Doxorubicine-Congestive Heart Failure-Increased Big Endothelin-1 Plasma Concentration: Reversal by Amlodipine, Losartan, and Gastric Pentadecapeptide BPC157 in Rat and Mouse

Abstract

Overall, doxorubicine-congestive heart failure (CHF) (male Wistar rats and NMRI mice; 6 challenges with doxorubicine (2.5 mg/kg, i.p.) throughout 15 days and then a 4-week-rest period) is consistently deteriorating throughout next 14 days, if not reversed or ameliorated by therapy (/kg per day): a stable gastric pentadecapeptide BPC157 (GEPPPGKPADDAGLV, MW 1419, promisingly studied for inflammatory bowel disease (Pliva; PL 10, PLD-116, PL 14736)) (10 microg, 10 ng), losartan (0.7 mg), amlodipine (0.07 mg), given intragastrically (i.g.) (once daily, rats) or in drinking water (mice). Assessed were big endothelin-1 (BET-1) and plasma enzyme levels (CK, MBCK, LDH, AST, ALT) before and after 14 days of therapy and clinical status (hypotension, increased heart rate and respiratory rate, and ascites) every 2 days. Controls (distilled water (5 ml/kg, i.g., once daily) or drinking water (2 ml/mouse per day) given throughout 14 days) exhibited additionally increased BET-1 and aggravated clinical status, while enzyme values maintained their initial increase. BPC157 (10 microg/kg) and amlodipine treatment reversed the increased BET-1 (rats, mice), AST, ALT, CK (rats, mice), and LDH (mice) values. BPC157 (10 ng/kg) and losartan opposed further increase of BET-1 (rats, mice). Losartan reduces AST, ALT, CK, and LDH serum values. BPC157 (10 ng/kg) reduces AST and ALT serum values. Clinical status of CHF-rats and -mice is accordingly improved by the BPC157 regimens and amlodipine.

Pentadecapeptide BPC157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine

“…Likely, this might also be the supportive part to the general interaction. Namely, very similar interactions of BPC 157 and the NO system, with both L-NAME and L-arginine, have been demonstrated by a large number of other previous studies [14,15,[18][19][20][21][22][23][24][25][26]. For instance, counteraction of both the L-arginine-induced disturbance and L-NAME-induced disturbance was seen, while maintaining blood pressure against both L-arginine (hypotension) and L-NAME (hypertension) (note, BPC 157 by itself does not affect basal blood pressure values [25] and likewise, BPC 157 by itself does not affect basal coagulation/platelets values [1]).…”

“…BPC 157 has been shown to exert beneficial effects against different pathological conditions [1,2,10-26], it induced gastroprotective, analgesic and anti-inflammatory wound healing effects [1,2,10-17], also effective against experimental colitis [10][11][12][13][14][15][16] and showing a particular interaction with the NO-system [14,15,[18][19][20][21][22][23][24][25][26]. Recently, we demonstrated the effect of BPC 157 against bleeding/thrombocytopenia after amputation, with or without anticoagulant and aspirin administration and abdominal aorta anastomotic site-thrombosis [1,2].…”

“…To counteract the consequences of L-NAME and/or L-arginine administration with the disturbed hemostasis, we administered the stable gastric pentadecapeptide BPC 157 [1,2,[10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] not only due to its special effect on hemostasis [1,2], but also owing to a particular beneficial combining [1,2,[10][11][12][13][14], wound healing capacity [1,2,[10][11][12][13][14][15][16][17] and particular interaction with NO-system [14,15,[18][19][20][21][22][23][24][25][26]. Previously, BPC 157 as an originally anti-...…”

“…Also, interactions with NO-system are shown in different models and various species [12,13,[18][19][20][21][22][23][24][25][26]. As an illustrative analogy for counteraction of the opposite effects of L-NAME and L-arginine in haemorrhage, we should emphasize that the particular effects of BPC 157 on blood pressure [18,20,25] and the anti-arrhythmic effect [18][19][20][21] include antagonization of both L-NAME (hypertension) and L-arginine (hypotension) [25] and counteraction of endothelin serum increase [20].…”

“…As an illustrative analogy for counteraction of the opposite effects of L-NAME and L-arginine in haemorrhage, we should emphasize that the particular effects of BPC 157 on blood pressure [18,20,25] and the anti-arrhythmic effect [18][19][20][21] include antagonization of both L-NAME (hypertension) and L-arginine (hypotension) [25] and counteraction of endothelin serum increase [20]. Note, endothelin per se, inhibited platelet aggregation and caused subarachnoid hemorrhage [27,28].…”