Barisic Ivan, Balenovic Diana, Klicek Robert, Radic Bozo, Nikitovic Bojana, Drmic Domagoj, Udovicic Mario, Strinic Dean, Bardak Darija, Berkopic Lidija, Djuzel Viktor, Sever Marko, Cvjetko Ivan, Romic Zeljko, Sindic Aleksandra, Bencic Martina Lovric, Seiwerth Sven, Sikiric Predrag
Department of Pharmacology, University of Zagreb, Medical School, Salata 11, 10000 Zagreb, Croatia.
Regul Pept. 2013 Feb 10;181:50-66. doi: 10.1016/j.regpep.2012.12.007. Epub 2013 Jan 14.
We demonstrate the full counteracting ability of stable gastric pentadecapeptide BPC 157 against KCl-overdose (intraperitoneal (i), intragastric (ii), in vitro (iii)), NO-system related. (i) We demonstrated potential (/kg) of: BPC 157 (10ng, 10μg ip, complete counteraction), l-arginine (100mg ip, attenuation) vs. L-NAME (5mg ip, deadly aggravation), given alone and/or combined, before or after intraperitoneal KCl-solution application (9mEq/kg). Therapy was confronted with promptly unrelenting hyperkalemia (>12mmol/L), arrhythmias (and muscular weakness, hypertension, low pressure in lower esophageal and pyloric sphincter) with an ultimate and a regularly inevitable lethal outcome within 30min. Previously, we established BPC 157-NO-system interaction; now, a huge life-saving potential. Given 30min before KCl, all BPC 157 regimens regained sinus rhythm, had less prolongation of QRS, and had no asystolic pause. BPC 157 therapy, given 10min after KCl-application, starts the rescue within 5-10min, completely restoring normal sinus rhythm at 1h. Likewise, other hyperkalemia-disturbances (muscular weakness, hypertension, low sphincteric pressure) were also counteracted. Accordingly with NO-system relation, deadly aggravation by L-NAME: l-arginine brings the values to the control levels while BPC 157 always completely nullified lesions, markedly below those of controls. Combined with l-arginine, BPC 157 exhibited no additive effect. (ii) Intragastric KCl-solution application (27mEq/kg) - (hyperkalemia 7mmol/L): severe stomach mucosal lesions, sphincter failure and peaked T waves were fully counteracted by intragastric BPC 157 (10ng, 10μg) application, given 30min before or 10min after KCl. (iii). In HEK293 cells, hyperkalemic conditions (18.6mM potassium concentrations), BPC 157 directly affects potassium conductance, counteracting the effect on membrane potential and depolarizations caused by hyperkalemic conditions.
我们展示了稳定的胃十五肽BPC 157对氯化钾过量（腹腔内（i）、胃内（ii）、体外（iii））的完全对抗能力，这与一氧化氮系统相关。（i）我们展示了以下物质的潜在（/千克）作用：BPC 157（10纳克、10微克腹腔内注射，完全对抗）、L-精氨酸（100毫克腹腔内注射，减轻作用）与L-硝基精氨酸甲酯（5毫克腹腔内注射，致命性加重作用），单独和/或联合使用，在腹腔内注射氯化钾溶液（9毫当量/千克）之前或之后。治疗面临迅速且持续的高钾血症（>12毫摩尔/升）、心律失常（以及肌肉无力、高血压、食管下括约肌和幽门括约肌低压），最终在30分钟内必然导致致命后果。此前，我们确立了BPC 157与一氧化氮系统的相互作用；现在，其具有巨大的挽救生命的潜力。在氯化钾注射前30分钟给予，所有BPC 157给药方案均恢复窦性心律，QRS波延长较少，且无心脏停搏期。在氯化钾注射后10分钟给予BPC 157治疗，在5 - 10分钟内开始挽救，1小时时完全恢复正常窦性心律。同样，其他高钾血症相关紊乱（肌肉无力、高血压、括约肌低压）也得到了对抗。与一氧化氮系统的关系一致，L-硝基精氨酸甲酯的致命性加重作用：L-精氨酸使各项指标恢复到对照水平，而BPC 157总是完全消除损伤，明显低于对照组。与L-精氨酸联合使用时，BPC 157未表现出相加作用。（ii）胃内注射氯化钾溶液（27毫当量/千克） - （高钾血症7毫摩尔/升）：胃内注射BPC 157（10纳克、10微克），在氯化钾注射前30分钟或后10分钟给予，可完全对抗严重的胃黏膜损伤、括约肌功能障碍和T波高尖。（iii）在HEK293细胞中，高钾血症条件（钾浓度18.6毫摩尔/升）下，BPC 157直接影响钾离子电导，对抗高钾血症条件对膜电位和去极化的影响。
