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. 1995 Mar 28;92(7):2924–2928. doi: 10.1073/pnas.92.7.2924

Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension.

C Chatziantoniou 1, X Ruan 1, W J Arendshorst 1
PMCID: PMC42331  PMID: 7708750

Abstract

The development of hypertension in the spontaneously hypertensive rat (SHR) is associated with renal dysfunction and vasoconstriction. The kidneys of young SHRs exhibit exaggerated reactivity to angiotensin II (Ang-II) and attenuated responses to vasodilators that normally activate the cAMP signal to buffer hormone-induced vasoconstriction. The present study investigates the mechanism(s) responsible for this abnormality in activation of the cAMP second-messenger pathway in hypertensive animals. Renal vascular reactivity was assessed in 7-week-old anesthetized SHRs and normotensive Wistar-Kyoto rats. The animals were pretreated with indomethacin to block prostanoid production throughout an experiment. Ang-II was injected into the renal artery either alone or mixed with the vasodilator fenoldopam, a dopamine-receptor agonist. These two opposing vasoactive agents were administered before and during intrarenal infusion of NaF or cholera toxin, two activators of G proteins that stimulate cAMP production. The results show that Ang-II reduced renal blood flow by 45% in both strains. In Wistar-Kyoto rats, fenoldopam reduced the Ang-II-induced decrease in renal blood flow from -45% to -30%. This protective effect of fenoldopam was increased further during infusion of NaF or cholera toxin (-18% or -19% decrease in renal blood flow). In SHRs, fenoldopam failed to attenuate Ang II-mediated vasoconstriction (-45% vs. -44%). In contrast, fenoldopam effectively blunted the Ang-II-induced vasoconstriction when it was given concurrently with NaF or cholera toxin (-27 or -31% decrease in renal blood flow). These findings provide evidence for defective interaction between receptor coupling and activation of guanine nucleotide stimulatory factor proteins in the renal microcirculation of 7-week-old SHRs. Such a deficiency could play an important role in renal dysfunction associated with the development of genetic hypertension.

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Selected References

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  1. Arendshorst W. J. Autoregulation of renal blood flow in spontaneously hypertensive rats. Circ Res. 1979 Mar;44(3):344–349. doi: 10.1161/01.res.44.3.344. [DOI] [PubMed] [Google Scholar]
  2. Arendshorst W. J., Beierwaltes W. H. Renal and nephron hemodynamics in spontaneously hypertensive rats. Am J Physiol. 1979 Mar;236(3):F246–F251. doi: 10.1152/ajprenal.1979.236.3.F246. [DOI] [PubMed] [Google Scholar]
  3. Arendshorst W. J., Chatziantoniou C., Daniels F. H. Role of angiotensin in the renal vasoconstriction observed during the development of genetic hypertension. Kidney Int Suppl. 1990 Nov;30:S92–S96. [PubMed] [Google Scholar]
  4. Beierwaltes W. H., Arendshorst W. J., Klemmer P. J. Electrolyte and water balance in young spontaneously hypertensive rats. Hypertension. 1982 Nov-Dec;4(6):908–915. doi: 10.1161/01.hyp.4.6.908. [DOI] [PubMed] [Google Scholar]
  5. Chatziantoniou C., Arendshorst W. J. Angiotensin and thromboxane in genetically hypertensive rats: renal blood flow and receptor studies. Am J Physiol. 1991 Aug;261(2 Pt 2):F238–F247. doi: 10.1152/ajprenal.1991.261.2.F238. [DOI] [PubMed] [Google Scholar]
  6. Chatziantoniou C., Arendshorst W. J. Angiotensin receptor sites in renal vasculature of rats developing genetic hypertension. Am J Physiol. 1993 Dec;265(6 Pt 2):F853–F862. doi: 10.1152/ajprenal.1993.265.6.F853. [DOI] [PubMed] [Google Scholar]
  7. Chatziantoniou C., Arendshorst W. J. Impaired ability of prostaglandins to buffer renal vasoconstriction in genetically hypertensive rats. Am J Physiol. 1992 Oct;263(4 Pt 2):F573–F580. doi: 10.1152/ajprenal.1992.263.4.F573. [DOI] [PubMed] [Google Scholar]
  8. Chatziantoniou C., Daniels F. H., Arendshorst W. J. Exaggerated renal vascular reactivity to angiotensin and thromboxane in young genetically hypertensive rats. Am J Physiol. 1990 Aug;259(2 Pt 2):F372–F382. doi: 10.1152/ajprenal.1990.259.2.F372. [DOI] [PubMed] [Google Scholar]
  9. Chatziantoniou C., Ruan X., Arendshorst W. J. Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension. Am J Physiol. 1993 Dec;265(6 Pt 2):F845–F852. doi: 10.1152/ajprenal.1993.265.6.F845. [DOI] [PubMed] [Google Scholar]
  10. Clark C. J., Milligan G., McLellan A. R., Connell J. M. Guanine nucleotide regulatory proteins in the spontaneously hypertensive rat. Hypertension. 1993 Feb;21(2):204–209. doi: 10.1161/01.hyp.21.2.204. [DOI] [PubMed] [Google Scholar]
  11. Dilley J. R., Stier C. T., Jr, Arendshorst W. J. Abnormalities in glomerular function in rats developing spontaneous hypertension. Am J Physiol. 1984 Jan;246(1 Pt 2):F12–F20. doi: 10.1152/ajprenal.1984.246.1.F12. [DOI] [PubMed] [Google Scholar]
  12. Felder R. A., Kinoshita S., Ohbu K., Mouradian M. M., Sibley D. R., Monsma F. J., Jr, Minowa T., Minowa M. T., Canessa L. M., Jose P. A. Organ specificity of the dopamine1 receptor/adenylyl cyclase coupling defect in spontaneously hypertensive rats. Am J Physiol. 1993 Apr;264(4 Pt 2):R726–R732. doi: 10.1152/ajpregu.1993.264.4.R726. [DOI] [PubMed] [Google Scholar]
  13. Graf C., Maser-Gluth C., de Muinck Keizer W., Rettig R. Sodium retention and hypertension after kidney transplantation in rats. Hypertension. 1993 May;21(5):724–730. doi: 10.1161/01.hyp.21.5.724. [DOI] [PubMed] [Google Scholar]
  14. Harrap S. B., Doyle A. E. Renal haemodynamics and total body sodium in immature spontaneously hypertensive and Wistar-Kyoto rats. J Hypertens Suppl. 1986 Oct;4(3):S249–S252. [PubMed] [Google Scholar]
  15. Harrap S. B., Wang B. Z., MacLellan D. G. Transplantation studies of the role of the kidney in long-term blood pressure reduction following brief ACE inhibitor treatment in young spontaneously hypertensive rats. Clin Exp Pharmacol Physiol. 1994 Feb;21(2):129–131. doi: 10.1111/j.1440-1681.1994.tb02480.x. [DOI] [PubMed] [Google Scholar]
  16. Jackson E. K., Herzer W. A. Defective modulation of angiotensin II-induced renal vasoconstriction in hypertensive rats. Hypertension. 1994 Mar;23(3):329–336. doi: 10.1161/01.hyp.23.3.329. [DOI] [PubMed] [Google Scholar]
  17. Kawabe K., Watanabe T. X., Shiono K., Sokabe H. Influence on blood pressure of renal isografts between spontaneously hypertensive and normotensive rats, utilizing the F1 hybrids. Jpn Heart J. 1978 Nov;19(6):886–894. doi: 10.1536/ihj.19.886. [DOI] [PubMed] [Google Scholar]
  18. Kinoshita S., Sidhu A., Felder R. A. Defective dopamine-1 receptor adenylate cyclase coupling in the proximal convoluted tubule from the spontaneously hypertensive rat. J Clin Invest. 1989 Dec;84(6):1849–1856. doi: 10.1172/JCI114371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kost C. K., Jr, Jackson E. K. Enhanced renal angiotensin II subtype 1 receptor responses in the spontaneously hypertensive rat. Hypertension. 1993 Apr;21(4):420–431. doi: 10.1161/01.hyp.21.4.420. [DOI] [PubMed] [Google Scholar]
  20. Moss J., Vaughan M. Activation of adenylate cyclase by choleragen. Annu Rev Biochem. 1979;48:581–600. doi: 10.1146/annurev.bi.48.070179.003053. [DOI] [PubMed] [Google Scholar]
  21. Raymond J. R. Hereditary and acquired defects in signaling through the hormone-receptor-G protein complex. Am J Physiol. 1994 Feb;266(2 Pt 2):F163–F174. doi: 10.1152/ajprenal.1994.266.2.F163. [DOI] [PubMed] [Google Scholar]
  22. Spiegel A. M., Shenker A., Weinstein L. S. Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction. Endocr Rev. 1992 Aug;13(3):536–565. doi: 10.1210/edrv-13-3-536. [DOI] [PubMed] [Google Scholar]
  23. Umemura S., Smyth D. D., Pettinger W. A. Defective renal adenylate cyclase response to prostaglandin E2 in spontaneously hypertensive rats. J Hypertens. 1985 Apr;3(2):159–165. doi: 10.1097/00004872-198504000-00009. [DOI] [PubMed] [Google Scholar]
  24. Yoshikawa H., Fukuda K., Baba A., Nishio H., Ueyama T., Yoshikawa A., Kuchii M., Nishio I., Masuyama Y. Deficient activity of nucleotide binding regulatory protein coupled with PGE2 receptor in renal medulla of spontaneously hypertensive rats. Am J Hypertens. 1990 Mar;3(3):230–233. doi: 10.1093/ajh/3.3.230. [DOI] [PubMed] [Google Scholar]

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