Oral NaCl produces a greater natriuresis and diuresis than the intravenous infusion of the same amount of NaCl.Gastrin is the major gastrointestinal hormone taken up by renal proximal tubule (RPT) cells.We hypothesized that renal gastrin and dopamine receptors interact to synergistically increase sodium excretion, an impaired interaction of which may be involved in the pathogenesis of hypertension.In Wistar-Kyoto (WKY) rats, infusion of gastrin induced natriuresis and diuresis, which was abrogated in the presence of a gastrin (CCKBR; CI-988) or D1-like receptor antagonist (SCH23390).Similarly, the natriuretic and diuretic effects of fenoldopam, a D1-like receptor agonist, were blocked by SCH23390, as well as by CI-988.However, the natriuretic effects of gastrin and fenoldopam were not observed in spontaneously hypertensive rats (SHRs).The gastrin/D1-like receptor interaction was also confirmed in RPT ceils.In RPT cells from WKY but not SHRs, stimulation of either D1-like or gastrin receptor inhibited Na+-K+-ATPase activity, an effect that was blocked in the presence of SCH23390 or CI-988.In RPT cells from WKY and SHRs, CCKBR and D1 receptor (D1R) co-immunoprecipitated, which was increased after stimulation of either D1R or CCKBR in RPT cells from WKY rats; stimulation of one receptor increased RPT cell membrane expression of the other receptor, effects that were not observed in SHRs.These data suggest that there is a syrergism between CCKBR and D1-like receptors to increase sodium excretion.An aberrant interaction between the renal CCKBR and D1-like receptors (e.g., D1R) may play a role in the pathogenesis of hypertension.