Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Apr 15;97(8):1916–1923. doi: 10.1172/JCI118623

Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.

S Rajagopalan 1, S Kurz 1, T Münzel 1, M Tarpey 1, B A Freeman 1, K K Griendling 1, D G Harrison 1
PMCID: PMC507261  PMID: 8621776

Abstract

We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.

Full Text

The Full Text of this article is available as a PDF (278.2 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Alderman M. H., Madhavan S., Ooi W. L., Cohen H., Sealey J. E., Laragh J. H. Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med. 1991 Apr 18;324(16):1098–1104. doi: 10.1056/NEJM199104183241605. [DOI] [PubMed] [Google Scholar]
  2. Arnal J. F., Michel J. B., Harrison D. G. Nitric oxide in the pathogenesis of hypertension. Curr Opin Nephrol Hypertens. 1995 Mar;4(2):182–188. doi: 10.1097/00041552-199503000-00012. [DOI] [PubMed] [Google Scholar]
  3. Berk B. C., Vekshtein V., Gordon H. M., Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension. 1989 Apr;13(4):305–314. doi: 10.1161/01.hyp.13.4.305. [DOI] [PubMed] [Google Scholar]
  4. Bolli R., Jeroudi M. O., Patel B. S., DuBose C. M., Lai E. K., Roberts R., McCay P. B. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc Natl Acad Sci U S A. 1989 Jun;86(12):4695–4699. doi: 10.1073/pnas.86.12.4695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Crawford D. C., Chobanian A. V., Brecher P. Angiotensin II induces fibronectin expression associated with cardiac fibrosis in the rat. Circ Res. 1994 Apr;74(4):727–739. doi: 10.1161/01.res.74.4.727. [DOI] [PubMed] [Google Scholar]
  6. Diederich D., Skopec J., Diederich A., Dai F. X. Endothelial dysfunction in mesenteric resistance arteries of diabetic rats: role of free radicals. Am J Physiol. 1994 Mar;266(3 Pt 2):H1153–H1161. doi: 10.1152/ajpheart.1994.266.3.H1153. [DOI] [PubMed] [Google Scholar]
  7. Everett A. D., Tufro-McReddie A., Fisher A., Gomez R. A. Angiotensin receptor regulates cardiac hypertrophy and transforming growth factor-beta 1 expression. Hypertension. 1994 May;23(5):587–592. doi: 10.1161/01.hyp.23.5.587. [DOI] [PubMed] [Google Scholar]
  8. Fernandez-Alfonso M. S., Ganten D., Paul M. Mechanisms of cardiac growth. The role of the renin-angiotensin system. Basic Res Cardiol. 1992;87 (Suppl 2):173–181. doi: 10.1007/978-3-642-72477-0_15. [DOI] [PubMed] [Google Scholar]
  9. Garg U. C., Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989 May;83(5):1774–1777. doi: 10.1172/JCI114081. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Geisterfer A. A., Peach M. J., Owens G. K. Angiotensin II induces hypertrophy, not hyperplasia, of cultured rat aortic smooth muscle cells. Circ Res. 1988 Apr;62(4):749–756. doi: 10.1161/01.res.62.4.749. [DOI] [PubMed] [Google Scholar]
  11. Griendling K. K., Minieri C. A., Ollerenshaw J. D., Alexander R. W. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res. 1994 Jun;74(6):1141–1148. doi: 10.1161/01.res.74.6.1141. [DOI] [PubMed] [Google Scholar]
  12. Himeno H., Crawford D. C., Hosoi M., Chobanian A. V., Brecher P. Angiotensin II alters aortic fibronectin independently of hypertension. Hypertension. 1994 Jun;23(6 Pt 2):823–826. doi: 10.1161/01.hyp.23.6.823. [DOI] [PubMed] [Google Scholar]
  13. Lin L., Mistry M., Stier C. T., Jr, Nasjletti A. Role of prostanoids in renin-dependent and renin-independent hypertension. Hypertension. 1991 Apr;17(4):517–525. doi: 10.1161/01.hyp.17.4.517. [DOI] [PubMed] [Google Scholar]
  14. Marrero M. B., Schieffer B., Paxton W. G., Heerdt L., Berk B. C., Delafontaine P., Bernstein K. E. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature. 1995 May 18;375(6528):247–250. doi: 10.1038/375247a0. [DOI] [PubMed] [Google Scholar]
  15. Mohazzab K. M., Kaminski P. M., Wolin M. S. NADH oxidoreductase is a major source of superoxide anion in bovine coronary artery endothelium. Am J Physiol. 1994 Jun;266(6 Pt 2):H2568–H2572. doi: 10.1152/ajpheart.1994.266.6.H2568. [DOI] [PubMed] [Google Scholar]
  16. Mohazzab K. M., Kaminski P. M., Wolin M. S. NADH oxidoreductase is a major source of superoxide anion in bovine coronary artery endothelium. Am J Physiol. 1994 Jun;266(6 Pt 2):H2568–H2572. doi: 10.1152/ajpheart.1994.266.6.H2568. [DOI] [PubMed] [Google Scholar]
  17. Mohazzab K. M., Wolin M. S. Properties of a superoxide anion-generating microsomal NADH oxidoreductase, a potential pulmonary artery PO2 sensor. Am J Physiol. 1994 Dec;267(6 Pt 1):L823–L831. doi: 10.1152/ajplung.1994.267.6.L823. [DOI] [PubMed] [Google Scholar]
  18. Mohazzab K. M., Wolin M. S. Sites of superoxide anion production detected by lucigenin in calf pulmonary artery smooth muscle. Am J Physiol. 1994 Dec;267(6 Pt 1):L815–L822. doi: 10.1152/ajplung.1994.267.6.L815. [DOI] [PubMed] [Google Scholar]
  19. Mügge A., Elwell J. H., Peterson T. E., Hofmeyer T. G., Heistad D. D., Harrison D. G. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res. 1991 Nov;69(5):1293–1300. doi: 10.1161/01.res.69.5.1293. [DOI] [PubMed] [Google Scholar]
  20. Münzel T., Sayegh H., Freeman B. A., Tarpey M. M., Harrison D. G. Evidence for enhanced vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Invest. 1995 Jan;95(1):187–194. doi: 10.1172/JCI117637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Naftilan A. J., Gilliland G. K., Eldridge C. S., Kraft A. S. Induction of the proto-oncogene c-jun by angiotensin II. Mol Cell Biol. 1990 Oct;10(10):5536–5540. doi: 10.1128/mcb.10.10.5536. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Neyses L., Nouskas J., Luyken J., Fronhoffs S., Oberdorf S., Pfeifer U., Williams R. S., Sukhatme V. P., Vetter H. Induction of immediate-early genes by angiotensin II and endothelin-1 in adult rat cardiomyocytes. J Hypertens. 1993 Sep;11(9):927–934. doi: 10.1097/00004872-199309000-00006. [DOI] [PubMed] [Google Scholar]
  23. Ohanian J., Heagerty A. M. Membrane-associated diacylglycerol kinase activity is increased by noradrenaline, but not by angiotensin II, in arterial smooth muscle. Biochem J. 1994 May 15;300(Pt 1):51–56. doi: 10.1042/bj3000051. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Ohara Y., Peterson T. E., Harrison D. G. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Invest. 1993 Jun;91(6):2546–2551. doi: 10.1172/JCI116491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pagano P. J., Ito Y., Tornheim K., Gallop P. M., Tauber A. I., Cohen R. A. An NADPH oxidase superoxide-generating system in the rabbit aorta. Am J Physiol. 1995 Jun;268(6 Pt 2):H2274–H2280. doi: 10.1152/ajpheart.1995.268.6.H2274. [DOI] [PubMed] [Google Scholar]
  26. Pfeffer M. A., Braunwald E., Moyé L. A., Basta L., Brown E. J., Jr, Cuddy T. E., Davis B. R., Geltman E. M., Goldman S., Flaker G. C. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med. 1992 Sep 3;327(10):669–677. doi: 10.1056/NEJM199209033271001. [DOI] [PubMed] [Google Scholar]
  27. Radomski M. W., Palmer R. M., Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987 Sep;92(1):181–187. doi: 10.1111/j.1476-5381.1987.tb11310.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ratajska A., Campbell S. E., Cleutjens J. P., Weber K. T. Angiotensin II and structural remodeling of coronary vessels in rats. J Lab Clin Med. 1994 Sep;124(3):408–415. [PubMed] [Google Scholar]
  29. Sakata A., Ida E., Tominaga M., Onoue K. Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fc gamma receptor-mediated superoxide generation in macrophages. J Immunol. 1987 Jun 15;138(12):4353–4359. [PubMed] [Google Scholar]
  30. Seyedi N., Xu X., Nasjletti A., Hintze T. H. Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension. 1995 Jul;26(1):164–170. doi: 10.1161/01.hyp.26.1.164. [DOI] [PubMed] [Google Scholar]
  31. Sumimoto H., Kage Y., Nunoi H., Sasaki H., Nose T., Fukumaki Y., Ohno M., Minakami S., Takeshige K. Role of Src homology 3 domains in assembly and activation of the phagocyte NADPH oxidase. Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5345–5349. doi: 10.1073/pnas.91.12.5345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Taubman M. B., Berk B. C., Izumo S., Tsuda T., Alexander R. W., Nadal-Ginard B. Angiotensin II induces c-fos mRNA in aortic smooth muscle. Role of Ca2+ mobilization and protein kinase C activation. J Biol Chem. 1989 Jan 5;264(1):526–530. [PubMed] [Google Scholar]
  33. Tesfamariam B. Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med. 1994 Mar;16(3):383–391. doi: 10.1016/0891-5849(94)90040-x. [DOI] [PubMed] [Google Scholar]
  34. Thomson L., Trujillo M., Telleri R., Radi R. Kinetics of cytochrome c2+ oxidation by peroxynitrite: implications for superoxide measurements in nitric oxide-producing biological systems. Arch Biochem Biophys. 1995 Jun 1;319(2):491–497. doi: 10.1006/abbi.1995.1321. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES