Angiotensin-II-Rezeptoren: Physiologische und pharmakologische Bedeutung

  • P. B. M. W. M. Timmermans
  • R. D. Smith

Zusammenfassung

Die Bedeutung des Renin-Angiotensin-Systems (RAS) für die Regulation des Blutdrucks und für die Entstehung kardiovaskulärer Erkrankungen ist gut untersucht [81, 146]. Angiotensin II (Ang II) ist der primäre Mediator des RAS. Der Name „RAS“ ist historisch zwar korrekt [122], er spiegelt jedoch nicht die Bedeutung des Ang II als dem zentralen Mediator aller physiologischen oder pathologischen Wirkungen des RAS wider [147]. Ang II ist ein Oktapeptid, das im Körper aus Angiotensinogen oder Angiotensin I (Ang I) synthetisiert wird (Abb. 1). Die Konversion des biologisch inaktiven Ang I zum biologisch aktiven Ang II wird primär durch das Angiotensin-Konversions-Enzym (ACE) (auch bekannt als Kininase II) in den Endothelzellen der Lunge bewirkt. Ang II kann jedoch auch lokal in verschiedenen Geweben synthetisiert werden; zudem können andere proteolytische Enzyme, wie z.B. die Chymasen [61], an der Synthese von Ang II beteiligt sein. Ang II interagiert mit spezifischen Rezeptoren, die entweder an das G-Protein/ Adenylatcyclase/cAMP-System oder aber an das Phospholipase/IP3/DG-System gekoppelt sind [26]. Ang-II-Rezeptoren sind ubiquitär im Organismus verteilt. Zirkulierendes Ang II übt wichtige hormonale Wirkungen auf diverse Zielgewebe und Zielorgane aus [119]. Zudem findet in der letzten Zeit die Bedeutung lokal freigesetzten Ang II, das auf benachbarte Zellen (sog. „parakrine Funktion“) oder auf die Ursprungszellen selbst (sog. „autokrine Funktion“) wirken kann [67], zunehmend Beachtung.

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Literatur

  1. 1.
    Abassi ZA, Kelly G, Golomb E et al. (1994) Losartan improves the natriuretic response to ANF in rats with high output heart failure. J Pharmacol Exp Ther 268(1):224–230PubMedGoogle Scholar
  2. 2.
    Alderman MH, Madhovan S, Ooi WL et al. (1991) Association of the renin-sodium profile with the risk of myocardial infarction in patients with hypertension. N Engl J Med 324:1098–1104PubMedGoogle Scholar
  3. 3.
    Ambuhl P, Felix D, Imboden H et al. (1992) Effects of angiotensin II and its selective antagonists on inferior olivary neurons. Regul Pept 41(l):19–26PubMedGoogle Scholar
  4. 4.
    Anderson GH Jr, Kutscher C, Sutterer JR et al. (1994) Reversal of stroke in the rat by using blockers of the renin angiotensin system. FASEB J 8 (No 5, Pt II). A3788, (Abstr)Google Scholar
  5. 5.
    Azuma H, Hamasaki H, Niimi Y (1992) Prevention of intimal thickening after endothelial removal by a nonpeptide angiotensin II receptor antagonist, losartan. Br J Pharmacol 106:665–671PubMedGoogle Scholar
  6. 6.
    Barnes JM, Barber PC, Barnes NM (1991) Identification of angiotensin II receptor subtypes in human brain. Neuroreport 2:605–608PubMedGoogle Scholar
  7. 7.
    Batin P, Gardiner SM, Compton AM et al. (1991) Regional and cardiac haemodynamic effects of the nonpeptide angiotensin II antagonist, DuP 753, in conscious rats. FASEB J 5/4, Part I: A841, (Abstr)Google Scholar
  8. 8.
    Blankley CJ, Hodges JC, Klutchko SR et al. (1991) Synthesis and structure-activity relationships of a novel series of nonpeptide angiotensin II receptor binding inhibitors specific for the AT2 subtype. J Med Chem 34:3248–3260PubMedGoogle Scholar
  9. 9.
    Böhm M, Lee M, Kreutz R et al. (1993) The angiotensin II antagonist BIBR277 normalized blood pressure and improves kidney damage in TGR (mREN2)27. FASEB J 7(3):A246 (Abstr)Google Scholar
  10. 10.
    Bottari SP, King IN, Reichlin S et al. (1992) The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. Biochem Biophys Res Commun 183(1): 206–211PubMedGoogle Scholar
  11. 11.
    Bottari SP, DeGasparo M, Steckelings UM et al. (1993) Angiotensin II receptor subtypes: Characterization, signalling mechanisms, and possible physiological implications. Front Neuroendocrinol 14(2): 123–172PubMedGoogle Scholar
  12. 12.
    Bourgeois R, Laparote S, Escher E (1993) The myoproliferative response of vascular smooth muscle after injury is angiotensin II mediated through the AT1 receptor. FASEB J 7(3): A47, (Abstr)Google Scholar
  13. 13.
    Brechler V, Jones PW, Levens NR et al. (1993) Agonistic and antagonistic properties of angiotensin analogs at the AT2 receptor in PC12W cells. Regul Pept 44:207–213PubMedGoogle Scholar
  14. 14.
    Broten T (1995) Evaluation of the hemodynamic effects of losartan, enalapril, and Captopril after myocardial infarction in rats. Pers ComGoogle Scholar
  15. 15.
    Bui JD, Kimura B, Phillips MI (1992) Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p. o. does not readily cross the blood brain barrier. Eur J Pharmacol 219(1): 147–152PubMedGoogle Scholar
  16. 16.
    Bumpus FM, Catt JK Chiu AT et al. (1991) Nomenclature for angiotensin receptors. Hypertension 17(5):720–721PubMedGoogle Scholar
  17. 17.
    Bunkenburg B, Schnell C, Baum HP et al. (1991) Prolonged angiotensin II antagonism in spontaneously hypertensive rats — hemodynamic and biochemical consequences. Hypertension 18(3): 278–288PubMedGoogle Scholar
  18. 18.
    Burns KD, Homma T, Harris RC (1993) The intrarenal renin angiotensin system. Semin Nephrol 13(1): 13–30PubMedGoogle Scholar
  19. 19.
    Cachofeiro V, Sakakibara T, Nasjletti A (1992) Kinins, nitric oxide, and the hypotensive effect of Captopril and ramiprilat in hypertension. Hypertension 19(2): 138–145PubMedGoogle Scholar
  20. 20.
    Camargo MJF, VonLutterotti N, Pecker MS et al. (1991) DuP 753 increases survival in spontaneously hypertensive stroke-prone rats fed a high sodium diet. Am J Hypertens 4/4, Part 2:341S–345SGoogle Scholar
  21. 21.
    Camargo MJF, VonLutterotti N, Campbell WG et al. (1993) Control of blood pressure and end organ damage in maturing salt loaded stroke prone spontaneously hypertensive rats by oral angiotensin II receptor blockade. J Hypertens 11(1): 31–40PubMedGoogle Scholar
  22. 22.
    Chang RSL, Lotti VJ (1991) Angiotensin receptor subtypes in rat, rabbit and monkey tissues: Relative distribution and species dependency. Life Sei 49(20): 1485–1490Google Scholar
  23. 23.
    Chansei D, Czekalski S, Pham P et al. (1992) Characterization of angiotensin II receptor subtpyes in human glomeruli and mesangial cells. Am J Physiol 262(3):F432-F441Google Scholar
  24. 24.
    Capasso JM, Li P, Meggs LG et al. (1994) Efficacy of angiotensin converting enzyme inhibition and AT1 receptor blockade on cardiac pump performance after myocardial infarction in rats. J Cardiovasc Pharmacol 23 (4): 584–593PubMedGoogle Scholar
  25. 25.
    Case DB, Wallace JM, Keim NJ et al. (1976) Usefulness and limitations of saralasin, a partial competitive agonist of angiotensin II, for evaluating the renin and sodium factors in hypertensive patients. Am J Med 60: 825–836PubMedGoogle Scholar
  26. 26.
    Catt KJ, Sandberg K, Balla T (1993) Angiotensin II receptors and signal transduction mechanism. In: Cellular and molecular biology of the renin angiotensin system. CRC Press, Boca Raton FL, Raizada MK, Phillips MI, Sumners C (eds) pp 307–356Google Scholar
  27. 27.
    Cazaubon C, Gougat J, Bousquet F et al. (1993) Pharmacological characterization of SR 47436, a new nonpeptide AT1 subtype angiotensin II receptor antagonist. J Pharmacol Exp Ther 265(2): 826–834PubMedGoogle Scholar
  28. 28.
    Chiu AT, McCall DE, Price WA et al. (1991) In vitro pharmacology of DuP 753, a nonpeptide All receptor antagonist. Am J Hypertens 4(4), part 2:282S-287SPubMedGoogle Scholar
  29. 29.
    Chiu AT, Herblin WF, Ardecky RJ et al. (1989) Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun 165(1): 196–203PubMedGoogle Scholar
  30. 30.
    Chiu AT, Carini DJ, Duncia JV et al. (1991) DuP 532: A second generation of nonpeptide angiotensin II receptor antagonists. Biochem Biophys Res Commun 177(1):209–217PubMedGoogle Scholar
  31. 31.
    Christ DD, Wong PC, Wong YN et al. (1994) The pharmacokinetics and pharmacodynamics of the angiotensin II receptor antagonist losartan potassium (DUP 753/MK954) in the dog. J Pharmacol Exp Ther 268(3): 1199–1205PubMedGoogle Scholar
  32. 32.
    Christen Y, Waeber B, Nussberger J et al. (1991) Oral administration of DuP 753, a specific angiotensin II antagonist, to normal male volunteers: Inhibition of pressor response to exogenous angiotensin I and II. Circulation 83(4): 1333–1342PubMedGoogle Scholar
  33. 33.
    Chua CC, Diglio CA, Siu BB et al. (1994) Angiotensin II induces TGF beta 1 production in rat heart endothelial cells. Biochim Biophys Acta 1223(1): 141–147PubMedGoogle Scholar
  34. 34.
    Cody RJ, Brown DM, Hunnicutt M et al. (1993) Hemodynamic and arterial compliance responses to chronic specific angiotensin II inhibition in the spontaneously hypertensive rat. Am J Hypertens 6(5 pt 2):3A (Abstr)Google Scholar
  35. 35.
    Cogan MG, Xie MH, Liu FY et al. (1991) Effects of DuP 753 on proximal nephron and renal transport. Am J Hypertens 4(4): 315S–320SPubMedGoogle Scholar
  36. 36.
    Deck CC, Gaballa MA, Raya TE (1993) Renal function in rats with experimental heart failure: Angiotensin II blockade versus converting enzyme inhibition. Circulation 88(4, Pt 2, Suppl): 1–514 (Abstr)Google Scholar
  37. 37.
    DeLeon H, Bonhomme MC, Thibault G et al. (1993) Reassessment of ANF and ANG II receptors in rat mesenteric arteries. Hypertension 22(3): 424 (Abstr)Google Scholar
  38. 38.
    Dostal DE, Baker KM (1992) Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart. Am J Hypertens 5:276–280PubMedGoogle Scholar
  39. 39.
    Duncia JV, Carini DJ, Chiu AT et al. (1992) The discovery of DuP 753, a potent, orally active nonpeptide angiotensin II receptor antagonist. Med Res Rev 12(2): 149–191PubMedGoogle Scholar
  40. 40.
    Edwards RM, Aiyar N, Ohlstein EH et al. (1992) Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F108566. J Pharmacol Exp Ther 260(1) 175–181PubMedGoogle Scholar
  41. 41.
    ElDahr SS, Gee J, Dipp S et al. (1993) Upregulation of renin angiotensin system and downregulation of kallikrein in obstructive nephropathy. Am J Physiol 264:F874-F881Google Scholar
  42. 42.
    Faison EP, Snavely DB, Thiyagarajan B et al. (1994) Effects of modulators of the renin angiotensin aldosterone system on cough. J Hypertens 12 (Suppl 3):#368 (Abstr)Google Scholar
  43. 43.
    Ferner RE (1994) Adverse effects of angiotensin converting enzyme inhibitors. Adv Drug React Bull 141:528–531Google Scholar
  44. 44.
    Feuillan P, Millan MA, Aguilera G (1993) Angiotensin II binding sites in the rat fetus: Characterization of receptor subtypes and interaction with guanyl nucleotides. Regual Pept 44(2): 159–169Google Scholar
  45. 45.
    Fitzpatrick MA, Rademaker MT, Charles CJ et al. (1992) Angiotensin II receptor antagonism in ovine heart failure: Acute hemodynamic, hormonal, and renal effects. Am J Physiol 263: H250–H256PubMedGoogle Scholar
  46. 46.
    Fleetwood G, Boutinet S, Meier M et al. (1991) Involvement of the renin-angiotensin system in ischemic damage and reperfusion arrhythmias in the isolated perfused rat heart. J Cardiovasc Pharmacol 17:351–356PubMedGoogle Scholar
  47. 47.
    Fogo A, Tanaka R, Yoshioka T et al. (1993) Proteinuria and glomerulosclerosis have different pathogenesis in puromycin aminonucleoside (PAN) nephrosis: Roles of angiotensin II and bradykinin. Congress of Nephrology Xllth: 34, (Abstr)Google Scholar
  48. 48.
    Fornes P, Richer C, Vacher E et al. (1993) Losartan’s protective effects in stroke prone spontaneously hypertensive rats persist durably after treatment withdrawal. J Cardiovasc Pharmacol 22:305–313PubMedGoogle Scholar
  49. 49.
    Gansevoort RT, DeZeeuw D, Dejong PE (1992) Antiproteinuric effect of the angiotensin II (All) receptor antagonist MK-954 in nondiabetic renal disease. J Am Soc Nephrol 3(3): 282 (Abstr)Google Scholar
  50. 50.
    Gekle M, Silbernagl S (1993) Mechanism of ochratoxin A induced reduction of — glomerular filtration rate in rats. J Pharmacol Exp Ther 267(1):316–321PubMedGoogle Scholar
  51. 51.
    Gibson RE, Thorpe HH, Cartwright ME et al. (1991) Angiotensin II receptor subtypes in the renal cortex of rat and rhesus monkeys. Am J Physiol 261(3 Pt 2): F512-F518PubMedGoogle Scholar
  52. 52.
    Goldberg MR, Tanaka W, Barchowsky A et al. (1993) Effects of losartan on blood pressure, plasma renin activity, and angiotensin II in volunteers. Hypertension 21 (5): 704–713PubMedGoogle Scholar
  53. 53.
    Gottlieb SS, Dickstein K, Fleck E et al. (1993) Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 88(4): 1602–1609PubMedGoogle Scholar
  54. 54.
    Gyurko R, Kimura B, Kurian P et al. (1992) Angiotensin II receptor subtypes play opposite roles in regulating phosphatidylinositol hydrolysis in rat skin slices. Biochem iBiophys Res Commun 186(1): 285–292Google Scholar
  55. 55.
    Hall JE (1991) Control of blood pressure by the renin-angiotensin-aldosterone system. Clin Cardiol 14 (Suppl IV):6–21Google Scholar
  56. 56.
    Hall JM (1993) Bradykinin receptors: Pharmacological properties and biological roles. Pharmacol Ther 56:131–190Google Scholar
  57. 57.
    Hajnoczky G, Csordas G, Bago A et al. (1992) Angiotensin II exerts its effect on aldosterone production and potassium permeability through receptor subtype AT1 in rat adrenal glomerulosa cells. Biochem Pharmacol 43(5): 1009–1012PubMedGoogle Scholar
  58. 58.
    Hartman JC, Hullinger TG, Wall TM et al. (1993) Reduction of myocardial infarct size by ramiprilat is independent of angiotensin II synthesis inhibition. Eur J Pharmacol 234 (2–3): 229–236PubMedGoogle Scholar
  59. 59.
    Hime NJ, Frewin DB, Head RJ (1992) Short term treatment with losartan attenuates contractile responses in the mesenteric vascular bed preparation in the spontaneously hypertensive rat. Clin Exp Pharmacol Physiol (Suppl) 21:28 (Abstr)Google Scholar
  60. 60.
    Honma H, Nakamura T, Ikeda Y et al. (1994) Renal protective effects of the angiotensin II antagonist CV-11974 in spontaneously hypertensive rats stroke prone. J Hypertens 12 (Suppl 3):#2075 (Abstr)Google Scholar
  61. 61.
    Husain A (1993) The chymase angiotensin system in humans. J Hypertens 11:1155–1159PubMedGoogle Scholar
  62. 62.
    Hutchison FN, Webster SK (1992) Effect of ANG-II receptor antagonist on albuminuria and renal function in passive Heymann nephritis. Am J Physiol 263(2):F311–F318Google Scholar
  63. 63.
    Inagami T, Iwai N, Sasaki K et al. (1993) Angiotensin II receptors cloning and regulation. Arzneimittelforschung Drug Res 43 (2 A): 226–228Google Scholar
  64. 64.
    Inagami T, Iwai N, Sasaki K et al. (1992) Cloning, expression, and regulation of angiotensin II receptors. In: CRC Press, Boca Raton, Raizada MK, Phillips MI, Sumners C (eds) pp 273–291Google Scholar
  65. 65.
    Janiak P, Pillon A, Prost JF et al. (1992) Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hypertension 20:737–745PubMedGoogle Scholar
  66. 66.
    Janiak P, Libert O, Vilaine JP (1994) Role of the renin angiotensin system in neointima formation after injury in rabbits. Hypertension 24:671–678PubMedGoogle Scholar
  67. 67.
    Johnston CI (1992) Renin angiotensin system: A dual tissue and hormonal system for cardiovascular control. J Hypertens 10 (Suppl 7): S13–S26Google Scholar
  68. 68.
    Johnston CI, Fabris B, Yoshida K (1993) The cardiac renin angiotensin system in heart failure. Am Heart J 126:756–760PubMedGoogle Scholar
  69. 69.
    Jonsson JR, Smid SD, Frewin DB et al. (1993) Angiotensin II-mediated facilitation of sympathetic neurotransmission in the spontaneously hypertensive rat is not associated with neuronal uptake of the peptide. J Cardiovasc Pharmacol 22(5): 750–753PubMedGoogle Scholar
  70. 70.
    Kakinuma Y, Kawamura T, Bills T et al. (1992) Blood pressure independent effect of angiotensin inhibition on vascular lesions of chronic renal failure. Kidney Int 42(l):46–55PubMedGoogle Scholar
  71. 71.
    Kambayashi Y, Bardan S, Takahashi K et al. (1993) Molecular cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem 268(33):24543–24546PubMedGoogle Scholar
  72. 72.
    Kang J, Sumners C, Posner P (1993) Angiotensin II type 2 receptor modulated changes in potassium currents in cultured neurons. Am J Physiol 265(3): C607-C616PubMedGoogle Scholar
  73. 73.
    Kauffman RF, Bean JS, Zimmerman KM et al. (1991) Losartan, a nonpeptide angioténsin II (ANG II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteris. Life Sei 49, No. 25: PL223–PL228Google Scholar
  74. 74.
    Kawano Y, Yoshida K, Kuramochi M et al. (1992) Chronic effects of losartan, an angiotensin AT1 receptor antagonist, on blood pressure and baro-receptor reflex in spontaneously hypertensive rats. J Hypertens 10 (Suppl 4): 244 (Abstr)Google Scholar
  75. 75.
    Keith DS, Torres VE, Johnson CM et al. (1994) Effect of sodium chloride, enalapril, and losartan on the development of polycystic kidney disease in Han: SPRD rats. Am J Kidney Dis 24(3):491–498PubMedGoogle Scholar
  76. 76.
    Kohara K, Mikami H, Okuda N et al. (1993) Angiotensin blockade and the progression of renal damage in the spontaneously hypertensive rat. Hypertension 21:975–979PubMedGoogle Scholar
  77. 77.
    Kost CK Jr, Jackson EK (1993) Enhanced renal angiotensin II subtype 2 receptor responses in the spontaneously hypertensive rat. Hypertension 21(4):420–431PubMedGoogle Scholar
  78. 78.
    Lacourciere Y, Lefebvre J, Snavely DP et al. (1994) Effects of modulators of the renin angiotensin aldosterone system on cough. J Hypertens 12 (Suppl 3): #368 (Abstr)Google Scholar
  79. 79.
    Lafayette RA, Mayer G, Park SK et al. (1992) Angiotensin II receptor blockade limits glomerular injury in rats with reduced renal mass. J Clin Invest 90(3): 766–771PubMedGoogle Scholar
  80. 80.
    Laporte S, Escher E (1992) Neointima formation after vascular injury is angiotensin II mediated. Biochem Biophys Res Commun 187(3): 1510–1516PubMedGoogle Scholar
  81. 81.
    Laragh JH (1993) The renin system and new understanding of the complications of hypertension and their treatment. Arzneimittelforschung/Drug Res 43 (I): 247–254Google Scholar
  82. 82.
    Lee RJ, Brunner HR (1993) Clinical experience with angiotensin II receptor antagonists. J Human Hypertens 7 (Suppl 2): S33–S36Google Scholar
  83. 83.
    Li Z, Ferguson AV (1993) Electrophysiological evidence that subfornical organ efferents to the paraventricular nucleus utilize angiotnesin as an excitatory neurotransmitter in the rate. Pers ComGoogle Scholar
  84. 84.
    Liu ECK, Hedberg A, Goldenberg HJ et al. (1992) DuP 753, the selective angiotensin II receptor blocker, is a competitive antagonist to human platelet thromboxane A2/prostaglandin H2 (TP) receptors. Prostaglandins 44(2): 89–99PubMedGoogle Scholar
  85. 85.
    Loutzenhiser R, Epstein M, Hayashi K et al. (1991) Characterization of the renal microvascular effects of angiotensin II antagonist, DuP 753: Studies in isolated perfused hydronephrotic kidneys. Am J Hypertens 4, No 4, Part 2:309S-314SPubMedGoogle Scholar
  86. 86.
    Madhun Z, Ernsberger P, Ke FC et al. (1993) Signal transduction mediated by angiotensin II receptor subtypes expressed in rat renal mesangial cells. Regul Pept 44(2): 149–157PubMedGoogle Scholar
  87. 87.
    Matsumoto A, Suzuki H, Naitoh M et al. (1994) Angiotensin II inhibition auguments natriuretic effect of candoxatril in congestive heart failure with renal dysfunction. J Hypertens 12 (Suppl 3):#586, (Abstr)Google Scholar
  88. 88.
    McDonald K, Garr M, Francis G et al. (1993) The effect of standard and low dose ACE inhibitor therapy and angiotensin II subtype 1 receptor blockade on left ventricular remodeling in the dog. Cardiovasc Drugs Ther 7 (Suppl 2): 426 (Abstr)Google Scholar
  89. 89.
    McDonald KM, Francis GS, Carlyle PF et al. (1992) Hemodynamic, left ventricular structural and hormonal changes after discrete myocardial damage in the dog. J Am Coll Cardiol 19:460–467PubMedGoogle Scholar
  90. 90.
    Miki T, Miura T, Shamamoto K et al. (1993) Do angiotensin converting enzyme inhibitors limit myocardial infarct size? Clin Exp Pharmacol Physiol 20(6): 429–434PubMedGoogle Scholar
  91. 91.
    Milavetz J J, Raya TE, Morkin E et al. (1994) Survival after large myocardial infarction in rats: Comparison of ACE inhibition with Captopril versus direct angiotensin II blockade with losartan. Pers ComGoogle Scholar
  92. 92.
    Millet D, Desgranges C, Campan M et al. (1992) Effects of angiotensins on cellular hypertrophy ad C-fos expression in cultured arterial smooth muscle cells. Eur J Biochem 206(2):367–372PubMedGoogle Scholar
  93. 93.
    Mizuno K, Niimura S, Tani M et al. (1992) Antihypertensive and hormonal activity of MK 954 in spontaneously hypertensive rats. Eur J Pharmacol 215: 305–308PubMedGoogle Scholar
  94. 94.
    Mizuno K, Niimura S, Tani M et al. (1992) Hypotensive activity of TCV-116, a newly developed angiotensin II receptor antagonist, in spontaneously hypertensive rats. Life Sci 51:183–187Google Scholar
  95. 95.
    Mizuno K, Tani M, Hashimoto S et al. (1992) Effects of losartan, a nonpeptide angiotensin II receptor antagonist, on cardiac hypertrophy and the tissue angiotensin II content in spontaneously hypertensive rats. Life Sci 51:367–374PubMedGoogle Scholar
  96. 96.
    Moreau N, Richer C, Vincent MP et al. (1993) Sympathoinhibitory effects of losartan in spontaneously hypertensive rats. J Cardiovasc Pharmacol 22: 126–134PubMedGoogle Scholar
  97. 97.
    Morton JJ, Beattie EC, MacPherson F (1992) Angiotensin II receptor antagonist losartan has persistent effects on blood pressure in the young spontaneously hypertensive rat: Lack of relation to vascular structure. J Vase Res 29(3): 264–269Google Scholar
  98. 98.
    Mukoyama M, Nakajima M, Horiuchi M et al. (1993) Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven transmembrane receptors. J Biol Chem 268(33): 24539–24542PubMedGoogle Scholar
  99. 99.
    Murakami M, Suzuki H, Naitoh M et al. (1991) Significance of action of angiotensin II in congestive heart failure in conscious dogs. Circulation 84 (Suppl II, #4): 107 (Abstr)Google Scholar
  100. 100.
    Nelson E, Arcuri K, Ikeda L et al. (1992) Efficacy and safety of losartan in patients with essential hypertension. J Hypertens 10 (Suppl 4): S122 (Abstr)Google Scholar
  101. 101.
    Nelissen Vrancken HJMG, Struijker-Boudier HAJ, Daemen MJAP et al. (1993) Antihypertensive therapy and adaptive mechanisms in peripheral ischemia. Hypertension 22:780–788PubMedGoogle Scholar
  102. 102.
    Nishikimi T, Ohmura T, Tani T et al. (1993) Role of angiotensin II type I receptor on the development of heart failure in rats. J Am Coll Cardiol 21 (2):27A (Abstr)Google Scholar
  103. 103.
    Norris LS, Schelhorn TM, Oates PJ et al. (1993) Losartan (DuP 753) reduces increased aortic DNA synthesis in spontaneously hypertensive rats. FASEB J 7(3):A339 (Abstr)Google Scholar
  104. 104.
    Oddie CJ, Dilley RJ, Bobik A (1992) Long term angiotensin II antagonism in spontaneously hypertensive rats: Effects on blood pressure and cardiovascular amplifiers. Clin Exp Pharmacol Physiol 19(5):392–395PubMedGoogle Scholar
  105. 105.
    O’Donnell MP, Kasiske BL, Katz SA et al. (1993) Angiotensin II receptor antagonism lowers blood pressure but does not reduce glomerular injury in obese Zucker rats. FASEB J 7(3): A454 (Abstr)Google Scholar
  106. 106.
    Ogihara T, Mikami H, Higaki J et al. (1992) Clinical application of a new potent angiotensin II receptor antagonist, TCV-116. J Hypertens 10 (Suppl 4): S129 (Abstr)Google Scholar
  107. 107.
    Okada M, Kobayashi M, Satoh N et al. (1993) Effect of chronic treatment with losartan on development of hypertension in stroke prone spontaneously hypertensive rats (SHRSP): Comparative study with enalapril and hydralazine. Hypertens Res 16:49–55Google Scholar
  108. 108.
    Okunishi H, Shiota N, Ishii K et al. (1993) Pathogenic role of non-ACE-dependent angiotensin II forming system in neointimal formation. Hypertens Res 16(4):278 (Abstr)Google Scholar
  109. 109.
    Osei S, Minkes RK, Bellan JA et al. (1993) Analysis of the inhibitory effects of DuP 753 and EXP3174 on responses to angiotensin II in the feline hindquarters vascular bed. J Pharmacol Exp Ther 264(3): 1104–1112PubMedGoogle Scholar
  110. 110.
    Oster L, Laflamme AK, Moreau P et al. (1994) Effect of losartan and enalaprilat on the endothelium dependent relaxation in spontaneously hypertensive rats. J Hypertens 12 (Suppl 3): #485 (Abstr)Google Scholar
  111. 111.
    Phillips MI, Kimura B, Gyurko R (1994) Angiotensin receptor stimulation of transforming growth factor-b in rat skin and wound healing. In: Saavedra JM, Timmermans PBMWM (eds) Angiotensin receptors. Plenum, New York, pp 377–396Google Scholar
  112. 112.
    Pollock DM, Divish BJ, Polakowski JS et al. (1993) Angiotensin II receptor blockade improves renal function in rats with reduced renal mass. J Pharmacol Exp Ther 267(2):657–663PubMedGoogle Scholar
  113. 113.
    Pratt RE, Dzau VJ (1994) Trophic effects of angiotensin on blood vessels and heart. In: Robertson JIS, Nicholls MG (eds) The renin angiotensin system. Gower Medical Publishing, London, pp 31.1–31.7Google Scholar
  114. 114.
    Pratt RE, Wang D, Hein L et al. (1992) The At2 isoform of the angiotensin receptor mediates myointimal hyperplasia following vascular injury. Hypertension 20(3):432 (Abstr)Google Scholar
  115. 115.
    Prescott MF, Webb RL, Reidy MA (1992) Angiotensin converting enzyme inhibitor versus angiotensin II, AT1 receptor antagonist. Am J Pathol 139(6): 1291–1296Google Scholar
  116. 116.
    Qadri F, Culman J, Veltmar A et al. (1993) Angiotensin II induced vasopressin release is mediated through alpha 1 adrenoceptors and angiotensin II AT1 receptors in the supraoptic nucleus. J Pharmacol Exp Ther 267(2):567–574PubMedGoogle Scholar
  117. 117.
    Qing G, Garcia R (1992) Chronic captopril and losartan (DuP 753) administration in rats with high output heart failure. Am J Physiol 263 (3): 833H–840HGoogle Scholar
  118. 118.
    Raya TE, Fonken S J, Lee RW et al. (1991) Hemodynamic effects of direct angiotensin II blockade compared to converting enzyme inhibition in rat model of heart failure. Am J Hypertens 4, No 4, Part 2:334S–340SPubMedGoogle Scholar
  119. 119.
    Regoli D (1979) Receptors for angiotensin: A critical analysis. Can J Physiol Pharmacol 57(2): 129–139PubMedGoogle Scholar
  120. 120.
    Remuzzi A, Perico N, Amuchastegui CS et al. (1993) Short and long term effect of angiotensin II receptor blockade in rats with experimental diabetes. J Am Soc Nephrol 4:40–49PubMedGoogle Scholar
  121. 121.
    Richard V, Ghaleh B, Berdeaux A et al. (1993) Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anesthetized dogs. Br J Pharmacol 110(3): 969–974PubMedGoogle Scholar
  122. 122.
    Robertson JIS (1994) Renin and angiotensin: A historical review. In: Robertson JIS, Nicholls MG (eds) The renin angiotensin system. Gower, London, pp 1.1–1.18Google Scholar
  123. 123.
    Ruzicka M, Yuan B, Harmsen E et al. (1993) The renin angiotensin system and volume overload-induced cardiac hypertrophy in rats. Circulation 87(3): 921–930PubMedGoogle Scholar
  124. 124.
    Saavedra JM (1992) Brain and pituitary angiotensin. Endocr Rev 13(2): 329–380PubMedGoogle Scholar
  125. 125.
    Sachinidis A, Ko Y, Nettekoven W et al. (1992) The effect of angiotensin II DNA synthesis varies considerably in vascular smooth muscle cells from different Wistar-Kyoto rats. J Hypertens 10(10): 1159–1164PubMedGoogle Scholar
  126. 126.
    Saladini D, Jover B, Ribstein J (1992) Renal compensation to uninephrectomy (UNX) and the renin angiotensin system. J Am Soc Nephrol 3(3): 478 (Abstr)Google Scholar
  127. 127.
    Schoemaker RG, Debets JJM, Struijker-Boudier HAJ et al. (1991) Delayed but not immediate captopril theraphy improves cardiac function in conscious rats, following myocardial infarction. J Mol Cell Cardiol 23:187–197PubMedGoogle Scholar
  128. 128.
    Shibouta Y, Inada Y, Ojima M et al. (1993) Pharmacological profile of a highly potent and long acting angiotensin II receptor antagonist [(2′-(1H-tetrazol- 5-yl)biphenyl-4-yl)methyl]-1H-benzimidazole-7-carboxylic acid (CV-11974), and its prodrug, (±)-1- (cyclohexyloxycarbonyloxy)-ethyl 2-ethoxy-1- [(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1H benzimidazole-7-carboxylate (TCV-116). J Pharmacol Exp Ther 266(1): 114–120PubMedGoogle Scholar
  129. 129.
    Siegel PKS, Chang RSL, Mantlo NB et al. (1992) In vivo pharmacology of L-158, 809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist. J Pharmacol Exp Ther 262(1): 139–144Google Scholar
  130. 130.
    Smith RD, Timmermans PBMWM (1994) Human angiotensin receptor subtypes. Curr Opin Nephrol Hypertens 3:112–122PubMedGoogle Scholar
  131. 131.
    Smits JFM, Schoemaker RG, Daemen MJAP et al. (1991) Haemodynamic consequences of interference with the renin-angiotensin system following myocardial infarction in rats. Br J Pharmacol 102 (Suppl 99P) (Abstr)Google Scholar
  132. 132.
    Smits JFM, VanKrimpen C, Schoemaker RG et al. (1992) Angiotensin II receptor blockade after myocardial infarction in rats: Effects on hemodynamics, myocardial DNA synthesis, and interstitial collagen content. J Cardiovasc Pharmacol 20:772–778PubMedGoogle Scholar
  133. 133.
    Smits JFM, Passier PCJJ, Daemen MJAP (1994) ACE inhibition and AT receptor inhibition following myocardial infarction in rats: Structural and functional consequences. Can J Cardiol 10 (Suppl A): 59A (Abstr)Google Scholar
  134. 134.
    Soltis EE (1993) Alterations in vascular structure and function after short term losartan treatment in spontaneously hypertensive rats. J Pharmacol Exp Ther 266(2): 642–646PubMedGoogle Scholar
  135. 135.
    Speakman A, Hogarty DC, Puig V et al. (1992) Central angiotensin II type 1 receptor blockade with losartan in the spontaneously hpyertensive rats. FASEB J 6(5): A1872 (Abstr)Google Scholar
  136. 136.
    Stauss HM, Zhu YC, Redlich T et al. (1994) Angiotensin converting enzyme inhibition in infarct induced heart failure in rats: Bradykinin versus angiotensin II. J Cardiovasc Risk 1:255–262PubMedGoogle Scholar
  137. 137.
    Stauss HM, Zhu YC, Redlich T et al. (1993) Early and late treatment of infarction induced heart failure with a converting enzyme inhibitor: Bradykinin potentiation versus angiotensin II reduction. Hypertension 22 (3): 429 (Abstr)Google Scholar
  138. 138.
    Stearns RA, Miller RR, Doss GA et al. (1992) The metabolism of DuP 753, a nonpeptide angiotensin II receptor antagonist, by rat, monkey and human liver slices. Drug Metab Dispos 20(2):281–287PubMedGoogle Scholar
  139. 139.
    Steinberg MI, Wiest SA, Palkowitz AD (1993) Nonpeptide angiotensin II receptor antagonists. Cardiovasc Drugs Rev 11 (3): 312–358Google Scholar
  140. 140.
    Stier CT Jr, Sim G, Mahboubi K et al. (1991) Prevention of stroke and hypertensive renal disease by the angiotensin II receptor antagonist DuP 753 in salt-loaded stroke-prone SHR. In: MacGregor GA, Sever PS (eds) Current advances in ACE inhibition 2. Churchill Livingstone, Edinburgh London Melbourne New York Tokyo, pp 252–255Google Scholar
  141. 141.
    Stoll M, Steckelings UM, Bottari SP et al. (1994) Role of angiotensin II receptor subtypes in endothelial growth regulation. J Hypertens 12 (Suppl 3):#396, (Abstr)Google Scholar
  142. 142.
    Stromberg C, Naveri L, Saavedra JM (1993) Nonpeptide angiotensin AT1 and AT2 receptor ligands modulate the upper limit of cerebral blood flow autoregulation in rats. J Cereb Blood Flow Metab 13(2): 298–303PubMedGoogle Scholar
  143. 143.
    Struthers AD (1992) The clinical pharmacology of angiotensin converting enzyme inhibitors in chronic hear failure. Pharmacol Ther 53:187–197PubMedGoogle Scholar
  144. 144.
    Sudhir K, MacGregor JS, Gupta M et al. (1993) Effect of selective angiotensin II receptor antagonism and angiotensin converting enzyme inhibition on the coronary vasculature in vivo: Intravascular two dimensional and Doppler ultrasound studies. Circulation 87(3): 931–938PubMedGoogle Scholar
  145. 145.
    Sweet CS, Emmert SE, Stabilito II et al. (1987) Increased survival in rats with congestive heart failure treated with enalapril J Cardiovasc Pharmacol 10: 636–642Google Scholar
  146. 146.
    The renin angiotensin system (1994) Gower, LondonGoogle Scholar
  147. 147.
    Timmermans PBMWM, Wong PC, Chiu AT et al. (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev 45(2): 205–251PubMedGoogle Scholar
  148. 148.
    Timmermans PBMWM, Smith RD (1994) Angiotensin II receptor subtypes: Selective antagonists and functional correlates. Eur Hart J (in press)Google Scholar
  149. 149.
    Tofovic S, Pong A, Jackson EK (1991) Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats. Hypertension 18(6): 774–782PubMedGoogle Scholar
  150. 150.
    Tomiyama H, Kushiro T, Abeta H et al. (1994) Kinins contribute to the improvement of insulin sensitivity during treatment with angiotensin converting enzyme inhibitor. Hypertension 23(4): 450–455PubMedGoogle Scholar
  151. 151.
    Toney GM, Porter JP (1993) Functional role of brian AT1 and AT2 receptors in the central angiotensin II pressor response. Brain Res 603(1): 57–63PubMedGoogle Scholar
  152. 152.
    Viswanathan M, Stromberg C, Seltzer A et al. (1992) Balloon angioplasty enhances the expression of angiotensin II AT1 receptors in neointima of rat aorta. J Clin Invest 90:1707–1712PubMedGoogle Scholar
  153. 153.
    Whitebread S, Meie M, Kamber B et al. (1989) Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun 163:284–291PubMedGoogle Scholar
  154. 154.
    Widdop RE, Gardiner SM, Kemp PA et al. (1993) Differential blockade of central effects of angiotensin II by AT2 receptor antagonists. Am J Physiol 265(34): H226-H231PubMedGoogle Scholar
  155. 155.
    Widdop RE, Bartholomeusz B (1994) Effect of EXP3174, an angiotensin AT1 receptor antagonist, on baroreflex function in spontaneously hypertensive rats. J Hypertens 12 (Suppl 3):#1886 (Abstr)Google Scholar
  156. 156.
    Williams GH (1988) Converting enzyme inhibitors in the treatment of hypertension. N Engl J Med 319(23): 1517–1525PubMedGoogle Scholar
  157. 157.
    Wollert KC, Meybrunn M, Wirger A et al. (1993) Angiotensin II receptor antagonist losartan restores minimal coronary vascular resistance in postinfarction reactive cardiac hypertrophy in rats. FASEB J 7(3): A316, (Abstr)Google Scholar
  158. 158.
    Wood JM, Schnell CR, Levens NR (1993) Kidney is an important target for the antihypertensive action of an angiotensin II receptor antagonist in spontaneously hpyertensive rats. Hypertension 21:1056–1061PubMedGoogle Scholar
  159. 159.
    Wong PC, Price WA, Chiu AT et al. (1991) In vivo pharmacology of DuP 753. Am J Hypertens 4(4):288S–298SPubMedGoogle Scholar
  160. 160.
    Wong PC, Tarn SW, Herblin WF et al. (1991) Further studies on the selectivity of DuP 753, a nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol 196:201–203PubMedGoogle Scholar
  161. 161.
    Wong PC, Price WA, Chiu AT et al. (1990) Nonpeptide angiotensin II receptor antagonists. IX. Antihypertensive activity in rats of DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther 252 (2): 726–732PubMedGoogle Scholar
  162. 162.
    Wong PC, Price WA, Chiu AT et al. (1989) Nonpeptide angiotensin II receptor antagonists, IV. EXP6155 and EXP6803. Hypertension 13:489–497PubMedGoogle Scholar
  163. 163.
    Wong PC, Christ DD, Timmermans PBMWM (1992) Enhancement of losartan (DuP 753) induced angiotensin II antagonism by PD 123177 in rats. Eur J Pharmacol 220:267–270PubMedGoogle Scholar
  164. 164.
    Wong PC, Price WA, Chiu AT et al. (1990) Nonpeptide angiotensin II receptor antagonists: Studies with EXP9270 and DuP 753. Hypertension 15:823–834PubMedGoogle Scholar
  165. 165.
    Wong PC, Hart SD, Duncia JY et al. (1991) Nonpeptide angiotensin II receptor antagonists. XIII. Studies with DuP 753 and EXP3174 in dogs. Eur J Pharmacol 202:323–330PubMedGoogle Scholar
  166. 166.
    Yamagishi H, Kim S, Nishikimi T et al. (1993) Contribution of cardiac angiotensin II to ventricular remodeling in rats with myocardial infarction. J Am Coll Cardiol 21(2):301A (Abstr)Google Scholar
  167. 167.
    Yayama K, Kawao M, Tujii H et al. (1993) DuP 753 prevents the development of puromycin aminonucleoside induced nephrosis. Eur J Pharmacol 236:337–338PubMedGoogle Scholar
  168. 168.
    Zusman RM (1987) Effects of converting enzyme inhibitors on the renin angiotensin aldosterone, bradykinin, and arachidonic acid-prostaglandin systems: Correlation of chemical structure and biological activity. Am J Kidney Dis 10 (Suppl 1): 13–23PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 1996

Authors and Affiliations

  • P. B. M. W. M. Timmermans
  • R. D. Smith

There are no affiliations available

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