Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodiumanesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15-120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 Ϯ 3% to 31 Ϯ 5%, and CAO60 from 60 Ϯ 3% to 47 Ϯ 6% (both P Յ 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 Ϯ 1% to 19 Ϯ 6% and CAO30 from 36 Ϯ 6 to 48 Ϯ 4% (both P Յ 0.05). This deleterious effect of 3POC30 was not stimulus sensitive because postconditioning with 3POC5 and 3POC15 after CAO30 also increased infarct size. The cardioprotection by 3POC30 after CAO60 was accompanied by an increased stimulation of Akt phosphorylation at 7 min of reperfusion and a 36% lower superoxide production, measured by dihydroethidium fluorescence, after 2 h of reperfusion. Consistent with these results, cardioprotection by 3POC30 was abolished by phosphatidylinositol-3-OH-kinase inhibition, as well as nitric oxide (NO) synthase inhibition. The deleterious effect of 3POC30 after CAO15 was accompanied by an increased superoxide production with no change in Akt phosphorylation and was not affected by NO synthase inhibition. In conclusion, the effect of cardiac POC depends critically on the duration of the index ischemia and can be either beneficial or detrimental. These paradoxical effects of POC may be related to the divergent effects on Akt phosphorylation and superoxide production.
Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p < 0.05), whereas systemic circulating plasma levels of TNFα and IL6 were not affected. The degree of cardioprotection could not be explained by the VNS-induced bradycardia or the VNS-induced decrease in the double product of heart rate and left ventricular systolic pressure. In the presence of NO-synthase inhibitor LNNA, VNS no longer attenuated infarct size and area of no-reflow, which was paralleled by similarly unaffected regional leukocyte infiltration. In conclusion, VNS is a promising novel adjunctive therapy that limits reperfusion injury in a large animal model of acute myocardial infarction.Electronic supplementary materialThe online version of this article (doi:10.1007/s00395-015-0508-3) contains supplementary material, which is available to authorized users.
Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
1 Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. 2 We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. 3 In pentobarbital-anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60-min coronary artery occlusion (CAO), using trypan blue and nitro-blue-tetrazolium staining, respectively. 4 IPC with a single 15-min CAO and a 15-min adenosine infusion (ADO, 200 mg min À1 i.v.) limited IS to the same extent (IS ¼ 4176% and IS ¼ 4074%, respectively) compared to control rats (IS ¼ 6373%, both Po0.05). However, IPC increased myocardial interstitial adenosine levels sevenfold from 4.370.7 to 27.1710.0 mM (Po0.05), while ADO had no effect on interstitial adenosine (4.171.2 mM), or any of the other purines. 5 The NO synthase inhibitor N o -nitro-L-arginine (LNNA), which did not affect IS (IS ¼ 6273%), attenuated the protection by ADO (IS ¼ 5673%; Po0.05 vs ADO, P ¼ NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS ¼ 6673%), blunted the protection by ADO (IS ¼ 5574%; Po0.05 vs ADO and vs hexamethonium). 6 These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.
Growing concerns have been expressed regarding cardiovascular performance in modern farm pigs, which has been proposed as a critical factor contributing to the reduced adaptability of modern pigs to stress. Here we tested the hypothesis that cardiac dimensions and pump function in modern heavy farm pigs are disproportionally low for their body weight, and investigated potential underlying mechanisms. The results from the present study indeed demonstrate disproportionally low values for stroke volume and cardiac output in pigs with bodyweights over 150 kg. Importantly, these low values were not the result of impaired left ventricular (LV) systolic contractile function, but were due to a disproportionally small LV end-diastolic volume. The latter was associated with changes in determinants of LV passive stiffness, including (i) an increase in LV myocardial collagen, (ii) a shift from the compliant N2BA titin isoform towards the stiff N2B, and (iii) a marked elevation of aortic blood pressure. Taken together, these results demonstrate reduced pumping capacity of the hearts of heavy modern pigs, due to structural abnormalities in the LV myocardium.Modern pigs originate from wild boar 1 with domestication starting in the Near East as early as 9000 years B.C. 2 . Domestication of the wild boar has, particularly during the last century, resulted in marked increases in litter size, body weight (BW) and muscularity 3,4 , which has inadvertently led to alterations of the cardiovascular system, including a lower blood volume and haemoglobin, as well as a lower relative heart weight (HW) and cardiac output (CO) 5,6 . These changes, which raised concerns with respect to function and adaptability to stress in modern farm pigs 5,7 , have been ascribed to a loss of proportionality of HW and CO with BW in modern fast growing pigs [5][6][7] . Early studies assessed proportionality by simply dividing HW and CO by BW 5,6 . However, more recent studies have shown that in mammals, HW and CO scales with BW to the power of 0.75, and stroke volume (SV) scales with BW to the power of 1.00 [8][9][10] . The observed scaling is typically a simple power law: Y = a·BW b , where Y is the observed variable, for example CO, "a" is a constant and the exponent b almost invariably approximates a multiple of 0.25.Previously we tested the scaling hypothesis for CO and SV in modern growing pigs and in adult sows at the end of their gestation, and found that, while CO and SV of pigs up to 75 kg scaled proportionally with BW 11 , adult sows demonstrated a disproportionally low CO and SV 12 . In our previous studies, we included two sets of pigs that had different genetic backgrounds, underwent different anesthesia regimens and were studied in different laboratory settings. Moreover, in our previous study we did not further investigate the mechanisms underlying the disproportionally low levels of SV in adult pigs. Consequently, in the present study we investigated the proportionality of the cardiovascular system over a wide range of BW (22-216 kg) in pig...
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