ORIGINAL ARTICLE Hypermagnesemia disturbances in rats, NO-related: pentadecapeptide BPC 157 abrogates, L-NAME and L-arginine worsen Maria Medvidovic-Grubisic 1 • Vasilije Stambolija 1 • Danijela Kolenc 2 • Jadranka Katancic 1 • Tamara Murselovic 1 • Ivna Plestina-Borjan 1 • Sanja Strbe 1 • Domagoj Drmic 1 • Ivan Barisic 1 • Aleksandra Sindic 3 • Sven Seiwerth 2 • Predrag Sikiric 1 Received: 9 November 2016 / Accepted: 2 February 2017 Ó Springer International Publishing 2017 Abstract Aim Stable gastric pentadecapeptide BPC 157, adminis- tered 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; parasym- pathetic 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, hyper- kalaemia, 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 lg, 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 exhib- ited all control values and normokalaemia. BPC 157 abrogated hypermagnesemia and counteracted all of the magnesium-induced disturbances (including those aggra- vated by L-NAME or L-arginine). Thus, cell depolarization due to increasing magnesium concentration was inhibited in the presence of BPC 157 (1 lM) 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 wors- ened 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. Keywords BPC 157 Á L-Arginine Á L-NAME Á Magnesium Á Rats Introduction We hypothesize that the stable gastric pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, M.W. 1419, PL-10, PLD-116, PL 14736) (Sikiric et al. 2014) administered before a high-dose magnesium injection in rats may serve as a useful peptide therapy against magnesium toxicity and magnesium-induced effects on cell depolarization, and that this might be an NO-system-related effect. BPC 157 was originally an anti-ulcer peptide (used in trials for ulcerative colitis and now is in trials for the treatment of multiple sclerosis) that largely interacts with NO-system (Sikiric et al. 2014); BPC 157 is known to counteract various induced potassium disturbances (Barisic et al. 2013; & Predrag Sikiric sikiric@mef.hr 1 Department of Pharmacology, School of Medicine, University of Zagreb, Salata 11, P.O. Box 916, 10000 Zagreb, Croatia 2 Department of Pathology, School of Medicine, University of Zagreb, Zagreb, Croatia 3 Department of Physiology and Immunology, School of Medicine, Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia Inflammopharmacol DOI 10.1007/s10787-017-0323-6 Inflammopharmacology 123