Laboratory Investigation

Kidney International (1990) 38, 473–479; doi:10.1038/ki.1990.228

Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin II receptor antagonist

Ming-Hong Xie, Fu-Ying Liu, Pancras C Wong, Pieter B M W M Timmermans and Martin G Cogan

Cardiovascular Research Institute and Departments of Medicine, University of California and Veterans Administration Medical Center, San Francisco, California, Medical Products Department, Pharmaceutical Research Division, E. I. du Pont de Nemours & Company, Inc., Wilmington, Delaware, USA

Correspondence: Martin G Cogan MD, Nephrology Section (111J) Veterans Administration Medical Center, 4150 Clement St., San Francisco, California 94121, USA.

Received 27 December 1989; Revised 19 March 1990; Accepted 26 April 1990.

Top

Abstract

Proximal nephron and renal effects of DuP 753, a nonpeptide angiotensin II receptor antagonist. The purpose of these studies was to quantitatively assess the role of endogenous angiotensin II activity in controlling transport in the proximal convoluted tubule (PCT) and whole nephron. We used the nonpeptide angiotensin II receptor antagonist DuP 753, which lacks the agonist and kinin/prostaglandin-inducing properties of saralasin and captopril, respectively. During in vivo microperfusion in the Munich-Wistar rat, we found that DuP 753 had a powerful inhibitory effect on bicarbonate (370 plusminus 3 to 200 plusminus 9 pEq/mm o min, P < 0.001), chloride (214 plusminus 3 to 105 plusminus 9 pEq/mm dot min, P < 0.001), and water (5.2 plusminus 0.1 to 2.8 plusminus 0.2 nl/mm dot min, P < 0.001) absorption in the S1 subsegment of the PCT. At maximally effective doses, DuP 753 (10 mg/kg i.v.) was significantly more effective than was captopril (3 mg/kg i.v.) in inhibiting sodium chloride transport in the S1 PCT. DuP 753 is the most potent diuretic ever described in this segment. Consistent with the axial decline of angiotensin II receptor density in the PCT, DuP 753 was a less effective transport inhibitor in the S2 subsegment of the PCT, similar to captopril. Though downstream reabsorptive elements partially compensate for the action in the earliest segment of the nephron, we also showed using free-flow micropuncture and clearance techniques that DuP 753 induces a substantial diuresis, natriuresis and chloruresis. In conclusion, the marked decrease in S1 PCT fluid and electrolyte absorption induced by DuP 753 indicates that endogenous angiotensin II exerts significant tonic support of proximal transport in vivo.

Top

References

  1. Cogan MG: Angiotensin II: A powerful controller of sodium transport in the early proximal tubule. Hypertension 15:451–458, 1990 | PubMed | ISI | ChemPort |
  2. Blantz RC: The glomerular and tubular actions of angiotensin II. Am J Kid Dis 10 (Suppl. 1):2–6, 1987
  3. Harris PJ, Navar LG: Tubular transport responses to angiotensin. Am J Physiol 248 (Renal Fluid Electrol Physiol 17):F621–F630, 1985 | PubMed | ISI | ChemPort |
  4. Liu F-Y, Cogan MG: Angiotensin II: A potent regulator of acidification in the rat early proximal convoluted tubule. J Clin Invest 80:272–275, 1987 | PubMed | ISI | ChemPort |
  5. Liu F-Y, Cogan MG: Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule. Modes of action, mechanism, and kinetics. J Clin Invest 82:601–607, 1988 | PubMed | ISI | ChemPort |
  6. Liu F-Y, Cogan MG: Angiotensin II stimulates early proximal bicarbonate absorption in the rat by decreasing cyclic adenosine monophosphate. J Clin Invest 84:83–91, 1989 | PubMed | ISI | ChemPort |
  7. Zusman RM: Renin- and non-renin-mediated antihypertensive actions of converting enzyme inhibitors. Kidney Int 25:969–983, 1984
  8. Carini DJ, Duncia JV: Angiotensin II Receptor Blocking Imidazoles. European patent application 0253310. Issued to E. I. du Pont de Nemours & Co., Inc., Wilmington, DE, 1988
  9. Chiu AT, McCall DE, Price WA, Wong PC, Carini DJ, Duncia JV, Wexler RR, Yoo SE, Johnson AL, Timmermans PBMWM: Nonpeptide angiotensin II receptor antagonists. VII. Cellular and biochemical pharmacology of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 252:711–718, 1990 | PubMed | ChemPort |
  10. Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM: Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 252:719–725, 1990 | PubMed | ChemPort |
  11. Wong PC, Price WA, Chiu AT, Duncia JV, Carini DJ, Wexler RR, Johnson AL, Timmermans PBMWM: Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 252:726–732, 1990
  12. Cogan MG, Maddox DA, Lucci MS, Rector FC Jr: Control of proximal bicarbonate reabsorption in normal and acidotic rats. J Clin Invest 64:1168–1180, 1979 | PubMed | ChemPort |
  13. Liu F-Y, Cogan MG: Axial heterogeneity of bicarbonate, chloride and water transport in the rat proximal convoluted tubule. Effects of change in luminal flow rate and of alkalemia. J Clin Invest 78:1547–1557, 1986 | PubMed | ISI | ChemPort |
  14. Liu F-Y, Cogan MG: Flow dependence of bicarbonate transport in the early (S1) proximal convoluted tubule. Am J Physiol 254 (Renal Fluid Electrol Physiol 23):F851–F855, 1988
  15. Liu F-Y, Cogan MG: Role of angiotensin II in glomerulo-tubular balance. Am J Physiol (in press)
  16. Brown J: Effects of interrupting the renin-angiotensin system on sodium excretion in man. J Physiol 395:17–40, 1988
  17. Hollenberg NK, Meggs LG, Williams GH, Katz J, Garnic JD, Harrington DP: Sodium intake and renal responses to captopril in normal man and in essential hypertension. Kidney Int 20:240–245, 1981 | PubMed | ISI | ChemPort |
  18. McNabb WR, Noormohamed FH, Brooks BA, Till AE, Lant AF: Effects of repeated doses of enalapril on renal function in man. Br J Clin Pharmacol 19:353–361, 1985 | PubMed |
  19. Steiner RW, Tucker BJ, Blantz RC: Glomerular hemodynamics in rats with chronic sodium depletion. Effect of saralasin. J Clin Invest 64:503–512, 1979 | PubMed | ChemPort |
  20. Pelayo JC, Blantz RC: Analysis of renal denervation in the hydropenic rat: Interactions with angiotensin II. Am J Physiol 246 (Renal Fluid Electrol Physiol 15):F87–F95, 1984
  21. Harris PJ, Navar LG, Ploth DW: Evidence for angiotensin-stimulated proximal tubular fluid reabsorption in normotensive and hypertensive rats: Effect of acute administration of captopril. Clin Sci 66:541–544, 1984
  22. Schuster VL, Kokko JP, Jacobson HR: Angiotensin II directly stimulates sodium transport in rabbit proximal convoluted tubules. J Clin Invest 73:507–515, 1984 | PubMed | ChemPort |
  23. Berry CA, Cogan MG: Influence of peritubular protein on solute absorption in the rabbit proximal tubule: A specific effect on NaCl transport. J Clin Invest 68:506–516, 1981

Extra navigation

.
ADVERTISEMENT