The cardiac pharmacology of tiotidine (LCL 125, 211): a new histamine H2-receptor antagonist

The cardiac pharmacology of tiotidine, a potent and specific antagonist of H2-receptors, was studied in isolated Langendorff-perfused guinea-pig hearts. At a concentration of 2.5 x 10(-6) M, tiotidine caused a slight prolongation of the P-R interval, but had no effect on rate, contractility or coronary function. Tiotidine competitively antagonized the positive chronotropic action of histamine with an apparent dissociation constant of 3.0 x 10(-8) M (2.3 x 10(-8)-3.8 x 10(-8) M). Tiotidine abolished H2-mediated increases in contractile force leaving H2-mediated negative inotropic responses unopposed. The actions of histamine at the A-V node, manifested by lengthening of the P-R interval and A-V block, were attenuated by 2.5 x 10(-7) M tiotidine; nevertheless, higher concentrations of the antagonist did not produce additional inhibition of the negative dromotropic response. As a function of concentration, tiotidine reduced the incidence and duration of histamine-induced idioventricular arrhythmias. Based on its high affinity and specificity for the H2-receptor and relative lack of cardio-depressant effects, tiotidine appears to be a useful new drug for investigating the role of histamine in cardiac function and dysfunction.