Recent studies have suggested that cytosolic calcium serves in the transmission of signals between distal tubular fluid and glomerular vascular elements. Since cAMP can modify calcium-mediated events, it was of interest to determine if agents that elevate intracellular cAMP could influence feedback responses and to assess the interaction of cAMP and intracellular calcium in the transmission of feedback signals. Stop flow pressure (SFP) was measured in the rat during retrograde microperfusion into the distal tubule at 15 nl/min. SFP averaged 37.5 +/- 0.5 mm Hg and decreased by 12.8 +/- 0.8 mm Hg (N = 44) during perfusion with an isotonic Ringer's solution. Addition of 3-isobutyl-1-methylxanthine (IBMX), a phosphodiesterase inhibitor, decreased the magnitude of SFP feedback responses; 89 +/- 4.5% (N = 16) inhibition was observed at an IBMX concentration of 500 microM. In addition, SFP decreased by only 3 +/- 1 mm Hg (N = 8) during perfusion with 10 mM dibutyryl cAMP in the presence of a low concentration of IBMX and by 1.6 +/- 0.7 mm Hg (N = 12) during perfusion with forskolin, an agent that stimulates adenylate cyclase activity. Calcium ionophore (A23187) significantly increased the magnitude of SFP feedback responses obtained with IBMX alone from 5 +/- 1.0 mm Hg (N = 9; 250 micron IBMX) to 10 +/- 1.2 mm Hg (N = 11). These results indicate that agents which elevate intracellular cAMP markedly attenuate tubuloglomerular feedback responses and that calcium ionophore can reverse the inhibitory effects of increased cAMP.