Sissel Skarra

Intracellular manganese ions provide strong T1 relaxation in rat myocardium.

The efficacy of manganese ions (Mn2+) as intracellular (ic) contrast agents was assessed in rat myocardium. T1 and T2 and Mn content were measured in ventricular tissue excised from isolated perfused hearts in which a 5‐min wash‐in with 0, 30, 100, 300, or 1000 μM of Mn dipyridoxyl diphosphate (MnDPDP) was followed by a 15‐min wash‐out to remove extracellular (ec) Mn2+. An inversion recovery (IR) analysis at 20 MHz revealed two T1 components: an ic and short T1‐1 (650–251 ms), and an ec and longer T1‐2 (2712–1042 ms). Intensities were about 68% and 32%, respectively. Tissue Mn content correlated particularly well with ic R1‐1. A two‐site water‐exchange analysis of T1 data documented slow water exchange with ic and ec lifetimes of 11.3 s and 7.5 s, respectively, and no differences between apparent and intrinsic relaxation parameters. Ic relaxivity induced by Mn2+ ions in ic water was as high as 56 (s mM)−1, about 8 times and 36 times higher than with Mn2+ aqua ions and MnDPDP, respectively, in vitro. This value is as high as any reported to date for any synthetic protein‐bound metal chelate. The increased rotational correlation time (τR) between proton and electron (Mn2+) spins, and maintained inner‐sphere water access, might make ic Mn2+ ions and Mn2+‐ion‐releasing contrast media surprisingly effective for T1‐weighted imaging. Magn Reson Med 52:506–514, 2004.

Myocardial manganese elevation and proton relaxivity enhancement with manganese dipyridoxyl diphosphate. Ex vivo assessments in normally perfused and ischemic guinea pig hearts.

Manganese (Mn) dipyridoxyl diphosphate (MnDPDP) is the active component of a contrast medium for liver MRI. By being metabolized, MnDPDP releases Mn2+, which is taken up and retained in hepatocytes. The study examined whether MnDPDP elevates Mn content and enhances proton relaxivity in normal myocardium, but not in ischemic myocardium with reduced coronary flow and impaired metabolism. Isolated guinea pig hearts were perfused at normal flow or low flow, inducing global subtotal ischemia. Ventricular ATP and Mn contents, T1 and T2 were measured. At normal flow tissue Mn content increased from the control level of 4.1 to 70.4 µmol/100g dry wt with MnDPDP (3000 µM), while low‐flow perfusion with MnDPDP (3000 µM) resulted in a Mn content of 16.6 µmol/100 g dry wt. Prolonged ischemia (35 and 90 min) reduced tissue Mn down to the control level. T1 shortening closely paralleled myocardial Mn elevations during both normal and low‐flow perfusion. The use of a Mn2+‐releasing contrast agent like MnDPDP may be a promising principle in MRI assessments of myocardial function and viability in coronary heart disease by revealing a differential pattern of changes in T1 relative to coronary flow, cell Mn uptake and retention, ion channel function and metabolism. Copyright

Oxidative stress and inflammatory response during and following coronary interventions for acute myocardial infarction

Background: In acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI), myocardial injury results from complex processes during both ischemia and reperfusion. Release of reactive oxygen species (ROS) may contribute to the accumulated myocardial damage. Aims: To examine by frequent sampling of peripheral blood oxidative stress and early inflammation in patients undergoing primary PCI for AMI. Secondly, to assess whether a correlation exists between these parameters and the extent of myocardial damage. Methods: Sixteen patients undergoing primary PCI within 6 h of AMI onset were included. Peripheral blood was sampled at start of procedure (t0) and repeatedly over 24 h following reperfusion. Main plasma analyses were: 8-iso-PGF2α (oxidative stress), 15-keto-dihydro-PGF2α (cyclooxygenase-mediated inflammation); and troponin-T (myocardial injury). Additional analyses included: total antioxidant status (TAS); vitamins; hsCRP and lipids. Results: 8-Iso-PGF2α increased following restoration of blood flow, returned to t0 values after 3 h and was reduced below t0 the following day. TAS decreased significantly from t0 to the next day. There was no significant correlation between 8-iso-PGF2α and troponin T values. 15-Keto-dihydro-PGF2α was elevated during the first hour. There was a major rise in hsCRP after 24 h. Conclusion: Following reperfusion by primary PCI in AMI, oxidative stress and an inflammatory response are induced immediately. A rise in 8-iso-PGF2α during ischemia indicate that ROS generation may also take place during severely reduced coronary blood flow and hypoxia. No direct relationship between 8-iso-PGF2α or 15-keto-dihydro-PGF2α and troponin T was evident. The present study adds to the increasingly complex pathophysiological roles of ROS acting both as signal molecules and as mediators of tissue injury.

Oxidative stress and myocardial damage during elective percutaneous coronary interventions and coronary angiography. A comparison of blood-borne isoprostane and troponin release.

The role of oxidative stress in clinical cardiology is still controversial. The aims of the present study were to examine if minor ischaemic episodes as may occur during elective percutaneous coronary intervention (PCI) induce oxidative stress and, eventually, if oxygen stress correlates with myocardial injury. Thirty eight and nine patients underwent PCI and diagnostic coronary angiography, respectively. Peripheral blood was sampled at different time points for plasma analyses of: 8-iso-PGF2α (free radical-mediated oxidative stress); 15-keto-dihydro-PGF2α (cyclooxygenase-mediated inflammation); troponin-T (myocardial injury); hsCRP, vitamin A and vitamin E; and, total antioxidants status (TAS). In both groups 8-iso-PGF2α increased transiently by approximately 80% (p<0.001) during the procedure. There was a minor troponin-T release (p<0.001) after PCI, but no correlation with 8-iso-PGF2α. Troponin-T did not increase after angiography. 15-keto-dihydro-PGF2α decreased by 50% after ended procedure, but increased by 100% after 24 h compared to baseline. hsCRP increased significantly (p<0.001) from baseline to the next day in the PCI-group, but not in the angiography group. Vitamins and TAS decreased slightly after the procedures. It is concluded that a moderate oxidative stress was induced by both elective PCI and coronary angiography but that no correlation was found between oxidative stress and myocardial injury in this setting. This indicates that other mechanisms than ischaemia–reperfusion episodes caused an elevation in plasma isoprostane such like the injury at a vascular site mutual for both procedures. A secondary finding from the study was elevated markers of early inflammatory response, not only after PCI, but also after angiography.

Oxidative stress during coronary artery bypass operations: importance of surgical trauma and drug treatment.

Objective. To investigate oxidative stress and myocardial injury at different stages of coronary artery bypass grafting (CABG). Design. Twenty patients underwent CABG with use of cardiopulmonary bypass (CPB) and with intermittent sampling of plasma and urine. Main markers were: 8-iso-PGF2α (oxidative stress); troponin T (myocardial injury); and 15-keto-dihydro-PGF2α and hsCRP (inflammation). Results. Plasma 8-iso-PGF2α increased after start of surgery, but there was no further rise during CPB or after aortic cross-clamp release and no significant myocardial arterio-venous differences. An increase in troponin T was seen early after the operation, but no relationship was established between 8-iso-PGF2α and troponin T. 8-iso-PGF2α levels were elevated by preoperative withdrawal of acetylsalicylic acid (ASA) but reduced by intraoperative use of heparin. 15-keto-dihydro-PGF2α was elevated during operation and hsCRP following operation. Conclusions. In the present study oxidative stress was multifactorial in origin with main impacts from surgical trauma, less from CPB and little if any from myocardial ischemia-reperfusion events. In addition, cardiovascular drugs in common use like ASA and heparin seemed to influence the pro- and antioxidant balance, a finding that has to be confirmed in future studies.

Hyperosmotic perfusion of the beating rat heart and the role of the Na + /K + /2CI − co-transporter and the Na + /H + exchanger

Abstract The aim of the present study was to investigate the role of the Na+/K+/2CI− co-transporter and the Na+/H+ exchanger on contractile function and electrolyte regulation during hyperosmotic perfusion of the heart.Langendorff perfused rat hearts were subjected to hyperosmolal perfusion in 10-min intervals. Perfusates were made hyperosmotic by adding mannitol to the buffer (370, 450 and 600 mOsmol/kg H2O). Cardiac contractile function was monitored with a balloon in the left ventricle (LV) coupled to a pressure transducer. Cardiac effluent was sampled repeatedly throughout and after hyperosmotic perfusion and analyzed for content of Na+, K+ and CI−.All three hyperosmotic perfusates initially reduced LV developed pressure (LVDP), but for 370 and 450 mOsmol/kg H2, LVDP recovered to baseline within 4 min of perfusion. With 600 mOsmol/kg H2, LVDP recovered slowly and was 50% below baseline after 10 min of hyperosmotic perfusion. Inhibition of the Na+/H+ exchanger with 5-(N-ethyl-N-isopropyl) amiloride (EIPA) and 3-methyl-sulfonyl-4-piperidinobenzoyl-guanidine methanesulfonate (HOE 694) abolished the recovery of LVDP to the 600 mOsmol/kg H2 perfusate, whereas inhibition of the Na+/K+/2CI− co-transporter had no impact on LVDP. Potassium was taken up by the heart during hyperosmotic perfusion and this uptake was significantly reduced with inhibition of the Na+/H+ exchanger. Intracellular pH was assessed with 31P magnetic resonance spectroscopy and hyperosmolality induced a significant alkalosis that was dependent upon the Na+/H+ exchanger.The rat heart responds to moderate elevations in osmolality with a transient reduction in contractile function, whereas an elevation of 300 mOsmol/kg H2 persistently reduces contractile function. The Na+/H+ exchanger, but not the Na+/K+/2CI− co-transporter, is of importance in contractile recovery and electrolyte regulation during hyperosmotic perfusion in the rat heart.

Effect of magnesium infusion on bleeding time in healthy male volunteers.

Intravenous magnesium has proved to be valuable in the treatment of cardiac arrhythmias and eclampsia, but the specific mode of action is not established. In this study the effect of magnesium sulphate (MgSO4) infusion on bleeding time and endogenous prostacyclin (PGI2) production in healthy male volunteers was investigated. Thirty-five males (age 18-30 years) randomized in a double-blind, placebo-controlled, cross-over study were investigated. MgSO4 was given as a bolus (8 mmol, 12 min) followed by continuous infusion (8 mmol in 108 ml saline, 120 min). Control was equal volumes of physiological saline. Heart rate, blood pressure and bleeding time (according to Ivy) were recorded as well as blood concentrations of magnesium and creatinine. Urine PGI2 was analysed as the stable metabolite 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha). Treatment with MgSO4 did not affect bleeding time (MgSO4; 8.4+/-3.5 vs. control 8.0+/-2.7 min) nor the production of PGI2 (MgSO4; 1.2 microg 6-keto-PGF1alpha/g creatinine vs. control; 1.1 microg 6-keto-PGF1alpha/g creatinine). Intravenous infusion of MgSO4 does not affect the PGI2/platelet axis in healthy male volunteers. Studies in patients with endothelium dysfunction and/or concomitant drug therapy are required before the anti-thrombogenic effect of MgSO4 in vivo is discarded.

Iodinated Radiographic Contrast Media Possess Antioxidant Properties in vitro

Purpose: To study potential properties of iodinated radiographic contrast media (IRCM) for intravascular use in in vitro free radical generating reactions. Material and Methods: Superoxide (·O2 −) and hydroxyl (·OH) radicals were generated in xanthine oxidase and Fenton reactions. ·O2 − was assayed by the nitroblue tetrazolium (NBT) method, whereas ·OH was assayed by an aromatic hydroxylation (2-hydroxy-benzoic acid) method. Total antioxidant status (TAS) of test substances was determined by a colorimetric assay. Finally, acetyl-cholinesterase (AChE) activity was measured in the absence and presence of IRCM. Results: High concentrations (>50 mM) of IRCM inhibited ·O2 − production, ionic more than non-ionic IRCM. Medium concentrations (25–50 mM) of IRCM reduced ·OH production, and both types of IRCM were equally potent. Low concentrations (<25 mM) of non-ionic IRCM displayed higher antioxidant capacity than their ionic counterparts when tested in the TAS assay. Visipaque 320® (iodixanol) was found to have the highest TAS value, followed by Omnipaque 350® (iohexol), Hexabrix 320® (ioxaglate), and Urografin 370® (diatrizoate). Conclusion: IRCM have in vitro antioxidant properties in concentrations relevant for their clinical application. These properties may therefore be of potential importance when evaluating IRCM effects in vivo, particularly those concerning cardiovascular and renal function.