Effect of BN 52256 and other mediator antagonists on ouabain-induced cardiac arrhythmia in a model of anaphylaxis in guinea-pigs.
Different mediators released by anaphylaxis seem to be involved in different pathophysiological conditions, including cardiac arrhythmia. Histamine, 5-HT and platelet-activating factor (PAF) could participate in the enhanced arrhythmogenicity during anaphylaxis in guinea-pigs. The threshold dose of ouabain-induced arrhythmia is decreased in actively sensitized guinea-pigs by i.p. administration of ovalbumin. The purpose of the present paper was to investigate the effect of different mediator antagonists. Antagonists of PAF (WEB 2170), histamine (clemastine) and 5-HT (cyproheptadine) in doses of 5.0 mg/kg, 5.0 mg/kg and 0.5 mg/kg, respectively, can increase the threshold dose of ouabain-induced arrhythmias signalling an antiarrhythmic effect. A combination of WEB 2170 and clemastine, each of them in inactive doses (2.0 mg/kg and 1.0 mg/kg, respectively) showed a statistically significant antiarrhythmic effect. A combination of the same dose of WEB 2170 and cyproheptadine (0.1 mg/kg) under the same conditions induced an antiarrhythmic effect, too. BN 52256 is a new antiallergic drug synthesized on the basis of a novel concept of combining inhibitory activity against various inflammatory mediators in one molecule. BN 52256 in doses of 20-80 micrograms/kg exhibited a statistically significant antiarrhythmic effect. BN 52256 needed a 12.5-125 fold lower dose to induce the same antiarrhythmic effect compared to the antagonists of PAF, histamine or 5-HT investigated in this study. Depending on the pathophysiological conditions, different mediators seem to be involved in the occurrence of cardiac arrhythmia. A complex inhibition of these mediators could induce a more specific influence on such kinds of cardiac arrhythmias.
Mest
H J
HJ
Department of Pharmacology and Toxicology, School of Medicine, Martin Luther University Halle-Wittenberg, Germany.
Hörhold
I
I
Rein
T
T
Riedel
A
A
Broquet
C
C
D000707:Anaphylaxis / Q000378:metabolism*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000188:drug therapy*; D001381:Azepines / Q000494:pharmacology*; D002974:Clemastine / Q000494:pharmacology*; D003533:Cyproheptadine / Q000494:pharmacology*; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D016566:Organoselenium Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D010042:Ouabain; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D014230:Triazoles / Q000494:pharmacology*; D014693:Ventricular Fibrillation / Q000188:drug therapy
D001381:Azepines; D006633:Histamine Antagonists; D016566:Organoselenium Compounds; D010880:Piperidines; D010972:Platelet Activating Factor; D014230:Triazoles; C075674:BN 52256; D003533:Cyproheptadine; D010042:Ouabain; D002974:Clemastine; C063964:bepafant