Heidi Brurok

Cardiovascular safety of MnDPDP and MnCl2

Purpose: To investigate the apparent discrepancy between expected basic physiological responses at the cellular level and the in vivo behaviour of both MnDPDP and MnCl2 adminstered i.v. prompted parallel investigations of these substances. Material and Methods: Studies were performed in isolated perfused rat hearts, isolated bovine mesenteric arteries, conscious dogs, and dogs with acute ischaemic heart failure. Results: These studies confirmed that Mn++ at high concentrations acted as a calcium antagonist inducing negative inotropy. Mn++ at low concentrations was an effective su-peroxide scavenger, conserving nitric oxide and facilitating vasodilation. Mn++ maintained or elevated heart rate (HR) and blood pressure (BP), and did not worsen existing cardiac failure. MnDPDP was about 10 times less potent than MnCl2 in eliciting these cardiovascular responses. Conclusion: The ex vivo properties of Mn++, inducing vasodilation and negative inotropy, are counter-balanced in vivo through the action of 2 mechanisms: extensive plasma protein binding reducing active M++, and the release of catecholamines which maintain or even raise HR and BP. Taken together with pharmacokinetic factors, including maximal plasma concentrations in humans given the recommended 5 μmol/kg dose, it is concluded that MnDPDP in normal clinical use represents no safety risk to the cardiovascular system.

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.

Effects of manganese dipyridoxyl diphosphate, dipyridoxyl diphosphate--, and manganese chloride on cardiac function. An experimental study in the Langendorff perfused rat heart.

RATIONALE AND OBJECTIVES.Manganese dipyridoxyl diphosphate (MnDPDP) is a promising contrast agent for magnetic resonance imaging of the liver. The authors explored the possibility that high concentrations of MnDPDP may cause manganese ion (Mn++)-induced side effects on cardiac function. METHODS.Potential cardiodepression by MnDPDP, DPDP– –, and manganese chloride (MnCl2) (100-3,0000 µmol/ L) was investigated in the isolated rat heart, with left ventricular developed (systolic—end-diastolic) pressure and heart rate as the primary indices of cardiac function. RESULTS.During 5-minute exposures, 10% and 50% decreases in left ventricular developed pressure were observed for MnDPDP, 250 µmol/L and 1580 /µmoI/L; DPDP– –, less than 100 µmol/L and 1000 /µmoI/L; MnCl2, 30 /µmol/L and 250 /µmol/L. Heart rate changes were not observed with MnDPDP. Cardiodepression was reversed within 2 minutes during a 14- minute recovery period for all investigated concentrations of MnDPDP and was less rapid for the highest concentrations of MnCl2. CONCLUSIONS.Manganese dipyridoxyl diphosphate is well tolerated in the rat heart at concentrations as high as 200 to 250 limol/L and is approximately 10 times less cardiotoxic than MnCl2. Cardiodepressive effects of MnDPDP in the present rat heart model, perfused in the absence of blood and proteins, are related primarily to the release of free Mn++ions and in part to the simultaneous release of DPDP¯ ¯.

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 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.

Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium

Purpose: To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury. Material and Methods: Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three μmol/kg MnDPDP, 1 μmol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 μmol/kg/h MnDPDP, 1 μmol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed. Results: Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED. During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39±6 and 16±5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10±4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites. Conclusion: MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.

Cardiac Metal Contents After Infusions of Manganese: An Experimental Evaluation in the Isolated Rat Heart

RATIONALE AND OBJECTIVES Manganese dipyridoxyl diphosphate (MnDPDP), a contrast agent for liver MRI, releases free Mn2+ in a graded manner. The aim of the study was to compare the effects of brief versus prolonged infusions of MnDPDP and manganese chloride (MnCl2) on cardiac function, metabolism, Mn accumulation, and tissue metal content. METHODS Isolated perfused rat hearts received 1-minute or 10-minute infusions of MnDPDP (100 microM, 1000 microM) or of MnCl2 (10 microM, 100 microM). Physiologic indices were measured intermittently, and tissue high-energy phosphate compounds and Ca/Fe/Mg/Mn/Zn contents were measured after a standardized Mn washout. RESULTS One-minute and 10-minute infusions induced, respectively, minor and marked depressions of contractile function and corresponding elevations in myocardial Mn content. MnCl2 was markedly more potent than MnDPDP. Ten-minute infusions of the highest concentration of MnDPDP and MnCl2 lowered tissue Mg and elevated tissue Ca (MnCl2), whereas high-energy phosphates were unaffected. CONCLUSIONS Mn uptake after Mn infusion is strongly related to the duration, concentration, and dose of free Mn ions. Differences in Mn accumulation between MnDPDP and MnCl2 were more pronounced after the 10-minute infusion.

Effects of MnDPDP, DPDP--, and MnCl2 on cardiac energy metabolism and manganese accumulation. An experimental study in the isolated perfused rat heart.

RATIONALE AND OBJECTIVES Recent studies indicate that manganese dipyridoxyl diphosphate (MnDPDP) may function as a slow release agent for manganese ions (Mn++) and that MnDPDP is approximately 10 times less potent than manganese chloride (MnCl2) in depressing cardiac function. The authors examined the possibility that MnDPDP and MnCl2 may influence cardiac metabolism and enzyme release and lead to a tissue accumulation of Mn. METHODS Manganese DPDP, DPDP--, or MnCl2 (1000 microM) was infused in isolated rat hearts, which were freeze-clamped at various time intervals during infusion (5 minutes) and recovery (14-minute washout). Enzyme (lactate dehydrogenase) release, tissue high energy phosphates, Mn contents, and physiologic indices were measured at various time intervals. RESULTS No significant differences were noted for: lactate dehydrogenase in the treated groups; tissue creatine phosphate (CrP) and adenosine triphosphate in MnDPDP, DPDP--, and control groups; and tissue Mn in DPDP-- and control groups. Manganese-chloride and MnDPDP-treated hearts accumulated and retained Mn in an 8:1 ratio. Manganese chloride depressed cardiac function more effectively than MnDPDP. CONCLUSIONS The study has shown that: heart tissue uptake and retention of Mn++ is rapid and effective; MnCl2 is approximately eight times more potent than MnDPDP in promoting these effects; and a rise in tissue Mn content to eight to nine times (MnDPDP) or 60 to 70 times (MnCl2) the normal level does not lead to acute side effects on cardiac energy metabolism, function, and enzyme release. The study indicates that MnDPDP may act like a slow release compound for Mn++ ions.

Analyzing equilibrium water exchange between myocardial tissue compartments using dynamical two-dimensional correlation experiments combined with manganese-enhanced relaxography

Water compartments were identified and equilibrium water exchange was studied in excised rat myocardium enriched with intracellular manganese (Mn2+). Standard relaxographic measurements were supplemented with diffusion‐T2 and T1‐T2 correlation measurements. In nonenriched myocardium, one T1 component (800 ms) and three T2 components (32, 120, and 350 ms) were identified. The correlation measurements revealed fast‐ and slow‐diffusing water fractions with mean diffusion coefficients of 1.2 × 10−5 and 3.0 × 10−5 cm2 s−1. The two shortest T2 components, which had different diffusivities, both originated from water in intracellular compartments. A component with longer relaxation time (T1 ≈ 2200 ms; T2 ≈ 1200 ms), originating from extra‐tissue water, was also observed. The presence of this component may lead to erroneous estimations of water exchange rates from multiexponential relaxographic analyses of excised tissues. The tissue T1 value is strongly reduced with increasing enrichment of Mn2+, and eventually a second tissue T1 component emerges, indicating a shift in the equilibrium water exchange between intra‐ and extracellular compartments from the fast‐exchange limit to the slow‐exchange regime. Using a two‐site water exchange analysis, the lifetime of intracellular water, Tic, was found to be 475 ms, with a fraction, pic, of 0.71. Magn Reson Med 58:674–686, 2007.

Manganese-calcium interactions with contrast media for cardiac magnetic resonance imaging: a study of manganese chloride supplemented with calcium gluconate in isolated Guinea pig hearts.

Objectives:Manganese ions (Mn2+) enter cardiomyocytes via calcium (Ca2+) channels and enhance relaxation intracellularly. To prevent negative inotropy, new Mn2+-releasing contrast agents have been supplemented with high Ca2+. The study aim was to investigate how this affects cardiac function and magnetic resonance efficacy. Materials and Methods:MnCl2 based contrast agents, manganese and manganese–calcium (Ca2+:Mn2+ 10:1), were infused during 4 repeated washin–washout sequences in perfused guinea pig hearts. [Mn2+] were 10, 50, 100 and 500 μM. Results:During washin, manganese depressed left ventricular developed pressure (LVDP) by 4, 9, 17, and 53% whereas manganese–calcium increased LVDP by 13, 18, 25, and 56%. After experiments, tissue Mn contents (nmol/g dry wt) were control <40, manganese 3720, and manganese–calcium 1620. T1 was reduced by 85–92% in Mn2+-enriched hearts. Conclusions:High Ca2+ supplements to Mn2+-releasing contrast agents may be counterproductive by inducing a strong positive inotropic response and by reducing the magnetic resonance efficacy.