The cimetidine-like moiety in impromidine was replaced by either alternative partial structures known from H2-antagonists or by H2-nonspecific lipophilic groups. The most potent H2-agonists were found in a series of compounds structurally derived from the H1-antagonist pheniramine. Arpromidine (N1-[3-(4-fluorophenyl)-3-(2-pyridinyl)propyl]-N2-[3-(1H-imidazol-4- yl)propyl]guanidine) may be considered a new lead for the development of "cardiohistaminergics". This guanidine combines both about 100 times the potency of histamine in the isolated guinea-pig atrium (pD2 = 8.0) and H1-antagonistic activity (pA2 = 7.65) in the range of pheniramine. Analogues difluorinated in 3,4-(BU-E-75) or 3,5-position (BU-E-76) or chlorinated in 3,4-position (BU-E-64) are up to 160 times more potent H2-agonists than histamine. In contrast to other types of guanidines, in the arpromidine series the order of potency found in guinea-pig atria was in good agreement with the results from isolated perfused guinea-pig hearts. In particular, the two-fold halogenated arpromidine analogues proved to be more potent positive inotropic agents than impromidine with lower stimulating effects on heart rate and reduced arrhythmogenic properties.