On the benefit of magnetic magnesium nanocarrier in cardiovascular toxicity of aluminum phosphide

Abstract

The present study was designed to determine the effect of a new ²⁵Mg²⁺-carrying nanoparticle (²⁵MgPMC16) on energy depletion, oxidative stress, and electrocardiographic (ECG) parameters on heart tissue of the rats poisoned by aluminum phosphide (AlP). ²⁵MgPMC16 at doses of 0.025, 0.05, and 0.1 median lethal dose (LD50 = 896 mg/kg) was administered intravenously (iv) 30 min after a single intragastric administration of AlP (0.25 LD50). Sodium bicarbonate (Bicarb; 2 mEq/kg, iv) was used as the standard therapy. After anesthesia, the animals were rapidly connected to an electronic cardiovascular monitoring device for monitoring of ECG, blood pressure (BP), and heart rate (HR). Later lipid peroxidation, antioxidant power, ATP/ADP ratio, and Mg concentration in the heart were evaluated. Results indicated that after AlP administration, BP and HR decreased while R-R duration increased. ²⁵MgPMC16 significantly increased the BP and HR at all doses used. We found a considerable increase in antioxidant power, Mg level in the plasma and the heart and a reduction in lipid peroxidation and ADP/ATP ratio at various doses of ²⁵MgPMC16, but ²⁵MgPMC16-0.025 + Bicarb was the most effective combination therapy. The results of this study support that ²⁵MgPMC16 can increase heart energy by active transport of Mg inside the cardiac cells.²⁵MgPMC16 seems ameliorating AlP-induced toxicity and cardiac failure necessitating further studies.

Keywords

Magnetic isotope of Mg nanoparticle pesticide oxidative stress ATP phosphorylation aluminium phosphide mitochondrial toxicity

Introduction

Aluminum phosphide (AlP) is used in the environment and grain stocks to control insects. AlP is sold as pallet, tablet, porous blister pack, sachets, and as dusts. When in contact with water or moisture or hydrochloric acid of stomach, AlP releases phosphine gas. Unfortunately in some countries, AlP is ingested in human suicide attempts (Moghadamnia and Abdollahi, 2002), and it is almost fatal by causing multiorgan damage through denaturation of cell membranes with the main outcome of cardiovascular collapse (Proudfoot, 2009; Shadnia et al., 2005, 2009). So far, no exact antidote was found for AlP, but it is known as a mitochondrial poison interfering with several enzymes or ion channels as well as protein synthesis. AlP is famous for its toxicity through the induction of severe oxidative stress (Abdollahi et al., 2004). Currently, to manage AlP poisoning, gastric lavage with potassium permanganate solution and oral sodium bicarbonate (Bicarb) with activated charcoal are used as a protocol but newly, oral coconut oil (Pajoumand et al., 2004) and intravenous (iv) magnesium (Shadnia et al., 2005) have been proposed to be effective. The benefit of magnesium in AlP poisoning returns to its anti-arrhythmia and antioxidant effects (Shadnia et al., 2005).

Recently, porphylleren MC16 (PMC16) nanocarrier of magnetic isotope of Mg known as ²⁵MgPMC16 was found effective in diminishing organophosphate (OP)-induced cardiovascular toxicity and repairing cardiac failure (Mohammadi et al., 2011; Shafiee et al., 2010) and in diabetic neuropathy (Hosseini et al., 2010) by compensation of cellular energy and protection against oxidative stress. In the present study, we aimed to investigate the potential of ²⁵MgPMC16 in protection of rat model of AlP-poisoning through examining electrocardiographic and biochemical parameters of toxicity.

Materials and methods

Chemicals

Adenosine diphosphate (ADP) sodium salt, adenosine triphosphate (ATP) disodium salt, malonedialdehyde (MDA), methanol (high-performance liquid chromatography [HPLC] grade), acetic acid, FeCl₃·6H₂O, sodium sulfate, trichloroacetic acid (TCA), potassium hydroxide, diethyl ether, tetrabutylammonium hydroxide (TBAHS), n-butanol, 2-thiobarbituric acid (TBA), KH₂PO₄ (analytical grade), 2,4,6-tripyridyl-s-triazine (TPTZ) from Sigma-Aldrich Chemie (Gmbh, Munich, Germany), AlP from Samiran Pesticide Formulating Co. (Tehran, Iran), ²⁵MgPMC16 from the Semenov institute (Russian Academy of Sciences), SUPELCOSIL™LC-18-T HPLC column from Supelco (Antrim, UK), and ketamine/xylazin from local pharmacy were used in this study.

Animals

All the research in animals were done according to the ethical guidelines on the use of animals and was approved by Tehran University of Medical Sciences review board. A total of 54 male Wistar rats weighing 200–250 g were used in this study. The animals were acclimatized to standard conditions of temperature (25°C), relative humidity (50–55%), and 12-h light/dark cycle with free access to stock laboratory diet and water. They were randomly divided into nine groups of six animals each. AlP (0.25 median lethal dose [LD50]) was dissolved in almond oil and administered by gavage. Stock solution of ²⁵MgPMC₁₆ was dissolved in saline (pH was adjusted to 7.86) and administered iv at doses of 22.4 mg/kg (0.025 LD50), 44.8 mg/kg (0.05 LD50), and 89.6 mg/kg (0.1 LD50). Doses were selected according to the previous experiences (Mohammadi et al., 2011). Bicarb was administered iv at a dose of 2 mEq/kg. Mixture of ketamin/xylazin (60/6 mg/kg) was used intraperitoneally (ip) for induction of anesthesia. Control animals received only almond oil in appropriate volume. Animals which received almond oil alone was named as control; only AlP as AlP; AlP + NaHCO₃ as AlP + Bicarb; AlP + ²⁵MgPMC16 (0.025 LD50) as PMC16-0.025; AlP + ²⁵MgPMC16 (0.05 LD50) as PMC16-0.05; AlP + ²⁵MgPMC16 (0.1 LD50) as PMC16-0.1; AlP + ²⁵MgPMC16 (0.025 LD50) + NaHCO₃ as PMC16-0.025 + Bicarb; AlP + ²⁵MgPMC16 (0.05 LD50) + NaHCO₃ as PMC16-0.05 + Bicarb; and AlP + ²⁵MgPMC16 (0.1 LD50) + NaHCO₃ as PMC16-0.1 + Bicarb.

First of all, AlP was administered intra-gastrically to all animals except the control. After 30 min, the animals were anesthetized with ip injection of ketamin/xylazin which was repeated at 30/3 mg/kg after 40 min and 2.5 h, respectively, to maintain full general anesthesia until the end of the experiment (3.5 h). After anesthesia, the animal was rapidly connected to Power Lab device (PowerLab 4/35 Data Acquisition Systems, AD Instruments, Australia) for complete noninvasive monitoring of electrocardiogram (ECG), blood pressure (BP), and heart rate (HR). All treatments to AlP-exposed animal were given after 30 min in all groups except control and AlP-alone groups. Twenty-four hours after administration of AlP, rats were anesthetized and blood was collected by cardiac puncture and plasma was separated by centrifugation in heparinized tubes and freezed at −80°C for subsequent biochemical analyses. The heart was also dissected out and rinsed in ice-cold saline to remove the blood and immediately frozen and stored at −80°C for various assays. For analysis of oxidative stress parameters, the heart was homogenized in suitable buffer using a tissue homogenizer at 4°C. The homogenates were centrifuged at 3500g for 20 min and the supernatant was used for oxidative stress analyses.

Determination of ALP LD50

At least 10 rats per group were used at each dose level. Initially, the gavage of 15 mg/kg body weight of AlP resulted in 100% mortality, but after reducing the dose to 8 mg/kg, no mortality was observed. Based on these observations, doses ranging between 8 and 15 mg/kg were used while other variables were kept constant. Control group received equivalent amount of vehicle orally. Mortality was recorded during 24-h observation period. LD50 of AlP was measured using probit.

ECG, BP, and HR

After the electrodes were connected to the skin of the right hand and both right and left paw of the anesthetized rat, the continuous ECG data were obtained for 3 h. QRS complexes and the segments of QT, R-R, and ST were measured. ECGs were analyzed by Power Lab system software (Australia).

To record the HR and systolic BP, the tail cuff of Power Lab was connected to anesthetized rat’s external tail where the pulse was detected. Systolic BP and HR were recorded for 3 h.

Measurement of heart cells and plasma oxidative stress

Lipid peroxides as by-products of polyunsaturated fatty acids oxidation give a complex with TBA called TBA-reactive substance (TBARS) that produce a pink color with an absorbance of 532 nm. The efficiency of antioxidants was measured by their ability to reduce Fe³⁺ to Fe²⁺. The interaction of TPTZ with Fe²⁺ leads to the formation of a blue color, which has a maximum absorbance at 593 nm. Both analyses were done as described previously (Mohammadi et al., 2011).

Measurement of cardiac ADP and ATP

As described, the frozen heart tissue was removed from ice and was quickly homogenized (4°C) in 1 ml of an ice-cold 6% TCA. The homogenate was centrifuged at 12,000g for 10 min at 4°C. The supernatant was neutralized to a pH 6.5 with 4 M KOH. Then it was filtered through a millipore filter (pore size 0.45 μm), and the neutralized extract was used to determine the concentrations of ATP and ADP (µg/ml per mg of tissue) using pair HPLC ([IP-HPLC] Hosseini et al., 2010).

Measurement of cardiac and plasma Mg

A total of 200 samples including plasma and tissue homogenates were digested by 10 μl concentrated HNO₃ for 3 h. After dilution using 5 ml deionized water, absorbance was recorded by flame atomic absorption spectroscopy at 285.2 nm as described previously (Shafiee et al., 2010).

Statistical analysis

All values were expressed as mean ± standard error of the mean (SEM). Data were statistically analyzed by analysis of variance (ANOVA) followed by Tukey post hoc test for multiple comparisons. p values less than 0.05 were considered statistically significant.

Results

LD50 of AlP

A straight line was drawn between probit values (% mortality) and different AlP concentrations, by linear regression analysis, which exhibited a direct relationship. According to this method, oral LD50 of AlP in male rats was calculated as 11.59 mg/kg. Therefore, 0.25 LD50 of AlP was used as the test dose in the study.

ECG, HR, and BP

The influence of treatments on rat ECG parameters is shown in Table 1. The R-R segment duration was prolonged significantly in AlP-treated rats as compared to the control. HR significantly decreased in all the groups after administration of AlP. In almost all treatment groups HR increased as compared with the AlP group. This increase was observed after 120–180 min of therapy (Table 2). BP significantly dropped after the administration of AlP in all treated groups except the group which received treatment between 60 and 90 min. BP in all treatment groups significantly increased after 90 min from start point of therapy procedure (Table 3).

Table 1.

Changes in ECG parameters of various groups.^a

Variable		Control	AlP	AlP + Bicarb	PMC16-0.025	PMC16-0.05	PMC16-0.1	PMC16-0.025 + Bicarb	PMC16-0.05 + Bicarb	PMC16-0.1 + Bicarb
0–30	R-R	170.98 ± 0.003	392.61 ± 0.02^b	395.47 ± 0.02^b	131.4 ± 0.001^c	171.05 ± 0.007^c	153.16 ± 0.002^c	161.62 ± 0.0003^c	173.1 ± 0.004^c	188.2 ± 0.003^c
	QRS	13.5 ± 0.0002	11.83 ± 0.001	11.83 ± 0.001	20.33 ± 0.0008	16.16 ± 0.0001	13 ± 0	14 ± 0	15.66 ± 0.0003	22.5 ± 0.0009
	QT	114.45 ± 0.002	67.11 ± 0.01	106.12 ± 0.02	134.7 ± 0.0009^c	107.17 ± 0.002	118.75 ± 0.005	107.68 ± 0.0004	129.76 ± 0.01^c	98.81 ± 0.001
	ST	64.00 ± 0.003	−59.005 ± 0.18	−59.005 ± 0.18	−3.39 ± 0.001	58.13 ± 0.004	92.36 ± 0.008	140.64 ± 0.003	75.03 ± 0.004	−8.3 ± 0.003
30–60	R-R	164.16 ± 0.002	354.4 ± 0.03^b	351.04 ± 0.03^b	130.45 ± 0.001^c	165.36 ± 0.001^c	155.06 ± 0.001^c	170.025 ± 0.01^c	170.76 ± 0.002^c	182.6 ± 0.003^c
	QRS	13 ± 0	12.71 ± 0.001	12.71 ± 0.001	21.16 ± 0.001^b,c	15.8 ± 0.0002	13.33 ± 0.0002	14.25 ± 0.0002	17.5 ± 0.0002^c	19.4 ± 0.0005^b,c
	QT	116.96 ± 0.001	94.90 ± 0.001^b	164.06 ± 0.01^b,c	132.16 ± 0.001	106.11 ± 0.001	122.6 ± 0.004^c	114.4 ± 0.003^c	112.4 ± 0.0008	105.3 ± 0.001
	ST	65.2 ± 0.003	241.98 ± 0.16	241.98 ± 0.16	−3.65 ± 0.003	50.78 ± 0.004	90.07 ± 0.001	136.5 ± 0.001	43.34 ± 0.003	3.86 ± 0.007
60–90	R-R	150 ± 0.001	299.72 ± 0.06	259.3 ± 0.06	157.71 ± 0.009	156.85 ± 0.001	160.98 ± 0.0009	156.27 ± 0.01	172.98 ± 0.0009	174.1 ± 0.001
	QRS	13 ± 0	20.28 ± 0.001^b	17.28 ± 0.001	25.5 ± 0.0003^b,c	15.2 ± 0.0002	13 ± 0^c	15 ± 0.0004	17.4 ± 0.0002	18.75 ± 0.0004
	QT	124.1 ± 0.0003	94.84 ± 0.001^b	205.62 ± 0.005^b,c	108.57 ± 0.005^b	110.25 ± 0.001^c	103.84 ± 0.001^b	124.3 ± 0.004^c	114.78 ± 0.0001^c	111.95 ± 0.001^c
	ST	70.15 ± 0.0003	−431.03 ± 0.31	−315.5 ± 0.34	−18.275 ± 0.001	61.89 ± 0.002	74.92 ± 0.004	127.32 ± 0.002	48.21 ± 0.001	17.55 ± 0.004
90–120	R-R	143.525 ± 0.001	218.7875 ± 0.002^b	185.25 ± 0.001^b,c	176.1 ± 0.002^b,c	162.66 ± 0.0007^b,c	162.42 ± 0.0002	145.775 ± 0.002^b,c	172.76 ± 0.001^b,c	167.35 ± 0.0002^b,c
	QRS	13 ± 0	19.57 ± 0.0002^b	14.85 ± 0.0001^b,c	23.66 ± 0.0006^b,c	15 ± 0^b,c	13 ± 0^c	14.75 ± 0.0002^b,c	16.6 ± 0.0002^b,c	22.75 ± 0.0002^b,c
	QT	119.8 ± 0.001	101.988 ± 0.001^b	194.16 ± 0.002^b,c	101.59 ± 0.001^b	104.08 ± 0.0002^b	100.1575 ± 0.0002^b	126.75 ± 0.001^c	117.66 ± 0.001^c	111 ± 0.0004^b,c
	ST	72.44 ± 0.002	−9.623 ± 0.003^b	217.15 ± 0.004^b	−12.91 ± 0.002^b	44.75 ± 0.001^b,c	71.69 ± 0.002^c	152.76 ± 0.009^b,c	50.838 ± 0.003^b,c	−17.71 ± 0.0007^b
120–180	R-R	154.75 ± 0.01	185.7 ± 0.006	189.27 ± 0.002	154.41 ± 0.004	160.38 ± 0.0006	160.82 ± 0.0002	189.425 ± 0.03	193.18 ± 0.005	170.15 ± 0.0009
	QRS	14.5 ± 0.001	19.57 ± 0.0002^b	15 ± 0^c	23.85 ± 0.001^b,c	15.00 ± 0^c	13.00 ± 0^c	15.25 ± 0.0004^c	17.33 ± 0.0002	22.25 ± 0.0004^b
	QT	129.95 ± 0.002	114.58 ± 0.004	173.91 ± 0.01^b,c	110.32 ± 0.001	105.52 ± 0.0007	99.935 ± 0.0002	112.6775 ± 0.007	111.6 ± 0.001	112.85 ± 0.0001
	ST	39.62 ± 0.02	−9.81 ± 0.002^b	176.98 ± 0.001^b	−8.01 ± 0.002^b	55.4425 ± 0.002^c	90.00 ± 0.002^b,c	148.1 ± 0.015^b,c	50.024 ± 0.003^c	−11.36 ± 0.003^b

^aData are mean ± SEM of six animals in each group. Control group received almond oil alone; AlP group (0.25 LD50) received only aluminium phosphide; AlP + Bicarb group received AlP (0.25 LD50) + NaHCO₃ (2 mEq/kg); PMC16-0.025, 0.05, and 0.1 groups received AlP (0.25 LD50) + ²⁵MgPMC16 (0.025, 0.05, and 0.1 LD50); PMC16-0.025, 0.05, and 0.1 + Bicarb groups received AlP (0.25 LD50) + ²⁵MgPMC16 (0.025, 0.05, and 0.1 LD50) + NaHCO₃ (2 mEq/kg).

^bSignificantly different from control group at p < 0.01.

^cSignificantly different from AlP group at p < 0.01.

Table 2.

Changes in heart rate in various groups.^a

	Time (min)
	0–30	30–60	60–90	90–120	120–180
Control	351.75 ± 7.66	365.96 ± 6.49	400.14 ± 2.67	418.1 ± 3.55	401.47 ± 38.92
AlP	155.88 ± 9.65	171.13 ± 15.86^b	220.32 ± 34.45^b	269.33 ± 1.51^b	281.6 ± 5.14^b
AlP + Bicarb	155.88 ± 9.65^b	179.25 ± 15.67^c	255.43 ± 35.99^b,c	318.31 ± 4.79^b,c	323.21 ± 0.59^b,c
PMC16-0.025	457.01 ± 5.08	460.43 ± 5.98	388.28 ± 25.19^c	341.13 ± 5.35	390.27 ± 10.77^b,c
PMC16-0.05	354.15 ± 15.60	363.05 ± 3.75^c	382.56 ± 2.49^b,c	368.85 ± 1.35^b,c	375.45 ± 1.05^b,c
PMC16-0.1	392.1 ± 5.56^b,c	387.06 ± 2.89	372.13 ± 1.95^b,c	370.33 ± 0.77^b,c	373.8 ± 0.47^b,c
PMC16-0.025 + Bicarb	371.3 ± 0.74	350.4 ± 19.52^b	414.07 ± 5.66^b	403.525 ± 7.16^b,c	320.16 ± 53.70^b,c
PMC16-0.05 + Bicarb	347.63 ± 8.39	351.8 ± 5.67^c	346.86 ± 1.81^c	342.95 ± 5.48^b,c	309.2 ± 9.64^b,c
PMC16-0.1 + Bicarb	319.28 ± 5.47	329.04 ± 6.02	344.76 ± 3.30^c	358.22 ± 0.51	351.1 ± 1.76^b,c

^bSignificantly different from control group at p < 0.01.

^cSignificantly different from AlP group at p < 0.01.

Table 3.

Changes in blood pressure in various groups.^a

	Time (min)
	0–30	30–60	60–90	90–120	120–180
Control	52.69 ± 6.97	86.89 ± 2.89	94.81 ± 2.50	103.10 ± 0.77	111.58 ± 3.54
AlP	62.08 ± 3.70	45.97 ± 1.79^b	34.51 ± 1.41	29.04 ± 0.45^b	26.33 ± 0.47^b
AlP + Bicarb	86.69 ± 2.47^b	97.25 ± 6.92^c	134.32 ± 1.72^b,c	155.40 ± 4.51^b,c	172.83 ± 1.97^b,c
PMC16-0.025	53.51 ± 7.01	73.68 ± 8.31	114.59 ± 11.17^c	116.29 ± 5.56^c	132.57 ± 1.73^b,c
PMC16-0.05	43.78 ± 2.02	83.38 ± 8.65^c	126.61 ± 3.98^b,c	140.73 ± 1.71^b,c	141.29 ± 0.64^b,c
PMC16-0.1	101.70 ± 9.94^b,c	64.46 ± 9.71	122.89 ± 2.17^b,c	133.52 ± 3.07^b,c	126.26 ± 2.34^b,c
PMC16-0.025 + Bicarb	52.66 ± 2.39	46.82 ± 1.13^b	41.16 ± 0.91^b	49.90 ± 2.68^b,c	52.76 ± 0.78^b,c
PMC16-0.05 + Bicarb	58.35 ± 6.84	91.26 ± 1.61^c	78.29 ± 1.59^c	82.24 ± 1.22^b,c	53.66 ± 5.80^b,c
PMC16-0.1 + Bicarb	52.21 ± 4.06	55.86 ± 6.80^b	80.28 ± 7.71^c	80.08 ± 0.85^c	87.35 ± 1.26^b,c

^bSignificantly different from control group at p < 0.01.

^cSignificantly different from AlP group at p < 0.01.

Oxidative stress markers

In both plasma and heart tissue, a significant decrease in the TBARS was found in the control, PMC16-0.025, and PMC16-0.025 + Bicarb as compared to AlP. There was decrease in TBARS levels in PMC16-0.025 and PMC16-0.025 + Bicarb groups in comparison to AlP + Bicarb group (Figures 1 and 2).

In plasma the antioxidant power was higher in PMC16 (at three doses), almond oil, and PMC16 + NaHCO₃ groups in comparison to AlP group in plasma (Figure 3). In the heart tissue, the antioxidant power was higher in PMC16-0.025, almond oil, and PMC16-0.025 + Bicarb groups as compared with the AlP group (Figure 4).

Cardiac energy as ADP/ATP

As observed in Figure 5, a significant increase in ADP/ATP ratio in AlP-treated animals is evident in comparison with the control group. The administration of PMC16 (at three doses) and PMC16 + NaHCO₃ groups reduced the ADP/ATP ratio in comparison to the AlP group.

Heart and plasma Mg level

As observed in Figure 6, a significant decrease in Mg level in the groups that received ALP was evident in comparison to the control group. The administration of PMC16 (at three doses) and PMC16 + NaHCO₃ increased the Mg level of plasma in comparison with the AlP group. The administration of PMC16 (0.025, 0.05, and 0.1 LD50) and PMC16-0.025 + NaHCO₃ increased plasma Mg level in the tissue in comparison to AlP group (Figure 7).

Discussion

The present study indicates a marked benefit of ²⁵MgPMC16 in AlP-induced toxicity through reduction of oxidative stress and increasing BP and HR. It also increased the cardiac ATP by active transport of Mg inside the cardiac cells. Interestingly, NaHCO₃ as standard therapy was not able to completely recover AlP toxicity in terms of QRS, HR, and BP changes but co-therapy of ²⁵MgPMC16 (0.025 LD₅₀) + NaHCO₃ was very successful.

Previous studies have shown that positive effects of ²⁵MgPMC16 result from three main mechanisms including rapid well distribution into myocardium, strong antioxidative potential, and ability to increase intracellular energy and ATP levels. These three effects were observed in our previous studies conducted in rat organophosphate model of cardiovascular toxicity (Mohammadi et al., 2011; Shafiee et al., 2010) and rat diabetic neuropathy (Hosseini et al., 2010). The present results are in favor of well-distributed Mg into the heart cells where it mediates the above-mentioned mechanisms of action. So far, no practical antidote for AlP toxicity has been proposed into clinical practice and thus the present findings are so important to us. AlP is thought to act through strong cytotoxicity mediated by generation of free radicals. It is also believed that AlP inhibits mitochondrial cytochrome c oxidase, which leads to further production of superoxide radicals and cellular peroxides. In this respect, AlP was found to act directly on cardiac myocytes (Mathai and Bhanu, 2010).

Also, AlP disturbs electron transport, which causes problem in cell energy demands and reduction of ATP levels. In this way, it increases cytosolic free calcium levels (Dua and Gill, 2004). According to the present findings, cardiac benefit of ²⁵MgPMC16 was well correlated with its biochemical markers. AlP in poisoning causes hypoxia, acidosis, depletion of mitochondrial energy, and induction of proteolytic enzymes which at last results in cell death that was observed in the present study. Thus, increased cardiac Mg levels confirm that ²⁵MgPMC16 has been accumulated in the heart mitochondria to release ²⁵Mg easily and to increase ATP synthesis (Rezayat et al., 2009). Recent studies have shown the positive role of Mg as a cardioprotective agent in patients with heart failure (Pajoumand et al., 2004; Shechter, 2010). Results of Mohammadi et al. (2011) have shown that small changes in free ionic Mg in the cardiac and vascular muscle membranes can have considerable effects on mechanical and electrical activities of these cells. And also other reports have shown that Mg is essential for the regulation of cardiovascular homeostasis especially in the treatment of hypertension and vasospasm disorders. We can conclude that magnetic Mg carried inside the cells with ²⁵MgPMC16 is useful in the treatment of cardiac failure. During hypoxia caused by AlP, cellular Mg is reduced and mitochondrial uptake of calcium increased leading to the inhibition of ATP synthesis. Thus, ²⁵MgPMC16 reduces the sensitivity of myocardium to oxygen and improves contractile response of stunned myocardium. In this study, PMC16 was effective on HR, and also showed positive effects on BP. This proves its effect on contractility power of heart. Also ²⁵MgPMC16 improved AlP-induced arrhythmia while therapy by bicarbonate could not overcome arrhythmia. Acidosis suppresses glycolytic activity, damages the excitation–contraction coupling, and causes negative effects. Acidosis and hypoxia lead to the reduction of intracellular pH and energy state which depresses contractility and exerts arrhythmia as observed in AlP group. In support of this belief, it has been reported that severe hyperglycemia during human AlP acute poisoning (Shadnia et al., 2008, 2011) was similar to that of organophosphates (Rahimi and Abdollahi, 2007). Therefore, ²⁵MgPMC16 has a quick clinical effect in a short time after a single injection. Of course, the benefit of ²⁵MgPMC16 in the heart tissue hypoxia and ATPase channels function cannot be declined (Mohammadi et al., 2011). One of the molecular mechanisms of tissue damage is production of oxidative stress that is seen with AlP toxicity (Abdollahi et al., 2004). Hypoxic cell injury can result from ATP deficiency or formation of free oxygen radicals. Therefore, antioxidant potential of ²⁵MgPMC16 helps cardiac cells to survive. Most interestingly, our study was the first to report the same benefit of normal Mg in human poisoning with organophosphates that act through the inhibition of cholinesterase and induction of oxidative stress (Pajoumand et al., 2004).

Practically, dose of 0.025 LD50 of ²⁵MgPMC16 was more effective than other doses for its antioxidative potential in this study that is in agreement with the findings of Mohammadi et al. (2011). So it is very important to specially note the ²⁵Mg²⁺-induced paramagnetic effect in myocardium once this isotope is targeted toward hypoxia suffering heart muscles that occurs due to AlP poisoning.

In conclusion, the results of this study are very novel and interesting and give a big hope to manage AlP fatal poisoning. Further steps should focus on human AlP poisoning trials.

Footnotes

Authors’ note

M Baeeri, M Shariatpanahi, and H Mohammadi designed the study, carried out biochemical analyses, and drafted the manuscript. A Baghaei and SF Ghasemi-Niri carried out animal studies and provided ECG data, BP, and HR. S Hassani analyzed ADP/ATP by HPLC. Z Bayrami analyzed Mg in the samples by atomic absorption spectroscopy. A Hosseini and SM Rezayat provided ²⁵MgPMC16 and helped in designing the study. A Mohammadirad conducted statistical analysis and helped draft the manuscript. M Abdollahi conceived and supervised the entire study and edited the manuscript.

Conflict of interest

The authors declare no conflicts of interest.

Funding

Financial support for this work was in part provided by Tehran University of Medical Sciences with reference number 89-02-33-10737.

References

Abdollahi

Ranjbar

Shadnia

. (2004) Pesticides and oxidative stress: a review. Medical Science Monitor 10(6): RA141–RA147.

Dua

Gill

(2004) Effect of aluminium phosphide exposure on kinetic properties of cytochrome oxidase and mitochondrial energy metabolism in rat brain. Biochimica Et Biophysica Acta 1674(1): 4–11.

Hosseini

Sharifzadeh

Rezayat

. (2010) Benefit of magnesium-25 carrying porphyrinfullerene nanoparticles in experimental diabetic neuropathy. International Journal of Nanomedicine 5: 517–523.

Mathai

Bhanu

(2010) Acute aluminium phosphide poisoning: can we predict mortality? Indian Journal of Anaesthesia 54(4): 302–307.

Moghadamnia

Abdollahi

(2002) An epidemiological study of poisoning in northern Islamic Republic of Iran. Eastern Mediterranean Health Journal 8(1): 88–94.

Mohammadi

Karimi

Rezayat

. (2011) Benefit of nanocarrier of magnetic magnesium in rat malathion-induced toxicity and cardiac failure using non-invasive monitoring of electrocardiogram and blood pressure. Toxicology and Industrial Health 27(5): 417–429.

Pajoumand

Shadnia

Rezaie

. (2004) Benefits of magnesium sulfate in the management of acute human poisoning by organophosphorus insecticides. Human & Experimental Toxicology 23(12): 565–569.

Proudfoot

(2009) Aluminium and zinc phosphide poisoning. Clinical Toxicology 47(2): 89–100.

Rahimi

Abdollahi

(2007) A review on the mechanisms involved in hyperglycemia induced by organophosphorus pesticides. Pesticide Biochemistry and Physiology 88(2): 115–121.

10.

Rezayat

Boushehri

Salmanian

. (2009) The porphyrin-fullerene nanoparticles to promote the ATP overproduction in myocardium: ²⁵Mg²⁺-magnetic isotope effect. European Journal of Medicinal Chemistry 44(4): 1554–1569.

11.

Shadnia

Mehrpour

Abdollahi

(2008) Unintentional poisoning by phosphine released from aluminum phosphide. Human & Experimental Toxicology 27(1): 87–89.

12.

Shadnia

Rahimi

Pajoumand

. (2005) Successful treatment of acute aluminium phosphide poisoning: possible benefit of coconut oil. Human & Experimental Toxicology 24(4): 215–218.

13.

Shadnia

Sasanian

Allami

. (2009) A retrospective 7-years study of aluminum phosphide poisoning in Tehran: opportunities for prevention. Human & Experimental Toxicology 28(4): 209–213.

14.

Shadnia

Soltaninejad

Hassanian-Moghadam

. (2011) Methemoglobinemia in aluminum phosphide poisoning. Human & Experimental Toxicology 30(3): 250–253.

15.

Shafiee

Mohammadi

Rezayat

. (2010) Prevention of malathion-induced depletion of cardiac cells mitochondrial energy and free radical damage by a magnetic magnesium-carrying nanoparticle. Toxicology Mechanisms and Methods 20(9): 538–543.

16.

Shechter

(2010) Magnesium and cardiovascular system. Magnesium Research 23(2): 60–72.