Protection by cimetidine, but not ranitidine, implies that H2 receptors do not mediate arrhythmogenesis in a rat model of regional ischaemia and reperfusion in vitro.
OBJECTIVE
Evidence suggests that histamine may function as one of many endogenous biochemical mediators of ischaemia- and reperfusion-induced ventricular fibrillation (VF). The H2 receptor subtype has been hypothesised to mediate this action. Our objective was to test this hypothesis.


METHODS
The hypothesis predicts that H2 antagonists should prevent VF. We tested this by evoking ischaemia- and reperfusion-induced VF using the isolated perfused rat heart (Langendorff preparation) and performing concentration-response studies with two H2 antagonists, cimetidine and ranitidine.


RESULTS
Continuous perfusion with cimetidine at the highest concentration (10 microM) reduced the incidence of ischaemia-induced VF from 57% in controls to 8% (P < 0.05) and the incidence of reperfusion-induced VF from 78 to 38% (P < 0.05). Surprisingly, the incidences of ischaemia- and reperfusion-induced arrhythmias were not reduced by ranitidine over an equivalent concentration range (0.1-10 microM). Electrocardiographic (ECG) variables (PR and QT interval) were not altered by cimetidine or ranitidine at any concentration, suggesting that neither drug produced direct electrophysiological actions on fast inward sodium, L-type calcium or potassium currents (blockade of which would have led to ECG changes).


CONCLUSIONS
Ranitidine does not possess antiarrhythmic activity during ischaemia or reperfusion in the isolated rat heart, indicating that specific H2 antagonism is unlikely to be an effective mechanism of VF suppression. Thus, if histamine functions as an arrhythmogenic factor, it is not likely to do so by activating H2 receptors. Furthermore, since ranitidine is marginally the more potent of the two drugs as an H2 antagonist, it would appear that cimetidine, which was found to protect against VF, possesses antiarrhythmic activity mediated by non-specific effects (i.e., not attributable to blockade of H2 receptors).
Banning
M M
MM
Cardiovascular Research Laboratories, King's College, University of London, UK.
Curtis
M J
MJ
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D002927:Cimetidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D017202:Myocardial Ischemia / Q000378:metabolism; D015428:Myocardial Reperfusion Injury / Q000150:complications / Q000378:metabolism*; D010477:Perfusion; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
D006635:Histamine H2 Antagonists; D002927:Cimetidine; D011899:Ranitidine