Pharmacological manipulation of Ins(1,4,5)P3 signaling mimics preconditioning in rabbit heart

1999 ◽  
Vol 277 (6) ◽  
pp. H2458-H2469 ◽  
Author(s):  
Anne Gysembergh ◽  
Stéphanie Lemaire ◽  
Christophe Piot ◽  
Catherine Sportouch ◽  
Sylvain Richard ◽  
...  
Keyword(s):  
Infarct Size ◽  
Coronary Occlusion ◽  
Rabbit Heart ◽  
Rat Cardiomyocytes ◽  
Pharmacological Manipulation ◽  
Inositol 1,4,5 Trisphosphate ◽  
Infarct Size Reduction ◽  
Tetrazolium Staining ◽  
Myocardium At Risk ◽  
Biphasic Profile

Recent evidence revealed biphasic alterations in myocardial concentrations of the second messenger inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] with ischemic preconditioning (PC), i.e., increase during brief PC ischemia and decrease early during sustained test occlusion. Our aim was to determine whether an agonist and an antagonist of Ins(1,4,5)P3signaling {d- myo-inositol-1,4,5-trisphosphate hexasodium salt [d- myo-Ins(1,4,5)P3] and 2-aminoethoxydiphenyl borate (2-APB), respectively}, given such that they mimic this biphasic profile, would mimic infarct size reduction with PC. To test this concept, isolated, buffer-perfused rabbit hearts received no intervention (control), ischemic PC,d- myo-Ins(1,4,5)P3,d- myo-Ins(1,4,5)P3+ PC, 2-APB, or 2-APB + PC. All hearts then underwent 30-min coronary occlusion and 2 h reflow, and infarct size was delineated by tetrazolium staining. In addition, the effects ofd- myo-Ins(1,4,5)P3and 2-APB on Ins(1,4,5)P3signaling were evaluated in isolated fura 2-loaded rat cardiomyocytes. Mean infarct size was reduced with PC and in alld- myo-Ins(1,4,5)P3- and 2-APB-treated groups versus control (59 and 42–55%, respectively, vs. 80% of myocardium at risk, P < 0.05). Thus pharmacological manipulation of Ins(1,4,5)P3 signaling mimics the cardioprotection achieved with ischemic PC in rabbit heart.

Anti-Stunning and Anti-Infarct Effects of Adenosine-Enhanced Ischemic Preconditioning

Circulation ◽  
2000 ◽  
Vol 102 (suppl_3) ◽  
Author(s):  
Yoshiya Toyoda ◽  
Vincenzo Di Gregorio ◽  
Robert A. Parker ◽  
Sidney Levitsky ◽  
James D. McCully
Keyword(s):  
At Risk ◽  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Bolus Injection ◽  
Ischemia Reperfusion ◽  
Area At Risk ◽  
Regional Ischemia ◽  
Infarct Size Reduction ◽  
Tetrazolium Staining

Background —Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing post-ischemic functional recovery. In this study, the anti-infarct effects and the anti-stunning effects of APC in contributing to enhanced post-ischemic functional recovery were determined and compared with IPC. Methods and Results —Sheep (n=96) were subjected to 15, 30, 45, or 60 minutes of regional ischemia and 120 minutes of reperfusion. IPC hearts received 5 minutes of regional ischemia and 5 minutes of reperfusion before ischemia/reperfusion. APC hearts received a bolus injection of adenosine coincident with IPC. Adenosine hearts (ADO) received a bolus injection of adenosine before ischemia/reperfusion. Regional ischemia (RI) hearts received no pretreatment. Infarct size/area at risk was determined by tetrazolium staining. Regional myocardial function was determined by sonomicrometry. Segment shortening after 15 minutes of ischemia in which no infarct was incurred was 32.1±10.6% in RI, 70.6±8.5% in IPC, and 77.4±6.0% in APC hearts. Segment shortening after 30 minutes of ischemia was 60.7±6.3% in APC hearts ( P <0.05 versus RI, ADO, IPC) but was <37% in all other groups. Infarct size/area at risk after 30 and 60 minutes of ischemia was, respectively, 25.8±5.7% and 49.8±6.0% in RI, 12.9±3.0% and 29.2±5.0% in ADO, 11.6±2.4% and 24.6±2.7% in IPC, and 5.1±1.6% and 12.4±2.0% in APC hearts ( P <0.05 versus RI, ADO, IPC). Conclusions —APC and IPC exhibit anti-infarct and anti-stunning effects in the ovine heart, but these effects are rapidly diminished with IPC. APC significantly extends these effects, providing for significantly enhanced infarct size reduction and post-ischemic functional recovery ( P <0.05 versus IPC).

Rabbit heart can be “preconditioned” via transfer of coronary effluent

1999 ◽  
Vol 277 (6) ◽  
pp. H2451-H2457 ◽  
Author(s):  
Eric W. Dickson ◽  
Mojca Lorbar ◽  
William A. Porcaro ◽  
Richard A. Fenton ◽  
Christopher P. Reinhardt ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Rabbit Heart ◽  
Remote Myocardium ◽  
Control Groups ◽  
Donor Control ◽  
Donor And Acceptor ◽  
Humoral Mechanism ◽  
Norepinephrine Content ◽  
Tetrazolium Staining

Brief myocardial ischemia not only evokes a local cardioprotective or “preconditioning” effect but also can render remote myocardium resistant to sustained ischemia. We propose the following hypotheses: remote protection is initiated by a humoral trigger; brief ischemia-reperfusion will result in release of the humoral trigger (possibly adenosine and/or norepinephrine) into the coronary effluent; and transfer of this effluent to a virgin acceptor heart will elicit cardioprotection. To test these concepts, effluent was collected during normal perfusion from donor-control hearts and during preconditioning ischemia-reperfusion from donor-preconditioned (PC) hearts. After reoxygenation occurred and aliquots for measurement of adenosine and norepinephrine content were harvested, effluent was transfused to acceptor-control and acceptor-PC hearts. All hearts then underwent 40 min of global ischemia and 60 min of reperfusion, and infarct size was delineated by tetrazolium staining. Mean infarct size was smaller in both donor- and acceptor-PC groups (9% of left ventricle) than in donor- and acceptor-control groups (36% and 34%; P < 0.01). Protection in acceptor-PC hearts could not, however, be attributed to adenosine or norepinephrine. Thus preconditioning-induced cardioprotection can be transferred between rabbit hearts by transfusion of coronary effluent. Although adenosine and norepinephrine are apparently not responsible, these results suggest that remote protection is initiated by a humoral mechanism.

First molecular evidence that inositol trisphosphate signaling contributes to infarct size reduction with preconditioning

2006 ◽  
Vol 291 (4) ◽  
pp. H2008-H2012 ◽  
Author(s):  
Karin Przyklenk ◽  
Michelle Maynard ◽  
Peter Whittaker
Keyword(s):  
Infarct Size ◽  
Treatment Phase ◽  
Size Reduction ◽  
Receptor Protein ◽  
Molecular Evidence ◽  
Infarct Size Reduction ◽  
Tetrazolium Staining ◽  
Sparing Effect ◽  
To Receive

Considerable attention has focused on the role of protein kinase C (PKC) in triggering the profound infarct-sparing effect of ischemic preconditioning (PC). In contrast, the involvement of inositol 1,4,5-trisphosphate [Ins( 1 , 4 , 5 )P3], the second messenger generated in parallel with the diacylglycerol-PKC pathway, remains poorly understood. We hypothesized that, if Ins( 1 , 4 , 5 )P3signaling [i.e., release of Ins( 1 , 4 , 5 )P3and subsequent binding to Ins( 1 , 4 , 5 )P3receptors] contributes to PC-induced cardioprotection, then the reduction of infarct size achieved with PC would be attenuated in mice that are deficient in Ins( 1 , 4 , 5 )P3receptor protein. To test this concept, hearts were harvested from 1) B6C3Fe- a/a-Itpr-1opt+/−/J mutants displaying reduced expression of Ins( 1 , 4 , 5 )P3receptor-1 protein, 2) Itpr-1opt+/+wild types from the colony, and 3) C57BL/6J mice. All hearts were buffer-perfused and randomized to receive two 5-min episodes of PC ischemia, pretreatment with d- myo-Ins( 1 , 4 , 5 )P3[sodium salt of native Ins( 1 , 4 , 5 )P3], the mitochondrial ATP-sensitive K+channel opener diazoxide, or no intervention (controls). After the treatment phase, all hearts underwent 30-min global ischemia followed by 2 h of reperfusion, and infarct size was delineated by tetrazolium staining. In both wild-type and C57BL/6J cohorts, area of necrosis in hearts that received PC, d- myo-Ins( 1 , 4 , 5 )P3, and diazoxide averaged 28–35% of the total left ventricle (LV), significantly smaller than the values of 52–53% seen in controls ( P < 0.05). In contrast, in Itpr-1opt+/−mutants, protection was only seen with diazoxide: neither PC nor d- myo-Ins( 1 , 4 , 5 )P3limited infarct size (52–58% vs. 56% of the LV in mutant controls). These data provide novel evidence that Ins( 1 , 4 , 5 )P3signaling contributes to infarct size reduction with PC.

Preservation of ischemia and isoflurane-induced preconditioning after brain death in rabbit hearts

2002 ◽  
Vol 283 (5) ◽  
pp. H1769-H1774 ◽  
Author(s):  
Pascal Chiari ◽  
Vincent Piriou ◽  
Guylaine Hadour ◽  
Claire Rodriguez ◽  
Joseph Loufouat ◽  
...  
Keyword(s):  
Brain Death ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Rabbit Heart ◽  
Catecholamine Release ◽  
Plasma Catecholamine ◽  
Balloon Inflation ◽  
Time Points ◽  
Catecholamine Levels

We sought to determine whether brain death-induced catecholamine release preconditions the heart, and if not, whether it precludes further protection by repetitive ischemia or isoflurane. Anesthetized rabbits underwent 30 min of coronary occlusion and 4 h of reperfusion. The effect on infarct size of either no intervention (controls), ischemic preconditioning (IPC), or isoflurane inhalation (Iso) was evaluated with or without previous brain death (BD) induced by subdural balloon inflation. Plasma catecholamine levels were measured at several time points. Although it dramatically increase plasma catecholamine levels, BD failed to reduce infarct size that averaged 0.49 ± 0.34 without BD versus 0.45 ± 0.27 g with BD. IPC and Iso, alone as well as after BD, significantly reduced infarct size that averaged 0.11 ± 0.04, 0.21 ± 0.15, 0.10 ± 0.09, and 0.22 ± 0.10 g in IPC, Iso, BD + IPC, and BD + Iso groups, respectively (means ± SD, P < 0.05 vs. controls). BD-induced catecholamines “storm” does not precondition the rabbit heart that however retains the ability to be protected by repetition of brief ischemia or isoflurane inhalation.

Progression of myocardial injury during coronary occlusion in the collateral-deficient heart: a non-wavefront phenomenon

2007 ◽  
Vol 293 (3) ◽  
pp. H1799-H1804 ◽  
Author(s):  
Bradley G. Leshnower ◽  
Hiroaki Sakamoto ◽  
Hirotsugu Hamamoto ◽  
Ahmad Zeeshan ◽  
Joseph H. Gorman ◽  
...  
Keyword(s):  
Infarct Size ◽  
Functional Capacity ◽  
Collateral Circulation ◽  
Coronary Occlusion ◽  
Regional Blood Flow ◽  
Microvascular Dysfunction ◽  
Canine Model ◽  
Ischemic Time ◽  
Coronary Collaterals ◽  
Wide Range

It is widely accepted that, during acute coronary occlusion, ischemic cell death progresses from the subendocardium to the subepicardium in a wavefront fashion. This concept, which implies that the subendocardium is the most susceptible myocardial region to ischemic injury, was established using a canine model with an extensive system of subepicardial coronary collaterals. In humans, particularly in those with coronary artery disease, there is a wide range in the distribution and functional capacity of the collateral circulation, which may affect the pattern of infarct evolution. Using an ovine model with a limited system of preformed subendocardial coronary collaterals, we characterized the effect of increasing lengths of ischemia on regional blood flow and infarct size in three regions of the ventricular wall: subendocardium, midmyocardium, and subepicardium. Our results demonstrate that the myocardium and microvasculature in these three regions are equally susceptible to injury after 45 min of ischemia. When ischemic time is increased to 1 h, infarct size in the midmyocardium (90 ± 2%) is greater than in the subendocardium (76 ± 4%, P = 0.004) and subepicardium (84 ± 3%, P = 0.13). Microvascular dysfunction as assessed as a percentage of baseline flow is also greater in the midmyocardium (14 ± 5%) compared with the subendocardium (20 ± 3%, P = 0.23) and subepicardium (51 ± 9%, P = 0.007). These findings suggest that, in subjects with a limited system of coronary collateral circulation, the midmyocardium is the most susceptible myocardial region to ischemia and the subendocardium is the most resistant. Myocardial viability during coronary occlusion appears to be primarily determined by the distribution and functional capacity of the collateral circulation.

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