We revealed that the stable gastric pentadecapeptide BPC 157, a useful peptide therapy against isoprenaline myocardial infarction, as well as against isoprenaline myocardial reinfarction, may follow the counteraction of the recently described occlusion-like syndrome, induced peripherally and centrally, which was described for the first time in isoprenaline-treated rats. BPC 157 (10 ng/kg, 10 µg/kg i.p.), L-NAME (5 mg/kg i.p.), and L-arginine (200 mg/kg i.p.) were given alone or together at (i) 30 min before or, alternatively, (ii) at 5 min after isoprenaline (75 or 150 mg/kg s.c.). At 30 min after isoprenaline 75 mg/kg s.c., we noted an early multiorgan failure (brain, heart, lung, liver, kidney and gastrointestinal lesions), thrombosis, intracranial (superior sagittal sinus) hypertension, portal and caval hypertension, and aortal hypotension, in its full presentation (or attenuated by BPC 157 therapy (given at 5 min after isoprenaline) via activation of the azygos vein). Further, we studied isoprenaline (75 or 150 mg/kg s.c.) myocardial infarction (1 challenge) and reinfarction (isoprenaline at 0 h and 24 h, 2 challenges) in rats (assessed at the end of the subsequent 24 h period). BPC 157 reduced levels of all necrosis markers, CK, CK-MB, LDH, and cTnT, and attenuated gross (no visible infarcted area) and histological damage, ECG (no ST-T ischemic changes), and echocardiography (preservation of systolic left ventricular function) damage induced by isoprenaline. Its effect was associated with a significant decrease in oxidative stress parameters and likely maintained NO system function, providing that BPC 157 interacted with eNOS and COX2 gene expression in a particular way and counteracted the noxious effect of the NOS-blocker, L-NAME.

In heart disturbances, stable gastric pentadecapeptide BPC 157 especial therapy effects combine the therapy of myocardial infarction, heart failure, pulmonary hypertension arrhythmias, and thrombosis prevention and reversal. The shared therapy effect occurred as part of its even larger cytoprotection (cardioprotection) therapy effect (direct epithelial cell protection; direct endothelium cell protection) that BPC 157 exerts as a novel cytoprotection mediator, which is native and stable in human gastric juice, as well as easily applicable. Accordingly, there is interaction with many molecular pathways, combining maintained endothelium function and maintained thrombocytes function, which counteracted thrombocytopenia in rats that underwent major vessel occlusion and deep vein thrombosis and counteracted thrombosis in all vascular studies; the coagulation pathways were not affected. These appeared as having modulatory effects on NO-system (NO-release, NOS-inhibition, NO-over-stimulation all affected), controlling vasomotor tone and the activation of the Src-Caveolin-1-eNOS pathway and modulatory effects on the prostaglandins system (BPC 157 counteracted NSAIDs toxicity, counteracted bleeding, thrombocytopenia, and in particular, leaky gut syndrome). As an essential novelty noted in the vascular studies, there was the activation of the collateral pathways. This might be the upgrading of the minor vessel to take over the function of the disabled major vessel, competing with and counteracting the Virchow triad circumstances devastatingly present, making possible the recruitment of collateral blood vessels, compensating vessel occlusion and reestablishing the blood flow or bypassing the occluded or ruptured vessel. As a part of the counteraction of the severe vessel and multiorgan failure syndrome, counteracted were the brain, lung, liver, kidney, gastrointestinal lesions, and in particular, the counteraction of the heart arrhythmias and infarction.

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Background. Monocrotaline selectively injures the lung’s vascular endothelium and induces pulmonary arterial hypertension. The stable gastric pentadecapeptide BPC 157 acts as a prototype cytoprotective agent that maintains endothelium, and its application may be a novel therapy. Besides, BPC 157 prevents and reverses thrombosis formation, maintains platelet function, alleviates peripheral vascular occlusion disturbances, and has anti-arrhythmic and anti-inflammatory effects. Monocrotaline-induced pulmonary arterial hypertension in rats (wall thickness, total vessel area, heart frequency, QRS axis deviation, QT interval prolongation, increase in right ventricle systolic pressure and bodyweight loss) can be counteracted with early or delayed BPC 157 therapy. Methods and Results. After monocrotaline (80 mg/kg subcutaneously), BPC 157 (10 μg/kg or 10 ng/kg, days 1–14 or days 1–30 (early regimens), or days 14–30 (delayed regimen)) was given once daily intraperitoneally (last application 24 h before sacrifice) or continuously in drinking water until sacrifice (day 14 or 30). Without therapy, the outcome was the full monocrotaline syndrome, marked by right-side heart hypertrophy and massive thickening of the precapillary artery’s smooth muscle layer, clinical deterioration, and sometimes death due to pulmonary hypertension and right-heart failure during the 4th week after monocrotaline injection. With all BPC 157 regimens, monocrotaline-induced pulmonary arterial hypertension (including all disturbed parameters) was counteracted, and consistent beneficial effects were documented during the whole course of the disease. Pulmonary hypertension was not even developed (early regimens) as quickly as the advanced pulmonary hypertension was rapidly attenuated and then completely eliminated (delayed regimen). Conclusions. Thus, pentadecapeptide BPC 157 prevents and counteracts monocrotaline-induced pulmonary arterial hypertension and cor pulmonale in rats.

Background: We focused on NO-system-relations (worsening/amelioration) of furosemide (100 mg/kg intraperitoneally)-diuresis-hypokalemia mortal course in rats and beneficial effect of BPC 157 therapy. Methods:Electrocardiographically 90-150 min post-furosemide application duration of PR, RR, QRS, QT intervals, P, R, S, T waves and its amplitude as well were analysed along with appearance of AV block, ventricular premature beats, ventricular tachycardia. Clinically, skeletal muscle myoclonal activity and lethality at 150 min were also analysed.Results: All NO-system-related agents (alone and/or combined, before/after furosemide) not changed hypokalemia and all averted to some extent furosemide-forced diuresis. NOS-blocker, L-NAME (5 mg/kg intraperitoneally) accelerated mortality, aggravated cardiac and extra-cardiac manifestations, thereby, NO-systemrelated. Prevented hypokalemia-mortality was with NO-precursor L-arginine (100 mg/kg intraperitoneally) and stable gastric pentadecapeptide BPC 157 (10 ug, 10 ng/kg intraperitoneally/intragastrically). Specifically, BPC 157 showed most complete benefit. i. BPC 157 given 15 min before furosemide. All BPC 157 regimens maintained sinus rhythm, had no ventricular premature beats, ventricular tachycardia, AV block, no prolongation of intervals and waves without reduction of amplitude. ii. BPC 157 given 90 min after furosemide (with hypokalemia, 3 rd grade AV block and/ or ventricular tachycardia being present). Within 5-10 minutes, BPC 157 regimens normalized P, R, S, T waves, PR, RR, QRS, QT interval duration, R, S, T wave amplitude, total AV block and terminated ventricular tachycardia. Likewise, BPC 157 eliminated skeletal muscle myoclonus. Conclusion:L-NAME/L-arginine was mutual counteraction while BPC 157 completely eliminated L-NAME (arrhythmias, myoclonus, mortality), without an additive benefit when combined with L-arginine. Thus, we showed potentially effective therapeutic interventions for acute hypokalemia.Mortal Furosemide-Hypokalemia-Disturbances in Rats NO-System Related Shorten Survival by L-NAME. Therapy Benefit with BPC 157 Peptide More Than With L-Arginine Keywords: Pentadecapeptide BPC 157; L-NAME; L-arginine; Hypokalemic lethal outcome; Arrhythmia; Rats Introduction NO-system is proposed as endogenous cardioprotectant and antifibrillatory factor [1,2]. Diuretic-hypokalemia is an increasingly common cause of arrhythmias [3]. Therefore, we attempted to define hypokalemia and/or hypokalemia disturbances as particular disturbances related to NO-system and possible therapeutic value of NOsystem-related agents: NO-synthase (NOS)-blocker, L-NAME, NOSsubstrate, L-arginine, and, particularly, stable gastric pentadecapeptide BPC 157 [4][5][6]. In this, we focused on so far not demonstrated with L-NAME/L-arginine application [1,2] NO-system-relations in mortal furosemide-diuresis-hypokalemia course; -ECG changes, carefully analyzed in rats [7] (prolongation of P, R, S, T waves and PR, RR, QRS, QT interval duration, and reduced amplitude of R, S, T wave (alt...