The effects of some substitutions in position 5(4) of the imidazole ring in the histamine and metiamide molecule were studied by means of isolated heart preparations from the guinea pig (atria and papillary muscle). Among the histamine analogues 5-methyl and 5-ethyl histamine were found to possess approximately the same intrinsic activity as histamine whereas 5-isopropylhistamine was shown to be absolutely inactive. Among the metiamide analogues the 5-ethyl derivative (etiamide) was found less effective than the parent substance but showed the same kind of competitive antagonism; the isopropyl derivative (isopropiamide) was found to be inactive up to a concentration of 3 X 10(-5) mol/l and to exert a non-competitive antagonism with 3 X 10(-4) mol/l. On the whole the atria and the papillary muscle preparations behaved quite similarly in regard to both the agonistic and the antagonistic compounds.