusions of a coronary artery also protect myocardium outside its perfusion territory, we subsequently investigated whether ischemia in remote organs can protect myocardium. Because of reports that development of infarct size may be temperature dependent, we also investigated whether the cardioprotection by remote organ ischemia was temperature dependent. In anesthetized rats a 15 min coronary artery occlusion was more effective in reducing infarct size produced by a subsequent 60 min total coronary artery occlusion when the experiments were performed at a body core temperature of 30-31 degrees C than at 36-37 degrees C, while infarct size of animals which were subjected to only the 60 min total coronary artery occlusion was the same for the two body core temperatures. In rats with a body core temperature of 36-37 degrees C a 15 min mesenteric artery occlusion, but not a 15 min renal artery occlusion, reduced infarct size produced by a subsequent 60 min coronary artery occlusion. When the experiments were performed at 30-31 degrees C both the mesenteric and renal artery occlusions were protective. These observations indicate the local myocardial ischemia is not required to protect the myocardium during a prolonged coronary occlusion. We further investigated whether myocardium could also be protected by a cardiac stimulus which does not produce ischemia at all. For this purpose we electrically paced the left ventricle of anesthetized pigs to produce heart rates of 200 bpm (which did not lead to ischemia as assessed by a number of functional and biochemical variables) and found that 30 min of ventricular pacing reduced myocardial infarct size produced by a subsequent 60 min coronary artery occlusion. The protection by ventricular pacing involved activation of K+ATP channels as pretreatment with glibenclamide abolished the protection by ventricular pacing. We conclude that a number of distinctly different stimuli can protect the myocardium suggesting that ischemic myocardial preconditioning could be just one feature of a more general protection phenomenon.