Pretreatment with tyrosine kinase inhibitors partially attenuates ischemic preconditioning in rat hearts

1998 ◽  
Vol 275 (6) ◽  
pp. H2009-H2015 ◽  
Author(s):  
Ryan M. Fryer ◽  
Jo El J. Schultz ◽  
Anna K. Hsu ◽  
Garrett J. Gross
Keyword(s):  
Tyrosine Kinase ◽  
Ischemic Preconditioning ◽  
Kinase Inhibitors ◽  
Coronary Artery Occlusion ◽  
Structural Analog ◽  
Artery Occlusion ◽  
Area At Risk ◽  
Rat Hearts ◽  
Tk Inhibitors ◽  
Occlusion Period

Ischemic preconditioning (IPC) confers cardioprotection against a prolonged ischemic insult. Tyrosine kinase (TK) inhibitors have been shown to attenuate IPC; however, it is unclear whether TK is involved in the initiation of and/or the maintenance of this phenomenon. Thus the hypothesis that TK acts primarily during the initiation of IPC was examined in a rat model of myocardial infarction. Hearts were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. IPC was elicited by three 5-min occlusions interspersed with 5 min of reperfusion before the prolonged occlusion period. Genistein, a nonspecific TK inhibitor, was administered before or during the final 2 min of the first or third occlusion period of IPC. Daidzein, an inactive structural analog of genistein, and lavendustin A, a more specific TK inhibitor, were also tested in this model. IPC markedly reduced infarct size expressed as a percentage of the area at risk compared with control (56.3 ± 2.8 to 7.1 ± 2.0%). This cardioprotection was attenuated by genistein pretreatment (5 mg/kg: 34.7 ± 2.2%, 10 mg/kg: 33.5 ± 5.9%). However, genistein administered during the first or third occlusion period of IPC did not significantly attenuate cardioprotection (10.3 ± 2.9% and 6.4 ± 2.0%). Lavendustin A (1.0 mg/kg) pretreatment also attenuated IPC (30.1 ± 2.2%), whereas daidzein (5 mg/kg) had no effect (7.9 ± 2.4%). These results suggest that activation of a TK is involved in the initiation but not the maintenance of IPC in the rat myocardium.

Importance of PKC and tyrosine kinase in single or multiple cycles of preconditioning in rat hearts

1999 ◽  
Vol 276 (4) ◽  
pp. H1229-H1235 ◽  
Author(s):  
Ryan M. Fryer ◽  
Jo El J. Schultz ◽  
Anna K. Hsu ◽  
Garrett J. Gross
Keyword(s):  
Tyrosine Kinase ◽  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Area At Risk ◽  
Kinase C ◽  
Rat Hearts ◽  
Multiple Cycle ◽  
In Series ◽  
Multiple Cycles

Both tyrosine kinase (TK) and protein kinase C (PKC) inhibitors have been shown individually to completely abolish the cardioprotective effects of ischemic preconditioning (IPC) in rabbits; however, blockade of both enzymes is necessary to totally abolish IPC in pigs. Recently, we have shown that TK inhibition partially attenuates the cardioprotective effect of IPC in intact rat hearts. Therefore, the present study was designed to test the hypothesis that inhibition of both TK and PKC is necessary to completely abolish IPC in the intact rat and that this effect is dependent on the intensity of the preconditioning stimulus. All animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. In series 1, multiple-cycle-induced IPC was produced via three 5-min occlusions interspersed with 5 min of reperfusion (3 × 5 IPC). Genistein (5 mg/kg), a TK inhibitor infused 30 min before IPC, and chelerythrine chloride (5 mg/kg), a PKC inhibitor infused 5 min before the prolonged ischemic insult, were administered alone or in combination in the absence or presence of 3 × 5 IPC. 3 × 5 IPC produced a marked reduction in infarct size as a percentage of area at risk compared with control (8.0 ± 0.8 vs. 56.1 ± 0.8%). The effects of 3 × 5 IPC were partially blocked by pretreatment with genistein (34.0 ± 2.0%) or chelerythrine (26.4 ± 2.8%) alone; however, combined administration of genistein and chelerythrine completely abolished the effects of 3 × 5 IPC (50.7 ± 3.6%). In series 2, single-cycle IPC was elicited by one 5-min occlusion followed by 10 min of reperfusion (1 × 5 IPC). Compared with control, 1 × 5 IPC also significantly reduced infarct size (15.4 ± 3.0%). Genistein or chelerythrine administered alone completely abolished 1 × 5 IPC-induced cardioprotection. These results suggest that the efficacy of TK and PKC inhibition to block IPC depends on the intensity of the preconditioning stimulus and that these kinases may work through parallel pathways.

Cardioprotection provided by adenosine receptor activation is abolished by blockade of the KATP channel

1994 ◽  
Vol 266 (2) ◽  
pp. H829-H839 ◽  
Author(s):  
D. M. Van Winkle ◽  
G. L. Chien ◽  
R. A. Wolff ◽  
B. E. Soifer ◽  
K. Kuzume ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Katp Channel ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Receptor Activation ◽  
Artery Occlusion ◽  
Area At Risk ◽  
A1 Receptor ◽  
Adenosine Agonists ◽  
Phenylisopropyl Adenosine

Adenosine agonists and openers of the ATP-sensitive potassium (KATP) channel have been reported to limit infarct size (IS). We tested the hypothesis that these phenomena are interdependent. Anesthetized swine underwent 60 min of coronary artery occlusion and 90 min of reperfusion. Preconditioning was elicited by two cycles comprising 10 min of occlusion and 10 min of reperfusion (n = 7 swine). An intracoronary infusion of adenosine (Ado; n = 10) or (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA; n = 7) replaced preconditioning ischemia. KATP channels were blocked with sodium 5-hydroxydecanoate (5-HD) in the absence (n = 6) or presence (n = 8) of R-PIA. Control pigs (n = 7) received saline vehicle. IS was assessed with tetrazolium and normalized as percentage of area at risk. Preconditioning resulted in a reduced IS compared with Control (3.9 +/- 1.8 vs. 43.5 +/- 6.9%, respectively; P < 0.0005). Ado and R-PIA also reduced IS [21.1 +/- 6.8 (P < 0.01) and 11.2 +/- 7.4% (P < 0.005), respectively]. 5-HD alone did not alter IS, but it abolished R-PIA-induced cardioprotection (IS 5-HD + R-PIA = 48.6 +/- 13.2%). Thus Ado A1-receptor agonists mimicked the cardioprotection of ischemic preconditioning. The Ado-induced limitation of IS was abolished by blockade of the KATP channel. We conclude that both Ado A1 receptors and KATP channels may be involved in ischemic preconditioning.

Role of the β1-Adrenergic Pathway in Anesthetic and Ischemic Preconditioning against Myocardial Infarction in the Rabbit Heart In Vivo 

2006 ◽  
Vol 105 (3) ◽  
pp. 503-510 ◽  
Author(s):  
Markus Lange ◽  
Thorsten M. Smul ◽  
Christoph A. Blomeyer ◽  
Andreas Redel ◽  
Karl-Norbert Klotz ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Coronary Artery ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Myocardial Infarct Size ◽  
Area At Risk

Background Anesthetic and ischemic preconditioning share similar signal transduction pathways. The authors tested the hypothesis that the beta1-adrenergic signal transduction pathway mediates anesthetic and ischemic preconditioning in vivo. Methods Pentobarbital-anesthetized (30 mg/kg) rabbits (n = 96) were instrumented for measurement of systemic hemodynamics and subjected to 30 min of coronary artery occlusion and 3 h of reperfusion. Sixty minutes before occlusion, vehicle (control), 1.0 minimum alveolar concentration desflurane, or sevoflurane, and esmolol (30.0 mg x kg(-1) x h(-1)) were administered for 30 min, respectively. Administration of a single 5-min cycle of ischemic preconditioning was instituted 35 min before coronary artery occlusion. In separate groups, the selective blocker esmolol or the protein kinase A inhibitor H-89 (250 microg/kg) was given alone and in combination with desflurane, sevoflurane, and ischemic preconditioning. Results Baseline hemodynamics and area at risk were not significantly different between groups. Myocardial infarct size (triphenyltetrazolium staining) as a percentage of area at risk was 61 +/- 4% in control. Desflurane, sevoflurane, and ischemic preconditioning reduced infarct size to 34 +/- 2, 36 +/- 5, and 23 +/- 3%, respectively. Esmolol did not alter myocardial infarct size (65 +/- 5%) but abolished the protective effects of desflurane and sevoflurane (57 +/- 4 and 52 +/- 4%, respectively) and attenuated ischemic preconditioning (40 +/- 4%). H-89 did not alter infarct size (60 +/- 4%) but abolished preconditioning by desflurane (57 +/- 5%) and sevoflurane (61 +/- 1%). Ischemic preconditioning (24 +/- 7%) was not affected by H-89. Conclusions The results demonstrate that anesthetic preconditioning is mediated by the beta1-adrenergic pathway, whereas this pathway is not essential for ischemic preconditioning. These results indicate important differences in the mechanisms of anesthetic and ischemic preconditioning.

Evidence for involvement of opioid receptors in ischemic preconditioning in rat hearts

1995 ◽  
Vol 268 (5) ◽  
pp. H2157-H2161 ◽  
Author(s):  
J. E. Schultz ◽  
E. Rose ◽  
Z. Yao ◽  
G. J. Gross
Keyword(s):  
Opioid Receptors ◽  
Ischemic Preconditioning ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Opioid Antagonist ◽  
Control Group ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
Group I ◽  
Male Wistar Rats

The purpose of the present study was to investigate a possible role of opioid receptors in ischemic preconditioning (PC). To test this hypothesis, anesthetized, open-chest, male Wistar rats were subjected to five different protocols. In group I, the control group was subjected to 30 min of left coronary artery occlusion and 2 h of reperfusion. In group II, ischemic PC was elicited by three 5-min occlusion periods interspersed with 5 min of reperfusion. In group III, naloxone (NL, 3 mg/kg iv), a nonselective opioid antagonist, was given to nonpreconditioned rats 10 min before the 30-min occlusion period. Finally, NL was administered 10 min before preconditioning (NL + PC, group IV) or immediately after the last 5-min preconditioning period (PC + NL, group V). Infarct size (IS) as a percentage of the area at risk (AAR) (IS/AAR) was determined by 2,3,5-triphenyltetrazolium chloride staining. PC resulted in a marked reduction in myocardial IS from 45 +/- 5 to 8 +/- 1 (P < 0.05). NL treatment before or immediately after PC abolished this protective effect; however, NL had no effect on IS in non-PC rats. These results are the first to support the hypothesis that activation of opioid receptors may play an important role in ischemic PC in the rat myocardium.

Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice

2001 ◽  
Vol 280 (5) ◽  
pp. H2313-H2320 ◽  
Author(s):  
Zhongyi Chen ◽  
Chu Chang Chua ◽  
Ye-Shih Ho ◽  
Ronald C. Hamdy ◽  
Balvin H. L. Chua
Keyword(s):  
Coronary Artery ◽  
Lactate Dehydrogenase ◽  
Transgenic Mice ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Fragmentation Pattern ◽  
Area At Risk ◽  
Antiapoptotic Protein

To test whether the antiapoptotic protein Bcl-2 prevents apoptosis and injury of cardiomyocytes after ischemia-reperfusion (I/R), we generated a line of transgenic mice that carried a human Bcl-2 transgene under the control of a mouse α-myosin heavy chain promoter. High levels of human Bcl-2 transcripts and 26-kDa Bcl-2 protein were expressed in the hearts of transgenic mice. Functional recovery of the transgenic hearts significantly improved when they were perfused as Langendorff preparations. This protection was accompanied by a threefold decrease in lactate dehydrogenase (LDH) released from the transgenic hearts. The transgenic mice were subjected to 50 min of ligation of the left descending anterior coronary artery followed by reperfusion. The infarct sizes, expressed as a percentage of the area at risk, were significantly smaller in the transgenic mice than in the nontransgenic mice (36.6 ± 5 vs 69.9 ± 7.3%, respectively). In hearts subjected to 30 min of coronary artery occlusion followed by 3 h of reperfusion, Bcl-2 transgenic hearts had significantly fewer terminal deoxynucleodidyl-transferase nick-end labeling-positive or in situ oligo ligation-positive myocytes and a less prominent DNA fragmentation pattern. Our results demonstrate that overexpression of Bcl-2 renders the heart more resistant to apoptosis and I/R injury.

Responses to coronary artery occlusion in conscious dogs with selective cardiac denervation

1988 ◽  
Vol 255 (3) ◽  
pp. H525-H533 ◽  
Author(s):  
Y. T. Shen ◽  
D. R. Knight ◽  
S. F. Vatner ◽  
W. C. Randall ◽  
J. X. Thomas
Keyword(s):  
At Risk ◽  
Blood Flow ◽  
Coronary Artery ◽  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Conscious Dogs ◽  
Wall Thickening ◽  
Area At Risk ◽  
Cardiac Denervation

The extent to which cardiac denervation alters responses to myocardial ischemia remains controversial. This study compared responses to 24-h coronary artery occlusion (CAO) on measurements of wall thickness (ultrasonic crystals), regional myocardial blood flow (microspheres), and infarct size (triphenyltetrazolium chloride technique) in three groups of conscious dogs with 1) selective posterior left ventricular (LV) wall denervation, 2) selective ventricular denervation, or in 3) intact dogs. After CAO, hemodynamic changes were not different among the three groups. Wall thickening in the ischemic zone became akinetic or paradoxical early after CAO and did not recover in any group over the 24-h monitoring period. Blood flow in the area at risk fell similarly in all groups. Infarct size, as a percentage of the area at risk, was 45 +/- 7% in intact, 48 +/- 6% in posterior LV wall-denervated, and 48 +/- 8% in ventricular-denervated group. There was, however, a lower (P less than 0.05) frequency of arrhythmic beats per minute after 3 h of CAO in the ventricular-denervated group (3.2 +/- 1.4) compared with the intact (11.3 +/- 4.1) or posterior wall-denervated (12.6 +/- 3.2) group. An additional group of ventricular-denervated dogs was studied to determine the effects of sequential, brief 2-min CAO at 2, 4, and 8 wk after denervation. Responses of regional wall thickening to CAO were not affected significantly even after 8 wk following ventricular denervation. Thus, in conscious dogs, neither selective ventricular denervation nor selective denervation of the posterior LV wall improved collateral blood flow, affected regional function favorably, or reduced infarct size after CAO.

scholarly journals TAN-67, a δ1-opioid receptor agonist, reduces infarct size via activation of Gi/oproteins and KATPchannels

1998 ◽  
Vol 274 (3) ◽  
pp. H909-H914 ◽  
Author(s):  
Jo El J. Schultz ◽  
Anna K. Hsu ◽  
Hiroshi Nagase ◽  
Garrett J. Gross
Keyword(s):  
Infarct Size ◽  
Opioid Receptor ◽  
Opioid Receptors ◽  
Coronary Artery Occlusion ◽  
Receptor Activation ◽  
Artery Occlusion ◽  
Cardioprotective Effect ◽  
Area At Risk ◽  
Opioid Receptor Agonist ◽  
Δ Opioid Receptor

We have previously shown that delta (δ)-opioid receptors, most notably δ1, are involved in the cardioprotective effect of ischemic preconditioning (PC) in rats; however, the mechanism by which δ-opioid receptor-induced cardioprotection is mediated remains unknown. Therefore, we hypothesized that several of the known mediators of ischemic PC such as the ATP-sensitive potassium (KATP) channel and Gi/oproteins are involved in the cardioprotective effect produced by δ1-opioid receptor activation. To address these possibilities, anesthetized, open-chest Wistar rats were randomly assigned to five groups. Control animals were subjected to 30 min of coronary artery occlusion and 2 h of reperfusion. To demonstrate that stimulating δ1-opioid receptors produces cardioprotection, TAN-67, a new selective δ1-agonist, was infused for 15 min before the long occlusion and reperfusion periods. In addition, one group received 7-benzylidenenaltrexone (BNTX), a selective δ1-antagonist, before TAN-67. To study the involvement of KATPchannels or Gi/oproteins in δ1-opioid receptor-induced cardioprotection, glibenclamide (Glib), a KATPchannel antagonist, or pertussis toxin (PTX), an inhibitor of Gi/oproteins, was administered before TAN-67. Infarct size (IS) as a percentage of the area at risk (IS/AAR) was determined by tetrazolium stain. TAN-67 significantly reduced IS/AAR as compared with control (56 ± 2 to 27 ± 5%, n = 5, P < 0.05). The cardioprotective effect of TAN-67 was completely abolished by BNTX, Glib, and PTX (51 ± 3, 53 ± 5, and 61 ± 4%, n = 6 for each group, respectively). These results are the first to suggest that stimulating the δ1-opioid receptor elicits a cardioprotective effect that is mediated via Gi/oproteins and KATPchannels in the intact rat heart.

Is Isoflurane-induced Preconditioning Dose Related?

2002 ◽  
Vol 96 (3) ◽  
pp. 675-680 ◽  
Author(s):  
Franz Kehl ◽  
John G. Krolikowski ◽  
Boris Mraovic ◽  
Paul S. Pagel ◽  
David C. Warltier ◽  
...  
Keyword(s):  
Blood Flow ◽  
Infarct Size ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Left Ventricular ◽  
Collateral Blood Flow ◽  
Area At Risk ◽  
Dose Dependent Fashion ◽  
Dose Dependent ◽  
Coronary Collateral Blood Flow

Background Volatile anesthetics precondition against myocardial infarction, but it is unknown whether this beneficial action is threshold- or dose-dependent. The authors tested the hypothesis that isoflurane decreases myocardial infarct size in a dose-dependent fashion in vivo. Methods Barbiturate-anesthetized dogs (n = 40) were instrumented for measurement of systemic hemodynamics including aortic and left ventricular pressures and rate of increase of left ventricular pressure. Dogs were subjected to a 60-min left anterior descending coronary artery occlusion followed by 3 h of reperfusion and were randomly assigned to receive either 0.0, 0.25, 0.5, 1.0, or 1.25 minimum alveolar concentration (MAC) isoflurane in separate groups. Isoflurane was administered for 30 min and discontinued 30 min before left anterior descending coronary artery occlusion. Results Infarct size (triphenyltetrazolium staining) was 29 +/- 2% of the area at risk in control experiments (0.0 MAC). Isoflurane produced significant (P &lt; 0.05) reductions of infarct size (17 +/- 3, 13 +/- 1, 14 +/- 2, and 11 +/- 1% of the area at risk during 0.25, 0.5, 1.0, and 1.25 MAC, respectively). Infarct size was inversely related to coronary collateral blood flow (radioactive microspheres) in control experiments and during low (0.25 or 0.5 MAC) but not higher concentrations of isoflurane. Isoflurane shifted the linear regression relation between infarct size and collateral perfusion downward (indicating cardioprotection) in a dose-dependent fashion. Conclusions Concentrations of isoflurane as low as 0.25 MAC are sufficient to precondition myocardium against infarction. High concentrations of isoflurane may have greater efficacy to protect myocardium during conditions of low coronary collateral blood flow.

scholarly journals Metoprolol blunts the time-dependent progression of infarct size

2020 ◽  
Vol 115 (5) ◽  
Author(s):  
Manuel Lobo-Gonzalez ◽  
Carlos Galán-Arriola ◽  
Xavier Rossello ◽  
Maribel González‐Del‐Hoyo ◽  
Jean Paul Vilchez ◽  
...  
Keyword(s):  
Infarct Size ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Primary Angioplasty ◽  
Primary Outcome Measure ◽  
Artery Occlusion ◽  
Area At Risk ◽  
Perfusion Computed Tomography ◽  
Myocardial Ischemia Reperfusion

Abstract Early metoprolol administration protects against myocardial ischemia–reperfusion injury, but its effect on infarct size progression (ischemic injury) is unknown. Eight groups of pigs (total n = 122) underwent coronary artery occlusion of varying duration (20, 25, 30, 35, 40, 45, 50, or 60 min) followed by reperfusion. In each group, pigs were randomized to i.v. metoprolol (0.75 mg/kg) or vehicle (saline) 20 min after ischemia onset. The primary outcome measure was infarct size (IS) on day7 cardiac magnetic resonance (CMR) normalized to area at risk (AAR, measured by perfusion computed tomography [CT] during ischemia). Metoprolol treatment reduced overall mortality (10% vs 26%, p = 0.03) and the incidence and number of primary ventricular fibrillations during infarct induction. In controls, IS after 20-min ischemia was ≈ 5% of the area AAR. Thereafter, IS progressed exponentially, occupying almost all the AAR after 35 min of ischemia. Metoprolol injection significantly reduced the slope of IS progression (p = 0.004 for final IS). Head-to-head comparison (metoprolol treated vs vehicle treated) showed statistically significant reductions in IS at 30, 35, 40, and 50-min reperfusion. At 60-min reperfusion, IS was 100% of AAR in both groups. Despite more prolonged ischemia, metoprolol-treated pigs reperfused at 50 min had smaller infarcts than control pigs undergoing ischemia for 40 or 45 min and similar-sized infarcts to those undergoing 35-min ischemia. Day-45 LVEF was higher in metoprolol-treated vs vehicle-treated pigs (41.6% vs 36.5%, p = 0.008). In summary, metoprolol administration early during ischemia attenuates IS progression and reduces the incidence of primary ventricular fibrillation. These data identify metoprolol as an intervention ideally suited to the treatment of STEMI patients identified early in the course of infarction and requiring long transport times before primary angioplasty.

KATP channels and memory of ischemic preconditioning in dogs: synergism between adenosine and KATP channels

1997 ◽  
Vol 272 (1) ◽  
pp. H334-H342 ◽  
Author(s):  
Z. Yao ◽  
T. Mizumura ◽  
D. A. Mei ◽  
G. J. Gross
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Katp Channels ◽  
Canine Heart ◽  
Ischemic Insult ◽  
Area At Risk ◽  
Adenosine Receptor Antagonist ◽  
Anesthetized Dogs ◽  
Drug Free ◽  
Occlusion Period

Results from numerous studies have shown that there is an important link between adenosine A1 receptors and ATP-sensitive potassium (KATP) channels in mediating the cardioprotective effects of ischemic preconditioning (PC). The major aim of the present study was to determine whether occupation of A1 receptors and/or the opening of KATP channels is involved in the time delay between the PC stimulus and the prolonged ischemic insult or the “memory” of PC to reduce infarct size. Barbital sodium-anesthetized dogs were subjected to 1 h of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Ischemic PC was elicited by 10 min of LAD occlusion followed by 1 h of reperfusion (1-h memory) before the 1-h occlusion period. Either adenosine (800 g/min), bimakalim (3 g/min), a combination of two lower doses of each agent (400 g/min of adenosine and 0.3 g/min of bimakalim), or an equivalent volume of saline was infused into the LAD for 10 min followed by a 1-h drug-free period before the 1-h ischemic insult. In another series, glibenclamide, 8-cyclopentyl-1,3-dipropylxanthine (a selective A1-receptor blocker), or PD-115199 (a nonselective adenosine-receptor antagonist) was administered 50 min after ischemic PC (10 min before the 1-h occlusion period). Infarct size (IS) was expressed as a percentage of the area at risk. PC with 1 h of reperfusion resulted in a marked reduction in IS (8.1 +/- 6.5 vs. 29.8 +/- 5.8% in control dogs). Administration of adenosine or bimakalim followed by a 1-h drug-free period had no effect on IS; however, the simultaneous administration of adenosine and bimakalim resulted in a marked decrease in IS (11.5 +/- 2.7%). One hour after ischemic PC, administration of glibenclamide blocked the protective effect of ischemic PC, whereas 8-cyclopentyl-1,3-dipropylxanthine or PD-115199 did not affect it. These results provide evidence that the opening of myocardial KATP channels may play an important role in the memory of ischemic PC in the canine heart and also suggest that adenosine and the KATP channel may have a synergistic interaction that is important for the memory phase of PC.

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