Abstract-Dopamine and angiotensin II negatively interact to regulate sodium excretion and blood pressure. D 3 dopamine receptors downregulate angiotensin type 1 (AT 1 ) receptors in renal proximal tubule cells from normotensive Wistar-Kyoto rats. We determined whether AT 1 receptors regulate D 3 receptors and whether the regulation is different in cultured renal proximal tubule cells from normotensive and spontaneously hypertensive rats. Angiotensin II (10
Ϫ8M/24 hours) decreased D 3 receptors in both normotensive (control, 36Ϯ3; angiotensin II, 24Ϯ3 U) and hypertensive (control, 30Ϯ3; angiotensin II, 11Ϯ3 U; nϭ9 per group) rats; effects that were blocked by the AT 1 receptor antagonist, losartan (10 Ϫ8 M/24 hours). However, the reduction in D 3 expression was greater in hypertensive (60Ϯ10%) than in normotensive rats (32Ϯ9%). In normotensive rats, angiotensin II (10 Ϫ8 M/24hr) also decreased AT 1 receptors. In contrast, in cells from hypertensive rats, angiotensin II increased AT 1 receptors. AT 1 and D 3 receptors coimmunoprecipitated in renal proximal tubule cells from both strains. Angiotensin II decreased D 3 /AT 1 receptor co-immunoprecipitation similarly in both rat strains, but basal D 3 /AT 1 co-immunoprecipitation was 6 times higher in normotensive than in hypertensive rats. Therefore, AT 1 and D 3 receptor interaction is qualitatively and quantitatively different between normotensive and hypertensive rats; angiotensin II decreases AT 1 expression in normotensive but increases it in hypertensive rats. In addition, angiotensin II decreases D 3 expression to a greater extent in hypertensive than in normotensive rats. Aberrant interactions between D 3 and AT 1 receptors may play a role in the pathogenesis of hypertension. Key Words: receptors, dopamine Ⅲ receptors, angiotensin II Ⅲ rats, spontaneously hypertensive Ⅲ kidney T he proximal tubule is a major site of salt and water reabsorption in the mammalian nephron, with up to 60% of the filtrate reabsorbed in this segment. 1,2 Renal proximal tubule (RPT) function is under hormonal control, with angiotensin II stimulating sodium reabsorption via activation of apical Na ϩ /H ϩ exchanger and basolateral [Na ϩ ]/[K ϩ ]ATPase, and with dopamine inhibiting reabsorption by inhibiting these proteins. [3][4][5] The paracrine regulation of sodium reabsorption in the proximal tubule by the renin-angiotensin system occurs via several angiotensin receptor subtypes (AT 1 , AT 2 , and AT 4 ). [5][6][7][8] The activation of AT 1 receptors by angiotensin II increases sodium transport, whereas the activation of AT 2 and AT 4 receptors decreases sodium reabsorption in this nephron segment. [5][6][7][8] However, under physiological conditions, the major effect of angiotensin II on sodium transport is stimulatory, via AT 1 receptors. [5][6][7][8] The dopaminergic system also exerts a paracrine regulatory role on renal sodium transport in the proximal tubule via several receptor subtypes. Dopamine receptors, pharmacologically grouped into D 1 -like (D 1 and D 5 ) and D 2 -like...