We have demonstrated an interaction between the effects of amiloride and atrial natriuretic factor (ANF) on the vascular system. In precontracted rabbit aortic strips the relaxant effect of a combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was synergistic. The production of cyclic (c)GMP, which parallels ANF-induced relaxation of the strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of 10(-8) mol/l ANF. In spontaneously hypertensive rats (SHR) ANF-induced decreases in blood pressure were potentiated by amiloride. Binding experiments revealed an interaction between amiloride and ANF at the receptor level; binding of labelled ANF to aortic tissue was increased by amiloride but decreased by ATP. These data show that amiloride and ATP influence a mechanism that determines the sensitivity of vessels to ANF and this interaction occurs both at receptor level and at the level of transduction.