dinoprost and Myocardial-Ischemia

Methylene blue (MB), generic name methylthioninium (C(16)H(18)ClN(3) S . 3H(2)O), is a blue dye synthesized in 1876 by Heinrich Caro for use as a textile dye and used in the laboratory and clinically since the 1890s, with well-known toxicity and pharmacokinetics. It has experimentally proven neuroprotective and cardioprotective effects in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. This effect has been attributed to MB's blocking effect on nitric oxide synthase and guanylyl cyclase, the latter blocking the synthesis of the second messenger of nitric oxide. The physiological effects during reperfusion include stabilization of the systemic circulation without significantly increased total peripheral resistance, moderately increased cerebral cortical blood flow, a decrease of lipid peroxidation and inflammation, and less anoxic tissue injury in the brain and the heart. The last two effects are recorded as less increase in plasma concentrations of astroglial protein S-100beta, as well as troponin I and creatine kinase isoenzyme MB, respectively.

Topics: Animals; Blood Pressure; Brain Ischemia; Cerebrovascular Circulation; Creatine Kinase, MB Form; Dinoprost; Disease Models, Animal; Enzyme Inhibitors; History, 19th Century; Methylene Blue; Myocardial Ischemia; Myocardial Reperfusion; Nerve Growth Factors; Nitric Oxide; Random Allocation; S100 Calcium Binding Protein beta Subunit; S100 Proteins; Survival Analysis; Swine; Time Factors; Troponin I

Topics: Biomarkers; Cerebrovascular Disorders; Dinoprost; Humans; Hypercholesterolemia; Immunoenzyme Techniques; Inflammation; Kidney Diseases; Myocardial Ischemia; Oxidative Stress; Radioimmunoassay; Reference Values; Specimen Handling

Recent studies have shown, that chronic flavonoids treatment improves vascular function and cardiovascular remodeling by decreasing superoxide anion production as well as by increasing NO realize from endothelial cells. A progressive decrease in systolic blood pressure and reduction of low-density lipoprotein oxidation (Ox-LDL) has also been reported. However, none of these studies were done in patient with coronary artery disease treated with statins. This was a double-blind, placebo-controlled, parallel trial. Forty-four patients (11 women and 33 men, mean age 66 years) who survived myocardial infraction and have received statin therapy for at least 6 months (80% dose of 40 mg/day simvastatin) were included in the study. The subjects were randomised to receive either 3 x 85 mg/day of chokeberry flavonoid extract (Aronia melanocarpa E) or placebo for a period of 6 weeks. The study extract was a commercially-available (OTC) product of the following declared composition: anthocyans (about 25%), polymeric procyanidines (about 50%) and phenolic acids (about 9%). Compared to placebo (ANOVA and Tukey's test), flavonoids significantly reduced serum 8-isoprostans (p<0.000) and Ox-LDL levels (p<0.000) (by 38 and 29%, respectively), as well as hsCRP (p<0.007) and MCP-1 (p<0.001) levels (by 23 and 29%, respectively). In addition, significant increase in adiponectin (p<0.03) levels and reduction in systolic and diastolic blood pressure by a mean average of 11 and 7.2 mmHg, respectively were found.. In view of the fact that chokeberry flavonoids reduce the severity of inflammation, regardless of statins, they can be used clinically for secondary prevention of ischaemic heart disease.

Topics: Adiponectin; Aged; Blood Pressure; C-Reactive Protein; Dinoprost; Double-Blind Method; Drug Therapy, Combination; Endopeptidases; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipoproteins, LDL; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Photinia; Phytotherapy; Plant Extracts

Ischemia modified albumin (IMA; Ischemia Technologies, Inc) blood levels rise in patients who develop ischemia during percutaneous coronary intervention (PCI). It is not known whether IMA elevations correlate with increases in other markers of oxidative stress, ie, 8-iso prostaglandin F2-A (iP).. We compared IMA versus iP plasma levels in 19 patients (mean age 62.8+/-11.9 years) undergoing PCI and 11 patients (mean age 64+/-13.6 years) undergoing diagnostic angiography (controls). In the PCI patients, blood samples for IMA and iP were taken from the guide catheter before PCI and after balloon inflations, and from the femoral sheath 30 minutes after PCI. IMA was measured by the albumin cobalt binding (ACB) test and plasma iP by enzyme immunoassay. During PCI, all 19 patients had chest pain and 18 had transient ischemic ST segment changes. IMA was elevated from baseline in 18 of the 19 patients after PCI. Median IMA levels were higher after PCI (101.4 U/mL, 95%CI 82 to 116) compared with baseline (72.8 U/mL, CI 55 to 93; P<0.0001). Levels remained elevated at 30 minutes (87.9 U/mL, CI 78 to 99; P<0.0001) and returned to baseline at 12 hours (70.3 U/mL, CI 65 to 87; P=0.65). iP levels were raised after PCI in 9 of the 19 patients. However, median iP levels were not significantly different immediately (P=0.6) or 30 minutes after PCI (P=0.1). In the control group, IMA and iP levels remained unchanged before and after angiography (P=0.2 and 0.16, respectively).. IMA is a more consistent marker of ischemia than iP in patients who develop chest pain and ST segment changes during PCI.

Topics: Aged; Albumins; Angina Pectoris; Angioplasty, Balloon, Coronary; Biomarkers; Blood Proteins; Chest Pain; Coronary Angiography; Dinoprost; Electrocardiography; F2-Isoprostanes; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Myocardial Ischemia; Postoperative Complications; Predictive Value of Tests; Sensitivity and Specificity; Troponin T

In the present study, we tested the hypothesis that oxidative stress could be implicated in myocardial damage during the acute phase of pneumonia. NOX2 activation, the catalytic subunit of NADPH oxidase, and high-sensitivity cardiac troponin T (hs-cTnT) elevation have been analyzed in two hundred forty-eight consecutive patients hospitalized for community-acquired pneumonia. Serum NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, and 8-isoprostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were measured upon admission; serum hs-cTnT and ECG were measured every 12 and 24 h, respectively. One hundred thirty-five patients (54%) showed elevated serum levels of hs-cTnT (>0.014 μg/L). A logistic regression analysis showed sNOX2-dp (p<0.001), Pneumonia Severity Index score (p<0.001), renal failure (p=0.024), and ejection fraction (p<0.001) as independent predictors of elevated serum levels of hs-cTnT. Serum sNOX2-dp was linearly correlated with hs-cTnT (Rs=0.538; p<0.001) and 8-iso-PGF2α (Rs=0.354; p<0.001). The study provides the first evidence of a significant association between serum cardiac Troponin T elevation and NOX2 upregulation in patients with pneumonia. This finding raises the hypothesis that NOX2-derived oxidative stress may be implicated in myocardial injury and that its inhibition could be a novel therapeutic strategy to limit it.

Topics: Aged; Aged, 80 and over; Biomarkers; Cohort Studies; Community-Acquired Infections; Dinoprost; Female; Humans; Logistic Models; Male; Membrane Glycoproteins; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardium; NADPH Oxidase 2; NADPH Oxidases; Odds Ratio; Oxidative Stress; Pneumonia; Reactive Oxygen Species; Severity of Illness Index; Troponin T; Up-Regulation

Platelet activation is involved in acute coronary syndromes (ACS). Incomplete suppression by low-dose aspirin treatment of thromboxane (TX) metabolite excretion (urinary 11-dehydro-TXB2) is predictive of vascular events in high-risk patients. Myeloid-related protein (MRP)-8/14 is a heterodimer secreted on activation of platelets, monocytes, and neutrophils, regulating inflammation and predicting cardiovascular events. Among platelet transcripts, MRP-14 has emerged as a powerful predictor of ACS.. We enrolled 68 stable ischemic heart disease (IHD) and 63 ACS patients, undergoing coronary angiography, to evaluate whether MRP-8/14 release in the circulation is related to TX-dependent platelet activation in ACS and IHD patients and to residual TX biosynthesis in low-dose aspirin-treated ACS patients. In ACS patients, plasma MRP-8/14 and urinary 11-dehydro-TXB2 levels were linearly correlated (r=0.651, P<0.001) but significantly higher than those in IHD patients (P=0.012, P=0.044) only among subjects not receiving aspirin. In aspirin-treated ACS patients, MRP-8/14 and 11-dehydro-TXB2 were lower versus those not receiving aspirin (P<0.001) and still significantly correlated (r=0.528, P<0.001). Higher 11-dehydro-TXB2 significantly predicted higher MRP-8/14 in both all ACS patients and ACS receiving aspirin (P<0.001, adj R(2)=0.463 and adj R(2)=0.497) after multivariable adjustment. Conversely, plasma MRP-8/14 (P<0.001) and higher urinary 8-iso-prostaglandin F2α (P=0.050) levels were significant predictors of residual, on-aspirin, TX biosynthesis in ACS (adjusted R(2)=0.384).. Circulating MRP-8/14 is associated with TX-dependent platelet activation in ACS, even during low-dose aspirin treatment, suggesting a contribution of residual TX to MRP-8/14 shedding, which may further amplify platelet activation. Circulating MRP-8/14 may be a target to test different antiplatelet strategies in ACS.

Topics: Acute Coronary Syndrome; Aged; Aspirin; Calgranulin A; Calgranulin B; Chronic Disease; Dinoprost; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Activation; Platelet Aggregation Inhibitors; Thromboxane B2

The aim of the present study was to look into the possible protective effects of glycyrrhizic acid (GA) against isoproterenol-induced acute myocardial infarction in Sprague-Dawley rats. The effect of three doses of glycyrrhizic acid in response to isoproterenol (ISO)-induced changes in 8-isoprostane, lipid hydroperoxides, super oxide dismutase and total glutathione were evaluated. Male Sprague-Dawley rats were divided into control, ISO-control, glycyrrhizic acid alone (in three doses-5, 10 and 20 mg/kg BW) and ISO with glycyrrhizic acid (in three doses) groups. ISO was administered at 85 mg/kg BW at two consecutive days and glycyrrhizic acid was administered intraperitoneally for 14 days. There was a significant increase in 8-isoprostane (IP) and lipid hydroperoxide (LPO) level in ISO-control group. A significant decrease in total superoxide dismutase (SOD) and total glutathione (GSH) was seen with ISO-induced acute myocardial infarction. Treatment with GA significantly increased SOD and GSH levels and decreased myocardial LPO and IP levels. Histopathologically, severe myocardial necrosis and nuclear pyknosis and hypertrophy were seen in ISO-control group, which was significantly reduced with GA treatment. Gycyrrhizic acid treatment proved to be effective against isoproterenol-induced acute myocardial infarction in rats and GA acts as a powerful antioxidant and reduces the myocardial lipid hydroperoxide and 8-isoprostane level.

Topics: Animals; Body Weight; Cardiotonic Agents; Dinoprost; Glutathione; Glycyrrhizic Acid; Isoproterenol; Lipid Peroxidation; Male; Myocardial Ischemia; Rats; Rats, Sprague-Dawley; Superoxide Dismutase

Hyperoxic pretreatment (>95% O(2)) can evoke myocardial adaptation to ischemia, a method which is potentially clinically usable. We wanted to investigate the role of tumor necrosis factor alpha (TNFalpha) and its p55 receptor (receptor I) in signaling of hyperoxic adaptation to ischemia. Mice deficient for TNFalpha (TNFalpha -/-) or the TNF receptor I (TNFRI -/-) gene and their wild types were subjected to 60 minutes of hyperoxia or sham treatment. Their lungs were then collected for immunoblotting, their hearts isolated and subjected to global ischemia and reperfusion in a Langendorff system, and aortic rings mounted in organ baths for reactivity studies. Hyperoxia increased expression of TNFalpha and TNFalpha converting enzyme in pulmonary proteins from wild type mice, in which hyperoxia increased myocardial tolerance to ischemia. Post-ischemic heart function was improved and infarct size reduced in wild type mice, but not in TNFalpha -/- or TNFRI -/-. The contractile response to TNFalpha on aortic rings was attenuated by hyperoxic pretreatment and by TNFRI -/-. Thus we conclude that TNFalpha, acting through TNFRI, appears important for the protective effects of hyperoxia.

Topics: Acetylcholine; ADAM Proteins; ADAM17 Protein; Animals; Aorta; Dinoprost; Enzyme-Linked Immunosorbent Assay; Hyperoxia; Ischemic Preconditioning, Myocardial; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Ischemia; Nitroprusside; Phenylephrine; Receptors, Tumor Necrosis Factor, Type I; Tumor Necrosis Factor-alpha; Vasoconstrictor Agents; Vasodilator Agents; Ventricular Pressure

The role of oxidation injury as an important factor in the pathophysiology of cardiomyopathy (CMP) has recently gained increasing interest. Semiquantitative analysis for isoprostane, 8-epi-prostaglandin F(2alpha) (8-epi-PGF(2alpha)), and oxidised low-density lipoprotein (ox-LDL) of coronary vascular tissue samples derived from CMP patients revealed an increased extent and intensity of uptake as compared to the respective controls. To evaluate oxidative stress in vivo, we examined plasma, serum, salivary, and urinary 8-epi-PGF(2alpha) in patients with dilated CMP (n=20) and ischemic CMP (n=20) with decreased left ventricular ejection fraction (LVEF). Patients with coronary heart disease (CHD) (n=20) and 20 healthy, age-matched, and sex-matched controls were investigated in parallel. 8-Epi-PGF(2alpha) levels were correlated with the functional severity of heart failure [New York Heart Association (NYHA) classification] and LVEF. 8-Epi-PGF(2alpha) levels were matched according to risk factors (smoking and hypercholesterolemia) and were significantly higher in patients with CMP as compared to healthy controls and patients with CHD in all investigated compartments. A positive correlation between NYHA stages and 8-epi-PGF(2alpha), as well as a negative correlation to LVEF, could be demonstrated in a subgroup analysis. These findings reflect the enhanced oxidation injury in patients with CMP and, to a lesser extent, in CHD as compared to healthy controls, thus highly indicating the relevance of oxidative stress for the pathogenesis and progression of cardiovascular disease.

Topics: Adult; Angina Pectoris; Cardiomyopathy, Dilated; Case-Control Studies; Dinoprost; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Oxidative Stress; Risk Factors; Saliva; Severity of Illness Index

Hypercholesterolemia (HC) and atherosclerosis can elicit oxidative stress, coronary endothelial dysfunction, and myocardial ischemia, which may induce growth-factor expression and lead to myocardial neovascularization. We tested the hypothesis that chronic antioxidant intervention in HC would attenuate neovascularization and preserve the expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF).. Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet or HC+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily). Myocardial samples were scanned ex vivo with a novel 3D micro-CT scanner, and the spatial density and tortuosity of myocardial microvessels were determined in situ. VEGF mRNA, protein levels of VEGF and VEGF receptor-1, HIF-1alpha, nitrotyrosine, and superoxide dismutase (SOD) were determined in myocardial tissue. The HC and HC+antioxidant groups had similar increases in serum cholesterol levels. HC animals showed an increase in subendocardial spatial density of microvessels compared with normal (160.5+/-11.8 versus 95.3+/-8.2 vessels/cm2, P<0.05), which was normalized in HC+antioxidant (92.5+/-20.5 vessels/cm2, P<0.05 versus HC), as was arteriolar tortuosity. In addition, HC induced upregulation of VEGF, HIF-1alpha, and nitrotyrosine expression and decreased SOD expression and activity, all of which were preserved by antioxidant intervention.. Changes in myocardial microvascular architecture invoked by HC are accompanied by increases in HIF-1alpha and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.

Topics: Animals; Antioxidants; Arteriosclerosis; Ascorbic Acid; Cardiotonic Agents; Coronary Circulation; Diet, Atherogenic; Dinoprost; Enzyme Induction; Female; Gene Expression Profiling; Gene Expression Regulation; Heart; Hypercholesterolemia; Hypoxia-Inducible Factor 1, alpha Subunit; Imaging, Three-Dimensional; Myocardial Ischemia; Neovascularization, Pathologic; Oxidative Stress; Superoxide Dismutase; Swine; Tomography, X-Ray Computed; Transcription Factors; Tyrosine; Vascular Endothelial Growth Factor A; Vitamin E

We examined the effects of propofol (2,6-diisopropylphenol) on functional recovery and 15-F2t-isoprostane generation during ischemia-reperfusion in Langendorff-perfused rat hearts. Before the induction of 40 min of global ischemia, hearts were perfused (10 min) with propofol at 5 (lo-P) or 12 microg/mL (hi-P) in saline or with saline only (control). During ischemia, saline, lo-P, or hi-P was perfused through the aorta at 60 microL/min. During the first 15 min of reperfusion, propofol (5 or 12 microg/mL) was continued, followed by perfusion with 5 microg/mL propofol for 75 min in both propofol-treated groups. After 90 min of reperfusion (Rep-90), heart tissues were harvested for assessment of antioxidant status. In hi-P, we observed increased latency to and greater reduction of ischemic contracture relative to the lo-P or control groups. 15-F2t-Isoprostane concentrations increased during ischemia and were significantly lower in hi-P and lo-P than in control (P < 0.01). At Rep-90, myocardial functional recovery was greater in both propofol-treated groups relative to control, and it correlated positively with tissue antioxidant capacity preservation. Tissue antioxidant capacity was better preserved in hi-P than in lo-P treatment (P < 0.05). We conclude that oxidant injury occurs during ischemia and reperfusion, and propofol provides dose-dependent protection primarily by enhancing tissue antioxidant capacity and reducing lipid peroxidation.

Topics: Anesthetics, Intravenous; Animals; Antioxidants; Dinoprost; Dose-Response Relationship, Drug; F2-Isoprostanes; Heart; In Vitro Techniques; Lipid Peroxidation; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Propofol; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

Short episodes of ischemia and reperfusion in various organs may protect the organ itself, and the heart both as an immediate and a delayed effect. The present study investigates whether a systemic protection of vascular function occurs during adaption to ischemia. Brain ischemia was induced by bilateral ligation of the internal carotid arteries in C57BL6 mice, and 24-36 hours later rings of the thoracic aorta were mounted to study in vitro relaxation and contraction, or proteins were extracted for immunoblotting for endothelial nitric oxide synthase (eNOS) or inducible NOS (iNOS). eNOS decreased, while iNOS increased in the aortic wall after carotid artery ligation. In vitro contraction to increasing concentrations of prostaglandin F(2alpha) (PGF(2alpha)) was attenuated, while relaxation to acetylcholine (ACh) was enhanced. The latter was abolished by the iNOS-inhibitor aminoguanidine. When brain ischemia was induced in iNOS deficient mice, an increase of aortic eNOS was found 24 hours later. The ischemia-induced attenuated relaxation to PGF(2alpha) and enhanced relaxation to ACh were abolished. Aortic rings from mice with severe atherosclerosis (apolipoprotein E and low density lipoprotein receptor double knockout (ApoE/LDLr KO) mice) and spontaneous ischemic events in the heart or brain in vivo were also studied. Spontaneous ischemic events in ApoE/LDLr KO animals did not influence iNOS and eNOS in the vessel wall. A reduced contraction to PGF(2alpha) was observed, but relaxation to ACh was unchanged. These findings suggest that induced brain ischemia as a model of delayed, remote preconditioning protects vessel reactivity, and this protection is mediated by iNOS.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Brain Ischemia; Dinoprost; Disease Models, Animal; In Vitro Techniques; Ischemic Attack, Transient; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Myocardial Ischemia; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phenylephrine; Reference Values

Inhibition of cyclooxygenase (COX) might favour non-enzymatic formation of cardiodepressive isoprostanes from arachidonic acid by radicals generated during reperfusion. This could explain deleterious effects of acetylsalicylic acid (ASA) on cardiac function. We examined the influence of COX inhibition on myocardial function after low-flow ischaemia and reperfusion, employing either ASA (100 micromol/l), the partially selective COX-2 inhibitor meloxicam (0.3 micromol/l and 3.0 micromol/l), or the highly selective COX-2 inhibitor SC 58125 (1.0 micromol/l and 3.0 microgmol/l). Isolated, buffer-perfused guinea pig hearts, performing pressure-volume work before and after consecutive low-flow ischaemia and reperfusion, were used for the study. Measurement of coronary and aortic flow, ejection time and heart rate served to calculate external heart work (EHW), before and after ischaemia. Additionally, release of prostacyclin and thromboxane A2, production of lactate, consumption of pyruvate and tissue concentration of the isoprostane 8-iso-PGF2alpha were measured. ASA significantly reduced recovery of EHW (46+/-18% vs. 82+/-15% for controls), whereas meloxicam and SC 58125 did not (64+/-15% and 74+/-13% recovery, respectively). Paradoxically, ASA increased reactive hyperaemia and consumption of pyruvate in the early reperfusion phase in comparison to all other groups, while lactate production did not differ. Prostacyclin production did not increase during reperfusion and was not significantly different between groups at any time point. In contrast, thromboxane A2 release increased about fivefold in the 2nd min of reperfusion under control conditions and in the presence of SC 58125, but was inhibited by ASA and by meloxicam in both concentrations. Isoprostane content of heart tissue was not detectably influenced under the mild reperfusion conditions used here. We conclude that ASA can aggravate postischaemic cardiac dysfunction, independent of COX inhibition. The deleterious effect in the present model might be due to uncoupling of mitochondrial oxidative phosphorylation rather than to direct effects of reduced eicosanoid release or radical induced formation of isoprostanes.

Topics: Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Eicosanoids; F2-Isoprostanes; Guinea Pigs; Heart; Hemodynamics; Isoenzymes; Male; Meloxicam; Myocardial Ischemia; Myocardial Reperfusion Injury; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Thiazines; Thiazoles; Thromboxane A2

Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane.. In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.

Topics: Anesthetics, Inhalation; Animals; Coronary Circulation; Dinoprost; Eicosanoids; Guinea Pigs; Hemodynamics; In Vitro Techniques; Isoflurane; Lactic Acid; Male; Methyl Ethers; Myocardial Ischemia; Myocardium; Pyruvic Acid; Sevoflurane; Thromboxane A2; Time Factors

We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E(2) and 6-keto-PGF(1alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGI(2) as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Celecoxib; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Gene Expression Regulation, Enzymologic; Ischemic Preconditioning; Isoenzymes; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Stunning; Myocardium; Nitrobenzenes; Prostaglandin-Endoperoxide Synthases; Prostaglandins E; Pyrazoles; Rabbits; Sulfonamides; Transcription, Genetic

1. The effects of simulated myocardial ischemic conditions on the contractile response of isolated human umbilical artery (HUA) strips to 5-hydroxytryptamine (5-HT) and prostaglandin F2 alpha (PGF2 alpha) were studied. 2. During simulated myocardial ischemic conditions the contractile response of HUA strips to 5-HT was lower than the response to the monoamine under oxygenated conditions. Under simulated ischemic conditions the response to 5-HT was further depressed by the cyclooxygenase inhibitor indomethacin (10 microM) and increased by the NO synthase inhibitor L-NAME (100 microM). 3. During simulated ischemic conditions the response of the HUA to a submaximal concentration of PGF2 alpha (3 microM) was reduced. Indomethacin (10 microM) further reduced the response to the prostanoid whereas L-NAME (100 microM) enhanced the response to PGF2 alpha. 4. It is concluded that during simulated myocardial ischemic conditions lactate negatively modulates the contractile response of HUA strips to 5-HT. Apparently, during simulated myocardial ischemic conditions in the HUA the production and/or release of EDRF/NO was not affected.

Topics: Culture Media; Cyclooxygenase Inhibitors; Dinoprost; Endothelins; Enzyme Inhibitors; Female; Humans; In Vitro Techniques; Indomethacin; Muscle, Smooth, Vascular; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Placenta; Pregnancy; Serotonin; Umbilical Arteries

We compared the effects of brief and prolonged myocardial ischemia on tissue prostaglandin synthesis. Regional ischemia was induced in dogs and maintained for 5 or 30 minutes. Isolated rat hearts were subjected to global ischemia in a working heart preparation for periods of 5 or 20 minutes. De novo synthesis of prostaglandins PGE2 and PGF2 alpha was measured in endocardial and epicardial explants from hearts subjected to transient ischemia. After 5 minutes of coronary ligation, PGE2 production by the ischemic canine endocardium increased by 68%, compared with non-ischemic tissue, and PGF2 alpha levels rose by 29%. In isolated rat hearts, 5-minute ischemia increased endocardial rate of PGE2 synthesis (13.2 +/- 1.7 pmol/g/h, as compared with 6.7 +/- 0.5 under normoxic conditions). Ischemic stimulation of eicosanoid production by the endocardium was no longer apparent after 30-minute regional or 20-minute global ischemia. In contrast, the epicardium showed significant changes only after 30-minute ischemia and only with respect to PGF2 alpha (12.0 +/- 6.2 in the ischemic vs 7.1 +/- 3.2 pmol/g/h in the non-ischemic tissue). Ischemia-induced differences in prostaglandin production were attenuated in the presence of arachidonic acid or aspirin.

Topics: Animals; Dinoprost; Dinoprostone; Dogs; Eicosanoids; Endocardium; In Vitro Techniques; Myocardial Ischemia; Myocardium; Prostaglandins; Rats; Time Factors

1. Functional and antiischaemic effects of monoacetyl-vitexinrhamnoside (AVR), a flavonoid with phosphodiesterase (PDE)-inhibitory properties contained in Crataegus species (Hawthorn, Rosaceae) were studied in several in-vitro models. 2. In rabbit isolated femoral artery rings, AVR concentration-dependently reduced developed tension. Vasodilation by AVR was reduced after inhibiting EDRF formation by L-NG-nitro arginine. 3. In spontaneously-beating Langendorff-guinea pig hearts, AVR concentration-dependently enhanced heart-rate, contractility, lusitropy and coronary flow. 4. In isolated electrically-driven Langendorff-rabbit hearts, acute regional ischemia (MI) was induced by coronary artery occlusion and quantified from epicardial NADH-fluorescence photography. AVR (5 x 10(-5) mol/l) induced a slight numerical increase of left ventricular pressure and coronary flow (p > 0.05). MI was reduced (p < 0.05). 5. Monoacetyl-vitexinrhamnoside is an inodilator whose vasodilatory action may be mediated in part by EDRF in addition to PDE-inhibition. Monoacetyl-vitexinrhamnoside does possess marked antiischemic properties even in isolated hearts, suggesting an improvement of myocardial perfusion.

Topics: Abortifacient Agents; Animals; Apigenin; Dinoprost; Femoral Artery; Flavonoids; Guinea Pigs; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Plant Extracts; Rabbits; Substance P; Vasoconstriction

The hypolipidemic, antiatherogenic and thrombolytic effects and decrease of prostaglandin F2 alpha (PG) excretion were observed in 55 patients suffering from Ischemic heart disease, hyperlipidemia and hypertension fed the antiatherosclerotic diet containing 20 g of eiconol during 55 days. The low initial level of natural antibodies to PGF2 alpha was increased significantly in blood serum. Authors consider that decrease of PGF2 alpha level under diet influence is connected not only with the change of fatty acid composition of cell membranes but also with increasing of natural antibody production.

Topics: Adult; Aged; Diet, Atherogenic; Dietary Fats, Unsaturated; Dinoprost; Fatty Acids, Omega-3; Female; Fish Oils; Humans; Hyperlipidemias; Hypertension; Hypolipidemic Agents; Immunity, Innate; Male; Middle Aged; Myocardial Ischemia

This study was done to determine whether abnormal receptor-dependent release of endothelium-derived relaxing factor (EDRF) might be caused by G-protein dysfunction. Dogs were exposed to global myocardial ischemia (45 minutes, induced by aortic cross-clamping) followed by reperfusion (60 minutes) while on cardiopulmonary bypass, and coronary arteries were then studied in vitro in organ chamber experiments. After reperfusion, endothelium-dependent relaxation to the receptor-dependent agonists adenosine diphosphate and acetyl-choline was significantly impaired as well as to sodium fluoride, which acts on a pertussis toxin-sensitive G-protein. In contrast, endothelium-dependent relaxations to the receptor-independent agonists A23187 and phospholipase C were normal. Furthermore, endothelium-dependent relaxation to poly-L-arginine (molecular weight, 139,200), which appears to induce endothelium-dependent relaxation of the canine coronary artery by a nonnitric oxide pathway, was unaffected by ischemia and reperfusion. These experiments suggest that global myocardial ischemia and reperfusion selectively impair receptor-mediated release of EDRF (nitric oxide) but that the ability of the endothelial cell to produce EDRF or generate endothelium-dependent relaxation to nonnitric oxide-dependent agonists remains intact. We hypothesize that coronary reperfusion injury leads to G-protein dysfunction in the endothelium.

Topics: Acetylcholine; Adenosine Diphosphate; Aluminum Chloride; Aluminum Compounds; Animals; Calcimycin; Cardiopulmonary Bypass; Chlorides; Coronary Vessels; Dinoprost; Dogs; Endothelium, Vascular; Female; GTP-Binding Proteins; Isoproterenol; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Nitric Oxide; Peptides; Sodium Fluoride; Type C Phospholipases

1. The effects of myocardial ischaemia/reperfusion were tested on the coronary vasorelaxant responses to agonists selective for the A1 and A2 adenosine receptor subtypes in the dog. The left anterior descending (LAD) coronary artery was occluded distal to the first diagonal branch. The occlusion was maintained for 1 h, followed by 1 h of reperfusion. 2. In the first series of experiments, LAD and circumflex arteries were excised and contracted with prostaglandin F2 alpha (PGF2 alpha). Ischaemia/reperfusion did not significantly alter the vasorelaxation produced by either sodium nitroprusside (endothelium-independent) or acetylcholine (endothelium-dependent). The A1 selective agonist, cyclopentyladenosine (CPA), produced coronary vasorelaxation in both normally perfused vessels and vessels subjected to ischaemia/reperfusion. In contrast, the relaxation produced by the A2-selective agonist N6-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl) ethyl] adenosine (DPMA) was significantly attenuated by ischaemia/reperfusion (14 fold shift in EC50). 3. In the second series of experiments, coronary blood flow was increased by administration of the A1 and A2 agonists before and after ischaemia/reperfusion of the LAD in anaesthetized dogs. Both compounds dose-dependently increased coronary blood flow. The slopes of the dose-response functions to CPA or DPMA were not significantly altered in the normally perfused circumflex vascular bed. Similarly, the CPA dose-response function in the LAD was unaltered by ischaemia/reperfusion. However, the slope of the coronary vasodilator response to the A2 agonist was significantly reduced following ischaemia/reperfusion of the LAD. 4. We conclude that ischaemia/reperfusion reduces responsiveness to an adenosine A2 receptor subtype agonist, but not an A1 receptor subtype agonist. These data confirm the independent nature of A1- and A2-mediated coronary vasodilatation.

Topics: Adenosine; Animals; Coronary Vessels; Dinoprost; Dogs; In Vitro Techniques; Myocardial Ischemia; Myocardial Reperfusion; Receptors, Purinergic P1; Vasodilation

The aim was to examine the effect on cardiac function, energy metabolism, and calcium uptake of either prostaglandin I2 (PGI2, prostacyclin) or prostaglandin F2 alpha (both 28.6 nM) on the response of isolated rat hearts to 25 min of total global ischaemia with or without 30 min reperfusion.. Rat hearts were perfused by the Langendorff method and function assessed by left ventricular pressure. Energy metabolites were measured using enzymatic techniques and 45Ca2+ uptake determined by radioisotopic analysis.. Although there was no effect of either prostaglandin on contractile depression during ischaemia, both compounds accelerated the onset of and increased the magnitude of ischaemic contracture. High energy phosphate content at the end of the ischaemic period was not affected by prostaglandin treatment; however, tissue lactate levels were increased by PGI2 as was tissue calcium content. Under control conditions mean recovery of left ventricular developed pressure ranged from 66% to 83%. In the presence of PGI2 and PGF2 alpha, recovery of developed pressure was reduced to 20% and 38% of preischaemic values, respectively. The reduced recovery in developed pressure was accompanied by an approximately threefold increase in diastolic pressure (p < 0.05). The depression of functional recovery in reperfused hearts treated with prostaglandins was associated with various disturbances of cellular metabolism including depressed ATP and creatine phosphate content and increased tissue lactate and calcium following 30 min of reperfusion. A significant correlation was found between the changes in developed pressure and diastolic pressure during reperfusion and the reduction in ATP and creatine phosphate repletion. The deficit in recovery of ventricular function also correlated significantly with increased lactate and calcium accumulation in the reperfused heart.. Low concentrations of PGI2 and PGF2 alpha can depress contractile recovery of the globally ischaemic heart through a mechanism associated with altered cellular energy metabolism and increased calcium accumulation.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Calcium; Dinoprost; Energy Metabolism; Epoprostenol; In Vitro Techniques; Lactates; Lactic Acid; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

Cardiac ischemia and reperfusion are associated with increased prostaglandin levels in the coronary venous effluent. This study implemented an in vivo-in vitro technique to investigate regional alterations in heart tissue PGE2 and PGF2 alpha de novo production. Canine endocardial and epicardial explants were incubated following 5 min regional ischemia, or 5 min ischemia with 10 min reperfusion, induced in vivo in two groups of animals (n = 10 and 6, respectively). Ischemia produced a significant upsurge in endocardial but not in epicardial prostaglandin synthesis as compared with the non-ischemic zone: 7.6 +/- 0.7 versus 4.5 +/- 0.5 pg/mg tissue per h in PGE2 (P < 0.001) and 8.8 +/- 1.2 versus 6.8 +/- 1.2 pg/mg per h PGF2 alpha (P < 0.01). Following reperfusion, PGE2 was higher in the apparently normal than in the affected endocardium (5.8 +/- 0.6 versus 4.4 +/- 0.5 pg/mg per h, P < 0.05). Opposite changes occurred in the reperfused epicardium: 8.2 + 0.9 versus 4.9 +/- 0.7 pg/mg per h PGE2 (P < 0.01) and 11.1 +/- 0.9 versus 6.0 +/- 0.6 pg/mg per h PGF2 alpha (P < 0.001), for the reperfused as compared to the "normal" region, respectively. Our findings imply that the left ventricular wall is not homogeneous in its eicosanoid response to ischemia and reperfusion. "In mirror" changes were found between endocardium end epicardium and between the injured and the apparently normal regions.

Topics: Animals; Dinoprost; Dinoprostone; Dogs; Endocardium; Myocardial Ischemia; Myocardial Reperfusion; Myocardium