Min Of Coronary Artery Ligation Research Articles

Chronic Pharmacological Modulation of Mitochondrial Dynamics Alleviates Prediabetes-Induced Myocardial Ischemia-Reperfusion Injury by Preventing Mitochondrial Dysfunction and Programmed Apoptosis.

There is an increasing body of evidence to show that impairment in mitochondrial dynamics including excessive fission and insufficient fusion has been observed in the pre-diabetic condition. In pre-diabetic rats with cardiac ischemia-reperfusion (I/R) injury, acute treatment with a mitochondria fission inhibitor (Mdivi-1) and a fusion promoter (M1) showed cardioprotection. However, the potential preventive effects of chronic Mdivi-1 and M1 treatment in a pre-diabetic model of cardiac I/R have never been elucidated. Male Wistar rats (n = 40) were fed with a high-fat diet (HFD) for 12weeks to induce prediabetes. Then, all pre-diabetic rats received the following treatments daily via intraperitoneal injection for 2weeks: (1) HFDV (Vehicle, 0.1% DMSO); (2) HFMdivi1 (Mdivi-1 1.2mg/kg); (3) HFM1 (M1 2mg/kg); and (4) HFCom (Mdivi-1 + M1). At the end of treatment protocols, all rats underwent 30min of coronary artery ligation followed by reperfusion for 120min. Chronic Mdivi-1, M1, and the combined treatment showed markedly improved cardiac mitochondrial function and dynamic control, leading to a decrease in cardiac arrhythmias, myocardial cell death, and infarct size (49%, 42%, and 51% reduction for HFMdivi1, HFM1, and HFCom, respectively vs HFDV). All of these treatments improved cardiac function following cardiac I/R injury in pre-diabetic rats. Chronic inhibition of mitochondrial fission and promotion of fusion exerted cardioprevention in prediabetes with cardiac I/R injury through the relief of cardiac mitochondrial dysfunction and dynamic alterations, and reduction in myocardial infarction, thus improving cardiac function.

Repeated cell transplantation and adjunct renal denervation in ischemic heart failure: exploring modalities for improving cell therapy efficacy

Enthusiasm for cell therapy for myocardial injury has waned due to equivocal benefits in clinical trials. In an attempt to improve efficacy, we investigated repeated cell therapy and adjunct renal denervation (RDN) as strategies for augmenting cardioprotection with cardiosphere-derived cells (CDCs). We hypothesized that combining CDC post-conditioning with repeated CDC doses or delayed RDN therapy would result in superior function and remodeling. Wistar-Kyoto (WKY) rats or spontaneously hypertensive rats (SHR) were subjected to 45min of coronary artery ligation followed by reperfusion for 12-14weeks. In the first study arm, SHR were treated with CDCs (0.5 × 106 i.c.) or PBS 20min following reperfusion, or additionally treated with CDCs (1.0 × 106 i.v.) at 2, 4, and 8weeks. In the second arm, at 4weeks following myocardial infarction (MI), SHR received CDCs (0.5 × 106 i.c.) or CDCs + RDN. In the third arm, WKY rats were treated with i.c. CDCs administered 20min following reperfusion and RDN or a sham at 4weeks. Early i.c. + multiple i.v. dosing, but not single i.c. dosing, of CDCs improved long-term left ventricular (LV) function, but not remodeling. Delayed CDC + RDN therapy was not superior to single-dose delayed CDC therapy. Early CDC + delayed RDN therapy improved LV ejection fraction and remodeling compared to both CDCs alone and RDN alone. Given that both RDN and CDCs are currently in the clinic, our findings motivate further translation targeting a heart failure indication with combined approaches.

Renal Sympathetic Denervation Protects the Failing Heart Via Inhibition of Neprilysin Activity in the Kidney

BackgroundSustained sympathetic activation contributes to the progression of myocardial cell injury, cardiac fibrosis, and left ventricular (LV) dysfunction in heart failure (HF). ObjectivesThis study investigated the effects of radiofrequency renal nerve denervation (RF-RDN) on the pathobiology of HF and the interaction between the renal sympathetic nerves and natriuretic peptide (NP) metabolism. MethodsSpontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were subjected to 45 min of coronary artery ligation and reperfusion for 12 weeks. At 4 weeks post-reperfusion, SHR and WKY underwent either bilateral RF-RDN or sham-RDN. ResultsFollowing RF-RDN in both strains, LV ejection fraction remained significantly above those levels in respective sham-RDN rats, and at the end of the 12-week study, rats in both strains had significantly reduced LV fibrosis and improved vascular function. RF-RDN therapy significantly improved vascular reactivity to endothelium-dependent and -independent vasodilators as well as vascular compliance in the setting of severe HF. Improvements in LV function were accompanied by significant elevations in circulating NP as compared to those associated with sham-RDN. Further investigation into the cause of increased circulating NP levels demonstrated that RF-RDN significantly inhibited renal neprilysin activity in SHR and WKY with HF. Likewise, chronic treatment with the beta1 antagonist bisoprolol inhibited renal neprilysin activity and increased circulation NP levels in WKY with HF. ConclusionsThis study identifies a novel endogenous pathway by which the renal nerves participate in the degradation of cardioprotective NP. Furthermore, removal of the influence of the renal nerves on kidney function attenuates renal neprilysin activity, augments circulating NP levels, reduces myocardial fibrosis, and improves LV function in the setting of HF.

Carbon monoxide form of PEGylated hemoglobin protects myocardium against ischemia/reperfusion injury in diabetic and normal mice

We investigated the pre-clinical utility of carbon monoxide form of PEGylated hemoglobin (PEG-Hb also named SANGUINATE™) in myocardial infarction (MI) and in particular the response of diabetic tissues to superimposed ischemia/reperfusion injury. SANGUINATE™ was evaluated in diabetic and normal mice subjected to 30 min of coronary artery ligation followed by either 48 h or 28 days of reperfusion. Our results demonstrate that SANGUINATE™ was effective in reducing infarct size when administered either prior to left anterior descending coronary artery (LAD) occlusion or during reperfusion. This finding is an important step in exploring the efficacy of a pharmacoinvasive strategy using SANGUINATE™ in patients with acute coronary syndromes.

Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia–reperfusion injury

Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia–reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (−30% day 1 and −55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling.

Toll-like Receptor Signaling during Myocardial Ischemia

Acute myocardial infarction and myocardial ischemia are leading causes of short- and long-term morbidity and mortality in the perioperative period. In part, this relates to the fact that treatment options for a myocardial infarction in surgical patients are extremely limited. For example, anti-coagulation or treatment with highly effective inhibitors of platelet aggregation may not be an option due to the risk for bleeding from the operative site. Therefore, it is not surprising that the search for new pharmacologic approaches to treat myocardial ischemia or to render the myocardium more resistant to limited oxygen availability is an area of intense investigation for perioperative scientists.1-4 In fact, the introduction of intraoperative beta-blockers for cardio-protection from ischemia was one of the most significant alterations in anesthesia practice during the past fifteen years. In line with the search for novel therapeutic approaches to render the myocardium more resistant to ischemia, a very exciting research study by Wang et al. from the research laboratory of Dr. Wei Chao from the Anesthesia Center for Critical Care Research of the Massachusetts General Hospital in Boston provides new insight into signaling pathways involving toll-like receptor (TLR)-elicited cardio-protection from ischemia.1

E0212 L-carnitine treatment improves survival and effects of transplanted bone marrow mesenchymal stem cells in post-infarct rats hearts

ObjectiveTo investigate if the L-carnitine can improve the survival rate of transplanted MSCs after myocardial infarction, and enhance therapeutic effect of MSCs.MethodsFive rats were separately obtained, MSCs were isolated and...

Arginase inhibition mediates cardioprotection during ischaemia-reperfusion

Nitric oxide (NO) is vital for the integrity of the cardiovascular system and protection against ischaemic heart disease. Arginase is up-regulated during ischaemia-reperfusion (IR) and this enzyme might compete with NO synthase (NOS) for arginine. The present study investigated whether arginase blockade protects from myocardial IR injury and whether such an effect is coupled to increased NO bioavailability. Sprague-Dawley rats were subjected to 30 min of coronary artery ligation, followed by 2 h of reperfusion. The animals were given either saline, or the arginase inhibitor N-omega-hydroxy-nor-l-arginine (nor-NOHA) with or without the NO scavenger carboxy-2-phenyl-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide (cPTIO) or the NOS inhibitor N(G)-monomethyl-l-arginine (l-NMMA) iv 15 min before ischaemia. The infarct size was 79 +/- 4% of the area at risk in the control group. Nor-NOHA treatment reduced the infarct size to 39 +/- 7% (P < 0.001). Administration of cPTIO or l-NMMA completely abolished the protective effect of nor-NOHA. Expression of arginase I was significantly (P < 0.05) increased in ischaemic myocardium. Nor-NOHA treatment resulted in higher plasma levels of nitrite (P < 0.05) and a 10-fold increase in the citrulline/ornithine ratio (P < 0.001), indicating a shift in arginine utilization towards NOS. Inhibition of arginase protects from myocardial infarction by a mechanism that is dependent on NOS activity and bioavailability of NO by shifting arginine utilization from arginase towards NOS. These findings suggest that targeting of arginase is a promising future therapeutic strategy for protection against myocardial IR injury.

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion

Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated. In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis. This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

The eNOS enhancer AVE 9488: a novel cardioprotectant against ischemia reperfusion injury

Nitric oxide (NO) is an important regulator of vascular and myocardial function. Cardiac ischemia/reperfusion injury is reduced in mice overexpressing endothelial NO synthase (eNOS) suggesting cardioprotection by eNOS. Novel pharmacological substances, so called eNOS enhancers, upregulate eNOS expression and thereby increase NO production. We tested the effects of the eNOS enhancer AVE 9488 on cardiac ischemia/reperfusion injury in vivo in mice. After treatment with the eNOS enhancer AVE 9488 (30 mg/kg/day) or placebo for one week mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. Ischemia-reperfusion damage was significantly reduced in mice treated with the eNOS enhancer when compared to placebo treated mice (infarct/area at risk 65.4 +/- 4.1 vs. 36.9 +/- 4.0%, placebo vs. eNOS enhancer, P = 0.0002). The protective effect was blunted in eNOS knockout mice treated with the eNOS enhancer (infarct/area at risk 64.1 +/- 6.2%, eNOS knockout + eNOS enhancer vs. WT + eNOS enhancer, P = ns). Reactive oxygen species were significantly reduced in mice treated with the eNOS enhancer as indicated by significantly lower malondialdehyde-thiobarbituric acid levels (placebo vs. eNOS enhancer, 3.2 +/- 0.5 vs. 0.8 +/- 0.07 micromol/l, P = 0.0003). Thus pharmacological interventions addressed to increase eNOS-derived NO production constitute a promising therapeutic approach to prevent myocardial ischemia/reperfusion injury.

Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

This study sought to examine whether exenatide is capable of reducing myocardial infarct size. Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI). Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress. Exenatide reduced myocardial infarct size (32.7 +/- 6.4% vs. 53.6 +/- 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 +/- 6.3% vs. 8.1 +/- 1.9%, p < 0.001; myocardial stiffness: 0.12 +/- 0.06 mm Hg/ml vs. 0.22 +/- 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels. These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Role of 5-lipoxygenase in myocardial ischemia-reperfusion injury in mice

Myocardial ischemia induces 5-lipoxygenase (LOX) translocation and leukotriene production in the heart. Leukotrienes increase inflammatory responses and could thereby aggravate ischemic injury. However, the role of lipoxygenase and leukotrienes in cardiac ischemia/reperfusion damage has not been well defined. Therefore, we tested the effect of ischemia reperfusion in mice with targeted deletion of 5-lipoxygenase, the enzyme converting arachidonic acid in leukotrienes. 5-LOX deficient (KO) and wild-type (WT) mice underwent 30 min of coronary artery ligation and 24 h of reperfusion in vivo. In mice with equivalent area at risk, infarct size was not significantly different between WT and KO mice (infarct/area at risk 61.7+/-3.9 vs. 55.8+/-6.6%, WT vs. KO, P=n.s.). However, neutrophil infiltration as well as tumor necrosis factor expression were increased in 5-lipoxygenase deficient mice. In summary, inhibition of 5-lipoxygenase does not affect cardiac ischemia-reperfusion injury but the post-ischemic inflammatory response.

Rosiglitazone Treatment in Zucker Diabetic Fatty Rats Is Associated With Ameliorated Cardiac Insulin Resistance and Protection From Ischemia/Reperfusion-Induced Myocardial Injury

The mechanism responsible for the enhanced myocardial susceptibility to ischemic insult in patients with type 2 diabetes is not clear. The present study examines the effect of rosiglitazone treatment on cardiac insulin sensitization and its association with cardioprotection from ischemia/reperfusion injury in an animal model of diabetes. Male Zucker diabetic fatty (ZDF) rats were treated with rosiglitazone (3 mg . kg(-1) . day(-1) orally) or vehicle for 8 days before undergoing 30 min of coronary artery ligation, followed by reperfusion for 4 h (apoptosis) or 24 h (infarction). Rosiglitazone reduced the blood levels of glucose, triglycerides, and free fatty acids; enhanced cardiac glucose oxidation; and increased Akt phosphorylation (Akt-pS473) 2.1-fold and Akt kinase activity 1.8-fold in the ischemic myocardium. The phosphorylation of two downstream targets of Akt, glycogen synthase kinase-3beta and FKHR (forkhead transcription factor), was also enhanced by 2- and 2.9-fold, respectively. In rosiglitazone-treated rats, the number of apoptotic cardiomyocytes and the myocardial infarct size were decreased by 58 and 46%, respectively, and the myocardial contractile dysfunction was improved. Blockade of the insulin-Akt signaling pathway by wortmannin in the 8-day rosiglitazone-treated ZDF rats resulted in a markedly diminished cardioprotective effect of rosiglitazone. In addition, 8-day rosiglitazone treatment in Zucker lean rats or 2-day rosiglitazone treatment in ZDF rats, both of which showed no change in whole-body insulin sensitivity, resulted in a significant reduction in cardiac infarct size, but to a lesser degree when compared with that observed in 8-day rosiglitazone-treated ZDF rats. These results suggest that chronic treatment with rosiglitazone protects the heart against ischemia/reperfusion injury in ZDF rats, and that the enhanced cardiac protection observed after rosiglitazone treatment might be attributable in part to an improvement in cardiac insulin sensitivity.

The role of the L-arginine/nitric oxide pathway in myocardial ischaemic and reperfusion injury.

Myocardial ischaemia followed by reperfusion (I/R) is associated with impaired endothelial function including diminished release and/or effects of nitric oxide (NO) which may contribute to the development of I/R injury. The aim of the present study was to investigate the role of the L-arginine/NO pathway in myocardial I/R injury. In isolated rat hearts subjected to global ischaemia followed by reperfusion L-arginine and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP), but not D-arginine, significantly enhanced the recoveries of mycardial performance and coronary flow, and reduced the area of no-reflow and creatine kinase outflow. The NO synthase inhibitor NG-nitro-L-arginine (L-NNA) abolished the protective effects of L-arginine. Endothelium-dependent vasodilatation after I/R was preserved in L-arginine treated but not in vehicle hearts. Following I/R Ca2+-dependent NO synthase activity was reduced by 90% in comparison with non-ischaemic hearts. L-arginine but not D-arginine significantly increased NO synthase activity. In anaesthetized pigs, L-arginine given by local coronary venous retroinfusion reduced myocardial infarct size induced by 45 min of coronary artery ligation and 4 h of reperfusion to 35% of the area at risk from 76% in controls. The protective effect of L-arginine was blocked by L-NNA. Acetylcholine-induced coronary vasodilatation following I/R was attenuated in controls but not in L-arginine treated pigs. It is concluded that L-arginine or the NO donor SNAP reduces I/R-induced myocardial and endothelial injury. The protective effect of L-arginine seems to be mediated through maintained production of NO by preserving the function of Ca2+-dependent NO synthase in the heart.

Heterogeneous fatty acid uptake early after reperfusion in rat hearts.

We determined whether spatial distributions of substrate uptake are heterogeneous within the area at risk during reperfusion. Quantitative autoradiography with imaging plates and two long-lived radioisotopes was applied to 15 open-chest, anesthetized rats subjected to 30 min of coronary artery ligation and 30 min of reperfusion. Regions showing increased beta-methyl-[1-14C]heptadecanoic acid ([14C]BMHDA) uptake (166 +/- 17% of that in the nonischemic area) appeared at the lateral borders and subepicardial layer within the area at risk, and 2-deoxy-D-[1-3H]glucose ([3H]DG) uptake was 103 +/- 24% in these regions. Regions with decreased [14C]BMHDA uptake (28 +/- 11%) occupied the midmyocardial layer except at the lateral borders within the area at risk, and [3H]DG uptake was 62 +/- 18% in these regions. The percentage interregional coefficients of variation (index of heterogeneity) in [14C]BMHDA uptake, [3H]DG uptake, and blood flow were higher in the area at risk than in the nonischemic area (76 +/- 23 vs. 21 +/- 7%, 39 +/- 10 vs. 21 +/- 7%, and 49 +/- 19 vs. 14 +/- 4%, respectively). Heterogeneous distributions of substrate uptake may explain the conflicting results concerning substrate metabolism during reperfusion.

Antiarrhythmic properties of specific inhibitors of sarcoplasmic reticulum calcium ATPase in the isolated perfused rat heart after coronary artery ligation

Objective. T. hypothesis tested was that sequestration of calcium by the sarcoplasmic reticulum and internal calcium oscillations may play a rote in the genesis of ischemic and reperfusion ventricular arrhythmias.Background. Previous data suggest that inhibition of the release of intracellular calcium from the sarcoplasmic reticulum by ryamodine may prevent ventricular fibrillation.Methods. The isolated Langendorff perfused rat heart was treated with two specific inhibitors of the calcium ATPase pump of the sarcoplasmic reticulum (thapsigargin [10−6mol/liter] or cyclopiazomic acid[10−7mol/liter]) for 5 min before left anterior descending coronary artery ligation was performed, One group of hearts was subject to 30 min of coronary artery ligation, and ischemic arrhythimias were monitored. In a second group, the incidence of reperfusion arrhythmias was measured after 10,15, 20, 25 and 30 min of coronary artery ligation.Results. Thapsigargin treatment during ischemia and reperfusion decreased the incidence of reperfusion ventricular fibrillation after 10 min of coronary artery ligation from 67% (n = 6) to 0% (n = 6) (p < 0.05), after 15 mm from 81% (n = 16) to 25% (n = 20) (p < 0.002) and after 20 mm of ischemia from 90% (n = 10) to 46% (n = 13) (p < 0.05). Thapsigargin treatment also decreased the incidence of ischemic ventricular fibrillation from 83% (a = 12) to 0% (n = 12) (p < 0.002). Cyclopiazonic acid treatment during ischemia and reperfusion likewise decreased the incidence of ischemic and reperfusion arrhythmias.Conclusions. The highly specific inhibitors of the calcium uptake pump of the sarcoplasmic reticulum—thapsigargin and cyclopiazonic acid—have antifibrilltory properties in the isolated perfused rat heart. They appear to act by restriction of calcium oscillations between the sarcoplasmic reticulum and the cytosol.

Effect of low calcium on high-energy phosphates and sarcolemmal Na +/K +-ATPase in the infarcted-reperfused heart

This study was undertaken to compare the effect of low to normal serum calcium on biochemical parameters in the myocardium of dogs subjected to 90 min of coronary artery ligation followed by 30 min reperfusion. The accumulation of calcium, the decrease of adenosine triphosphate (ATP) and creatine phosphate (CP) and the inhibition of sarcolemmal ouabain-sensitive Na +/K +-ATPase which are prominent findings in the ischemic-reperfused myocardium, were studied under normal and low serum Ca produced by normal and modified hemodialysis (HD). The results showed a lower accumulation of Ca ( P < 0.002) in the ligated-reperfused myocardium of dogs subjected to low-calcium HD. In the same group of animals ATP was protected to some extent while CP was completely preserved. This may indicate that during reperfusion with low Ca, restored ATP is further utilized for CP regeneration. The activity of Na +/K +-ATPase was within normal values in the ligated-reperfused myocardium of the low-calcium group. The significantly ( P < 0.001) negative correlation between tissue calcium concentration and Na +/K +-ATPase activity under various conditions examined, provided additional evidence that low calcium is a protective factor of the enzyme activity during ischemia and reperfusion.

Effects of the myocardial-selective alpha 1-adrenoceptor antagonist UK-52046 and atenolol, alone and in combination, on experimental cardiac arrhythmias in dogs.

1. Adrenaline-induced arrhythmias in anaesthetized dogs respired with halothane were attenuated in 3 groups of 6 dogs by either UK-52046, 3.8 +/- 1.4 micrograms kg-1 (mean +/- s.e.mean), atenolol 14.6 +/- 2.1 micrograms kg-1, or a combination containing equal amounts of the two drugs of 0.36 +/- 0.1 microgram kg-1. The pressor response to adrenaline was reduced (P less than 0.01) by UK-52046 but not by atenolol or the combination of both drugs. 2. In a group of 6 dogs with multiventricular ectopic beats 24 h after coronary artery ligation (CAL), UK-52046, 32 micrograms kg-1, increased the number of sinus beats in each 5 min period from 137 +/- 47 to 662 +/- 99 (P less than 0.01); this was associated with a significant (P less than 0.01) fall in blood pressure. Atenolol in doses of up to 800 micrograms kg-1 had no effect. 3. UK-52046, 3.7 +/- 1.4 micrograms kg-1, prevented adrenaline-induced arrhythmias 3-4 days after CAL in 6/6 conscious dogs; atenolol in doses of up to 100 micrograms kg-1 produced an 84.4 +/- 7.4% reduction in the number of ventricular ectopic beats. A combination containing 3.7 +/- 1.1 micrograms kg-1 of each drug prevented the arrhythmia in 6/6 dogs. The pressor response to adrenaline was attenuated (P less than 0.05) by UK-52046, but resting blood pressure was unaffected by the different treatments. An increase (P less than 0.01) in heart rate was associated with both UK-52046 and the combination. 4. Neither UK-52046 (doses up to 64 micrograms kg-1) nor atenolol (up to 800 micrograms kg-1) had any effect upon ouabain-induced arrhythmias in 2 groups of 6 anaesthetized dogs. 5. In a study of the early (1a/1b) arrhythmias of acute myocardial ischaemia, the total number of ventricular ectopic beats occurring within 30 min of CAL was not reduced by 4 micrograms kg-1 UK-52046 but fell (P less than 0.01 compared with placebo) after 8 micrograms kg-1 [median values with ranges for placebo, 4 micrograms kg-1 and 8 micrograms kg-1 respectively 190 (4-674), 246 (9-1204) and 12 (1-154)]. Both doses of UK-52046 were associated with significant falls in blood pressure. 6. The arrhythmias produced by programmed electrical stimulation were studied in 2 groups of 6 conscious dogs, 7-30 days after CAL. With placebo, 4/6 dogs remained unchanged and 2 died: UK-52046 prevented arrhythmias in 2/6, 2 remained unchanged and 2 died (P = 0.29). Compared with placebo, blood pressure fell with doses greater than 4jg kg- '. 7. These results indicate antiarrhythmic effects of UK-52046 in a number of experimental models and suggest an enhanced role of alpha-receptors in the genesis of ischaemia-related arrhythmias. In several of the models used, UK-52046 produced haemodynamic changes in keeping with peripheral alpha-adrenoceptor antagonism.

Effects of OKY-046, a selective thromboxane A2 synthetase inhibitor, on ventricular arrhythmias and prostaglandins during coronary artery ligation and reperfusion in anesthetized dogs.

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on ischemia-induced ventricular arrhythmias were investigated in anesthetized dogs. OKY-046 (30 mg/kg, intravenously) decreased ventricular arrhythmias significantly both during 30 min of coronary artery ligation and subsequent reperfusion, which corresponded with a significant reduction of thromboxane concentration, suggesting that thromboxane released during ligation is an important factor in the development of ventricular arrhythmias. Inhibition of thromboxane synthesis with OKY-046 might be useful for the prevention of ischemia-induced ventricular arrhythmias.

Effects of OKY-046, a Selective Thromboxane A2 Synthetase Inhibitor, on Ventricular Arrhythmias and Prostaglandins during Coronary Artery Ligation and Reperfusion in Anesthetized Dogs

Effects of OKY-046, a selective thromboxane synthetase inhibitor, on ischemia-induced ventricular arrhythmias were investigated in anesthetized dogs. OKY-046 (30 mg/kg, intravenously) decreased ventricular arrhythmias significantly both during 30 min of coronary artery ligation and subsequent reperfusion, which corresponded with a significant reduction of thromboxane concentration, suggesting that thromboxane released during ligation is an important factor in the development of ventricular arrhythmias. Inhibition of thromboxane synthesis with OKY-046 might be useful for the prevention of ischemia-induced ventricular arrhythmias.