Effects of histamine on the tone and intracellular calcium level (Ca2+i) in porcine coronary arteries were simultaneously investigated by use of the fura-2 microscopic fluorometric method. Histamine (10(-6)-10(-4) M) induced concentration-dependent increases in tone and Ca2+i, but these responses were not sustained. Histamine induced a larger contraction than did KCl with a similar increase in Ca2+i. Depletion of the caffeine-sensitive Ca2+ store with ryanodine (3 x 10(-5) M) and repetitive applications of caffeine (2.5 x 10(-2) M) scarcely affected contractile and Ca2+i responses to histamine. In Ca2(+)-free medium or in the presence of verapamil (10(-6) M), histamine produced a briefer increase in Ca2+i and a smaller contraction than in normal medium. When histamine or caffeine was repetitively applied in Ca2(+)-free medium, the first application produced an increase in Ca2+i but the second application produced no increase. Although caffeine increased Ca2+i after repetitive histamine applications, histamine failed to increase Ca2+i after repetitive caffeine applications in Ca2(+)-free medium. These results indicate that vascular contraction induced by histamine may involve the following mechanisms: an increase in Ca2+ influx through Ca2+ channels, release of Ca2+ from the intracellular Ca2+ store which has an interaction with the caffeine-sensitive Ca2+ store, and sensitization of contractile proteins to Ca2+.