Abstract
Although recent clinical trials have shown that amlodipine exerts antiatherogenic effects, the mechanism of these effects remains unknown. This study was designed to examine which signal transduction pathway might be important for the antiatherogenic property of amlodipine, as assessed by aortic smooth muscle cell (SMC) phenotypes in hypertension in vivo. Stroke-prone spontaneously hypertensive rats (SHRSP) were randomly treated with a vehicle, amlodipine, or enalapril while Wistar-Kyoto rats (WKY) used as controls were treated with only the vehicle. Both drugs were equally effective at reducing systolic blood pressure, and inhibiting the progression of aortic remodeling and fibrosis in comparison to those of vehicle-treated SHRSP. In the aortas of vehicle-treated SHRSP, the level of contractile-type smooth muscle (SM) myosin heavy chain (MHC) SM2 was significantly lower, whereas the level of synthetic-type MHC NMHC-B/SMemb was significantly higher compared with those in the WKY aortas. Compared to the vehicle-treated SHRSP group, both drugs significantly and equally shifted the aortic SMC phenotype in SHRSP toward the differentiated state by reducing NMHC-B/SMemb and increasing SM2. The levels of MKK6, p38 MAPK, MEK1 and p-42/44 ERK were significantly higher in the vehicle-treated SHRSP than in the WKY. Both drugs significantly reduced these values in the SHRSP aorta. Furthermore, the levels of MEK1 and p-42/44 ERK were significantly lower in the amlodipine- than in the enalapril-treated SHRSP group, whereas enalapril was more effective than amlodipine at increasing p-Akt and endothelial NO synthase in SHRSP aortas, which were significantly lower in the vehicle SHRSP group than in the WKY group. Thus, the MEK-ERK pathway might be one of the crucial determinants of the aortic SMC phenotype activated by amlodipine treatment of hypertension in vivo.
Similar content being viewed by others
Article PDF
References
Owens GK : Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 1995; 75: 487–517.
Fujii K, Umemoto S, Fujii A, et al: Angiotensin II type 1 receptor antagonist downregulates nonmuscle myosin heavy chains in spontaneously hypertensive rat aorta. Hypertension 1999; 33: 975–980.
Kawahara S, Umemoto S, Tanaka M, et al: Up-regulation of Akt and eNOS induces vascular smooth muscle cell differentiation in hypertension in vivo. J Cardiovasc Pharmacol 2005; 45: 367–374.
Kubo M, Umemoto S, Fujii K, et al: Effects of angiotensin II type 1 receptor antagonist on smooth muscle cell phenotype in intramyocardial arteries from spontaneously hypertensive rats. Hypertens Res 2004; 27: 685–693.
Hayashi K, Takahashi M, Kimura K, et al: Changes in the balance of phosphoinositide 3-kinase/protein kinase B (Akt) and the mitogen-activated protein kinases (ERK/p38MAPK) determine a phenotype of visceral and vascular smooth muscle cells. J Cell Biol 1999; 145: 727–740.
Opie LH, Schall R : Evidence-based evaluation of calcium channel blockers for hypertension: equality of mortality and cardiovascular risk relative to conventional therapy. J Am Coll Cardiol 2002; 39: 315–322.
Staessen JA, Wang JG, Thijs L : Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001; 358: 1305–1315.
Staessen JA, Li Y, Thijs L, et al: Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trials. Hypertens Res 2005; 28: 385–407.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group: Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002; 288: 2981–2997.
Mason RP, Marche P, Hintze TH : Novel vascular biology of third-generation L-type calcium channel antagonists: ancillary actions of amlodipine. Arterioscler Thromb Vasc Biol 2003; 23: 2155–2163.
Pitt B, Byington RP, Furberg CD, et al, for the PREVENT Investigators : Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. Circulation 2000; 102: 1503–1510.
Nissen SE, Tuzcu EM, Libby P, et al: Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004; 292: 2217–2225.
Umemoto S, Tanaka M, Kawahara S, et al: Calcium antagonist reduces oxidative stress by upregulating Cu/Zn superoxide dismutase in stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 877–885.
Ishimitsu T, Kobayashi T, Honda T, et al: Protective effects of an angiotensin II receptor blocker and a long-acting calcium channel blocker against cardiovascular organ injuries in hypertensive patients. Hypertens Res 2005; 28: 351–359.
Mason RP : Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence. Atherosclerosis 2002; 165: 191–199.
Umemoto S, Sellers JR : Characterization of in vitro motility assays using smooth muscle and cytoplasmic myosins. J Biol Chem 1990; 265: 14864–14869.
Sobue K, Hayashi K, Nishida W : Molecular mechanism of phenotypic modulation of smooth muscle cells. Horm Res 1998; 50 ( Suppl 2): 15–24.
Gollasch M, Haase H, Ried C, et al: L-type calcium channel expression depends on the differentiated state of vascular smooth muscle cells. FASEB J 1998; 12: 593–601.
Stepien O, Zhang Y, Zhu D, et al: Dual mechanism of action of amlodipine in human vascular smooth muscle cells. J Hypertens 2002; 20: 95–102.
Berridge MJ : Unlocking the secrets of cell signaling. Annu Rev Physiol 2005; 67: 1–21.
Yamagata K, Ichinose S, Tagami M : Amlodipine and carvedilol prevent cytotoxicity in cortical neurons isolated from stroke-prone spontaneously hypertensive rats. Hypertens Res 2004; 27: 271–282.
Stepien O, Gogusev J, Zhu DL, et al: Amlodipine inhibition of serum-, thrombin-, or fibroblast growth factor–induced vascular smooth-muscle cell proliferation. J Cardiovasc Pharmacol 1998; 31: 786–793.
Ko Y, Totzke G, Graack GH, et al: Action of dihydropyridine calcium antagonists on early growth response gene expression and cell growth in vascular smooth muscle cells. J Hypertens 1993; 11: 1171–1178.
Mancini GB : Antiatherosclerotic effects of calcium channel blockers. Prog Cardiovasc Dis 2002; 45: 1–20.
Zhang YZ, Gao PJ, Wang XY, et al: The inhibitory mechanisms of amlodipine in human vascular smooth muscle cell proliferation. Hypertens Res 2000; 23: 403–406.
Lai YM, Fukuda N, Su JZ, et al: Novel mechanisms of the antiproliferative effects of amlodipine in vascular smooth muscle cells from spontaneously hypertensive rats. Hypertens Res 2002; 25: 109–115.
Jackson CL, Bush RC, Bowyer DE : Mechanism of antiatherogenic action of calcium antagonists. Atherosclerosis 1989; 80: 17–26.
Laplante MA, Wu R, El Midaoui A, et al: NAD(P)H oxidase activation by angiotensin II is dependent on p42/44 ERK-MAPK pathway activation in rat's vascular smooth muscle cells. J Hypertens 2003; 21: 927–936.
Touyz RM, El Mabrouk M, He G, et al: Mitogen-activated protein/extracellular signal–regulated kinase inhibition attenuates angiotensin II–mediated signaling and contraction in spontaneously hypertensive rat vascular smooth muscle cells. Circ Res 1999; 84: 505–515.
Su B, Mitra S, Gregg H, et al: Redox regulation of vascular smooth muscle cell differentiation. Circ Res 2001; 89: 39–46.
Ushio-Fukai M, Alexander RW, Akers M, et al: Reactive oxygen species mediate the activation of Akt/protein kinase B by angiotensin II in vascular smooth muscle cells. J Biol Chem 1999; 274: 22699–22704.
Reusch HP, Zimmermann S, Schaefer M, et al: Regulation of Raf by Akt controls growth and differentiation in vascular smooth muscle cells. J Biol Chem 2001; 276: 33630–33637.
On YK, Kim CH, Oh BH, et al: Effects of angiotensin converting enzyme inhibitor and calcium antagonist on endothelial function in patients with essential hypertension. Hypertens Res 2002; 25: 365–371.
Berkels R, Taubert D, Rosenkranz A, et al: Vascular protective effects of dihydropyridine calcium antagonists. Involvement of endothelial nitric oxide. Pharmacology 2003; 69: 171–176.
Gohlke P, Stoll M, Lamberty V, et al: Cardiac and vascular effects of chronic angiotensin converting enzyme inhibition at subantihypertensive doses. J Hypertens Suppl 1992; 10: S141–S144.
Touyz RM, Deschepper C, Park JB, et al: Inhibition of mitogen-activated protein/extracellular signal–regulated kinase improves endothelial function and attenuates Ang II–induced contractility of mesenteric resistance arteries from spontaneously hypertensive rats. J Hypertens 2002; 20: 1127–1134.
Stegemann JP, Hong H, Nerem RM : Mechanical, biochemical, and extracellular matrix effects on vascular smooth muscle cell phenotype. J Appl Physiol 2005; 98: 2321–2327.
Raines EW, Ferri N : Thematic review series: the immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J Lipid Res 2005; 46: 1081–1092.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Umemoto, S., Kawahara, S., Hashimoto, R. et al. Different Effects of Amlodipine and Enalapril on the Mitogen-Activated Protein Kinase/Extracellular Signal-Regulated Kinase Kinase–Extracellular Signal-Regulated Kinase Pathway for Induction of Vascular Smooth Muscle Cell Differentiation In Vivo. Hypertens Res 29, 179–186 (2006). https://doi.org/10.1291/hypres.29.179
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1291/hypres.29.179
Keywords
This article is cited by
-
p38 MAPK Inhibition Improves Synaptic Plasticity and Memory in Angiotensin II-dependent Hypertensive Mice
Scientific Reports (2016)
-
TLR4 is a critical regulator of angiotensin II-induced vascular remodeling: the roles of extracellular SOD and NADPH oxidase
Hypertension Research (2015)
-
Effects of telmisartan or amlodipine monotherapy versus telmisartan/amlodipine combination therapy on vascular dysfunction and oxidative stress in diabetic rats
Naunyn-Schmiedeberg's Archives of Pharmacology (2013)
-
Inhibitory Effect of Antihypertensive Drugs on Calcineurin in Cardiomyocytes
American Journal of Hypertension (2009)
-
Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition
Nature Reviews Cancer (2007)