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Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, l-NAME and l-arginine worsen

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Abstract

Aim

Stable gastric pentadecapeptide BPC 157, administered before a high-dose magnesium injection in rats, might be a useful peptide therapy against magnesium toxicity and the magnesium-induced effect on cell depolarization. Moreover, this might be an NO-system-related effect. Previously, BPC 157 counteracts paralysis, arrhythmias and hyperkalaemia, extreme muscle weakness; parasympathetic and neuromuscular blockade; injured muscle healing and interacts with the NOS-blocker and NOS-substrate effects.

Main methods

Assessment included magnesium sulfate (560 mg/kg intraperitoneally)-induced muscle weakness, muscle and brain lesions, hypermagnesemia, hyperkalaemia, increased serum enzyme values assessed in rats during and at the end of a 30-min period and medication (given intraperitoneally/kg at 15 min before magnesium) [BPC 157 (10 µg, 10 ng), l-NAME (5 mg), l-arginine (100 mg), alone and/or together]. In HEK293 cells, the increasing magnesium concentration from 1 to 5 mM could depolarize the cells at 1.75 ± 0.44 mV.

Key findings

l-NAME + magnesium-rats and l-arginine + magnesium-rats exhibited worsened severe muscle weakness and lesions, brain lesions, hypermagnesemia and serum enzymes values, with emerging hyperkalaemia. However, l-NAME + l-arginine + magnesium-rats exhibited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggravated by l-NAME or l-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 µM) in vitro.

Significance

BPC 157 likely counteracts the initial event leading to hypermagnesemia and the life-threatening actions after a magnesium overdose. In contrast, a worsened clinical course, higher hypermagnesemia, and emerging hyperkalaemia might cause both l-NAME and l-arginine to affect the same events adversely. These events were also opposed by BPC 157.

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References

  • Balenovic D, Bencic ML, Udovicic M et al (2009) Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: a relation with NO-system. Regul Pept 156(1–3):83–89

    Article  CAS  PubMed  Google Scholar 

  • Barisic I, Balenovic D, Klicek R et al (2013) Mortal hyperkalemia disturbances in rats are NO-system related. The life saving effect of pentadecapeptide BPC 157. Regul Pept 181:50–66

    Article  CAS  PubMed  Google Scholar 

  • Boban Blagaic A, Blagaic V, Mirt M et al (2005) Gastric pentadecapeptide BPC 157 effective against serotonin syndrome in rats. Eur J Pharmacol 512(2–3):173–179

    Article  CAS  PubMed  Google Scholar 

  • Bowman WC (1983) Peripherally acting muscle relaxants. In: Parnham MJ, Bruinvels J (eds) Discoveries in pharmacology, volume I: psycho- and neuro-pharmacology. Elsevier Science Publishers BV, Amsterdam, pp 106–159

    Google Scholar 

  • Cengiz M, Ülker P, Üyüklü M et al (2016) Effect of magnesium supplementation on blood rheology in NOS inhibition-induced hypertension model. Clin Hemorheol Microcirc 63(1):57–67

    Article  PubMed  Google Scholar 

  • Cesarec V, Becejac T, Misic M et al (2013) Pentadecapeptide BPC 157 and the esophagocutaneous fistula healing therapy. Eur J Pharmacol 701(1–3):203–212

    Article  CAS  PubMed  Google Scholar 

  • Chang CH, Tsai WC, Lin MS, Hsu YH, Pang JH (2011) The promoting effect of pentadecapeptide BPC 157 on tendon healing involves tendon outgrowth, cell survival, and cell migration. J Appl Physiol (1985) 110(3):774–780

    Article  CAS  Google Scholar 

  • Chang CH, Tsai WC, Hsu YH, Pang JH (2014) Pentadecapeptide BPC 157 enhances the growth hormone receptor expression in tendon fibroblasts. Molecules 19(11):19066–19077

    Article  PubMed  Google Scholar 

  • Collier HOJ, Dinnen LC, Johnson CA, Schneide C (1968) The abdominal constriction response and its suppression by analgesic drugs in the mouse. Br J Pharmacol Chemother 32:295–310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Euser AG, Cipolla MJ (2009) Magnesium sulfate treatment for the prevention of eclampsia: a brief review. Stroke 40(4):1169–1175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gerard SK, Hernandez C, Khayam-Bashi H (1988) Extreme hypermagnesemia caused by an overdose of magnesium-containing cathartics. Ann Emerg Med 17(7):728–731

    Article  CAS  PubMed  Google Scholar 

  • Guay J, Grenier Y, Varin F (1998) Clinical pharmacokinetics of neuromuscular relaxants in pregnancy. Clin Pharmacokinet 34(6):483

    Article  CAS  PubMed  Google Scholar 

  • Gyires K, Torma Z (1984) The use of the writhing in mice for screening different types of analgesics. Arch Int Pharmacodyn Ther 267:131–140

    CAS  PubMed  Google Scholar 

  • Huang T, Zhang K, Sun L et al (2015) Body protective compound-157 enhances alkali-burn wound healing in vivo and promotes proliferation, migration, and angiogenesis in vitro. Drug Des Dev Ther 9:2485–2499

    Article  Google Scholar 

  • Ilic S, Brcic I, Mester M et al (2009) Over-dose insulin and stable gastric pentadecapeptide BPC 157. Attenuated gastric ulcers, seizures, brain lesions, hepatomegaly, fatty liver, breakdown of liver glycogen, profound hypoglycemia and calcification in rats. J Physiol Pharmacol 60(Suppl 7):107–114

    PubMed  Google Scholar 

  • Ilic S, Drmic D, Zarkovic K et al (2010) High hepatotoxic dose of paracetamol produces generalized convulsions and brain damage in rats. A counteraction with the stable gastric pentadecapeptide BPC 157 (PL 14736). J Physiol Pharmacol 61(2):241–250

    CAS  PubMed  Google Scholar 

  • Ilic S, Drmic D, Franjic S et al (2011a) Pentadecapeptide BPC 157 and its effects on a NSAID toxicity model: diclofenac-induced gastrointestinal, liver, and encephalopathy lesions. Life Sci 88(11-12):535–542 A

    Article  CAS  PubMed  Google Scholar 

  • Ilic S, Drmic D, Zarkovic K et al (2011b) Ibuprofen hepatic encephalopathy, hepatomegaly, gastric lesion and gastric pentadecapeptide BPC 157 in rats. Eur J Pharmacol 667(1-3):322–329 B

    Article  CAS  PubMed  Google Scholar 

  • Klicek R, Kolenc D, Suran J et al (2013) Stable gastric pentadecapeptide BPC 157 heals cysteamine-colitis and colon-colon-anastomosis and counteracts cuprizone brain injuries and motor disability. J Physiol Pharmacol 64(5):597–612

    CAS  PubMed  Google Scholar 

  • Kokot A, Zlatar M, Stupnisek M et al (2016) NO system dependence of atropine-induced mydriasis and l-NAME- and l-arginine-induced miosis: reversal by the pentadecapeptide BPC 157 in rats and guinea pigs. Eur J Pharmacol 771:211–219

    Article  CAS  PubMed  Google Scholar 

  • Krendel DA (1990) Hypermagnesemia and neuromuscular transmission. Semin Neurol 10:42–45

    Article  CAS  PubMed  Google Scholar 

  • Lojo N, Rasic Z, Zenko Sever A et al (2016) Effects of diclofenac, l-NAME, l-Arginine, and pentadecapeptide BPC 157 on gastrointestinal, liver, and brain lesions, failed anastomosis, and intestinal adaptation deterioration in 24 hour-short-bowel rats. PLoS One 11(9):e0162590

    Article  PubMed  PubMed Central  Google Scholar 

  • Manzo-Avalos S, Pérez-Vázquez V, Ramírez J et al (2002) Regulation of the rate of synthesis of nitric oxide by Mg(2 +) and hypoxia. Studies in rat heart mitochondria. Amino Acids 22(4):381–389

    Article  CAS  PubMed  Google Scholar 

  • Meinen S, Lin S, Rüegg MA, Punga AR (2012) Fatigue and muscle atrophy in a mouse model of myasthenia gravis is paralleled by loss of sarcolemmal nNOS. PLoS One 7:441–448

    Article  Google Scholar 

  • Moncada S, Palmer RM, Higgs EA (1991) Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 43:109–142

    CAS  PubMed  Google Scholar 

  • Nordt SP, Williams SR, Turchen S, Manoguerra A, Smith D, Clark RF (1996) Hypermagnesemia following an acute ingestion of Epsom salt in a patient with normal renal function. J Toxicol Clin Toxicol 34(6):735–739

    Article  CAS  PubMed  Google Scholar 

  • Novinscak T, Brcic L, Staresinic M et al (2008) Gastric pentadecapeptide BPC 157 as an effective therapy for muscle crush injury in the rat. Surg Today 38(8):716–725

    Article  CAS  PubMed  Google Scholar 

  • Pevec D, Novinscak T, Brcic L et al (2010) Impact of pentadecapeptide BPC 157 on muscle healing impaired by systemic corticosteroid application. Med Sci Monit 16(3):BR81–88

    CAS  PubMed  Google Scholar 

  • Quamme GA (2010) Molecular identification of ancient and modern mammalian magnesium transporters. Am J Physiol Cell Physiol 298:C407–429

    Article  CAS  PubMed  Google Scholar 

  • Rizzo MA, Fisher M, Lock JP (1993) Hypermagnesemic pseudocoma. Arch Intern Med 153:1130–1132

    Article  CAS  PubMed  Google Scholar 

  • Sato K, Nishiwaki K, Kuno N et al (2000) Unexpected hyperkalemia following succinylcholine administration in prolonged immobilized parturients treated with magnesium and ritodrine. Anesthesiology 93(6):1539–1541

    Article  CAS  PubMed  Google Scholar 

  • Sikiric P, Gyires K, Seiwerth S et al (1993) The effect of pentadecapeptide BPC 157 on inflmammatory, non-inflammatory, direct and indirect pain and capsaicin neortoxicity. Inflammopharmacology 2:121–127

    Article  CAS  Google Scholar 

  • Sikiric P, Seiwerth S, Rucman R et al (2014) Stable gastric pentadecapeptide BPC 157-NO-system relation. Curr Pharm Des 20(7):1126–1135

    Article  CAS  PubMed  Google Scholar 

  • Sikiric P, Seiwerth S, Rucman R et al (2016) Brain-gut axis and pentadecapeptide BPC 157. Theoretical and practical implications. Curr Neuropharmacol [Epub ahead of print]

  • Stambolija V, Stambolija TP, Holjevac JK et al (2016) BPC 157: the counteraction of succinylcholine, hyperkalemia, and arrhythmias. Eur J Pharmacol 781:83–91

    Article  CAS  PubMed  Google Scholar 

  • Staresinic M, Petrovic I, Novinscak T et al (2006) Effective therapy of transected quadriceps muscle in rat: gastric pentadecapeptide BPC 157. J Orthop Res 24(5):1109–1117

    Article  CAS  PubMed  Google Scholar 

  • Tkalcević VI, Cuzić S, Brajsa K et al (2007) Enhancement by PL 14736 of granulation and collagen organization in healing wounds and the potential role of egr-1 expression. Eur J Pharmacol 570(1–3):212–221

    Article  PubMed  Google Scholar 

  • Whang R, Papper S, Llach F (1988) Arginine-induced hypermagnesemia and hyperkalemia in nephrectomized rats. Magnesium 7(1):23–26

    CAS  PubMed  Google Scholar 

  • Whittle BJ, Lopez-Belmonte J, Moncada S (1992) Nitric oxide mediates rat mucosal vasodilatation induced by intragastric capsaicin. Eur J Pharmacol 218:339–341

    Article  CAS  PubMed  Google Scholar 

  • Xie J, Sun B, Du J et al (2011) Phosphatidylinositol 4,5-bisphosphate [PIP(2)] controls magnesium gatekeeper TRPM6 activity. Sci Rep 1:146

    Article  PubMed  PubMed Central  Google Scholar 

  • Zivanovic Posilovic G, Balenovic D, Barisic I et al (2016) Stable gastric pentadecapeptide BPC 157 and bupivacaine. Eur J Pharmacol 793:56–65

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported by the Ministry of Science, Education and Sports, Republic of Croatia (Grant Number 108-1083570-3635).

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Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000, Zagreb, Croatia

    Maria Medvidovic-Grubisic, Vasilije Stambolija, Jadranka Katancic, Tamara Murselovic, Ivna Plestina-Borjan, Sanja Strbe, Domagoj Drmic, Ivan Barisic & Predrag Sikiric

  2. Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia

    Danijela Kolenc & Sven Seiwerth

  3. Department of Physiology and Immunology, School of Medicine, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia

    Aleksandra Sindic

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  1. Maria Medvidovic-Grubisic
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Correspondence to Predrag Sikiric.

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Medvidovic-Grubisic, M., Stambolija, V., Kolenc, D. et al. Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, l-NAME and l-arginine worsen. Inflammopharmacol 25, 439–449 (2017). https://doi.org/10.1007/s10787-017-0323-6

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  • DOI: https://doi.org/10.1007/s10787-017-0323-6

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