Abstract
We investigated the effects of co-administration of an angiotensin-converting enzyme inhibitor (ACEI) and angiotensin type 1 receptor blocker (ARB) on nitric oxide (NO) bioavailability in genetically hyperlipidemic rabbits with our newly developed NO sensor. Plasma NO was measured using the new NO sensor in the abdominal aorta of anesthetized Watanabe heritable hyperlipidemic (WHHL) rabbits. Acetylcholine (ACh)-stimulated (20 μg in 5 min into the aortic arch) NO production was recorded after an 8 week per os pretreatment with 1) vehicle (control), 2) the ACEI enalapril (E: 3 mg/kg/day), 3) the ARB losartan (L: 30 mg/kg/day) and 4) enalapril (1.5 mg/kg/day) + losartan (15 mg/kg/day) (E+L). Intra-aortic infusion of ACh produced an increase in plasma NO concentration, which was significantly greater with all the drug treatments than with the control. E increased ACh-induced NO significantly more than L (by 6.9 nmol/L, and 4.7 nmol/L, respectively). E+L increased ACh-induced NO by 9.5 nmol/L, significantly more than either E or L. Plasma peroxynitrite concentration was 1.2 pmol/mg protein in the control group and significantly less than in the E- and L-group. The lowest peroxynitrite concentration was observed in the E+L group (0.5 pmol/mg protein), which was significantly lower than in the E-group and the L-group. Optical coherence tomography and histology of the thoracic aorta revealed that the plaque area decreased significantly more with the combination than with the monotherapy (p<0.01). In conclusion, the combined treatment with an ACEI and an ARB may have additive protective effects on endothelial function as well as atherosclerotic change.
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Ignarro LJ, Napoli C : Novel features of nitric oxide, endothelial nitric oxide synthesis, and atherosclerosis. Curr Atheroscler Rep 2004; 6: 281–287.
Voetsch B, Jin RC, Loscalzo J : Nitric oxide insufficiency and atherothrombosis. Histochem Cell Biol 2004; 122: 353–367.
Dinerman JL, Lowenstein CJ, Snyder SH : Molecular mechanisms of nitric oxide regulation. Circ Res 1993; 73: 217–222.
Wennmalm A, Benthin G, Petersson AS : Dependence of the metabolism of nitric oxide (NO) in healthy human whole blood or the oxygenation of its red cell haemoglobin. Br J Pharmacol 1992; 106: 507–508.
Schechter AN, Gladwin MT : Hemoglobin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 2003; 348: 1483–1485.
Stamler JS, Jia L, Eu JP, et al: Blood flow regulation by S-nitrosohemoglobin in the physiological oxygen gradient. Science 1997; 276: 2034–2037.
Mochizuki S, Miyasaka T, Goto M, et al: Measurement of acetylcholine-induced endothelium-derived nitric oxide in aorta using a newly developed catheter-type nitric oxide sensor. Biochem Biophy Res Commun 2003; 306: 505–508.
Neishi Y, Mochizuki S, Miyasaka T, et al: Evaluation of bioavailability of nitric oxide in coronary circulation by direct measurement of plasma nitric oxide concentration. Proc Natl Acad Sci U S A 2005; 102: 11456–11461.
Imanishi T, Kobayashi K, Kuroi A, et al: Effects of angiotensin II on NO bioavailability evaluated using a catheter-type NO sensor. Hypertension 2006; 48: 1058–1065.
O'Driscoll G, Green D, Rankin J, Stanton K, Taylor R : Improvement in endothelial function by angiotensin converting enzyme inhibition in insulin-dependent diabetes mellitus. J Clin Invest 1997; 100: 678–684.
Cheetham C, Collis J, O'Driscoll G, Stanton K, Taylor R, Green D : Losartan, an angiotensin type 1 receptor antagonist, improves endothelial function in non–insulin-dependent diabetes. J Am Coll Cardiol 2000; 36: 1461–1466.
Hornig B, Landmesser U, Kohler C, et al: Comparative effect of ACE inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dismutase. Circulation 2001; 103: 799–805.
Shiomi M, Ito T, Tsukada T, Yata T, Ueda M : Cell compositions of coronary and aortic atherosclerotic lesions in WHHL rabbits differ: an immunohistochemical study. Arterioscler Thromb 1994; 14: 931–937.
Tanaka E, Shimokawa H, Kamiuneten H, et al: Disparity of MCP-1 mRNA and protein expressions between the carotid artery and the aorta in WHHL rabbits. One aspect involved in the regional difference in atherosclerosis. Arterioscler Thromb Vasc Biol 2003; 23: 244–250.
Griendling KK, Minieri CA, Ollerenshaw JD, Alexander RW : Angiotensin II stimulates NADH and NADPH oxidase activity in cultured smooth muscle cells. Circ Res 1994; 74: 1141–1148.
Rajagopalan S, Kurz S, Munzel T, et al: Angiotensin II–mediated hypertension in the rat increase vascular superoxide production via membrane NADH/NADPH oxidase activation. J Clin Invest 1996; 97: 1916–1923.
Ter Steege JCA, Koster-Kamphuis L, Van Straaten EA, Forget P, Buurman WA : Nitrotyrosine in plasma of celiac disease patients as detected by a new sandwich ELISA. Free Radic Biol Med 1998; 25: 953–963.
Jang IK, Tearney GJ, MacNeill B, et al: In vivo characterization of coronary atherosclerotic plaque by use of optical coherence tomography. Circulation 2005; 111: 1551–1555.
Imanishi T, McBride J, Ho Q, O'Brien KD, Schwartz SM, Han DK : Expression of cellular FLICE-inhibitory protein in human coronary arteries and in a rat vascular injury model. Am J Pathol 2000; 156: 125–137.
Mochizuki S, Himi N, Miyasaka T, et al: Evaluation of basic performance and applicability of a newly developed in vivo nitric oxide sensor. Physiol Meas 2002; 23: 261–268.
Yagi S, Morita T, Kataoka S : Combined treatment with an AT1 receptor blocker and angiotensin converting enzyme inhibitor has an additive effect on inhibiting neointima formation via improvement of nitric oxide production and suppression of oxidative stress. Hypertens Res 2004; 27: 129–135.
Misko TP, Schilling RJ, Salvemini D, Moore WM, Currie MG : A fluorometric assay for the measurement of nitrite in biological samples. Anal Biochem 1993; 214: 11–16.
Kelly RA, Balligand J-L, Smith TW : Nitric oxide and cardiac function. Circulation Res 1996; 79: 363–380.
Landmesser U, Drexler H : Effect of angiotensin type 1 receptor antagonism on endothelial function: role of bradykinin and nitric oxide. J Hypertens Suppl 2006; 24: S39–S43.
Wanholtz A, Nickenig G, Schulz E, et al: Increased NADH-oxidase–mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of renin-angiotensin system. Circulation 1999; 99: 2027–2033.
Matsubara H : Pathological role of angiotensin II type 2 receptor in cardiovascular and renal disease. Circulation 1998; 83: 1182–1191.
Tsutsumi Y, Matsubara H, Masaki H, et al: Angiotensin II type 2 receptor overexpression activates the vascular kinin system and causes vasodilation. J Clin Invest 1999; 104: 925–935.
Gohlke P, Pees C, Unger T : AT2 receptor stimulates increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 1998; 31: 349–355.
Searles CD, Harrison DG : The interaction of nitric oxide, bradykinin, and the angiotensin II type 2 receptor: lessons learned from transgenic mice. J Clin Invest 1999; 104: 1013–1014.
Griendling KK, FitzGerald GA : Oxidative stress and cardiovascular injury: Part I: basic mechanisms and in vivo monitoring of ROS. Circulation 2003; 108: 1912–1916.
Landmesser U, Dikalov S, Price SR, et al: Oxidation of tetrahydropterin leads to uncoupling of endothelial cell nitric oxide synthesis in hypertension. J Clin Invest 2003; 111: 1201–1209.
Kawashima S, Yokoyama M : Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler Thromb Vasc Biol 2004; 24: 998–1005.
Ozaki M, Kawashima S, Yamashita T, et al: Overexpression of endothelial nitric oxide synthase accelerates atherosclerotic lesion formation in apo E–deficient mice. J Clin Invest 2002; 110: 331–340.
Kim S, Izumi Y, Izumiya Y, et al: Beneficial effects of combined blockade of ACE and AT1 receptor on intimal hyperplasia in balloon-injured artery. Arterioscler Thromb Vasc Biol 2002; 22: 1299–1304.
Jang IK, Bouma BE, Kang DH, et al: Visualization of coronary atherosclerotic plaques in patients using optical coherence tomogrphy: comparison with intravascular ultrasound. J Am Coll Cardiol 2002; 39: 604–609.
Yabushita H, Bouma BE, Houser SL, et al: Characterization of human atherosclerosis by optical coherence tomography. Circulation 2002; 106: 1640–1645.
Kume T, Akasaka T, Kawamoto T, et al: Assessment of coronary thrombus by optical coherence tomography. Am J Cardiol 2006; 97: 1713–1717.
Cohn JN, Tognoni G, for the Valsartan Heart Failure Investigators : A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–1675.
Teo K, Yusuf S, Anderson C, et al: 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 Asseeemenst Study in ACE intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND). Am Heart J 2004; 148: 52–61.
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Imanishi, T., Kuroi, A., Ikejima, H. et al. Effects of Angiotensin Converting Enzyme Inhibitor and Angiotensin II Receptor Antagonist Combination on Nitric Oxide Bioavailability and Atherosclerotic Change in Watanabe Heritable Hyperlipidemic Rabbits. Hypertens Res 31, 575–584 (2008). https://doi.org/10.1291/hypres.31.575
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DOI: https://doi.org/10.1291/hypres.31.575
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