Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H₁R - H₄R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H₁R, H₂R and H₃R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H₄R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H₄ receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H₁ receptor inhibits heart dilatation but does not prolong the life.