Effect of luminal angiotensin II receptor antagonists on proximal tubule transport

Abstract

The proximal tubule can endogenously synthesize and secrete luminal angiotensin II at a concentration approximately 100- to 1000-fold higher than that in the systemic circulation. We have recently shown that this endogenously produced and luminally secreted angiotensin II regulates proximal tubule volume reabsorption, which is a reflection of sodium transport within this segment. In this study, we use in vivo microperfusion of angiotensin II receptor antagonists into the lumen of the proximal tubule to examine the role of the luminal AT1 and AT2 receptor in the regulation of volume reabsorption. Systemically administered (intravenous) AT1 and AT2 receptor antagonists, acting through basolateral angiotensin II receptors, have previously been shown to inhibit proximal tubule transport. Luminal perfusion of 10(-6) mol/L Dup 753 (AT1 antagonist) and 10(-6) mol/L PD 123319 (AT2 antagonist) decreased proximal tubule volume reabsorption from 2.94 +/- 0.18 to 1.65 +/- 0.18 and 1.64 +/- 0.19 nL/mm x min, respectively, P < .01. Luminal perfusion of 10(-4) mol/L CGP 42112A, another AT2 antagonist, similarly decreased volume reabsorption to 1.32 +/- 0.36 nL/nm x min, P < .01. The inhibition of transport with AT1 and AT2 antagonist was additive, as luminal perfusion of 10(-6) mol/L Dup 753 plus 10(-6) mol/L 123319 resulted in a decrease in volume reabsorption to 0.41 +/- 0.31 nL/mm x min, P < .001 v control, P < .05 v Dup 753, and P < .01 v PD 123319. These results show that endogenously produced angiotensin II regulates proximal tubule volume transport via both luminal AT1 and AT2 receptors.

FIGURE 1

Comparison of proximal tubule volume reabsorptive rate (Jv) with luminal perfusion of 10⁻⁶ mol/L Dup 753 (AT1 antagonist), 10⁻⁶ mol/L PD 123319 (AT2 antagonist), 10⁻⁴ mol/L CGP 42112A (AT2 antagonist) and 10⁻⁶ mol/L Dup 753 × 10⁻⁶ mol/L PD 123319. The inhibition of volume reabsorption noted with Dup 753 and PD 123319 were additive. (*P < .01 compared with control; **P < .001 compared with control; ***P < .05 compared with Dup 753 or CGP 42112A; ‡P < 0.01 compared with PD 123319.)