Opening of mitochondrial KATPchannel induces early and delayed cardioprotective effect: role of nitric oxide

1999 ◽  
Vol 277 (6) ◽  
pp. H2425-H2434 ◽  
Author(s):  
Ramzi Ockaili ◽  
Venkata R. Emani ◽  
Shinji Okubo ◽  
Michael Brown ◽  
Kavitha Krottapalli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Vehicle Group ◽  
Blue Dye ◽  
Risk Area ◽  
Tetrazolium Staining ◽  
Delayed Phase

Opening of mitochondrial ATP-sensitive (mitoKATP) channel with diazoxide induces an early phase (EP) of cardioprotection. It is unknown whether diazoxide also induces a delayed phase (DP) of cardioprotection. Because nitric oxide (NO) modulates ATP sensitivity of the KATPchannel, we hypothesized that NO may play a role in diazoxide-induced cardioprotection. Diazoxide (1 mg/kg) was administered either 30 min (for EP) or 24 h (DP) before 30 min of lethal ischemia. Blockers of mitoKATPchannel [5-hydroxydecanoate (5-HD)] or NO synthase [ NG-nitro-l-arginine methyl ester (l-NAME)] were given 10 min before ischemia-reperfusion performed by 30 min of left anterior descending coronary artery occlusion and 3 h of reperfusion. A risk area (RA) was demarcated by Evans blue dye, and infarct size (IS) was measured by tetrazolium staining. Diazoxide caused a decrease in IS (%RA) from 27.8 ± 4.2% in the vehicle group to 12.9 ± 1.2% during EP and from 30.4 ± 4.2% in vehicle-treated rabbits to 19.6 ± 2.4% during DP ( P < 0.05). IS increased to 31.3 ± 1.1% and 27.9 ± 1.0% (EP) and 29.9 ± 2.3% and 35.1 ± 1.8% (DP) with 5-HD andl-NAME, respectively ( P < 0.05). 5-HD andl-NAME caused no proischemic effect in controls. Diazoxide induced both early and delayed anti-ischemic effects via opening of mitoKATPchannels, which was NO dependent.

Reduction of infarct size with d-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial KATP channels

2006 ◽  
Vol 290 (2) ◽  
pp. H830-H836 ◽  
Author(s):  
Karin Przyklenk ◽  
Michelle Maynard ◽  
Peter Whittaker
Keyword(s):  
Infarct Size ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Additional Treatment ◽  
Pi3 Kinase ◽  
Mitochondrial Katp Channels ◽  
Tetrazolium Staining ◽  
Sparing Effect

Prophylactic treatment with d- myo-inositol 1,4,5-trisphosphate hexasodium [d- myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying d- myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal KATP channels) in the infarct-sparing effect of d- myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with d- myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, d- myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+ (KATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both d- myo-Ins(1,4,5)P3- and PC-treated hearts versus controls. d- myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, KATP channels. Moreover, the benefits of d- myo-Ins(1,4,5)P3 were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: d- myo-Ins(1,4,5)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective ε-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial KATP channels participate in the reduction of infarct size afforded by prophylactic administration of d- myo-Ins(1,4,5)P3.

Role of nitric oxide in gut ischemia-reperfusion-induced hepatic microvascular dysfunction

1997 ◽  
Vol 273 (5) ◽  
pp. G1007-G1013 ◽  
Author(s):  
Yoshinori Horie ◽  
Robert Wolf ◽  
D. Neil Granger
Keyword(s):  
Nitric Oxide ◽  
Important Determinant ◽  
Leukocyte Adhesion ◽  
Ischemia Reperfusion ◽  
Protective Action ◽  
Microvascular Dysfunction ◽  
Artery Occlusion ◽  
No Donor ◽  
Synthase Inhibitor

The overall objective of this study was to assess the contribution of an altered bioavailability of nitric oxide (NO) to the leukocyte adhesion and hypoxic stress elicited in the liver by gut ischemia-reperfusion (I/R). The accumulation of leukocytes, number of nonperfused sinusoids (NPS), and NADH autofluorescence were monitored (by intravital microscopy) in mouse liver after 15 min of superior mesenteric artery occlusion and 60 min of reperfusion. Leukostasis, NPS, and NADH autofluorescence (indicating hypoxia) were all increased in the liver at 60 min after gut I/R. The NO synthase inhibitor N G-monomethyl-l-arginine (l-NMMA) exaggerated the liver leukostasis elicited by gut I/R, responses that were prevented by coadministration of l-arginine. The NO donor diethylenetriamine-NO (DETA-NO) andl-arginine were both effective in attenuating the gut I/R-induced leukostasis and increased NADH autofluorescence, whereas neither DETA nord-arginine exerted a protective action. These findings indicate that NO is an important determinant of the liver leukostasis, impaired sinusoidal perfusion, and tissue hypoxia elicited by gut I/R.

Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial KATP channel

2001 ◽  
Vol 280 (5) ◽  
pp. H2406-H2411 ◽  
Author(s):  
Ramzi A. Ockaili ◽  
Peeyush Bhargava ◽  
Rakesh C. Kukreja
Keyword(s):  
Infarct Size ◽  
Early Phase ◽  
Ischemia Reperfusion ◽  
Late Phase ◽  
Saline Group ◽  
Risk Area ◽  
Nitropropionic Acid ◽  
Delayed Phase ◽  
3 Nitropropionic Acid

We investigated the cardioprotective effect of 3-nitropropionic acid (3-NPA), an inhibitior of mitochondrial succinate dehydrogenase, and we wanted to show whether this protection is mediated by of opening mitochondrial ATP-sensitive potassium (KATP) channels. Adult rabbits were treated with either 3-NPA (3 mg/kg iv) or saline ( n = 6 rabbits/group). After 30 min (for early phase) or 24 h (for late phase) of the treatment, the animals were subjected to 30 min of ischemia and 3 h of reperfusion (ischemia-reperfusion). 5-Hydroxydecanoate (5-HD, 5 mg/kg iv),the mitochondrial KATP channel blocker, was administered 10 min before ischemia-reperfusion in the saline- and 3-NPA-treated rabbits. 3-NPA caused a decrease in the infarct size from 27.8 ± 4.2% in the saline group to 16.5 ± 1.0% in the 3-NPA-treated rabbits during early phase and from 30.4 ± 4.2% in the saline group to 17.6 ± 1.05 in the 3-NPA group during delayed phase ( P < 0.05, % of risk area). The anti-infarct effect of 3-NPA was blocked by 5-HD as shown by an increase in infarct size to 33 ± 2.7% (early phase) and 31 ± 2.4% (delayed phase) ( P < 0.05 vs. 3-NPA groups). 5-HD had no proischemic effect in control animals. Also, 3-NPA had no effect on systemic hemodynamics. We conclude that 3-NPA induces long-lasting anti-ischemic effects via opening of mitochondrial KATP channels.

B-type natriuretic peptide limits infarct size in rat isolated hearts via KATP channel opening

2003 ◽  
Vol 284 (5) ◽  
pp. H1592-H1600 ◽  
Author(s):  
Savio P. D'Souza ◽  
Derek M. Yellon ◽  
Claus Martin ◽  
Rainer Schulz ◽  
Gerd Heusch ◽  
...  
Keyword(s):  
Infarct Size ◽  
Natriuretic Peptide ◽  
Risk Ratio ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Channel Opening

B-type natriuretic peptide (BNP) has been reported to be released from the myocardium during ischemia. We hypothesized that BNP mediates cardioprotection during ischemia-reperfusion and examined whether exogenous BNP limits myocardial infarction and the potential role of ATP-sensitive potassium (KATP) channel opening. Langendorff-perfused rat hearts underwent 35 min of left coronary artery occlusion and 120 min of reperfusion. The control infarct-to-risk ratio was 44.8 ± 4.4% (means ± SE). BNP perfused 10 min before ischemia limited infarct size in a concentration-dependent manner, with maximal protection observed at 10−8 M (infarct-to-risk ratio: 20.1 ± 5.2%, P < 0.01 vs. control), associated with a 2.5-fold elevation of myocardial cGMP above the control value. To examine the role of KATP channel opening, glibenclamide (10−6 M), 5-hydroxydecanoate (5-HD; 10−4 M), or HMR-1098 (10−5 M) was coperfused with BNP (10−8 M). Protection afforded by BNP was abolished by glibenclamide or 5-HD but not by HMR-1098, suggesting the involvement of putative mitochondrial but not sarcolemmal KATP channel opening. We conclude that natriuretic peptide/cGMP/KATPchannel signaling may constitute an important injury-limiting mechanism in myocardium.

Effect of modulating cardiac A1adenosine receptor expression on protection with ischemic preconditioning

2006 ◽  
Vol 290 (4) ◽  
pp. H1469-H1473 ◽  
Author(s):  
Amy R. Lankford ◽  
Jiang-Ning Yang ◽  
Roselyn Rose'Meyer ◽  
Brent A. French ◽  
G. Paul Matherne ◽  
...  
Keyword(s):  
Ischemic Preconditioning ◽  
Myocardial Protection ◽  
Ischemia Reperfusion ◽  
Coronary Artery Occlusion ◽  
Single Copy ◽  
Artery Occlusion ◽  
Receptor Expression ◽  
Myocardial Ischemia Reperfusion ◽  
Developed Pressure

Activation of A1adenosine receptors (A1ARs) may be a crucial step in protection against myocardial ischemia-reperfusion (I/R) injury; however, the use of pharmacological A1AR antagonists to inhibit myocardial protection has yielded inconclusive results. In the current study, we have used mice with genetically modified A1AR expression to define the role of A1AR in intrinsic protection and ischemic preconditioning (IPC) against I/R injury. Normal wild-type (WT) mice, knockout mice with deleted (A1KO−/−) or single-copy (A1KO+/−) A1AR, and transgenic mice (A1TG) with increased cardiac A1AR expression underwent 45 min of left anterior descending coronary artery occlusion, followed by 60 min of reperfusion. Subsets of each group were preconditioned with short durations of ischemia (3 cycles of 5 min of occlusion and 5 min of reperfusion) before index ischemia. Infarct size (IF) in WT, A1KO+/−, and A1KO−/−mice was (in % of risk region) 58 ± 3, 60 ± 4, and 61 ± 2, respectively, and was less in A1TG mice (39 ± 4, P < 0.05). A strong correlation was observed between A1AR expression level and response to IPC. IF was significantly reduced by IPC in WT mice (35 ± 3, P < 0.05 vs. WT), A1KO+/−+ IPC (48 ± 4, P < 0.05 vs. A1KO+/−), and A1TG + IPC mice (24 ± 2, P < 0.05 vs. A1TG). However, IPC did not decrease IF in A1KO−/−+ IPC mice (63 ± 2). In addition, A1KO−/−hearts subjected to global I/R injury demonstrated diminished recovery of developed pressure and diastolic function compared with WT controls. These findings demonstrate that A1ARs are critical for protection from myocardial I/R injury and that cardioprotection with IPC is relative to the level of A1AR gene expression.

dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts

2002 ◽  
Vol 283 (5) ◽  
pp. H1968-H1974 ◽  
Author(s):  
Zhitian Zou ◽  
Shiro Sasaguri ◽  
Katare Gopalrao Rajesh ◽  
Ryoko Suzuki
Keyword(s):  
Coronary Artery ◽  
Infarct Size ◽  
Ischemia Reperfusion ◽  
Myocardial Damage ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Rat Hearts ◽  
High Concentrations ◽  
Myocardial Infarction Size

To investigate the role of high concentrations of dl-3-hydroxybutyrate (DL-3-HB) in preventing heart damage after prolonged fasting, infarct size and the incidence of apoptosis caused by ischemia-reperfusion were determined in four groups of Wistar rats. Fed rats (±DL-3-HB group) and fasted rats (±DL-3-HB group) were subjected to 30 min of left coronary artery occlusion and 120 min of reperfusion. DL-3-HB was administered intravenously 60 min before the coronary artery occlusion. Infarct size, defined by triphenylyetrazolium chloride (TTC) staining, was reduced from 72 ± 3% (fed group), 75 ± 5% (fed + DL-3-HB group), and 70 ± 5% (fasting group), respectively, to 26 ± 4% ( P < 0.01 vs. fasting + DL-3-HB group). Apoptosis, as defined by single-stranded DNA staining, was significantly reduced in the subendocardial region in the fasting + DL-3-HB group (9 ± 2%) compared with the other groups (39 ± 6% in the fed group, 37 ± 5% in the fed + DL-3-HB group, and 34 ± 3% in the fasting group; P < 0.01). In addition, levels of ATP in the fasting + DL-3-HB group were significantly higher compared with other groups after 30 min of ischemia and 120 min of reperfusion ( P < 0.01). In conclusion, the present study demonstrates that high concentrations of DL-3-HB reduces myocardial infarction size and apoptosis induced by ischemia-reperfusion, possibly by providing increased energy substrate to the fasted rat myocardium.

The Role of Reactive Oxygen Species, Kinases, Hydrogen Sulfide, and Nitric Oxide in the Regulation of Autophagy and Their Impact on Ischemia and Reperfusion Injury in the Heart

2020 ◽  
Vol 16 ◽  
Author(s):  
Andrey Krylatov ◽  
Leonid Maslov ◽  
Sergey Y. Tsibulnikov ◽  
Nikita Voronkov ◽  
Alla Boshchenko ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Hydrogen Sulfide ◽  
Ischemia Reperfusion ◽  
Reactive Oxygen ◽  
Ischemia And Reperfusion ◽  
Oxygen Species ◽  
Ischemia And Reperfusion Injury ◽  
Adaptive Process

: There is considerable evidence in the heart that autophagy in cardiomyocytes is activated by hypoxia/reoxygenation (H/R) or in hearts by ischemia/reperfusion (I/R). Depending upon the experimental model and duration of ischemia, increases in autophagy in this setting maybe beneficial (cardioprotective) or deleterious (exacerbate I/R injury). Aside from the conundrum as to whether or not autophagy is an adaptive process, it is clearly regulated by a number of diverse molecules including reactive oxygen species (ROS), various kinases, hydrogen sulfide (H2S) and nitric oxide (NO). The purpose this review is to address briefly the controversy regarding the role of autophagy in this setting and to examine a variety of disparate molecules that are involved in its regulation.

Role of nitric oxide in hepatic and pulmonary injury following ischemia-reperfusion of rat liver

2003 ◽  
Vol 124 (4) ◽  
pp. A719-A720
Author(s):  
Yuji Takamatsu ◽  
Kazuo Shimada ◽  
Koji Yamaguchi ◽  
Kazuo Chijiiwa ◽  
Masao Tanaka
Keyword(s):  
Nitric Oxide ◽  
Rat Liver ◽  
Ischemia Reperfusion ◽  
Pulmonary Injury

scholarly journals Role of β-Adrenergic Receptors and Nitric Oxide Signaling in Exercise-Mediated Cardioprotection

Physiology ◽  
2013 ◽  
Vol 28 (4) ◽  
pp. 216-224 ◽  
Author(s):  
John W. Calvert ◽  
David J. Lefer
Keyword(s):  
Nitric Oxide ◽  
Risk Factors ◽  
Adrenergic Receptors ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Nitric Oxide Signaling ◽  
Factors Associated ◽  
Cardioprotective Effects ◽  
Β Adrenergic Receptors

Exercise promotes cardioprotection in both humans and animals not only by reducing risk factors associated with cardiovascular disease but by reducing myocardial infarction and improving survival following ischemia. This article will define the role that nitric oxide and β-adrenergic receptors play in mediating the cardioprotective effects of exercise in the setting of ischemia-reperfusion injury.

Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide

2006 ◽  
Vol 291 (3) ◽  
pp. F619-F628 ◽  
Author(s):  
Zhengrong Guan ◽  
Glenda Gobé ◽  
Desley Willgoss ◽  
Zoltán H. Endre
Keyword(s):  
Nitric Oxide ◽  
Renal Failure ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Artery Occlusion ◽  
Tubuloglomerular Feedback ◽  
Sprague Dawley ◽  
Endothelial Nitric Oxide

Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase (eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide (NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral (U) or bilateral (B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC50 was increased, and endothelium-derived hyperpolarizing factor (EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance (RVR) in B60 kidneys; this facilitated autoregulation, and the increase in RVR was abolished by 100 μM furosemide. Autoregulation was enhanced by Nω-nitro-l-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.

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