The prejunctional effects of clonidine and phenylephrine were studied in guinea-pig isolated atria by means of field stimulation of the sympathetic nerve terminals during the cardiac refractory period, in the presence of 1 microM atropine. Clonidine (10-100 nM) produced a dose-dependent decrease in the stimulus-inotropic response curve; the IC50 for clonidine was increased about 70 times by the pretreatment of the preparations with 1 microM yohimbine. The effect of clonidine was not modified by 0.5 microM prazosin. Unlike clonidine, phenylephrine (1-10 microM) induced a statistically insignificant increase in the contractile force of preparations stimulated at 4 Hz. The inhibitory effect of phenylephrine (1-10 microM) was partially prevented by either 1 microM yohimbine or 0.5 microM prazosin. However, it was antagonized, to about the same degree as that observed with clonidine, by the pretreatment of the preparations with both 1 microM yohimbine and 0.5 microM prazosin. The results seem to indicate that one component of the prejunctional effects of phenylephrine may be mediated by presynaptic alpha-adrenoceptors belonging to the alpha 1-subtype.