Abstract 569:: The Blockade Of Histamine H2 Receptors Ameliorates The Severity Of Heart Failure Induced By Rapid Pacing In Dogs
Backgrounds; Because histamine H2 receptors are highly expressed in hearts as well as stomach and the stimulation of H2 receptors as well as β-adrenergic receptors provokes positive inotropic effects via Gs protein. Therefore, we hypothesized that blockade of histamine H2 receptors mediates cardioprotective effects same as in β-adrenergic blockers, and tested this hypothesis using pacing-induced heart failure model in dogs.
Methods and Results; We induced heart failure by rapid right ventricular pacing at 230 bpm for 4 weeks in dogs and randomly assigned to two groups; the control group was consisted of 8 dogs with the administration of vehicle, and the famotidine group was consisted of 5 dogs with the oral administration of famotidine (1mg/kg/day, n=5). Both cardiac catheterization and echocardiography were performed before (baseline) and 4 weeks after the onset of pacing (4 weeks pacing). Furthermore, we measured cyclic AMP (cAMP) levels in left ventricular myocardial samples of dogs. Immunohistochemical studies showed the appearance of mast cells and histamine in the myocardium after 4 weeks pacing. In the control group, fractional shortening (%FS) at 4weeks pacing was significantly reduced compared with those at baseline (%FS: 34±2 to 10±1 %, p<0.05) and induced pulmonary hypertension (mean pulmonary arterial pressure (mPAP): 14±2 to 25±4 mmHg). On the other hand, the treatment of dogs with famotidine attenuated the decreases in %FS (35±2 to 19±3 %) and the increases in mPAP (13±2 to 18±1 mmHg). Myocardial cAMP levels in the famotidine group decreased compared with those of the control group (796±111 vs. 578±28 pmol/g wet weight). Furthermore, the cardioprotective effects of famotidine were observed even in the dogs with the beta-blocker, carvedilol (n=10).
Conclusion; The blockade of histamine H2 receptors preserved the cardiac systolic function in canine pacing-induced heart failure and attenuated the accumulation of cAMP in the myocardium. Thus, we can conclude that histamine H2 receptor antagonists will be one of promising drugs for the adjunctive therapy for heart failure in the clinical settings.