Advertisement

Clinical and physiologic significance of local tissue renin-angiotensin systems

      This paper is only available as a PDF. To read, Please Download here.
      Increasing and compelling evidence continues to amass that favors the existence of local tissue renin-angiotensin systems. All renin-angiotensin system components have been demonstrated in kidney, brain, arteries, adrenals, and other organs. Favoring its clinical importance are direct demonstration of its components in tissues; dissociation between hemodynamic and structural effects of renin-angiotensin system inhibition; evidence for local modulating roles with other humoral, autocrine/paracrine, and growth factors; and the effects of renin-angiotensin system inhibitors in patients who are anephric or have low plasma renin activity. Evidence will be presented demonstrating the hemodynamic/structural dissociation of pharmacologic agents that reduce cardiac mass in spontaneously hypertensive rats with left ventricular hypertrophy. Although centrally active adrenolytic agents, angiotensin-converting enzyme inhibitors, and calcium antagonists all reduce cardiac mass, their structural and cardiac functional effects differ greatly. Even within the angiotensin-converting enzyme inhibitor group their effects vary: improving, impairing, or not changing the Frank-Starling relationships. It is postulated that there is great variability of cardiac intramyocytic penetration of the pharmacologic agents and of their local intracellular effects on mitogenesis. The implications for cardiac function and therapy are vast.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Haber E
        • Carlson W
        The biochemistry of the renin-angiotensin system.
        in: Genest J Kuchel O Hamet P Cantin M Hypertension: physiopathology and treatment. 2nd ed. McGraw-Hill, New York1983: 171-184
        • Jin M
        • Wilhelm MJ
        • Lang RE
        • Unger T
        • Undpaintner K
        • Ganten D
        Endogenous tissue renin-angiotensin systems.
        Am J Med. 1988; 84: 28-36
        • Dzau VJ
        Circulating versus local renin-angiotensin system in cardiovascular homeostasis.
        Circulation. 1988; 77: 4-13
        • Ohkubo H
        • Nakayama K
        • Tanaka T
        • Nakanishi S
        Tissue distribution of rat angiotensinogen mRNA and structural analysis of its heterogeneity.
        J Biol Chem. 1986; 261: 319-323
        • Campbell DJ
        • Habener JF
        Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat.
        J Clin Invest. 1986; 78: 31-39
        • Dzau VJ
        • Ellison KE
        • Brody T
        • Ingelfinger J
        • Pratt RE
        A comparative study of the distributions of renin and angiotensinogen messenger ribonucleic acids in rat and mouse tissues.
        Endocrinology. 1987; 120: 2334-2338
        • Cassis LA
        • Lynch KR
        • Peach MJ
        Localization of angiotensinogen messenger RNA in rat aorta.
        Circ Res. 1988; 62: 1259-1262
        • Imai T
        • Miyazaki H
        • Hirose S
        • et al.
        Cloning and sequence analysis of cDNA for human renin precursor.
        in: Proc Natl Acad Sci USA. 80. 1983: 7405-7409
        • Field U
        • McGowan RA
        • Dickinson DP
        • Gross KW
        Tissue and gene specificity of mouse renin expression.
        Hypertension. 1984; 6: 597-603
        • Samani NJ
        • Morgan K
        • Brammar WJ
        • Swales JD
        Detection of renin messenger RNA in rat tissues: increased sensitivity using an RNAse protection technique.
        J Hypertens. 1987; 5: S19-S21
        • Paul M
        • Wagner D
        • Metzger R
        • et al.
        Quantification of renin mRNA in various mouse tissues by a novel solution hybridization assay.
        J Hypertens. 1988; 6: 247-252
        • Cohen ML
        • Kurz KD
        Angiotensin converting enzyme inhibition in tissues from spontaneously hypertensive rats after treatment with captopril or MK-421.
        J Pharmacol Exp Ther. 1982; 220: 63-69
        • Strittmarter SM
        • de Souza EB
        • Lynch DR
        • Snyder SH
        Angiotensin-converting enzyme localized in the rat pituitary and adrenal glands by [3H]captopril autoradiography.
        Endocrinology. 1986; 118: 1690-1699
        • Rosenthal J
        • von Lutterotti N
        • Thurnreiter M
        • et al.
        Suppression of renin-angiotensin system in the heart of spontaneously hypertensive rats.
        J Hypertens. 1987; 5: S23-S31
        • Rosenthal JH
        • Pfeifle B
        • Michailov ML
        • Pschorr J
        • Jacob ICM
        • Dahlheim H
        Investigations of components of the renin-angiotensin system in rat vascular tissue.
        Hypertension. 1984; 6: 383-390
        • Rightsel WA
        • Okamura T
        • Inagami T
        • et al.
        Juxtaglomerular cells grown as monolayer cell culture contain renin, angiotensin I-converting enzyme, and angiotensin I and II/III.
        Circ Res. 1982; 50: 822-829
        • Unger T
        • Badoer E
        • Ganten D
        • Lang RE
        • Rettig R
        Brain angiotensin: pathways and pharmacology.
        Circulation. 1988; 77: 40-54
        • Ganten D
        • Hermann K
        • Bayer C
        • Unger T
        • Lang RE
        Angiotensin synthesis in the brain and increased turnover in hypertensive rats.
        Science. 1983; 221: 869-871
        • Lindpaintner K
        • Wilhelm MJ
        • Jin M
        • et al.
        Tissue renin-angiotensin systems: focus on the heart.
        J Hypertens. 1987; 5: S33-S38
        • Mizuno K
        • Nakamaru M
        • Higashimori K
        • Inagami T
        Local generation and release of angiotensin II in peripheral vascular tissue.
        Hypertension. 1988; 11: 223-229
        • Levens NR
        • Peach MJ
        • Carey RM
        Role of the intrarenal renin-angiotensin system in the control of renal function.
        Circ Res. 1981; 48: 157-167
        • Ganten D
        • Hermann K
        • Unger T
        • Lang RE
        The tissue renin-angiotensin systems: focus on brain angiotensin, adrenal gland and arterial wall.
        Clin Exp Hypertens [A]. 1983; 5: 1099-1118
        • Dzau VJ
        • Burt DW
        • Pratt RE
        Molecular biology of the renin-angiotensin system.
        Am J Physiol. 1988; 255: F563-F573
        • Makrides SC
        • Mulinari R
        • Zannis VI
        • Gavras H
        Regulation of renin gene expression in hypertensive rats.
        Hypertension. 1988; 12: 405-410
        • Campbell DJ
        Circulating and tissue angiotensin systems.
        J Clin Invest. 1987; 79: 1-6
        • Aguilera G
        • Schirar A
        • Baukal A
        • Catt KJ
        Circulating angiotensin II and adrenal receptors after nephrectomy.
        Nature. 1981; 289: 507-509
        • Yu R
        • Anderton J
        • Skinner SL
        • Best JB
        Renin in anephric man.
        Am J Med. 1972; 52: 707-711
        • Fei DTW
        • Scoggins BA
        • Tregear GW
        • Coghlan JP
        Angiotensin I, II and III in sheep: a model of angiotensin production and metabolism.
        Hypertension. 1981; 3: 730-737
        • Campbell DJ
        The site of angiotensin production.
        J Hypertens. 1985; 3: 199-207
        • Brunner HR
        • Gavras H
        • Waeber B
        • et al.
        Oral angiotensin-converting enzyme inhibitor in long-term treatment of hypertensive patients.
        Ann Intern Med. 1979; 90: 19-23
        • Blane EH
        • Schorn TW
        • Bogen T
        Statine-containing renin inhibitor. Dissociation of blood pressure lowering and renin inhibition in sodium-deficient dog.
        Hypertension. 1984; 6: I111-I118
        • Haber E
        • Zusman R
        • Burton J
        • Dzau VJ
        • Barger AC
        Is renin a factor in the etiology of essential hypertension?.
        Hypertension. 1983; 5: 8-15
        • Dzau VJ
        • Gibbons GH
        Autocrine-paracrine mechanisms of vascular myocytes in systemic hypertension.
        Am J Cardiol. 1987; 60: 99I-103I
        • Re RN
        Emerging issues in the cellular biology of the cardiovascular system.
        Am J Cardiol. 1988; 62: 7G-12G
        • Oliver JA
        • Sciacca RR
        Local generation of angiotensin II as a mechanism of regulation of peripheral vascular tone in the rat.
        J Clin Invest. 1984; 74: 1247-1251
        • Zimmerman BG
        Adrenergic facilitation by angiotensin: does it serve a physiological function?.
        Clin Sci. 1981; 60: 343-348
        • Gimbrone M
        • Alexander RW
        Angiotensin II stimulation of prostaglandin production in cultured human vascular endothelium.
        Science. 1975; 189: 219-220
        • Yamaguchi K
        • Nishimura H
        Endothelium-dependent relaxation of fowl aorta induced by angiotensin II (abstr).
        Fed Proc. 1986; 54: 869
        • Reid JL
        • Rubin PC
        Peptides and central neural regulation of the circulation.
        Physiol Rev. 1987; 67: 725-749
      1. (suppl 4)
        • Lind RW
        • Johnson AK
        Central and peripheral mechanisms mediating angiotensin-induced thirst.
        in: Ganten D Printz M Phillips MI Schölkens BA The renin-angiotensin system in the brain. Experimental brain research. Springer-Verlag, Berlin1982: 353-364
        • Williams GH
        • McDonnell LM
        • Raux MC
        • Hollenberg NK
        Evidence for different angiotensin II receptors in rat adrenal glomerulosa and rabbit vascular smooth muscle cells.
        Circ Res. 1974; 34: 384-390
        • Dunn FG
        • de Carvalho JGR
        • Kem DC
        • Higgins JR
        • Frohlich ED
        Pheochromocytoma crisis induced by saralasin: relationship of angiotensin analog to catecholamine release.
        N Engl J Med. 1976; 295: 605-607
        • Kastner PR
        • Hall JE
        • Guyton AC
        Control of glomerular filtration rate: role of intrarenal angiotensin II.
        Am J Physiol. 1984; 246: F897-F906
        • Romero JC
        • Knox FG
        Mechanisms underlying pressure-related natriuresis: the role of the renin-angiotensin and prostaglandin systems.
        Hypertension. 1988; 11: 724-738
        • Faubert PF
        • Chou SY
        • Porush JG
        Regulation of papillary plasma flow by angiotensin II.
        Kidney Int. 1987; 32: 472-478
        • Schuster VL
        • Kokko JP
        • Jacobson HR
        Angiotensin II directly stimulates sodium transport in rabbit proximal convoluted tubules.
        J Clin Invest. 1984; 73: 507-515
        • Hall JE
        Regulation of glomerular filtration rate and sodium excretion by angiotensin II.
        Fed Proc. 1986; 45: 1431-1437
        • Berk BC
        • Aronow MS
        • Brock TA
        • Cragoe Jr, E
        • Gimbrone Jr, MA
        • Alexander RW
        Angiotensin II-stimulated Na+/H+ exchange in cultured vascular smooth muscle cells.
        J Biol Chem. 1987; 262: 5057-5064
        • Liu F-Y
        • Cogan MG
        Angiotensin II stimulation of hydrogen ion secretion in the rat early proximal tubule.
        J Clin Invest. 1988; 82: 601-607
        • Khairallah PA
        • Robertson AL
        • Davila D
        Effects of angiotensin II on DNA, RNA and protein synthesis.
        in: Genest J Koiw E Hypertension. Springer-Verlag, New York1972: 212-220
        • Gill GN
        • Ill CR
        • Simonian MH
        Angiotensin stimulation of bovine adrenocortical cell growth.
        in: Proc Natl Acad Sci USA. 74. 1977: 5569-5573
        • Owens GK
        Influence of blood pressure on development of aortic medial smooth muscle hypertrophy in spontaneously hypertensive rats.
        Hypertension. 1987; 9: 178-187
        • Campbell-Boswell M
        • Robertson AL
        Effects of angiotensin II and vasopression on human smooth muscle cells ef in vitro.
        Exp Mol Pathol. 1981; 35: 265-276
        • Geisterfer AAT
        • Owens GK
        Hypertropic response of cultured vascular smooth muscle cells to angiotensin II (abstr.).
        Fed Proc. 1986; 45: 584
        • Dazu VJ
        • Gibbons GH
        Cell biology of vascular hypertrophy in systemic hypertension.
        Am J Cardiol. 1988; 62: 30G-35G
        • Re RN
        Emerging issues in the cellular biology of the cardiovascular system.
        Am J Cardiol. 1988; 62: 7G-12G
        • Frohlich ED
        Hemodynamics of hypertension.
        in: Genest J Koiw E Kuchel O Hypertension: physiopathology and treatment. McGraw-Hill, New York1977: 15-49
        • Mulvany MJ
        The 4th Sir George Pickering Memorial Lecture: The structure of the resistance vasculature in essential hypertension.
        J Hypertension. 1987; 5: 129-136
        • Folkow B
        • Hallback M
        • Lundgren Y
        • Silvertson R
        • Weiss L
        Importance of adaptive changes in vascular design for establishment of primary hypertension studied in man and in spontaneously hypertensive rats.
        Circ Res. 1975; 32: 2-16
        • Frohlich ED
        State of the art: the heart in hypertension: unresolved conceptual challenges.
        Hypertension. 1988; 11: 19-24
        • Frohlich ED
        State of the art: the first Irvine H. Page lecture: the mosaic of hypertension; past, present, and future.
        J Hypertension. 1988; 6: S2-S11
        • Frohlich ED
        Hemodynamics and other determinants in development of left ventricular hypertrophy: Conflicting factors in its regression.
        Fed Proc. 1983; 42: 2709-2715
        • Frohlich ED
        • Tarazi RC
        Is arterial pressure the sole factor responsible for hypertensive cardiac hypertrophy?.
        Am J Cardiol. 1979; 44: 959-963
        • Tarazi RC
        • Frohlich ED
        Is reversal of cardiac hypertrophy a desirable goal of hypertensive therapy?.
        Circulation. 1987; 75: 113-117
        • Pegram BL
        • Ishise S
        • Frohlich ED
        Effect of methyldopa, clonidine, and hydralazine on cardiac mass and haemodynamics in Wistar-Kyoto and spontaneously hypertensive rats.
        Cardiovasc Res. 1982; 16: 40-46
        • Kobrin I
        • Sesoko S
        • Pegram BL
        • Frohlich ED
        Reduced cardiac mass by nitrendipine is dissociated from systemic or regional haemodynamic changes in rats.
        Cardiovasc Res. 1984; 18: 158-162
        • Dunn FG
        • Ventura HO
        • Messerli FH
        • Kobrin I
        • Frohlich ED
        Time course of regression of left ventricular hypertrophy in hypertensive patients treated with atenolol.
        Circulation. 1987; 76: 254-258
        • Amodeo C
        • Kobrin I
        • Ventura HO
        • Messerli FH
        • Frohlich ED
        Immediate and short-term hemodynamic effects of diltiazem in patients with hypertension.
        Circulation. 1986; 76: 108-113
        • Schmieder RE
        • Messerli FH
        • Garavaglia GE
        • Nunez BD
        Cardiovascular effects of verapamil in patients with essential hypertension.
        Circulation. 1987; 75: 1030-1036
        • Pfeffer JM
        • Pfeffer MA
        • Mirsky I
        • Braunwald E
        Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat.
        in: Proc Natl Acad Sci USA. 79. 1982: 3310-3314
        • Freis ED
        • Ragan DO
        Relative effectiveness of chlorothiazide, reserpine, and hydralazine in spontaneously hypertensive rats.
        Clin Sci Mol Med. 1976; 51: 635s-637s
        • Natsume T
        • Kardon MB
        • Pegram BL
        • Frohlich ED
        Ventricular performance in spontaneously hypertensive rats (SHR) with reduced cardiac mass.
        Cardiovasc Drugs Ther. 1989; 3: 433-439
        • Sasaki O
        • Kardon MB
        • Pegram BL
        • Frohlich ED
        Aortic distensibility and left ventricular pumping ability after methyldopa in Wistar-Kyoto and spontaneously hypertensive rats.
        J Vasc Med Biol. 1989; 1: 59-66
        • Starksen NF
        • Simpson PC
        • Bishopric N
        • et al.
        Cardiac myocyte hypertrophy is associated with c-myc protooncogene expression.
        in: Proc Natl Acad Sci USA. 83. 1986: 8348-8350
        • Re RN
        The myocardial intracellular renin-angiotensin system.
        Am J Cardiol. 1987; 59: 56A-58A
        • Dzau VJ
        • Re RN
        Evidence for the existence of renin in the heart.
        Circulation. 1987; 75: 134-136
        • Komuro I
        • Kurabayashi M
        • Takaku F
        • Yazaki Y
        Expression of cellular oncogenes in the myocardium during the developmental stage and pressure-overloaded hypertrophy of the rat heart.
        Circ Res. 1988; 62: 1075-1079
      2. Frohlich ED, Sasaki O: Calcium antagonists variably change cardiovascular mass and improve function in rats (abstr). J Am Coll Cardiol (in press).

        • Sen S
        • Tarazi RC
        • Bumpus FM
        Biochemical changes associated with development and reversal of cardiac hypertrophy in spontaneously hypertensive rats.
        Cardiovasc Res. 1976; 10: 254-261
        • Pauletto P
        • Vescovo G
        • Scannapieco G
        • et al.
        Progression and regression of cardiac hypertrophy in hypertensive rats: biochemical and moleuclar changes in ventricular myosin.
        J Hypertension. 1986; 4: S135-S137
        • Morano I
        • Gagelmann M
        • Amer A
        • Ganten U
        • Ruegg JC
        Myosin isoenzymes of vascular smooth and cardiac muscle in the spontaneously hypertensive and normotensive male and female rat: a comparative study.
        Clin Res. 1986; 59: 456-462
        • Garathoff B
        • Kazda S
        • Knorr A
        • Thomas G
        Factors involved in the antihypertensive action of calcium antagonists.
        Hypertension. 1983; 5: II34-II38
        • Morgan KG
        • DeFeo TT
        • Wenc K
        • Weinstein R
        Alterations of excitation-contraction coupling by platelet-derived growth factor in enzymatically isolated and cultured vascular smooth muscle cells.
        Pflugers Arch. 1985; 405: 77-79
        • Betsholtz C
        • Westermark B
        Growth factor-induced proliferation of human fibroblasts in serum-free culture depends on cell density and extracellular calcium concentration.
        J Cell Physiol. 1984; 118: 203-210
        • Re RN
        The myocardial intracellular renin-angiotensin system.
        Am J Cardiol. 1987; 59: 56A-58A