Post-conditioning in the early reperfusion period confers protection to the heart after a potentially lethal episode of prolonged ischemia. Protection from this novel intervention has been documented in rat, rabbit and canine hearts, but one group has reported that it is ineffective in pigs, a large-animal species that should be most relevant to humans. We hypothesized that this negative result was related to an inappropriate post-conditioning protocol rather than the species. The present study, therefore, tested whether an effective post-conditioning protocol could be identified that limits infarct size in anesthetized pigs. Domestic Landrace pigs weighing 25-29 kg were anesthetized, and after a mid-sternal thoracotomy and pericardiotomy the left anterior descending coronary artery was ligated for 60 min followed by 3 h of reperfusion. Three groups were studied: control group (n = 5) with no other intervention, 4-30 PostC group (n = 5) with 4 cycles of 30-s reperfusion/30-s ischemia, and 8-30 PostC group (n = 6) with 8 cycles of 30-s reperfusion/30-s ischemia. The two post-conditioning protocols started immediately after termination of the 60-min coronary occlusion. Region at risk and infarct size were delineated with the aid of pre-mortem monastral blue injection and postmortem staining with triphenyltetrazolium chloride, respectively. In control hearts 33.5 +/- 7.6% of the risk zone infarcted and 36.7 +/- 3.7% in the 4-30 PostC group (P = NS). But there was only 10.5 +/- 0.5% infarction in the 8-30 PostC group (P < 0.01 vs. the other two groups). Post-conditioning confers protection in pigs but requires more than 4 ischemia/reperfusion cycles. Post-conditioning may protect by inhibiting mitochondrial permeability transition pore formation by keeping the heart acidotic as it is reoxygenated. If true, then it would be difficult to employ too many occlusion cycles.

Objective-To examine the contribution of endothelin type A (ET A ) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans. Design-Controlled clinical study. Setting-Tertiary cardiovascular referral centre. Patients-14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years. Interventions-After diagnostic coronary arteriography, BQ-123 (a selective ET A receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone. Main outcome measures-Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments. Results-The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p < 0.05 v baseline). Coronary blood flow increased from 75 (10) to 92 (10) ml/min and coronary vascular resistance decreased from 1.99 (0.36) to 1.44 (0.22) mm Hg/ml/min after BQ-123 (both p < 0.05 v baseline). The response to BQ-123 of patients with and without coronary artery disease was similar. There was no eVect of saline in the controls. Conclusions-Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans by ET A receptor stimulation. The role of ET B receptors remains to be defined. (Heart 2000;84:176-182) Keywords: endothelins; arteries; blood flow; coronary circulation; angiographyThe endothelins are a family of 21 amino acid peptides with potent and characteristically sustained vasoconstrictor and vasopressor actions.1 Endothelin-1 (ET-1) is the predominant isopeptide generated by the vascular endothelium.2 ET-1 binds to at least two receptors. The ET A receptor appears to be the major one, causing vasoconstriction in arteries, while the ET B receptor mediates the release of endothelium dependent vasodilator substances and is also present in some resistance and capacitance arteries, where it can contribute to vasoconstriction.3 ET-1 may play a role in the pathophysiology of several conditions associated with vasoconstriction, including chronic heart failure, hypertension, Raynaud's disease, and renal failure.3 4 Recently described inhibitors of endothelin converting enzyme and endothelin receptor antagonists may therefore have therapeutic potential as vasodilator drugs in these conditions. Endogenous production of ET-1 contributes importantly to the maintenance of basal peripheral vascular tone 5 and blood pressure 6 in healthy volunteers, mainly through an eVect on ET A receptors. In contrast, the main eVect of endogenous ET-1 on ET B receptors in resistance arteries appears to be vasodilatation. ET-1 constricts human epicardi...

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The data provide further evidence that apoptosis and necrosis contribute independently to infarct size after ischemia and reperfusion. Inhibition of the myocardial apoptotic processes by IPC may involve modulation of the expression of anti-apoptotic proteins, Bcl-2 and Bcl-xL. ERK1/2 may be involved in the inhibition of both apoptosis and necrosis.

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Previous studies have shown that the cardioprotective effect of ischemic preconditioning (IPC) can be mimicked pharmacologically with clinically relevant agents, including nitric oxide (NO) donors. However, whether pharmacological preconditioning shares the same molecular mechanism with IPC is not fully elucidated. The present study aimed to determine the activation of mitogen-activated protein kinases (MAPKs) (ERK1/2, p38 MAPK and p46/p54 JNKs) during ischemia and at reperfusion in nitroglycerin-induced preconditioning as compared to IPC and to correlate this with the conferred cardioprotection in anesthetized rabbits. Sixty minutes of intravenous administration of nitroglycerin was capable of inducing both early and late phase preconditioning in anesthetized rabbits, as it was expressed by the reduction of infarct size. Despite the cardioprotective effect conferred by both ischemic and nitroglycerin-induced preconditioning, there was a differential phosphorylation of MAPKs between the studied groups. p38 MAPK was activated early in ischemia in both ischemic and the early nitroglycerin-induced preconditioning while JNKs were markedly increased only after IPC. Furthermore, in these groups, ERK1/2 were activated during reperfusion. A different profile was observed in the late preconditioning induced by nitroglycerin with increased p38 MAPK and ERK1/2 phosphorylation during late ischemia. No activation of JNKs was observed at any time point in this group. It seems that activation of individual MAPK subfamilies depends on the nature of preconditioning stimulus.

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