Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: role of NOS and KATP channels

2005 ◽  
Vol 288 (1) ◽  
pp. H62-H68 ◽  
Author(s):  
Colleen M. Fitzpatrick ◽  
Yang Shi ◽  
William C. Hutchins ◽  
Jidong Su ◽  
Garrett J. Gross ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Chronic Hypoxia ◽  
Katp Channels ◽  
Left Ventricular ◽  
Adaptation To Hypoxia ◽  
Isolated Hearts ◽  
Percent Recovery ◽  
Subsequent Exposure ◽  
Developed Pressure ◽  
Oxide Synthase

Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (KATP) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (FiO2 = 0.21) or hypoxic (FiO2 = 0.12) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts ( n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 ± 4%) than normoxic controls (43 ± 4%). At 10 days of age, NG-nitro-l-arginine methyl ester (200 μM) and glibenclamide (3 μM) abolished the cardioprotective effects of chronic hypoxia (45 ± 4% and 46 ± 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 ± 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 ± 4%). l-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 ± 4% and 39 ± 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of KATP channels.

scholarly journals Role of tetrahydrobiopterin in resistance to myocardial ischemia in Brown Norway and Dahl S rats

2009 ◽  
Vol 297 (5) ◽  
pp. H1783-H1791 ◽  
Author(s):  
Jianzhong An ◽  
Jianhai Du ◽  
Na Wei ◽  
Hao Xu ◽  
Kirkwood A. Pritchard ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Myocardial Ischemia ◽  
Ischemia Reperfusion ◽  
Heat Shock Protein 90 ◽  
Left Ventricular ◽  
Brown Norway ◽  
Myocardial Ischemia Reperfusion ◽  
Developed Pressure ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Previously we showed that Brown Norway (BN/Mcw) rats are more resistant to myocardial ischemia-reperfusion (I/R) injury than Dahl S (SS/Mcw) rats due to increased nitric oxide (·NO) generation secondary to increased heat shock protein 90 (HSP90) association with endothelial nitric oxide synthase (NOS3). Here we determined whether increased resistance to I/R injury in BN/Mcw hearts is also related to tetrahydrobiopterin (BH4) and GTP cyclohydrolase I (GCH-1), the rate-limiting enzyme for BH4 synthesis. We observed that BH4 supplementation via sepiapterin (SP) and inhibition of GCH-1 via 2,4-diamino-6-hydroxypyrimidine (DAHP) differentially modulate cardioprotection and that SP alters the association of HSP90 with NOS3. BH4 levels were significantly higher and 7,8-dihydrobiopterin (BH2) levels were significantly lower in BN/Mcw than in SS/Mcw hearts. The BH4-to-BH2 ratio in BN/Mcw was more than two times that in SS/Mcw hearts. After I/R, BH4 decreased and BH2 increased in hearts from both strains compared with their preischemia levels. However, the increase in BH2 in SS/Mcw hearts was significantly higher than in BN/Mcw hearts. Real-time PCR revealed that BN/Mcw hearts contained more GCH-1 transcripts than SS/Mcw hearts. SP increased recovery of left ventricular developed pressure (rLVDP) following I/R as well as decreased superoxide (O2•−) and increased·NO in SS/Mcw hearts but not in BN/Mcw hearts. DAHP decreased rLVDP as well as increased O2•− and decreased·NO in BN/Mcw hearts compared with controls but not in SS/Mcw hearts. SP increased the association of HSP90 with NOS3. These data indicate that BH4 mediates resistance to I/R by acting as a cofactor and enhancing HSP90-NOS3 association.

Abstract 33: Prostaglandin E2 Reduces Cardiac Contractility via EP3 Receptor

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Xiaosong Gu ◽  
Jiang Xu ◽  
Xiao-Ping Yang ◽  
Edward Peterson ◽  
Pamela Harding
Keyword(s):  
Prostaglandin E2 ◽  
Cardiac Contractility ◽  
Peak Height ◽  
Left Ventricular ◽  
Reduced Ejection Fraction ◽  
Langendorff Preparation ◽  
Cell Contractility ◽  
Isolated Hearts ◽  
Developed Pressure ◽  
Ep3 Receptor

Prostaglandin E2 (PGE2) EP receptors EP3 and EP4 are present in the heart and signal via decreased and increased cAMP production, respectively. Previously we reported that cardiomyocyte-specific EP4 KO mice develop a phenotype of dilated cardiomyopathy with reduced ejection fraction. We thus hypothesized that PGE2 decreases contractility via EP3. To test this hypothesis, the effects of PGE2 and the EP1/EP3 agonist sulprostone (sulp) were examined in the mouse langendorff preparation and in adult mouse cardiomyocytes (AVM) using the IonOptix cell contractility system. Isolated hearts of 18-20 wk old male C57Bl/6 mice were mounted and equilibrated for 10 min, then perfused with PGE2 (10 -6 mol/l) or sulp (10 -6 mol/l) for 30 min. Values at the end of equilibration were set to 100%. Compared to vehicle, PGE2 decreased +dp/dt (77.8±3% vs 96.7±3%, p<0.01) and left ventricular developed pressure, LVDP (77.2±2% vs 96.8±3%, p<0.001). Sulp decreased +dp/dt (75.9±2% vs 96.7±3%, p<0.001), -dp/dt (72.2±1% vs 85.7±1%, p<0.01) and LVDP (70.9±1% vs 96.8±3%, p<0.001). The effects of both PGE2 and sulp were reversed by the EP3 antagonist, L789,106 (10 -6 mol/l). Myocyte contractility was evaluated on the IonOptix system with pacing at 1Hz. Treatment with PGE2 (10 -9 M) for 10 min reduced contractility as measured by peak height (3.69 ± 0.48% for vehicle vs 2.00 ± 0.22% for PGE2, p < 0.05 ), departure velocity (-171.9 ± 22.9 um/sec for vehicle vs -106.3± 12.5 um/sec for PGE2, p < 0.05) and return velocity (87.7 ± 16.3 um/sec for vehicle vs 36.7 ± 6.6 um/sec for PGE2, p < 0.05) with similar effects noted for sulp. Sulp reduced change in peak height (4.79 ± 1.15% for vehicle vs 1.81 ± 0.37% for sulp, p < 0.05), departure velocity (-169.1 ± 35.8 um/sec for vehicle vs -59.4 ± 10.3 um/sec for sulp, p < 0.05) and return velocity (86.5 ± 23.8 um/sec for vehicle vs 16.9 ± 14.7 um/sec for sulp, p < 0.05). We then examined the acute effects of PGE2 and sulp on expression of phosphorylated phospholamban (PLN) and SERCA using Western blot. Treatment of AVM for 15min with either PGE2 or sulp decreased expression of phosphorylated PLN corrected to total PLN, by 67% and 43%. SERCA2a expression was unaffected. In conclusion, PGE2 and sulp reduce contractility via the EP3 receptor through effects on PLN.

Adenosine antagonism decreases metabolic but not functional recovery from ischemia

1991 ◽  
Vol 260 (1) ◽  
pp. H193-H200 ◽  
Author(s):  
D. A. Angello ◽  
J. P. Headrick ◽  
N. M. Coddington ◽  
R. M. Berne
Keyword(s):  
Functional Recovery ◽  
Left Ventricular ◽  
Low Flow ◽  
Ischemia And Reperfusion ◽  
Constant Flow ◽  
Hemodynamic Parameters ◽  
Isolated Hearts ◽  
Rat Hearts ◽  
Adenosine Antagonism ◽  
Developed Pressure

The effect of adenosine receptor antagonism on function and metabolism was examined in isolated hearts during low flow ischemia and reperfusion. Isovolumic rat hearts perfused at constant flow were subjected to 30 min of ischemia followed by 30 min of reperfusion. Infusion of vehicle or 10 microM 8-phenyltheophylline (8-PT) was initiated 10 min before ischemia and maintained throughout reperfusion. 8-PT infusion had no significant effects on hemodynamic parameters or metabolism preischemia. During ischemia, left ventricular developed pressure declined to approximately 15% of preischemic values in control and 8-PT hearts, and ATP and PCr decreased to approximately 73 and 60% of preischemic values. Inorganic phosphate (Pi) increased to 353 = 41 and 424 +/- 53% of preischemic values in control and 8-PT hearts, respectively. After reperfusion, function recovered to greater than 95% of preischemic levels in control and 8-PT hearts. Unlike control hearts, recovery of metabolites was significantly different during reperfusion in 8-PT hearts (P less than 0.05); ATP, phosphocreatine, and Pi recovered to 82 +/- 8, 71 +/- 8, and 281 +/- 27% of preischemic values, respectively. Venous purine washout was significantly greater (P less than 0.05) during reperfusion in 8-PT hearts (327 +/- 113 nmol) than in control hearts (127 +/- 28 nmol). Blockade of adenosine receptors appears to adversely affect metabolic but not functional recovery in the ischemic-reperfused myocardium.

Endogenous endothelin-1 impairs endothelium-dependent relaxation after myocardial ischemia and reperfusion

1994 ◽  
Vol 267 (5) ◽  
pp. H1833-H1841 ◽  
Author(s):  
J. M. Hagar
Keyword(s):  
Myocardial Ischemia ◽  
Control Release ◽  
Microvascular Dysfunction ◽  
Coronary Perfusion Pressure ◽  
Left Ventricular ◽  
Coronary Perfusion ◽  
Ischemia And Reperfusion ◽  
Myocardial Ischemia And Reperfusion ◽  
Developed Pressure ◽  
Eta Receptor Antagonist

Endothelin (ET)-1 is produced in response to myocardial ischemia and reperfusion. It is a potent constrictor of coronary resistance vessels and may therefore contribute to myocardial injury and postischemic microvascular dysfunction. Isolated buffer-perfused rabbit hearts, under conditions of constant flow and isovolumic contraction, underwent 60 min of global ischemia and 60 min of reperfusion after pretreatment with selective ETA receptor antagonist BQ-123 (10(-7) M) in perfusate, exogenous ET-1 (10(-11) M), or control. Release of ET increased significantly at 20 and 60 min of reperfusion. BQ-123 did not enhance the recovery of left ventricular developed pressure or coronary perfusion pressure, whereas exogenous ET tended to worsen them. Cumulative creatine kinase release over 20 min of reperfusion did not differ significantly between groups. Maximum endothelium-dependent dilation to acetylcholine (ACh) was initially 62 +/- 6, 71 +/- 6, and 63 +/- 8% (SE) of U-46619-induced preconstriction in control, BQ-123-, and ET-treated hearts. At 20 min of reperfusion it was 37 +/- 5, 73 +/- 9, and 22 +/- 5%, and at 60 min of reperfusion it was 35 +/- 7, 79 +/- 6, and 22 +/- 3% (P < 0.001 for BQ-123 vs. control at 20 min and P < 0.0001 at 60 min). Endothelium-independent dilation to nitroglycerin was unaltered by ischemia and reperfusion. Neither BQ-123 alone nor a 1-h infusion of ET (10(-10) M) altered the response to ACh in nonischemic hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Delayed cardioprotection by isoflurane: role of KATP channels

2002 ◽  
Vol 283 (1) ◽  
pp. H61-H68 ◽  
Author(s):  
Marija Tonkovic-Capin ◽  
Garrett J. Gross ◽  
Zeljko J. Bosnjak ◽  
James S. Tweddell ◽  
Colleen M. Fitzpatrick ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Katp Channels ◽  
Left Ventricular ◽  
Cardioprotective Effect ◽  
Area At Risk ◽  
Perfused Heart ◽  
Memory Phase ◽  
Developed Pressure ◽  
Delayed Cardioprotection

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (KATP) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7–10 days of age ( n = 5–16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means ± SD) by 50% (10 ± 5%) versus untreated controls (20 ± 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 ± 4%) versus untreated controls (54 ± 6%). The mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD) completely (55 ± 3%) and the sarcolemmal KATPchannel blocker HMR 1098 partially (62 ± 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 ± 5%). We conclude that both mitochondrial and sarcolemmal KATP channels contribute to isoflurane-induced delayed cardioprotection.

Bax ablation protects against myocardial ischemia-reperfusion injury in transgenic mice

2003 ◽  
Vol 284 (6) ◽  
pp. H2351-H2359 ◽  
Author(s):  
Edith Hochhauser ◽  
Shaye Kivity ◽  
Daniel Offen ◽  
Nilanjana Maulik ◽  
Hajime Otani ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Electron Microscopic ◽  
Isolated Hearts ◽  
Microscopic Evaluation ◽  
Myocardial Ischemia Reperfusion ◽  
Bax Gene

The role of the proapototic Bax gene in ischemia-reperfusion (I/R) injury was studied in three groups of mice: homozygotic knockout mice lacking the Bax gene (Bax−/−), heterozygotic mice (Bax+/−), and wild-type mice (Bax+/+). Isolated hearts were subjected to ischemia (30 min, 37°C) and then to 120 min of reperfusion. The left ventricular developed force of Bax-deficient vs. Bax+/+ hearts at stabilization and at 120 min of reperfusion was 1,411 ± 177 vs. 1,161 ± 137 mg and 485 ± 69 vs. 306 ± 68 mg, respectively. Superior cardiac function of Bax−/− hearts after I/R was accompanied by a decrease in creatine kinase release, caspase 3 activity, irreversible ischemic injury, and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. Electron microscopic evaluation revealed reduced damage to mitochondria and the nuclear chromatin structure in Bax-deficient mice. In the Bax+/− hearts, the damage markers were moderate. The superior tolerance of Bax knockout hearts to I/R injury recommends this gene as a potential target for therapeutic intervention in patients with severe and intractable myocardial ischemia.

Phosphorylated compounds and function in isolated hearts: a 31P-NMR study

1991 ◽  
Vol 260 (1) ◽  
pp. H110-H117
Author(s):  
J. Aussedat ◽  
A. Ray ◽  
S. Lortet ◽  
H. Reutenauer ◽  
S. Grably ◽  
...  
Keyword(s):  
Work Load ◽  
Creatine Phosphate ◽  
Myocardial Cell ◽  
Left Ventricular ◽  
Mitochondrial Activity ◽  
Isolated Hearts ◽  
Nmr Study ◽  
Phosphorylated Compounds ◽  
Developed Pressure ◽  
And Function

The potential role of phosphorylated compounds in the control of myocardial cell respiration was investigated by means of 31P-nuclear magnetic resonance (NMR) spectroscopy. Isolated isovolumic rat hearts, perfused with a 9 mM glucose, 2 mM pyruvate medium at a constant beating rate (6 Hz) and temperature (37 degrees C), were subjected to changes in work load by varying the calcium concentration ([Ca2+]) in the perfusion fluid from 0.5 to 1.0, 1.5, or 2.0 mM. Each change in left ventricular developed pressure (LVDP) induced by the [Ca2+] change was accompanied by alterations in the inorganic phosphate-to-creatine phosphate ratio ([Pi]/[PCr]), with the ATP level remaining constant. The relationship between [Pi]/[PCr] and LVDP followed a Michaelis-Menten pattern with an apparent Michaelis constant (Km) of 0.09 and a maximal LVDP of 91 mmHg. This Km corresponded to intracellular concentrations of 1.2 mM for Pi and 13.0 mM for PCr. The calculated [ADP] and phosphorylation potential corresponding to these values were 44 microM and 151,000 M-1, respectively. All these values are close to those estimated under in situ physiological conditions. These results support the assumption that in the rat heart, as in skeletal muscle, mitochondrial activity could be controlled by changes in phosphorylated compound concentrations under normoxic conditions.

NFATc3 is necessary for macrophage iNOS expression during myocardial ischemia and reperfusion

2018 ◽  
Vol 6 (4) ◽  
pp. 336-348
Author(s):  
You-lin Lee ◽  
Qiong Chung
Keyword(s):  
Cardiac Function ◽  
Myocardial Damage ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Relaxation Rates ◽  
Myocardial Ischemia And Reperfusion ◽  
Developed Pressure ◽  
Perfusion Period ◽  
Contraction And Relaxation ◽  
Oxide Synthase

In the present study, we sought to examine whether inhibition NFATc3, improves cardiac function and reduces heart damage during IR. Hearts of male C57BL/J6 and NFATc3 knockout (KO) mice perfused by Langendorff were subjected to 25 min of global ischemia followed by 30 min reperfusion. Cardiac function was monitored throughout the perfusion period. Myocardial damage was extrapolated from LDH activity in the coronary effluent. At the end of reperfusion. Our data show that NFATc3 regulates expression of inducible nitric oxide synthase (iNOS) in macrophages stimulated after I/R. In the NFATc3 knockout (KO) mice, left ventricular developed pressure, rate pressure product, contraction and relaxation rates and coronary flow significantly improved following reperfusion compared with C57BL/J6 mice.

scholarly journals Propylthiouracil-induced hypothyroidism is associated with increased tolerance of the isolated rat heart to ischaemia-reperfusion

2003 ◽  
Vol 178 (3) ◽  
pp. 427-435 ◽  
Author(s):  
C Pantos ◽  
V Malliopoulou ◽  
I Mourouzis ◽  
K Sfakianoudis ◽  
S Tzeis ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Isolated Rat Heart ◽  
Isolated Hearts ◽  
Global Ischaemia ◽  
Basal Expression ◽  
Kinase C ◽  
Ischaemia Reperfusion ◽  
Protein Kinase C Epsilon ◽  
Developed Pressure ◽  
Jnk Activation

The present study investigated the response of the hypothyroid heart to ischaemia-reperfusion. Hypothyroidism was induced in Wistar rats by oral administration of propylthiouracil (0.05%) for 3 weeks (HYPO rats), while normal animals (NORM) served as controls. Isolated hearts from NORM and HYPO animals were perfused in Langendorff mode and subjected to zero-flow global ischaemia followed by reperfusion (I/R). Post-ischaemic recovery of left ventricular developed pressure was expressed as % of the initial value (LVDP%). Basal expression of protein kinase C epsilon (PKCepsilon) and PKCdelta and phosphorylation of p46 and p54 c-jun NH(2)-terminal kinases (JNKs) in response to I/R were assessed by Western blotting. LVDP% was found to be significantly higher in HYPO hearts than in NORM. At baseline, PKCepsilon expression was 1.4-fold more in HYPO than in NORM hearts, P<0.05, while PKCdelta was not changed. Furthermore, basal phospho-p54 and -p46 JNK levels were 2.2- and 2.6-fold more in HYPO than in NORM hearts, P<0.05. In response to I/R, in NORM hearts, phospho-p54 and -p46 JNK levels were 5.5- and 6.0-fold more as compared with the baseline values, P<0.05, while they were not significantly altered in HYPO hearts. HYPO hearts seem to display a phenotype of cardioprotection against ischaemia-reperfusion and this is associated with basal PKCepsilon overexpression and attenuated JNK activation after I/R.

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