The efficacy of manganese ions (Mn 2؉ ) as intracellular (ic) contrast agents was assessed in rat myocardium. T 1 and T 2 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 M of Mn dipyridoxyl diphosphate (MnDPDP) was followed by a 15-min wash-out to remove extracellular (ec) Mn 2؉ . An inversion recovery (IR) analysis at 20 MHz revealed two T 1 components: an ic and short T 1-1 (650 -251 ms), and an ec and longer T 1-2 (2712-1042 ms). Intensities were about 68% and 32%, respectively. Tissue Mn content correlated particularly well with ic R 1-1. A two-site water-exchange analysis of T 1 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 Mn 2؉ ions in ic water was as high as 56 (s mM) - Key words: manganese; MnDPDP; heart; T 1 relaxation; R 1 relaxivity Recent studies (1-3) have shown that divalent manganese ions (Mn 2ϩ ) are promising intracellular (ic) contrast agents, and that Mn 2ϩ -releasing contrast media may be used for cardiac MRI in ischemic heart disease (4). The key factors in the potential success of these agents are that Mn-based MRI (MnMRI) utilizes physiological pathways, and Mn 2ϩ ions are tightly bound to both extracellular (ec) and ic proteins. Thus, cardiac cell uptake of Mn 2ϩ occurs in competition with the calcium ion (Ca 2ϩ ) (5), and Mn-MRI may mirror slow Ca 2ϩ channel function (2). Competition with Ca 2ϩ for cell efflux is less effective, since it may lead to cell Mn 2ϩ retention for hours, as well as to the possibility of delayed MRI. After uptake, Mn 2ϩ ions exert paramagnetic properties inside cardiac cells, and, as we recently demonstrated (3), proton relaxation is greatly enhanced compared to Mn 2ϩ ions in vitro-most probably due to extensive binding to slowly tumbling macromolecules (6). These unique endogenous properties of Mn 2ϩ ions may be exploited in both basic research and future clinical diagnostic techniques.The development of MnMRI has been hampered by the notion that Mn 2ϩ ions are cardiotoxic (7,8), since they may inhibit Ca 2ϩ channels in the cardiac cell membrane. However, recent studies have shown that the fear of cardiotoxicity in this case is largely unfounded (9 -11). Thus, while Mn 2ϩ entry in cardiomyocytes undoubtedly occurs via Ca 2ϩ channels (2,5,9,12), an inhibition of Ca 2ϩ influx that initiates cardiac contraction will not occur before ec [Mn 2ϩ ] exceeds ϳ25 M (1,3). However, extensive plasma protein binding ensures that only a very few M of Mn 2ϩ may exist in the free form in the blood pool or the interstitial space (13,14).We recently studied ic proton relaxation in rat myocardium with MnCl 2 present in the perfusate of isolated rat hearts (3). Relaxography performed after wash-in plus wash-out experiments revealed slow water exchange in the excised nonperfused cardiac tissue. Biexponential T 1 behavior dominated, and reve...

This nasal naloxone formulation had a rapid, systemic uptake and higher bioavailability than naloxone formulations not designed for IN use. This indicates that an optimized high-concentration/low-volume nasal spray formulation may deliver a therapeutic dose. The 1.6 mg nasal dose provided serum concentrations that surpassed those of 1.0 mg IV after 15-20 min and stayed above for the rest of the study period.

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Following reperfusion by primary PCI in AMI, oxidative stress and an inflammatory response are induced immediately. A rise in 8-iso-PGF2a during ischemia indicate that ROS generation may also take place during severely reduced coronary blood flow and hypoxia. No direct relationship between 8-iso-PGF2alpha or 15-keto-dihydro-PGF2alpha 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.

Manganese (Mn) dipyridoxyl diphosphate (MnDPDP) is the active component of a contrast medium for liver MRI. By being metabolized, MnDPDP releases Mn 2 , 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, T 1 and T 2 were measured. At normal flow tissue Mn content increased from the control level of 4.1 to 70.4 mmol/100g dry wt with MnDPDP (3000 mM), while low-flow perfusion with MnDPDP (3000 mM) resulted in a Mn content of 16.6 mmol/ 100 g dry wt. Prolonged ischemia (35 and 90 min) reduced tissue Mn down to the control level. T 1 shortening closely paralleled myocardial Mn elevations during both normal and low-flow perfusion. The use of a Mn 2 -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 T 1 relative to coronary flow, cell Mn uptake and retention, ion channel function and metabolism.