Biomedical subjects

Petra Gres

Publications and source records attributed to Petra Gres.

16 recordsLinked to original sources

PubMed2006

Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction.

In patients with unstable angina, plaque rupture and coronary microembolization (ME) can precede complete coronary artery occlusion and impending infarction. ME-induced microinfarcts initiate an inflammatory reaction with increased tumor necrosis factor-alpha (TNF-alpha) expression, resulting in progressive contractile dysfunction. However, TNF-alpha is not only a negative inotrope but can also protect the myocardium against infarction. In anesthetized pigs, we studied whether ME protects against infarction when TNF-alpha expression is increased. ME (group1; n=7) was induced by intracoronary infusion of microspheres (42 microm; 3000 per mL/min inflow). Controls (group 2; n=8) received saline. Groups 3 and 4 (n=4 each) were pretreated with ovine TNF-alpha antibodies (25 mg/kg body weight) 30 minutes before ME or placebo, respectively. Ischemia (90 minutes) was induced 6 hours after ME when TNF-alpha was increased (66+/-21 pg/g wet weight; mean+/-SEM) or after placebo (TNF-alpha, 21+/-10 pg/g; P<0.05). Infarct size (percentage area at risk) was determined after 2 hours of reperfusion (triphenyl tetrazolium chloride staining). ME decreased systolic wall thickening progressively over 6 hours (group 1 versus group 2, 65+/-4% versus 90+/-1%; percentage of baseline; P<0.05). TNF-alpha antibodies attenuated the progressive decrease in systolic wall thickening following ME (group 3, 77+/-5% of baseline; P<0.05 versus group 1) with no effect in controls (group 4; 90+/-8% of baseline). With ME, infarct size was decreased to 18+/-4% versus 33+/-4% in group 2 (P<0.05). The infarct size reduction was abolished by TNF-alpha antibodies (group 3 versus group 4, 29+/-3% versus 35+/-5%). In ME, TNF-alpha is responsible for both progressive contractile dysfunction and delayed protection against infarction.

Animals↗

PubMed2006

Prevention of the ischemia-induced decrease in mitochondrial Tom20 content by ischemic preconditioning.

Preserved mitochondrial function (respiration, calcium handling) and integrity (cytochrome c release) is central for cell survival following ischemia/reperfusion. Mitochondrial function also requires import of proteins from the cytosol via the translocase of the outer and inner membrane (TOM and TIM complexes). Since mitochondrial function following ischemia/reperfusion is better preserved by ischemic preconditioning (IP), we now investigated whether expression of parts of the import machinery is affected by ischemia/reperfusion without or with IP in vivo. We analyzed the mitochondrial content of the presequence receptor Tom20, the pore forming unit Tom40 and Tim23. Goettinger minipigs were subjected to 90 min of low-flow ischemia without or with preconditioning by 10 min ischemia and 15 min reperfusion. Mitochondria were isolated from the ischemic or preconditioned anterior wall of the left ventricle and from the control posterior wall. Infarct size was significantly reduced by IP (20.1 +/- 1.6% of area at risk (non-preconditioned) vs. 6.5 +/- 2.5% of area at risk (IP)). Using Western blot analysis, the ratio of Tom20 (normalized to Ponceau S) between mitochondria isolated from the anterior ischemic and posterior control wall was reduced (0.72 +/- 0.11, a.u., n = 8), whereas the mitochondrial Tom20 content was preserved by IP (1.17 +/- 0.16 a.u., n = 7, P < 0.05). The mitochondrial Tom40, Tim23 and adenine nucleotide transporter (ANT) contents were not significantly different between non-preconditioned and preconditioned myocardium. The preservation of the mitochondrial Tom20 protein level may contribute to the improved mitochondrial function after IP.

Animals↗

PubMed2006

Translocation of connexin 43 to the inner mitochondrial membrane of cardiomyocytes through the heat shock protein 90-dependent TOM pathway and its importance for cardioprotection.

We have previously shown that connexin 43 (Cx43) is present in mitochondria, that its genetic depletion abolishes the protection of ischemia- and diazoxide-induced preconditioning, and that it is involved in reactive oxygen species (ROS) formation in response to diazoxide. Here we investigated the intramitochondrial localization of Cx43, the mechanism of Cx43 translocation to mitochondria and the effect of inhibiting translocation on the protection of preconditioning. Confocal microscopy of mitochondria devoid of the outer membrane and Western blotting on fractionated mitochondria showed that Cx43 is located at the inner mitochondrial membrane, and coimmunoprecipitation of Cx43 with Tom20 (Translocase of the outer membrane 20) and with heat shock protein 90 (Hsp90) indicated that it interacts with the regular mitochondrial protein import machinery. In isolated rat hearts, geldanamycin, a blocker of Hsp90-dependent translocation of proteins to the inner mitochondrial membrane through the TOM pathway, rapidly (15 minutes) reduced mitochondrial Cx43 content by approximately one-third in the absence or presence of diazoxide. Geldanamycin alone had no effect on infarct size, but it ablated the protection against infarction afforded by diazoxide. Geldanamycin abolished the 2-fold increase in mitochondrial Cx43 induced by 2 preconditioning cycles of ischemia/reperfusion, but this effect was not associated with reduced protection. These results demonstrate that Cx43 is transported to the inner mitochondrial membrane through translocation via the TOM complex and that a normal mitochondrial Cx43 content is important for the diazoxide-related pathway of preconditioning.

Animals↗

PubMed2006

Oxidative modification of tropomyosin and myocardial dysfunction following coronary microembolization.

AIMS: We addressed a potential mechanism of myocardial dysfunction following coronary microembolization at the level of myofibrillar proteins. METHODS AND RESULTS: Anaesthetized pigs underwent intracoronary infusion of microspheres. After 6 h, the microembolized areas (MEA) had decreased systolic wall thickening to 38 +/- 7% of baseline and a 2.62 +/- 0.40-fold increase in the formation of disulphide cross-bridges (DCB) in tropomyosin relative to that in remote areas. The impairment in contractile function correlated inversely with DCB formation (r = -0.68; P = 0.015) and was associated with increased TNF-alpha content. DCB formation was reflected by increased tropomyosin immunoreactivity and abolished in vitro by dithiothreitol. Ascorbic acid prevented contractile dysfunction as well as increased DCB and TNF-alpha. In anaesthetized dogs, 8 h after intracoronary microspheres infusion, contractile function was reduced to 8+/-10% of baseline and DCB in MEA was 1.48+/-0.12 higher than that in remote areas. In conscious dogs, 6 days after intracoronary microspheres infusion, myocardial function had returned to baseline and DCB was no longer different between remote and MEA. Again contractile function correlated inversely with DCB formation (r = -0.83; P = 0.005). CONCLUSION: Myofibrillar protein oxidation may represent a mechanistic link between inflammation and contractile dysfunction following coronary microembolization.

Analysis of Variance↗

PubMed2006

Coronary microembolization.

Atherosclerotic plaque rupture is the key event in the pathogenesis of acute coronary syndromes and it also occurs during coronary interventions. Atherosclerotic plaque rupture does not always result in complete thrombotic occlusion of the epicardial coronary artery with subsequent impending myocardial infarction, but may in milder forms result in the embolization of atherosclerotic and thrombotic debris into the coronary microcirculation. This review summarizes the present experimental pathophysiology of coronary microembolization in animal models of acute coronary syndromes and highlights the main consequences of coronary microembolization--reduced coronary reserve, microinfarction, inflammation and oxidative modification of contractile proteins, contractile dysfunction and perfusion-contraction mismatch.Furthermore, the review presents the available clinical evidence for coronary microembolization in patients and compares the clinical observations with observations in the experimental model.

Animals↗

PubMed2005

Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning.

OBJECTIVE: Connexin 43 (Cx43) is involved in infarct size reduction by ischemic preconditioning (IP); the underlying mechanism of protection, however, is unknown. Since mitochondria have been proposed to be involved in IP's protection, the present study analyzed whether Cx43 is localized at mitochondria of cardiomyocytes and whether such localization is affected by IP. METHODS AND RESULTS: Western blot analysis on mitochondrial preparations isolated from rat, mouse, pig, and human hearts showed the presence of Cx43. The preparations were not contaminated with markers for other cell compartments. The localization of Cx43 to mitochondria was also confirmed by FACS sorting (double staining with MitoTracker Red and Cx43) and immuno-electron and confocal microscopy. To study the role of Cx43 in IP, mitochondria were isolated from the ischemic anterior wall (AW) and the control posterior wall (PW) of pig myocardium at the end of 90 min low-flow ischemia without (n=13) or with (n=13) a preceding preconditioning cycle of 10 min ischemia and 15 min reperfusion. With IP, the mitochondrial Cx43/adenine nucleotide transporter ratio was 3.4+/-0.7 fold greater in AW than in PW, whereas the ratio remained unchanged in non-preconditioned myocardium (1.1+/-0.2, p<0.05). The enhancement of the mitochondrial Cx43 protein level occurred rapidly, since an increase of mitochondrial Cx43 was already detected with two cycles of 5 min ischemia/reperfusion in isolated rat hearts to 262+/-63% of baseline. CONCLUSION: These data demonstrate that Cx43 is localized at cardiomyocyte mitochondria and that IP enhances such mitochondrial localization.

Animals↗

PubMed2005

Preinfarction angina: no interference of coronary microembolization with acute ischemic preconditioning.

Transient episodes of angina preceding acute myocardial infarction may both, protect the myocardium by ischemic preconditioning or damage it when associated with coronary microembolization. We now studied the potential loss of ischemic preconditioning with coronary microembolization. Anesthetized pigs (group 1; n=8) were subjected to 90 min sustained low-flow ischemia. Group 2 (n=8) was subjected to coronary microembolization (i.e. microspheres; 42 microm slashed circle; 3000 per ml min-1 inflow) 35 min before sustained ischemia. In group 3, coronary microembolization was followed 10 min later by one cycle of ischemic preconditioning (10 min ischemia/15 min reperfusion) before subsequent sustained ischemia. Infarct size was determined after 2 h reperfusion by triphenyl tetrazolium chloride staining. Infarct size after sustained ischemia alone (group 1) was 19.4+/-3.4% of the area at risk (mean+/-S.E.M.). With coronary microembolization before sustained ischemia (group 2) infarct size was only slightly larger (23.6+/-4.6%, ns). In group 3 with microembolization followed by ischemic preconditioning, infarct size was reduced to 12.7+/-3.0% (P<0.05 vs. group 2). The relationships between infarct size and transmural blood flow in groups 1 and 3 were not different, giving the impression that ischemic preconditioning failed to protect microembolized myocardium. However, additional coronary microembolization shifted the relationship between infarct size and blood flow upwards to a larger infarct size at any given blood flow. Thus when comparing the relationship of group 3 to its true control (group 2), it was shifted downwards (P<0.05; analysis of covariance (ANCOVA)) indicating persistent protection of microembolized myocardium by ischemic preconditioning. Coronary microembolization induces additional infarction when superimposed on sustained ischemia but does not interfere with the endogenous protection by ischemic preconditioning.

Adenosine↗

PubMed2004

Regional differences of myocardial infarct development and ischemic preconditioning.

UNLABELLED: The spatial and temporal development of myocardial infarction depends on the area at risk (AAR), the severity and duration of blood flow reduction (energy supply) as well as on heart rate and regional wall function (energy demand). Both supply and demand can vary within the AAR of a given heart, potentially resulting in differences in infarct development. We therefore retrospectively analyzed infarct size (IS, %AAR, TTC) in 24 anesthetized pigs in vivo following 90 min hypoperfusion and 120 min reperfusion of the LAD coronary artery, which supplies parts of the LV septum (LVS) and anterior free wall (LVAFW). The total LAD perfusion territory averaged 49.8 +/- 14.2 (SD) g (49.2 +/- 8.4% of LV); 61.4 +/- 8.1% of the AAR was LVAFW. IS within the LVS was 25.3 +/- 15.1%, while IS within the LVAFW was 16.6 +/-10.1% (p<0.05). While ischemic blood flow (radiolabeled microspheres) did not differ between LVS (0.05 +/- 0.02 ml/min/g) and LVAFW (0.05 +/- 0.03 ml/min/g), perivascular connective tissue (56 +/- 9 vs. 38+/-7 microm(2), p < 0.05) and the capillary-to-myocyte distance (1.65 +/- 0.23 vs. 1.18 +/- 0.23 mm, p < 0.05) were larger in LVS than in LVAFW. Interestingly, IS in LVS (9.3 +/- 9.6%, n = 24) and LVAFW (9.2 +/- 9.1%) were reduced to the same absolute extent by ischemic preconditioning with one cycle of 10 min ischemia and 15 min reperfusion, suggesting that a similar regional difference exists also in the protection afforded by ischemic preconditioning. The mechanism(s) for that remain(s) to be established. CONCLUSION: In pigs, regional differences in infarct development and protection from it exist in the LAD perfusion territory, which are independent of ischemic blood flow but apparently related to pre-existing structural differences.

Animals↗

PubMed2004

Coronary microembolization does not induce acute preconditioning against infarction in pigs-the role of adenosine.

OBJECTIVE: After coronary microembolization (ME) adenosine is released from ischemic areas of the microembolized myocardium. This adenosine dilates vessels in adjacent nonembolized myocardium and increases coronary blood flow. For ischemic preconditioning (IP) to protect the myocardium against infarction, an increase in the interstitial adenosine concentration (iADO) prior to the subsequent ischemia/reperfusion is necessary. We hypothesized that the adenosine release after ME is sufficient to increase iADO and protect the myocardium against infarction from subsequent ischemia/reperfusion. We have therefore compared myocardial protection by either coronary microembolization or ischemic preconditioning prior to ischemia/reperfusion. METHODS: In anesthetized pigs, the left anterior descending (LAD) was cannulated and perfused from an extracorporeal circuit. In 11 pigs, sustained ischemia was induced by 85% inflow reduction for 90 min (controls). Two other groups of pigs were subjected either to IP (n = 8; 10-min ischemia/15-min reperfusion) or coronary ME (n = 9; i.c. microspheres; 42 microm Ø; 3000 x ml(-1) x min inflow) prior to sustained ischemia. Coronary venous adenosine concentration (vADO) and iADO (microdialysis) were measured. Infarct size was determined after 2-h reperfusion by triphenyl tetrazolium chloride staining. RESULTS: In pigs subjected to IP, infarct size was reduced to 2.6 +/- 1.1% (mean +/- S.E.M.) vs. 17.0 +/- 3.2% in controls. iADO was increased from 2.4 +/- 1.3 to 13.1 +/- 5.8 micromol x l(-1) during the reperfusion following IP. In pigs subjected to ME, at 10 min after ME, coronary blood flow (38.6 +/- 3.6 to 53.6 +/- 4.3 ml x min(-1)) and vADO (0.25 +/- 0.04 to 0.48 +/- 0.07 micromol x l(-1)) were increased. However, iADO (2.0 +/- 0.5 at baseline vs. 2.3 +/- 0.6 micromol x l(-1) at 10 min after ME) did not increase. Infarct size induced by sustained ischemia following ME (22.5 +/- 5.2%) was above that of controls for any given subendocardial blood flow. CONCLUSION: ME released adenosine into the vasculature and increased coronary blood flow. The failure of iADO to increase with ME possibly explains the lack of protection against infarction after ME.

Adenosine↗

PubMed2003

Ischemic preconditioning preserves connexin 43 phosphorylation during sustained ischemia in pig hearts in vivo.

During myocardial ischemia, connexin 43 (Cx43) is dephosphorylated in vitro, and the subsequent opening of gap junctions formed by two opposing Cx43 hexamers was suggested to propagate ischemia/reperfusion injury. Reduction of infarct size (IS) by ischemic preconditioning (IP) involves activation of protein kinase C (PKC) and p38 mitogen activated protein kinase (MAPK), both of which can phosphorylate Cx43. We now studied in anesthetized pigs whether IP impacts on Cx43 phosphorylation by measuring the density of non-phosphorylated and total Cx43 (confocal laser) during normoperfusion and 90-min ischemia in non-preconditioned and preconditioned hearts. Co-localization of PKCalpha, p38MAPKalpha, and p38MAPKbeta with Cx43 and the activity of p38MAPK were assessed. IP by 10 min ischemia and 15 min reperfusion reduced IS. Non-phosphorylated Cx43 remained unchanged during ischemia in preconditioned hearts, while it increased from 35+/-3 to 75+/-8 AU (P<0.05) in non-preconditioned hearts. Co-localization of PKCalpha, p38MAPKalpha, and p38MAPKbeta with Cx43 during ischemia increased only in preconditioned hearts. While the ischemia-induced increase in p38MAPKalpha activity was comparable in preconditioned and non-preconditioned hearts, p38MAPKbeta activity was increased only in preconditioned hearts. Blockade of p38MAPK by SB203580 attenuated the IS-reduction and the increased p38MAPK-Cx43 co-localization by IP. We conclude that IP increases co-localization of protein kinases with Cx43 and preserves phosphorylation of Cx43 during ischemia.

Animals↗

PubMed2003

Effect of NO synthase inhibition on myocardial metabolism during moderate ischemia.

Nitric oxide (NO) is involved in the control of myocardial metabolism. In normoperfused myocardium, NO synthase inhibition shifts myocardial metabolism from free fatty acid (FFA) toward carbohydrate utilization. Ischemic myocardium is characterized by a similar shift toward preferential carbohydrate utilization, although NO synthesis is increased. The importance of NO for myocardial metabolism during ischemia has not been analyzed in detail. We therefore assessed the influence of NO synthase inhibition with N(G)-nitro-l-arginine (l-NNA) on myocardial metabolism during moderate ischemia in anesthetized pigs. In control animals, the increase in left ventricular pressure with l-NNA was mimicked by aortic constriction. Before ischemia, l-NNA decreased myocardial FFA consumption (MV(FFA); P < 0.05), while consumption of carbohydrate and O(2) (MVo(2)) remained constant. ATP equivalents [calculated with the assumption of complete oxidative substrate decomposition (ATP(eq))] decreased with l-NNA (P < 0.05), associated with a decrease of regional myocardial function (P < 0.05). In contrast, aortic constriction had no effect on MV(FFA), while MVo(2) increased (P < 0.05) and ATP(eq) and regional myocardial function remained constant. During ischemia, alterations in myocardial metabolism were similar in control and l-NNA-treated animals: MV(FFA) decreased (P < 0.05) and net lactate consumption was reversed to net lactate production (P < 0.05). Regional myocardial function was decreased (P < 0.05), although more markedly in animals receiving l-NNA (P < 0.05). We conclude that the efficiency of oxidative metabolism was impaired by l-NNA per se, paralleled by impaired regional myocardial function. During ischemia, l-NNA had no effect on myocardial substrate consumption, indicating that NO synthases were no longer effectively involved in the control of myocardial metabolism.

Animals↗

PubMed2003

Activation of ATP-dependent potassium channels is a trigger but not a mediator of ischaemic preconditioning in pigs.

1. Activation of ATP-dependent potassium channels (K(ATP)) is involved in ischaemic preconditioning (IP). In isolated buffer-perfused rabbit hearts, activation of mitochondrial K(ATP)--through a generation of free radicals--acted as a trigger rather than a mediator of IP; the isolated buffer-perfused heart preparation, however, favours free radical generation. In contrast, in vivo studies in rats and dogs suggested that activation of K(ATP) acts as a mediator of IP's protection. A detailed analysis on the role of K(ATP) in IP's protection in vivo by varying the time and dose of K(ATP) blocker administration is, however, lacking. 2. In 54 enflurane-anaesthetized pigs, the left anterior descending coronary artery was perfused by an extracorporeal circuit. Infarct size (IS, %, TTC) following 90 min sustained low-flow ischaemia and 120 min reperfusion was 26.6+/-3.5 (s.e.m.) (n=8). IP with one cycle of 10 min ischaemia and 15 min reperfusion reduced IS to 6.5+/-2.1 (n=7, P<0.05). Blockade of K(ATP) with glibenclamide (0.5 mg kg(-1) i.v., 50 microg min(-1) continuous infusion) starting 10 min before or immediately following the preconditioning ischaemia abolished IS reduction by IP (20.7+/-2.7, n=7 and 21.9+/-6.6, n=6, respectively) while having no effect on IS per se (22.2+/-5.2, n=7), supporting a trigger role of K(ATP) in IP. In contrast, starting glibenclamide following the preconditioning ischaemia 10 min prior to the sustained ischaemia did not prevent IS reduction by IP (3.7+/-2.3, n=6), even when its bolus dose was increased to 1.5 mg kg(-1) (26.6+/-3.8 with IP vs 37.5+/-2.9 without IP; n=7 and 6 respectively, P<0.05), thereby refuting a mediator role of K(ATP) in IP. 3. In conclusion, activation of K(ATP) in the immediate reperfusion following the preconditioning ischaemia is pivotal for triggering IP.

Adenosine Triphosphate↗

PubMed2003

Parathyroid hormone-related peptide improves contractile function of stunned myocardium in rats and pigs.

The effect of synthetic parathyroid hormone (PTH)-related peptide [PTHrP(1-34)] on regional myocardial function was studied in 11 anesthetized pigs. Intracoronary infusion of PTHrP (cumulative dose: 14 +/- 1 microg) decreased coronary resistance to 33 +/- 2% of baseline (P < 0.05) and regional myocardial function to 90 +/- 3% of baseline (not significant). Ischemia-reperfusion alters the activity of several kinases and therefore possibly the myocardial effects of PTHrP. In stunned myocardium, induced by 20-min ischemia and 30-min reperfusion, the dose of PTHrP reducing coronary resistance to a minimum of 29 +/- 2% was decreased to 8 +/- 2 microg (P < 0.05). Regional myocardial function was no longer decreased but increased to 132 +/- 9% (P < 0.05). The increase in regional myocardial function during PTHrP was inversely related to baseline function at 30-min reperfusion in vivo (r = 0.9) as well as in myocytes isolated from stunned pig hearts (r = 0.7). In isolated rat hearts subjected to 30-min global ischemia followed by 30-min reperfusion, blockade of endogenous PTHrP by d-Trp(12)-Tyr(34)-PTH(7-34) attenuated the recovery of left ventricular developed pressure by 30 +/- 14% (P < 0.05). Thus endogenous and exogenous PTHrP impact on the function of stunned myocardium.

Animals↗

PubMed2002

Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid.

Free oxyradicals are involved in the signal transduction of ischemic preconditioning in rats and rabbits. Data from larger mammals in which the infarct development is closer to that in humans are lacking. We have therefore investigated the impact of the radical scavenger ascorbic acid on ischemic preconditioning in pigs. In 33 anesthetized pigs, the left anterior descending coronary artery was perfused from an extracorporeal circuit. Infarct size (measured as percent area at risk) was determined by triphenyltetrazolium chloride staining. In placebo-treated animals undergoing 90 min of severe ischemia and 120 min of reperfusion, infarct size averaged 26.9 +/- 3.9% (mean +/- SE; n = 9). Ischemic preconditioning by 10 min of ischemia and 15 min of reperfusion reduced infarct size to 6.4 +/- 2.4% (P < 0.05 vs. placebo; n = 9). Intravenous infusion of ascorbic acid (30 min before ischemic preconditioning or ischemia; 2-g bolus followed by 25 mg/min until the end of ischemia) had no effect on infarct size per se (22.6 +/- 6.5%; n = 6), but largely abolished the infarct size reduction by ischemic preconditioning (19.1 +/- 5.4%; n = 9). Scavenging of free oxyradicals with ascorbic acid largely attenuates the beneficial effect of ischemic preconditioning in pigs.

Animals↗

PubMed2002

Involvement of endogenous prostaglandins in ischemic preconditioning in pigs.

OBJECTIVE: In pigs, the infarct size (IS) reduction achieved by a strong preconditioning stimulus (IPs) of 10 min ischemia and 15 min reperfusion is greater than that by a weaker preconditioning stimulus (IPw) of 3 min ischemia and 15 min reperfusion. The cardioprotection achieved by IPw is completely abolished by blockade of bradykinin-B(2)-receptors. Since activation of bradykinin-B(2)-receptors subsequently activates cyclooxygenase, we now tested whether or not inhibition of cyclooxygenase with indomethacin interferes with IS reduction by IP. METHODS AND RESULTS: In 42 enflurane-anesthetized pigs, the LAD coronary artery was cannulated, and subendocardial blood flow (ENDO, microspheres, ml/min/g) and IS (%, TTC-staining) were determined. Following 90 min ischemia and 120 min reperfusion, IS averaged 25.5+/-3.8 (S.E.M.) (ENDO: 0.05+/-0.01). IS was reduced by IPw to 6.3+/-2.1 (ENDO: 0.07+/-0.01) and further reduced by IPs to 2.4+/-1.0 (ENDO: 0.06+/-0.01). Indomethacin (10 mg/kg i.v.) did not alter IS per se (20.9+/-5.4, ENDO: 0.06+/-0.02), but completely abolished the IS reduction by IPw (23.2+/-5.9, ENDO: 0.06+/-0.01). In contrast, indomethacin abolished the IS reduction by IPs in only two of seven pigs (16.1+/-7.4, ENDO: 0.05+/-0.01). CONCLUSION: Prostaglandins are involved in IP. However, with stronger IP stimuli other triggers/mediators can compensate for the lack of prostaglandins.

Analysis of Variance↗

PubMed2002

p38 MAP kinase is a mediator of ischemic preconditioning in pigs.

OBJECTIVE: The role of p38MAPK in ischemic preconditioning (IP) is still equivocal, insofar as the p38MAPK-inhibitor SB203580 abolished IP in rats, rabbits and dogs, but not in pigs. Blockade of p38MAPK prior to the sustained ischemia also generated contradictory findings, insofar as p38MAPK acted as trigger in dogs but as mediator in rats. We have now tested whether the two structurally unrelated p38MAPK-inhibitors, BIX-645 and SB203580, abolished infarct size (IS) reduction by IP in pigs and whether their effects depended on the time of administration. METHODS: Sixty-five enflurane-anesthetized pigs underwent 90 min low-flow ischemia and 120 min reperfusion without or with one preceding cycle of 10 min preconditioning ischemia and 15 min reperfusion. Pigs received BIX-645 (1 mg/kg, i.v.) or SB203580 (10 microM, i.c.) prior to either IP or the sustained ischemia. RESULTS: IS (% TTC-staining) was reduced by IP [4.8+/-3.1(S.E.M.), P<0.05] compared to placebo (25.8+/-5.5). BIX-645 or SB203580 per se had no effect on IS (23.5+/-5.2 and 21.8+/-4.4, respectively). IS reduction by IP was abolished by BIX-645 (26.2+/-6.4 or 25.5+/-4.7) and SB203580 (19.9+/-4.3 or 16.7+/-4.7), given either prior to IP or the sustained ischemia, respectively. The supernatant of homogenized myocardial biopsies taken during the sustained ischemia from preconditioned pigs receiving either BIX-645 or SB203580 inhibited the anisomycin-stimulated ATF-2 phosphorylation in cultured Rat1 fibroblasts. This in vitro inhibition of ATF-2 phosphorylation correlated to the actual IS. CONCLUSION: The attenuation of the IS-reducing effect of IP depends on the effectiveness of blockade of p38MAPK activity. p38MAPK is a mediator of IP in pigs.

Analysis of Variance↗