Dose Of MnCl2 Research Articles

Manganese stimulates luteinizing hormone releasing hormone secretion in prepubertal female rats: hypothalamic site and mechanism of action

We have shown recently that Mn2+ stimulates gonadotropin secretion via an action at the hypothalamic level, and a diet supplemented with a low dose of the element is capable of advancing the time of female puberty. In this study, we used an in vitro approach to investigate the mechanism by which Mn2+ induces luteinizing hormone-releasing hormone (LHRH) secretion from prepubertal female rats. The medial basal hypothalamus from 30-day-old rats was incubated in Locke solution for 30 min to assess basal LHRH secretion, then incubated with buffer alone or buffer plus either a nitric oxide synthase (NOS) inhibitor (N-monomethyl-L-arginine (NMMA); 300 or 500 microM) or a soluble guanylyl cyclase (sGC) inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ); 100 or 250 microM) for another 30 min. Finally, the incubation continued for a further 30 min, but in the presence of MnCl2 (50 or 250 microM) to assess the effect of the blockers on stimulated LHRH secretion. Both 50 and 250 microM MnCl2 stimulated LHRH release (P < 0.05 and P < 0.01, respectively). The addition of 300-500 microM NMMA to the medium did not block Mn2+-stimulated release of LHRH, even with the higher dose of MnCl2. Furthermore, while 50, 100 and 250 microM MnCl2 all significantly induced LHRH release, the two lowest doses did not stimulate total nitrite released from the same tissue, an effect only observed with the highest dose. Taken together, these data suggest that Mn2+ is not an effective stimulator of NO. Conversely, inhibiting sGC with ODQ blocked the Mn2+-stimulated secretion of LHRH in a dose-dependent manner, indicating that GC is the site of action of Mn2+. Additionally, we showed that Mn2+ stimulated cGMP and LHRH from the same tissues, and that downstream blocking of protein kinase G formation with KT5823 (10 microM) inhibited Mn2+-induced LHRH release. These data demonstrate that the principal action of Mn2+ within the hypothalamus is to activate sGC directly and/or as a cofactor with available NO, hence generating cGMP and resulting in prepubertal LHRH release.

IR-SE and IR-MEMRI allowin vivo visualization of oscine neuroarchitecture including the main forebrain regions of the song control system

Songbirds share with humans the capacity to produce learned vocalizations (song). Recently, two major regions within the songbird's neural substrate for song learning and production; nucleus robustus arcopallii (RA) and area X (X) are visualized in vivo using Manganese Enhanced MRI (MEMRI). The aim of this study is to extend this to all main interconnected forebrain Song Control Nuclei. The ipsilateral feedback circuits allow Mn2+ to reach all main Song Control Nuclei after stereotaxic injection of very small doses of MnCl2 (10 nl of 10 mM) into HVC of one and MAN (nucleus magnocellularis nidopallii anterioris) of the other hemisphere. Application of a high resolution (80 micron) Spin Echo Inversion Recovery sequence instead of conventional T1-weighted Spin Echo images improves the image contrast dramatically such that some Song Control Nuclei, ventricles, several laminae, fibre tracts and other specific brain regions can be discerned. The combination of this contrast-rich IR-SE sequence with the transsynaptic transport property of Manganese (Inversion Recovery based MEMRI (IR-MEMRI)) enables the visualization of all main interconnected components of the Song Control System in telencephalon and thalamus.

Manganese enhanced magnetic resonance imaging of normal and ischemic canine heart

The ability of MnCl2 to enhance canine myocardium and to delineate ischemic areas is demonstrated. A dose-response curve was measured using T1 weighted images in 11 dogs. MnCl2 (36, 113, 360, and 3600 micromol) was infused over a period of 3 min. Signal intensity increased linearly with MnCl2 dose. At 113 micromol ( approximately 10 micromol/kg) the steady-state increase in intensity averaged 212 +/- 34%. No significant physiologic effects due to the infused MnCl2 were detected except at the highest dose where there was a cardiac depressive effect. Ischemia was induced by occluding the left anterior descending coronary artery in 5 dogs. At an infused dose of 113 micromol, MnCl2 clearly demarcated the ischemic zone during coronary occlusion. Contrast enhancement in the ischemic zone was less than 30% compared with normal tissue (P < 0.03). In conclusion, the intracellular contrast agent MnCl2 enhances the canine heart and shows promise in detecting ischemia at doses that do not cause adverse cardiac effects.

Comparative Toxicokinetics of Manganese Chloride and Methylcyclopentadienyl Manganese Tricarbonyl (MMT) in Sprague-Dawley Rats

The toxicokinetics of manganese (Mn) was investigated in male and female rats either following a single intravenous (iv) or oral dose of MnCl2 (6.0 mg Mn/kg), or following a single oral dose of methylcyclopentadienyl manganese tricarbonyl (MMT) (20 mg MMT/kg or 5.6 mg Mn/kg). The plasma concentrations of manganese were quantified by atomic absorption spectrophotometry (AAS). Upon iv administration of MnCl2, manganese rapidly disappeared from blood with a terminal elimination t1/2 of 1.83 h and CL8 of 0.43 L/h/kg. The plasma concentration-time profiles of manganese could be described by C = 41.9e(-424t) + 2.1e(-0.44t). Following oral administration of MnCl2, manganese rapidly entered the systemic circulation (Tmax = 0.25 h). The absolute oral bioavailability was about 13%. Oral dose of MMT resulted in a delayed Tmax(7.6 h), elevated Cmax (0.93 microg/ml), and prolonged terminal t1/2 (55.1 h). The rats receiving MMT had an apparent clearance (CL/F = 0.09 L/h x kg) about 37-fold less than did those who were dosed with MnCl2. Accordingly, the area under the plasma concentration-time curves (AUC) of manganese in MMT-treated rats was about 37-fold greater than that in MnCl2-treated rats. A gender-dependent difference in toxicokinetic profiles of plasma manganese was also observed. Female rats displayed a greater AUC than that of male rats. Although the apparent volume of distribution of manganese was similar in both sexes, the apparent clearance in males was about twice that observed in females. The results indicated that after oral administration, the MMT-derived manganese displayed higher and more prolonged plasma concentration-time profiles than MnCl2-derived manganese. Thus, MMT-derived manganese appeared likely to accumulate in the body following repeated exposure.

Toxicity of subacute intravenous manganese chloride administration in beagle dogs.

Manganese (Mn), a naturally occurring essential trace element, is currently being used as a metal complex for pharmaceutical and magnetic resonance imaging agents. Despite its popularity in these practices, minimal attention has focused on possible toxicity of released free Mn ions, which could occur if these agents decomplexed. There is especially limited information available regarding acute toxicity of Mn in dogs. In this study, we performed an in-depth evaluation of acute toxicologic potential of manganese chloride (MnCl2) when administered as a 4-hr/day intravenous infusion to male beagle dogs. The dose of MnCl2 used (16 mg/kg/day) was equivalent to approximately 3-5 times the daily dose of Mn typically administered in some of the Mn-complexed agents. All routine toxicologic endpoints were evaluated, including cardiovascular parameters. This dosing regimen resulted in the death or moribund sacrifice of all the animals within 4 days of initiation of treatment. Clinical evidence of toxicity included loss of appetite, reduction in blood pressure with reflex tachycardia, and a marked increase in liver enzymes, beginning with the first dose and increasing in severity with successive doses. Gross and histopathologic evaluations confirmed severe hepatotoxicity, which was characterized by massive hepatocellular necrosis, periportal hemorrhages, and mild biliary epithelial hyperplasia. These results indicate that acute treatment of beagle dogs with MnCl2 causes severe hepatotoxicity and hypotension with reflex tachycardia and suggest that dogs are very sensitive to toxic effects of Mn.

Cardiovascular toxicity and tissue proton T1 response to manganese injection in the dog and rabbit

Paramagnetic substances that shorten proton T1 relaxation time have promise as nuclear magnetic resonance (NMR) contrast agents. The cardiovascular toxicity and tissue T1 response to 0.01-0.1 mM/kg intravenous doses of MnCl2 in rabbits and dogs were studied. There were dose-dependent changes in cardiac electrophysiology and arterial blood pressure consistent with the calcium-blocking properties of manganous ion. There were also dose-dependent and organ-specific changes in tissue proton T1. The sensitivity of organ T1 was expressed as the dose of manganese required to shorten the normal T1 by 50%. Liver, kidney, and heart were most sensitive, while skeletal muscle and adipose tissue were insensitive. MnCl2 is an effective NMR contrast agent, but its toxicity may be excessive for clinical use.

Dose-related effects of manganese on the canine electrocardiogram

We studied the dose-related effects of manganese, a slow channel blocker, on the ECG in seven anesthetized dogs. Incremental bolus doses of MnCl2, providing 0.1, 0.5, 1.0, 5.0, and 10.0 mg/kg Mn, were injected intravenously at sequential 10 minute intervals. Heart rate decreased from 175 +/- 5 beats/min (mean +/- SEM) to 137 +/- 6 after 5.0 mg/kg Mn (p less than .001). No significant decrease in rat occurred with lower doses. Mn at 10.0 mg/kg was lethal in six dogs following brief profound hypotension and bradycardia. The PR interval increased slightly after 0.5 mg/kg Mn, from 99 +/- 3 msec to 103 +/- 3 (p less than .01), to 106 +/- 4 msec (p less than .01) after 1.0 mg/kg, and to 117 +/- 4 msec (p less than .005) after 5.0 mg/kg. QRS width increased from 57 +/- 2 msec to 65 +/- 1 (p less than .005) after 1.0 mg/kg Mn and was not further prolonged after 5.0 mg/kg. The observed QT interval increased from 186 +/- 2 msec to 201 +/- 1 (p less than .025) after 1.0 mg/kg Mn and to 222 +/- 2 (p less than .01) after 5.0 mg/kg. The rate-corrected QT interval was also increased at these doses. These data suggest that important in vivo effects of manganese on atrioventricular and intraventricular conduction occur at doses which do not affect the heart rate.