Abstract
From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors.
-
a)
In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (10 μg/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadmistration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and NG-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect.
-
b)
In spontaneously hypertensive rats (SHR) the preventive effects of chronic treatment with ramipril on myocardial LVH was investigated. SHR were treated in utero and, subsequently, up to 20 weeks of age with a high dose (1 mg/kg/day) or with a low dose (10 μg/kg/day) of ramipril. Animals on a high dose remained normotensive, whereas those on a low dose developed hypertension in parallel to vehicle-treated controls. Left ventricular mass was reduced only in high-dose-treated, but not in low-dose treated animals but both groups revealed an increase in myocardial capillary length density. In SHR stroke prone animals cardiac function and metabolism was improved by ramipril and abolished by coadministration of icatibant. In contrast to the prevention studies, in a regression study ramipril reduced cardiac hypertrophy also by low dose treatment.
-
c)
In rats chronic nitric oxide (NO) inhibition by NG-nitro-L-arginine-methyl ester (L-NAME) treatment induced hypertension and LVH. Ramipril protected against blood pressure increase and partially against myocardial hypertrophy.
These experimental findings in different models of LVH characterise ACE inhibitors as remarkable antihypertrophic and antifibrotic substances.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Messerli FH, Ketelhut R: Left ventricular hypertrophy: an independent risk factor. J Cardiovasc Pharmacol 17 (suppl 4): S59-S67, 1991
Schelling P, Fischer H, Ganten D: Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertension 9: 3–15, 1991
Giacomelli F, Anversa P, Wiener J: Effect of angiotensin-induced hypertension on rat coronary arteries and myocardium. Am J Pathol 84: 111–125, 1976
Kato H, Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, Saruta T: Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertension 9: 7–22, 1991
Dzau VJ, Re RN: Evidence for the existence of renin in the heart. Circulation 75 (suppl I): I-34–I-36, 1987
Griendling KK, Murphy TJ, Wayne R, Alexander RW: Molecular biology of the renin-angiotensin system. Circulation 87 (6): 1816–1828, 1993
Kifor I, Dzau VJ: Endothelial renin-angiotensin pathway: Evidence for intracellular synthesis and secretion of angiotensins. Circ Res 60: 422–428, 1987
Lindpaintner K, Jin M, Wilhelm MJ, Suzuki F, Linz W, Schölkens BA, Ganten D: Intracardiac generation of angiotensin and its physiologic role. Circulation 77 (suppl I): 1–18, 1988
Linz W, Schölkens BA, Lindpaintner K, Ganten D: Cardiac reninangiotensin system. Am J Hypertension 2: 307–310, 1989
Schunkert H, Dzau VJ, Tang SS, Hirsch AT, Apstein CS, Lorell BH: Increased rat cardiac angiotensin converting enzyme activity and mRNA expression in pressure overload left ventricular hypertrophy. J Clin Invest 36: 1913–1920, 1990
Yamada H, Fabris B, Allen AM, Jackson B, Johnston CI, Mendelsohn AO: Localization of angiotensin converting enzyme in rat heart. Circ Res 68: 141–149, 1991
Unger T, Gohlke P, Paul M, Rettig R: Tissue renin-angiotensin systems: fact or fiction? J Cardiovasc Pharmacol 18 (Suppl. 2). S20-S25, 1991
Unger T, Gohlke P, Gruber MG: Converting enzyme inhibitors. In: D. Ganten and P.J. Mulrow (eds). Handbook of Experimental Pharmacology, vol. 93. Springer Verlag Berlin Heidelberg, 1990
Unger T, Gohlke P: Converting enzyme inhibitors in cardiovascular therapy: current status and future potential. Cardiovasc Res 28: 146–158, 1994
Kramer HJ, Glänzer K, Meyer-Lehnert H, Mohaupt M, Predel HG: Kinin- and non-kinin-mediated interactions of converting-enzyme inhibitors with vasoactive hormones. J Cardiovasc Pharmacol 15 (Suppl 6): S91-S98, 1990
Scherf H, Pietsch R, Landsberg G, Kramer HJ, Düsing R: Convertingenzyme inhibitor ramipril stimulates prostacyclin synthesis by isolated rat aorta: Evidence for a kinin-dependent mechanism. Klin Wochenschr 64: 742–745, 1986
Dahlöf B, Pennert K, Hansson L: Reversal of left ventricular hypertrophy in hypertensive patients. Am J Hypertens 5: 95–110, 1992
Schunkert H, Jackson B, Tang SS, Schoen FJ, Smits JFM, Apstein CS, Lorell B: Distribution and functional significance of cardiac angiotensin converting enzyme in hypertrophied rat hearts. Circulation 87: 1328–1339, 1993
Schunkert H, Tang SS, Litwin SE, Diamant D, Riegger G, Dzau VJ, Ingelfinger J: Regulation of intrarenal and circulating reninangiotensin systems in severe heart failure in the rat. Cardiovasc Res 27: 731–735, 1993
Shirmada Y, Hearse DJ, Avkiran M: ACE inhibition and hypertrophy: short-term treatment with ramipril in the rat reduces vulnerability to arrhythmias without regression of hypertrophy. Circulation 90 (4/2), 1994 abstract
Gonzalez-Fernandez RA, Rivera M, Rodriguez PJ, Fernandez-Martinez J, Soltero LH, Diaz LM, Lugo JE: Prelevance of ectopic ventricular activity after left ventricular regression. Am J Hypertens 6: 308–313, 1993
Katz AM: Angiotensin II: hemodynamic regulator or growth factor? J Mol Cell Cardiol 22: 739–747, 1990
Re RN: The biology of angiotensin: paracrine, autocrine and intracrine actions in cardiovascular tissues. J Mol Cell Cardiol 21 (Suppl 5): 63–69, 1989
Linz W, Schölkens BA, Ganten D: Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats. Clin and Exper Hypertens A 11(7): 1325–1350, 1989
Linz W, Schaper J, Wiemer G, Albus U, Schölkens BA: Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: A one year study in rats. Br J Pharmacol 107: 970–975, 1992
Linz W, Henning R, Schölkens BA: Role of angiotensin II receptor antagonism and converting enzyme inhibition in the progression and regression of cardiac hypertrophy in rats. J Hypertension 9 (Suppl 6): S400-S401, 1991
Mohabir R, Young SD, Strosberg AM: Role of angiotensin in pressure overload-induced hypertrophy in rats: effects of angiotensinconverting enzyme inhibitors, an AT1 receptor antagonist, and surgical reversal. J Cardiovasc Pharmacol 23: 291–299, 1994
Lièvre M, Guéret P, Gayet C, Roudaut R, Haugh MC, Delair S, Boissel J-P, on behalf of the HYCAR Study Group: Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individuals. Hypertension 25: 92–97, 1995
Linz W, Schölkens BA: A specific B2 bradykinin receptor antagonist HOE 140 abolishes the antihypertrophic effect of ramipril. Br J Pharmacol 105: 771–772, 1992
Linz W, Wiemer G, Schölkens BA: Bradykinin prevents left ventricular hypertrophy in rats. J Hypertension 11 (Suppl 5): S96-S97, 1993
Garg UC, Hassid A: Nitric oxide-generating vasodilators and 8-bromocyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 83: 1774–1777, 1989
Thiemermann C: Biosynthesis and interaction of endothelium-derived vasoactive mediators. Eicosanoids 4: 187–202, 1991
Shirotani P, Yui Y, Hattori R, Kawai C: U-61, 431F, a stable prostacyclin analogue, inhibits the proliferation of bovine vascular smooth muscle cells with little antiproliferative effect on endothelial cells. Prostaglandins 41: 97–110, 1991
Wiemer G, Schölkens BA, Linz W: Endothelial protection by converting enzyme inhibitors. Cardiovasc Res 28: 166–172, 1994
Kim NN, Villarreal FJ, Printz MP, Dillmann WH: Rat cardiac fibroblasts mediate angiotensin II (ANG II) induced cardiac myocyte hypertrophy through a paracrine mechanism. FASEB Meeting, abstract 294, 1994
Nagasawa K, Zimmermann R, Linz W, Schölkens BA, Schaper J: The angiotensin converting enzyme inhibitor ramipril prevents upregulation of collagen mRNA expression in hypertensive rat hearts. American Heart Association, 67th Scientific Session, Nov. 14–17, 1994
Brilla CG, Maisch B, Weber KT: Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease:in vivo andin vitro studies on collagen matrix regulation. Clin Invstig 71: S35-S41, 1993
Doering CW, Jalil JE, Janicki JS, Pick R, Aghili S, Abrahams C, Weber KT: Collagen network remodeling and diastolic stiffness of the rat left ventricle with pressure overload hypertrophy. Cardiovasc Res 22: 686–695, 1988
Pick R, Jalil JE, Janicki JS, Weber KT: Myocardial fibrosis in nonhuman primate with pressure overload hypertrophy. AM J Pathol 135: 771–781, 1989
Jalil JE, Janicki JS, Pick R, Shroff SG, Weber KT: Fibrillar cellagen and myocardial myocardial stiffness in the intact hypertrophied rat left ventricle. Circ Res 64: 1041–1050, 1989
Weber KT, Janicki JS, Pick R, Capasso J, Anversa P: Myocardial fibrosis and pathologic hypertrophy in the rat with renovascular hypertension. Am J Cardiol 65: 1G-7G, 1990
Silver MA, Pick R, Brilla CG, Jalil JE, Janicki JS, Weber KT: Reactive and reparative fibrosis in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis. Cardiovasc Res 24: 741–747, 1990
Weber KT, Sun Y, Tyagi SC, Cleutjens JPM: Collagen network of the myocardium: function, structural remodeling and regulatory mechanisms. J Mol Cell Cardiol 26: 279–292, 1994
Unger T, Fleck T, Ganten D, Lang RE, Rettig R: 2-[N-[(S)]-1-ethoxycarbonyl-3-phenylpropyl-L-alanyl]-(1S.3S.5S)-2-azabicyclo [3.3.0]octane-3-carboxylic acid (HOE 498): antihypertensive action and peristent inhibition of tissue converting enzyme activity in spontaneously hypertensive rats. Drug Research 34: 1426–1430, 1984
Unger T, Ganten D, Lang RF, Schölkens BA: Is tissue converting enzyme inhibition a determinant of the antihypertensive efficacy of converting enzyme inhibitors? Studies with the two different compounds HOE 498 and MK 421 in spontaneously hypertensive rats. J Cardiovasc Pharmacol 6: 872, 1984
Becker RHA, Linz W, Schölkens BA: Pharmacological interference with the cardiac renin-angiotensin system. J Cardiovasc Pharmacol 14 (suppl 4): S10-S15, 1989
Gohlke P, Stoll M, Lamberty V, Mattfeldt T, Mall G, van Even P, Martorana PA, Unger T: Cardiac and vascular effects of chronic angiotensin converting enzyme inhibition at subantihypertensive doses. J Hypertension 10 (Suppl 6): S141-S144, 1992
Unger T, Mattfeld T, Lamberty V, Bock P, Mall G, Linz W, Schölkens BA, Gohlke P: Effect of early onset ACE inhibition on myocardial capillaries in SHR. Hypertension 20: 478–482, 1992
Gohlke P, Linz W, Schölkens BA, Kuwer I, Bartenbach S, Schnell A, Unger T: Angiotensin converting enzyme inhibition improves cardiac function. Role of bradykinin. Hypertension 23: 411–418, 1994
Gohlke P, Linz W, Schölkens BA, Wiemer G, Martorana P, van Even P, Unger T: Effect of chronic high- and low-dose ACE inhibitor treatment on cardiac and vascular hypertrophy and vascular function in spontaneously hypertensive rats. Exp Nephrol 2: 93, 1994
Gohlke P, Lamberty V, Kuwer I, Bartenbach S, Schnell A, Unger T: Vascular remodelling in systemic hypertension. Am J Cardiol 71: 2E-7E, 1993
Linz W, Martorana PA, Schölkens BA: Local inhibition of bradykinin degradation in ischemic hearts. J Cardiovasc Pharmacol 15 (Suppl 6): S99-S109, 1990
Mall G, Zimmer G, Baden S, Mattfeld T: Capillary neoformation in the rat heart stereological studies on papillary muscles in hypertrophy and physiologic growth. Basic Res Cardiol 85: 531–540, 1990
Odori T, Paskins-Hurlburt A, Hollengberg N: Increase in collateral endothelial cell proliferation induced by captopril after renal artery stenosis in the rat. Hypertension 5: 307–311, 1993
Rösen P, Eckel J, Reinauer H: Influence of bradykinin on glucose uptake and metabolism studied in isolated cardiac myocytes and isolated perfused rat hearts. Hoppe-Seyler's Z Physiol Chem 364: 431–438, 1983
Ferder L, Inserra F, Romano L, Ercole L, Pszemy V: Effects of angiotensin-converting enzyme inhibition on mitochondrial number in the aging mouse. Am J Physiol 265: C15-C18, 1993
Kass RW, Kotler MN, Yazdanfar S: Stimulation of coronary collateral growth: current developments in angiogenesis and future clinical applications. Am Hart J 123(2): 486–496, 1992
Baker KM, Chernin MI, Wixson SK, Aceto JF: Renin-angiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am J Physiol 259: H324-H332, 1990
Kromer EP, Riegger AJ: Effects of long-term angiotensin converting enzyme inhibition on myocardial hypertrophy in experimental aortic stenosis in the rat. Am J Cardiol 62: 161–163, 1988
Nakamura F, Nagano M, Higaki J, Higashimori K, Morishita R, Mikami H, Ogihara T: The antiotensin-converting enzyme inhibitor, perindopril, prevents cardiac hypertrophy in low-renin hypertensive rats. Clin Exp Pharmacol Physiol 20: 135–140, 1993
Matsubara BB, Matsubara LS, Janicki JS: Low dose angiotensinconverting enzyme inhibitor (ACEI) prevents myocardial fibrosis but not hypertrophy in young rats with renovascular hypertension. FASEB Meeting, 1994
Rhaleb N-E, Yang X-P, Scicli AG, Carretero OA: Increase in blood pressure induced by aortic coarctation is a primary determinat of left ventricular hypertrophy in rats. Hypertension 22: 440, 1993, abstract
Gohlke P, Lamberty V, Kuwer I, Bartenbach S, Schnell A, Linz W, Schölkens BA, Wiemer G, Unger T: Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic Guanosine 3′,5′-monophosphate. Hypertension 22: 682–687, 1993
Palmer RM, Ferrige AG, Moncada S: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327: 524–526, 1987
Rees DD, Palmer RM, Schulz R, Hodson HF, Moncada S: Characterization of three inhibitors of endothelial nitric oxide synthasein vitro andin vivo. Br J Pharmacol 101: 746–752, 1990
Gardiner SM, Compton AM, Kemp PA, Bennett T: Regional and cardiac hemodynamic effects of NG-nitro-L-arginine methyl ester in conscious, Long Evans rats. Br J Pharmacol 101: 625–631, 1990
Wang YX, Gavras I, Wierzba T, Lammek B, Gavras H: Inhibition of nitric oxide, bradykinin and prostaglandins in normal rats. Hypertension 19 (Suppl II): II-225–II-261, 1992
Amal JF, Warin L, Michel JB: Determinants of aortic cyclic guanosine monophosphate in hypertension induced by chronic inhibition of nitric oxyde synthase. J Clin Invest 90: 647–652, 1992
Baylis C, Mitruka B, Deng A: Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 90: 278–281, 1992
Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R: Chromic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 20: 298–303, 1992
Salazar FJ, Pinilla JM, Lopez F, Romero JC, Quesade T: Renal effects of prolonged synthesis inhibition of endothelium-derived nitric oxide. Hypertension 20: 113–117, 1992
Hropot M, Grötsch H, Klaus E, Langer KH, Linz W, Wiemer G, Schölkens BA: Ramipril prevents the detrimental sequels of chronic NO synthase inhibition in rats: hypertension, cardiac hypertrophy and renal insufficiency. Naunyn Schmiedeberg's Arch 350: 646–652, 1994
Linz W, Wiemer G, Schölkens BA: ACE inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol 24: 909–919, 1992
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Linz, W., Wiemer, G., Schaper, J. et al. Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis. Mol Cell Biochem 147, 89–97 (1995). https://doi.org/10.1007/BF00944788
Issue Date:
DOI: https://doi.org/10.1007/BF00944788