Inhibition of methyldigoxin-induced arrhythmias by pentadecapeptide BPC 157: a relation with NO-system.
Pentadecapeptide BPC 157 (GEPPPGKPADDAGLV, MW 1419) reversed congestive heart failure and various arrhythmias, influenced the NO-system and showed no proarrhythmic effect. In therapy analogy, we challenged rats with digitalis, to show attenuation by BPC 157 and the relation between the NO-system and digitalis toxicity. (i). BPC 157 prophylactic effect. Development of cumulative intravenous digitalis toxicity, BPC 157 (50 microg, 10 microg, 10 ng/kg applied intravenously immediately before a methyldigoxin increment regimen (2.0/1.5/1.5/1.0 mg/kg at 15 min-intervals, total dose 6.0 mg/kg/45 min)) reduced the number of ventricular premature beats, prolonged the time before onset of ventricular tachycardia, reduced ventricular tachycardia and AV-block duration (microg-regimes) or reduced mainly the AV-block duration (ng-regimen). (ii). BPC 157 therapy. Advanced methyldigoxin toxicity (6.0 mg/kg i.v. bolus). BPC 157 applied at the 20th second of the grade 3 AV-block shortened AV-blocks, mitigated a further digitalis toxicity course. Ventricular tachycardias were either avoided (50 microg), or markedly reduced (10 microg, 10 ng). Fatal outcome was either avoided (50 microg), reduced (10 microg), or only delayed (10 ng) (iii) BPC 157, L-NAME, l-arginine, L-NAME+l-arginine application. L-NAME-application (5 mg/kg i.p.) aggravated methyldigoxin-arrhythmias. l-arginine (200 mg/kg i.p.) alone had no effect but blunted L-NAME-exaggeration (L-NAME+l-arginine). In this respect, BPC 157 (50 microg/kg i.p.) was prophylactically and therapeutically more effective: the antagonism of L-NAME with BPC 157 produced an effect similar to BPC 157 alone. In conclusion, digitalis-induced arrhythmias in rats could be prevented and counteracted by pentadecapeptide BPC 157, mainly through an interaction with the NO-system.
Balenovic
Dijana
D
Department of Pharmacology, University of Zagreb Medical School, Salata 11, 10000 Zagreb, Croatia.
Bencic
Martina Lovric
ML
Udovicic
Mario
M
Simonji
Karol
K
Hanzevacki
Jadranka Separovic
JS
Barisic
Ivan
I
Kranjcevic
Stjepan
S
Prkacin
Ingrid
I
Coric
Vedran
V
Brcic
Luka
L
Coric
Marijana
M
Brcic
Iva
I
Borovic
Suzana
S
Radic
Bozo
B
Drmic
Domagoj
D
Vrcic
Hrvoje
H
Seiwerth
Sven
S
Sikiric
Predrag
P
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control; D006339:Heart Rate / Q000187:drug effects*; D008297:Male; D008520:Medigoxin / Q000494:pharmacology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D011506:Proteins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000889:Anti-Arrhythmia Agents; D000897:Anti-Ulcer Agents; D010446:Peptide Fragments; D011506:Proteins; D009569:Nitric Oxide; C083833:BPC 157; D001120:Arginine; D008520:Medigoxin; D019331:NG-Nitroarginine Methyl Ester