Clinical Pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. Today, it should be a major task of the clinical pharmacologist in academia to provide support in the interpretation of preclinical and clinical study data, to develop evidence-based treatment guidelines and to serve as drug expert supporting all disciplines of clinical medicine with specific pharmacological and therapeutic knowledge. The results of the ONTARGET-trial confront both researchers and clinicians with the unexpected truth that AT1-receptor-blockade with an angiotensin-receptor-blocker (ARB) does not seem to have superior therapeutic benefit compared with an ACE-inhibitor (ACE-I) at reducing fatal and nonfatal cardiovascular events. The combination of the two drugs was associated with more adverse events without an increase in benefit. Therefore, the crucial question `ACE-I, ARB, or both?' requires a new and critical appraisal depending on the medical indication for which these renin-angiotensin-system (RAS)-inhibitors are used: In a population of high-risk patients suffering from cardiovascular disease or diabetes mellitus, the evidence to favor an ARB over an ACE-I is still limited after ONTARGET and because of the higher costs for ARBs one can rather support the old therapeutic advice that ARBs are equally effective as ACE-Is and therefore therapeutic alternatives for patients with ACE-I intolerance. With respect to a very moderate additive BP-lowering effect of dual therapy with an ACE-I and an ARB seen in metaanalysis which was not even clearly attributable to dual RAS-inhibition and the increased adverse event rate in the combination treatment group of ONTARGET, this regimen seems not to be recommendable for the treatment of hypertension. Dual-RAS-blockade using an ACE-I-ARB-combination is an effective therapy to treat proteinuria and might be of therapeutic benefit especially in diabetic patients without concomitant diseases. There may be a therapeutic rationale to prefer ARBs over ACE-Is in well-selected patients with congestive heart failure (CHF) because a considerable amount of angiotensin II (Ang II) is produced independent of angiotensin-conversion-enzyme (ACE) in the failing heart and is therapeutically unaffected by ACE-I treatment. The results of the Val-HeFt and the CHARM-added-study revealed additive effects of an ARB on heart failure related morbidity and mortality when added to existing therapy with an ACE-I suggesting a role for ACE-I-ARB-combination treatment in well selected heart failure patients. Independent of the medical indication for its use, the concept of dual RAS-blockade with an ARB-ACE-I-combination should clinically be used with caution and a close monitoring of potassium levels and kidney function. Although the results of ONTARGET revealed equity of ramipril and telmisartan at reducing fatal and nonfatal cardiovascular events, we should not forget that pharmacologically not all ARBs are the same and the question if the study results of ONTARGET with telmisartan are transferable to the complete class of ARBs still merits further investigation.
Aire-Study-Investigators (1993) Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators . Lancet342: 821-828.
3.
Anderson, C. (2005) Rationale and design of the cardiac magnetic resonance imaging substudy of The ONTARGET Trial Programme . J Int Med Res33 (Suppl 1): 50A-57A.
4.
Barnett, A.H. , Bain, S.C. , Bouter, P. , Karlberg, B. , Madsbad, S. , Jervell, J. et al. (2004) Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy . N Engl J Med351: 1952-1961.
5.
Benter, I.F. , Yousif, M.H. , Anim, J.T. , Cojocel, C. and Diz, D.I. (2006) Angiotensin-(1-7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with L-NAME . Am J Physiol Heart Circ Physiol290: H684-691.
6.
Benter, I.F. , Yousif, M.H. , Cojocel, C. , Al-Maghrebi, M. and Diz, D.I. (2007) Angiotensin-(1-7) prevents diabetes-induced cardiovascular dysfunction . Am J Physiol Heart Circ Physiol292: H666-672.
7.
Bohm, M. (2007) Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do we stand now?Am J Cardiol100: 38J-44J.
8.
Bonner, G. , Preis, S. , Schunk, U. , Toussaint, C. and Kaufmann, W. (1990) Hemodynamic effects of bradykinin on systemic and pulmonary circulation in healthy and hypertensive humans . J Cardiovasc Pharmacol15 (Suppl 6): S46-S56.
9.
Braunwald, E. , Domanski, M.J. , Fowler, S.E. , Geller, N.L. , Gersh, B.J. , Hsia, J. , et al. (2004) Angiotensin-converting-enzyme inhibition in stable coronary artery disease . N Engl J Med351: 2058-2068.
10.
Brenner, B.M. , Cooper, M.E. , De Zeeuw, D. , Keane, W.F. , Mitch, W.E. , Parving, H.H. , et al. (2001) Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy . N Engl J Med345: 861-869.
11.
Brillante, D.G. , Johnstone, M.T. and Howes, L.G. (2005) Effects of intravenous PD 123319 on haemodynamic and arterial stiffness indices in healthy volunteers . J Renin Angiotensin Aldosterone Syst6: 102-106.
12.
Brillante, D.G. , O'sullivan, A.J. , Johnstone, M.T. and Howes, L.G. (2008a) Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome . Clin Sci (Lond)114: 139-147.
13.
Brillante, D.G. , O'sullivan, A.J. , Johnstone, M.T. and Howes, L.G. (2008b) Evidence for functional expression of vascular angiotensin II type 2 receptors in patients with insulin resistance . Diabetes Obes Metab10: 143-150.
14.
Brunner, H. , Cockcroft, J.R. , Deanfield, J. , Donald, A. , Ferrannini, E. , Halcox, J. et al. (2005) Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension . J Hypertens23: 233-246.
15.
Burnier, M. and Brunner, H.R. (1999) Comparative antihypertensive effects of angiotensin II receptor antagonists . J Am Soc Nephrol10 (Suppl 12): S278-S282.
16.
Burnier, M. and Brunner, H.R. (2000) Angiotensin II receptor antagonists . Lancet355: 637-645.
17.
Burnier, M. and Maillard, M. (2001) The comparative pharmacology of angiotensin II receptor antagonists . Blood Press (Suppl 1): 6-11.
18.
Carey, R.M. (2005) Update on the role of the AT2 receptor . Curr Opin Nephrol Hypertens14: 67-71.
19.
Cohn, J.N. and Tognoni, G. (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure . N Engl J Med345: 1667-1675.
20.
Consensus-Trial-Study-Group (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). The CONSENSUS Trial Study Group . N Engl J Med316: 1429-1435.
21.
Dahlof, B. , Devereux, R.B. , Kjeldsen, S.E. , Julius, S. , Beevers, G. , De Faire, U. et al. (2002) Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol . Lancet359: 995-1003.
22.
Dendorfer, A. , Dominiak, P. and Schunkert, H. (2005) ACE inhibitors and angiotensin II receptor antagonists . Handb Exp Pharmacol407-442.
23.
Diamant, M. and Vincent, H.H. (1999) Lisinopril versus enalapril: evaluation of trough:peak ratio by ambulatory blood pressure monitoring . J Hum Hypertens13: 405-412.
24.
Dickstein, K. and Kjekshus, J. (2002) Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan . Lancet360: 752-760.
25.
Doran, D.E. , Weiss, D. , Zhang, Y. , Griendling, K.K. and Taylor, W.R. (2007) Differential effects of AT1 receptor and Ca2+ channel blockade on atherosclerosis, inflammatory gene expression, and production of reactive oxygen species . Atherosclerosis195: 39-47.
26.
Doulton, T.W. , He, F.J. and Macgregor, G.A. (2005) Systematic review of combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade in hypertension . Hypertension45: 880-886.
27.
Elliott, W.J. (2000) Therapeutic trials comparing angiotensin converting enzyme inhibitors and angiotensin II receptor blockers . Curr Hypertens Rep2: 402-411.
28.
Feldman, A.M. , Koch, W.J. and Force, T.L. (2007) Developing strategies to link basic cardiovascular sciences with clinical drug development: another opportunity for translational sciences . Clin Pharmacol Ther81: 887-892.
29.
Ferrari, P. , Marti, H.P. , Pfister, M. and Frey, F.J. (2002) Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade . J Hypertens20: 125-130.
30.
Ferrario, C.M. (2006) Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research . J Renin Angiotensin Aldosterone Syst7: 3-14.
31.
Ferrario, C.M. , Jessup, J. , Chappell, M.C. , Averill, D.B. , Brosnihan, K.B. , Tallant, E.A. et al. (2005a) Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2 . Circulation111: 2605-2610.
32.
Ferrario, C.M. , Jessup, J. , Gallagher, P.E. , Averill, D.B. , Brosnihan, K.B. , Ann Tallant, E. et al. (2005b) Effects of renin-angiotensin system blockade on renal angiotensin-(1-7) forming enzymes and receptors . Kidney Int68: 2189-2196.
33.
Ferrario, C.M. , Richmond, R.S. , Smith, R. , Levy, P. , Strawn, W.B. and Kivlighn, S. (2004) Renin-angiotensin system as a therapeutic target in managing atherosclerosis . Am J Ther11: 44-53.
34.
Ferrario, C.M. , Trask, A.J. and Jessup, J.A. (2005c) Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function . Am J Physiol Heart Circ Physiol289: H2281-2290.
35.
Fogari, R. , Derosa, G. , Zoppi, A. , Preti, P. , Lazzari, P. , Destro, M. et al. (2007) Effect of telmisartan-amlodipine combination at different doses on urinary albumin excretion in hypertensive diabetic patients with microalbuminuria . Am J Hypertens20: 417-422.
36.
Fox, K.M. (2003) Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study) . Lancet362: 782-788.
37.
Garg, R. and Yusuf, S. (1995) Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials . Jama273: 1450-1456.
38.
Gilles, R. , Vingerhoedt, N. , Howes, J. , Griffin, M. and Howes, L.G. (2004) Increase in systemic blood pressure during intra-arterial PD123319 infusion: evidence for functional expression of angiotensin type 2 receptors in normal volunteers . Blood Press13: 110-114.
39.
Gottlieb, S.S. , Dickstein, K. , Fleck, E. , Kostis, J. , Levine, T.B. , Lejemtel, T. et al. (1993) Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure . Circulation88: 1602-1609.
40.
Granger, C.B. , Mcmurray, J.J. , Yusuf, S. , Held, P. , Michelson, E.L. , Olofsson, B. et al. (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial . Lancet362: 772-776.
41.
Gross, M.L. , Adamczak, M. and Ritz, E. (2005) Renal failure and ACE inhibition: how much is too much ? Z Kardiol94: 81-86.
42.
Hasler, C. , Nussberger, J. , Maillard, M. , Forclaz, A. , Brunner, H.R. and Burnier, M. (2005) Sustained 24-hour blockade of the renin-angiotensin system: a high dose of a long-acting blocker is as effective as a lower dose combined with an angiotensin-converting enzyme inhibitor . Clin Pharmacol Ther78: 501-507.
43.
Hunt, S.A. (2005) ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
44.
Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure) . J Am Coll Cardiol46: e1-e82.
45.
Igase, M. , Strawn, W.B. , Gallagher, P.E. , Geary, R.L. and Ferrario, C.M. (2005) Angiotensin II AT1 receptors regulate ACE2 and angiotensin-(1-7) expression in the aorta of spontaneously hypertensive rats . Am J Physiol Heart Circ Physiol289: H1013-1019.
46.
Ishiyama, Y. , Gallagher, P.E. , Averill, D.B. , Tallant, E.A. , Brosnihan, K.B. and Ferrario, C.M. (2004) Upregulation of angiotensin-converting enzyme 2 after myocardial infarction by blockade of angiotensin II receptors . Hypertension43: 970-976.
47.
Iwanaga, T. , Sato, M. , Maeda, T. , Ogihara, T. and Tamai, I. (2007) Concentration-dependent mode of interaction of angiotensin II receptor blockers with uric acid transporter . J Pharmacol Exp Ther320: 211-217.
48.
Iyer, S.N. , Ferrario, C.M. and Chappell, M.C. (1998) Angiotensin-(1-7) contributes to the antihypertensive effects of blockade of the renin-angiotensin system . Hypertension31: 356-361.
49.
Jamerson, K. (2008) Avoiding cardiovascular events through combination therapy in patients living with systolic hypertension, the early termination of the ACCOMPLISH trial. ACC2008. Chicago .
50.
Jessup, J. , Gallagher, P.E. , Averill, D.B. , Brosnihan, K.B. , Tallant, E.A. , Chappell, M. et al. (2006) Effect of Angiotensin II Blockade on a New Congenic Model of Hypertension Derived from Transgenic Ren-2 Rats . Am J Physiol Heart Circ Physiol Epub. 291: H2166-72.
51.
Johansson, M.E. , Fagerberg, B. and Bergstrom, G. (2008) Angiotensin type 2 receptor is expressed in human atherosclerotic lesions . J Renin Angiotensin Aldosterone Syst9: 17-21.
Julius, S. , Kjeldsen, S.E. , Weber, M. , Brunner, H.R. , Ekman, S. , Hansson, L. et al. (2004) Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial . Lancet363: 2022-2031.
54.
Karalliedde, J. and Viberti, G. (2006) Evidence for renoprotection by blockade of the renin-angiotensin-aldosterone system in hypertension and diabetes . J Hum Hypertens20: 239-253.
55.
Kober, L. , Torp-Pedersen, C. , Carlsen, J.E. , Bagger, H. , Eliasen, P. , Lyngborg, K. et al. (1995) A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group . N Engl J Med333: 1670-1676.
56.
Koka, V. , Huang, X.R. , Chung, A.C. , Wang, W. , Truong, L.D. and Lan, H.Y. (2008) Angiotensin II Up-Regulates Angiotensin I-Converting Enzyme (ACE), but Down-Regulates ACE2 via the AT1-ERK/p38 MAP Kinase Pathway . Am J Pathol172: 1174-83.
57.
Komine, N. , Khang, S. , Wead, L.M. , Blantz, R.C. and Gabbai, F.B. (2002) Effect of combining an ACE inhibitor and an angiotensin II receptor blocker on plasma and kidney tissue angiotensin II levels . Am J Kidney Dis39: 159-164.
58.
Lewis, E.J. , Hunsicker, L.G. , Clarke, W.R. , Berl, T. , Pohl, M.A. , Lewis, J.B. et al. (2001) Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes . N Engl J Med345: 851-860.
59.
Li, P. , Fukuhara, M. , Diz, D.I. , Ferrario, C.M. and Brosnihan, K.B. (2000) Novel angiotensin II AT(1) receptor antagonist irbesartan prevents thromboxane A(2)-induced vasoconstriction in canine coronary arteries and human platelet aggregation . J Pharmacol Exp Ther292: 238-246.
60.
Lindholm, L.H. , Ibsen, H. , Dahlof, B. , Devereux, R.B. , Beevers, G. , De Faire, U. et al. (2002) Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol . Lancet359: 1004-1010.
61.
Lithell, H. , Hansson, L. , Skoog, I. , Elmfeldt, D. , Hofman, A. , Olofsson, B. et al. (2003) The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial . J Hypertens21: 875-886.
62.
Mcmurray, J.J. , Ostergren, J. , Swedberg, K. , Granger, C.B. , Held, P. , Michelson, E.L. et al. (2003) Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial . Lancet362: 767-771.
63.
Meredith, P. (2000) Achieving quality 24-h blood pressure control with candesartan cilexetil . Blood Press (Suppl 1): 23-26.
64.
Meredith, P.A. (2001) Clinical comparative trials of angiotensin II type 1 (AT1)-receptor blockers. Blood Press (Suppl): 11-17.
65.
Monton, M. , Jimenez, A. , Nunez, A. , Lopez-Blaya, A. , Farre, J. , Gomez, J. et al. (2000) Comparative effects of angiotensin II AT-1-type receptor antagonists in vitro on human platelet activation . J Cardiovasc Pharmacol35: 906-913.
66.
Mori-Takeyama, U. , Minatoguchi, S. , Murata, I. , Fujiwara, H. , Ozaki, Y. , Ohno, M. et al. (2008) Dual blockade of the rennin-angiotensin system versus maximal recommended dose of angiotensin II receptor blockade in chronic glomerulonephritis . Clin Exp Nephrol12: 33-40.
67.
Mueller, C.F. and Nickenig, G. (2008) Angiotensin II: one driving force behind atherogenesis . Hypertension51: 175-176.
68.
Nakao, N. , Yoshimura, A. , Morita, H. , Takada, M. , Kayano, T. and Ideura, T. (2003) Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial . Lancet361: 117-124.
69.
Ogihara, T. , Saruta, T. , Shimamoto, K. , Matsuoka, H. and Rakugi, H. (2008) Clinical efficacy of a new angiotensin II type 1 receptor blocker, pratosartan, in hypertensive patients . Hypertens Res31: 281-287.
70.
Ontarget-Investigators (2008) Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events . N Engl J Med358: 1547-59.
71.
Parving, H.H. , Lehnert, H. , Brochner-Mortensen, J. , Gomis, R. , Andersen, S. and Arner, P. (2001) The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes . N Engl J Med345: 870-878.
72.
Pfeffer, M.A. , Mcmurray, J.J. , Velazquez, E.J. , Rouleau, J.L. , Kober, L. , Maggioni, A.P. et al. (2003) Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both . N Engl J Med349: 1893-1906.
73.
Phillips, C.O. , Kashani, A. , Ko, D.K. , Francis, G. and Krumholz, H.M. (2007) Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials . Arch Intern Med167: 1930-1936.
74.
Phoon, S. and Howes, L.G. (2001) Role of angiotensin type 2 receptors in human forearm vascular responses of normal volunteers . Clin Exp Pharmacol Physiol28: 734-736.
75.
Phoon, S. and Howes, L.G. (2002) Forearm vasodilator response to angiotensin II in elderly women receiving candesartan: role of AT(2)-receptors . J Renin Angiotensin Aldosterone Syst3: 36-39.
76.
Pilote, L. , Abrahamowicz, M. , Eisenberg, M. , Humphries, K. , Behlouli, H. and Tu, J.V. (2008) Effect of different angiotensin-converting-enzyme inhibitors on mortality among elderly patients with congestive heart failure . Cmaj178: 1303-1311.
77.
Porogress-Study-Investigators (2001) Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack . Lancet358: 1033-1041.
78.
Rossing, K. , Jacobsen, P. , Pietraszek, L. and Parving, H.H. (2003) Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy: a randomized double-blind crossover trial . Diabetes Care26: 2268-2274.
79.
Ruilope, L.M. , Redon, J. and Schmieder, R. (2007) Cardiovascular risk reduction by reversing endothelial dysfunction: ARBs, ACE inhibitors, or both? Expectations from the ONTARGET Trial Programme . Vasc Health Risk Manag3: 1-9.
80.
Rutherford, J.D. , Pfeffer, M.A. , Moye, L.A. , Davis, B.R. , Flaker, G.C. , Kowey, P.R. et al. (1994) Effects of captopril on ischemic events after myocardial infarction. Results of the Survival and Ventricular Enlargement trial . SAVE Investigators. Circulation90: 1731-1738.
81.
Santos, R.A. , Ferreira, A.J. and Simoes, E.S.A.C. (2008) Recent advances in the ACE2-Ang-(1-7)-Mas axis . Exp Physiol93: 519-27.
82.
Savoia, C. , Touyz, R.M. , Volpe, M. and Schiffrin, E.L. (2007) Angiotensin type 2 receptor in resistance arteries of type 2 diabetic hypertensive patients . Hypertension49: 341-346.
83.
Schindler, C. , Bramlage, P. , Kirch, W. and Ferrario, C.M. (2007a) Role of the vasodilator peptide angiotensin-(1-7) in cardiovascular drug therapy . Vasc Health Risk Manag3: 125-137.
84.
Schindler, C. , Brosnihan, K.B. , Ferrario, C.M. , Bramlage, P. , Maywald, U. , Koch, R. et al. (2007b) Comparison of inhibitory effects of irbesartan and atorvastatin treatment on the renin angiotensin system (RAS) in veins: a randomized double-blind crossover trial in healthy subjects . J Clin Pharmacol47: 112-120.
85.
Schindler, C. , Mueller, A. , Bramlage, P. , Boecking, W. , Kirch, W. and Schweizer, J. (2007c) Comparison of selective AT1-receptor blockade versus ACE inhibition for restenosis prophylaxis in patients with peripheral occlusive arterial disease after stent angioplasty: a randomized, controlled, proof-of-concept study . Angiology58: 710-716.
86.
Schrader, J. , Luders, S. , Kulschewski, A. , Hammersen, F. , Plate, K. , Berger, J. et al. (2005) Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES) . Stroke36: 1218-1226.
87.
Shargorodsky, M. , Hass, E. , Boaz, M. , Gavish, D. and Zimlichman, R. (2008) High dose treatment with angiotensin II receptor blocker in patients with hypertension: differential effect of tissue protection versus blood pressure lowering . Atherosclerosis197: 303-310.
Solomon, S.D. , Appelbaum, E. , Manning, W.J. , Verma, A. , Berglund, T. , Lukashevich, V. et al. (2008) Effect of the Direct Renin Inhibitor Aliskiren, either alone or in combination with losartan, compared to losartan, on left ventricular mass in patients with hypertension and left ventricular hypertrophy: The ALiskiren Left Ventricular Assessment of HypertrophY Trial (ALLAY). American College of Cardiology .
90.
Solvd-Investigators (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. The SOLVD Investigators . N Engl J Med325: 293-302.
91.
Staessen, J.A. , Li,Y. and Richart, T. (2006) Oral renin inhibitors . Lancet368: 1449-1456.
92.
Strawn, W.B. , Chappell, M.C. , Dean, R.H. , Kivlighn, S. and Ferrario, C.M. (2000) Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia . Circulation101: 1586-1593.
93.
Teo, K. , Yusuf, S. , Sleight, P. , Anderson, C. , Mookadam, F. , Ramos, B. et al. (2004) Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials . Am Heart J148: 52-61.
94.
Toto, R. and Palmer, B.F. (2007) Rationale for Combination Angiotensin Receptor Blocker and Angiotensin-Converting Enzyme Inhibitor Treatment and End-Organ Protection in Patients with Chronic Kidney Disease . Am J Nephrol28: 372-380.
95.
Tran, D. , Phoon, S. and Howes, L. (2001) The effects of candesartan on vascular responses to angiotensin II and norepinephrine in normal volunteers . J Renin Angiotensin Aldosterone Syst2: 199-203.
96.
Trask, A.J. , Averill, D.B. , Ganten, D. , Chappell, M.C. and Ferrario, C.M. (2007) Primary role of angiotensin-converting enzyme-2 in cardiac production of angiotensin-(1-7) in transgenic Ren-2 hypertensive rats . Am J Physiol Heart Circ Physiol292: H3019-3024.
97.
Unger, T. (1999) Significance of angiotensin type 1 receptor blockade: why are angiotensin II receptor blockers different?Am J Cardiol84: 9S-15S.
98.
Unger, T. (2002) The role of the renin-angiotensin system in the development of cardiovascular disease . Am J Cardiol89: 3A-9A; discussion 10A .
99.
Urata, H. , Nishimura, H. and Ganten, D. (1995) Mechanisms of angiotensin II formation in humans . Eur Heart J, 16 (Suppl N): 79-85.
100.
Van De Wal, R.M. , Van Der Harst, P. , Wagenaar, L.J. , Wassmann, S. , Morshuis, W.J. , Nickenig, G. et al. (2007) Angiotensin II type 2 receptor vasoactivity in internal mammary arteries of patients with coronary artery disease . J Cardiovasc Pharmacol50: 372-379.
101.
Vogt, L. , Navis, G. and De Zeeuw, D. (2005) Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients: a feasible strategy ? J Am Soc Nephrol16 (Suppl 1): S53-S57.
102.
Wassmann, S. and Nickenig, G. (2006) Pathophysiological regulation of the AT1-receptor and implications for vascular disease . J Hypertens (Suppl) 24: S15-S21.
103.
Wehling, M. (2006) Translational medicine: can it really facilitate the transition of research "from bench to bedside "? Eur J Clin Pharmacol62: 91-95.
104.
Weiss, D. and Taylor, W.R. (2008) Deoxycorticosterone acetate salt hypertension in apolipoprotein E-/- mice results in accelerated atherosclerosis: the role of angiotensin II . Hypertension51: 218-224.
105.
Wong, M. , Staszewsky, L. , Latini, R. , Barlera, S. , Volpi, A. , Chiang,Y.T. et al. (2002) Valsartan benefits left ventricular structure and function in heart failure: Val-HeFT echocardiographic study . J Am Coll Cardiol40: 970-975.
106.
Young, C.L. , Dias, V.C. and Stangier, J. (2000) Multiple-dose pharmacokinetics of telmisartan and of hydrochlorothiazide following concurrent administration in healthy subjects . J Clin Pharmacol40: 1323-1330.
107.
Yusuf, S. , Sleight, P. , Pogue, J. , Bosch, J. , Davies, R. and Dagenais, G. (2000) Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators . N Engl J Med342: 145-153.
