Abstract--The renin-angiotensin and endothelin systems regulate blood pressure, in part, by affecting renal tubular sodium transport. In rodents, ETB receptors decrease proximal tubular reabsorption, whereas AT₁ receptors produce the opposite effect. We hypothesize that ETB and AT₁ receptors interact at the receptor level, and that the interaction is altered in spontaneously hypertensive rats (SHRs). In immortalized renal proximal tubule (RPT) cells from Wistar-Kyoto (WKY) rats, angiotensin II, via AT₁ receptors, increased ETB receptor protein in a time- and concentration-dependent manner. In contrast, in SHR RPT cells, angiotensin II (10^-8 M/24 hours) had no effect on ETB receptor protein. AT₁/ETB receptors colocalized and co-immunoprecipitated in both rat strains but long-term angiotensin II (10^-8 M/24 hours) treatment increased AT₁/ETB co-immunoprecipitation in WKY but not in SHR cells. Short-term angiotensin II (10^-8 M/15 minutes) treatment decreased ETB receptor phosphorylation in both WKY and SHR cells, and increased ETB receptors in RPT cell surface membranes of RPT cells in WKY but not SHRs. Basal cell surface membrane ETB receptor expression was also higher in WKY than in SHRs. We conclude that AT₁ receptors regulate ETB receptors by receptor interaction and modulation of receptor expression. The altered AT₁ receptor regulation of ETB receptors in SHRs may play a role in the pathogenesis of hypertension.