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Research Area
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Description
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Cardiovascular Disease |
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Biological Activity
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Description
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Ramipril (Altace) is an angiotensin-converting enzyme (ACE) inhibitor with IC50 of 5 nM. |
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Targets
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ACE |
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IC50 |
5 nM [1] |
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In Vitro
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Ramipril is an angiotensin-converting enzyme (ACE) inhibitor with IC50 of 5 nM. [1] Ramipril enhances the activity of ACE-associated CK2 and the phosphorylation of ACE Ser1270 in cultured endothelial cells, but is unable to activate JNK or stimulate the nuclear accumulation of c-Jun in endothelial cells expressing a S1270A ACE mutant or in ACE-deficient cells. Prolonged Ramipril treatment increases ACE expression in primary cultures of human endothelial cells and in vivo (mouse lung), which can be prevented by pretreatment with the JNK inhibitor SP600125. [2] Ramipril displays little enhanced effect on the rate of in vitro endothelial apoptosis induced by the serum deprivation method. [3] |
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In Vivo
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Chronic in vivo administration of Ramipril to rats at a dosage that has similar hypotensive effects in vitro HUVECs significantly reduces the rate of LPS-induced apoptosis compared to the other ACE inhibitors, which contrasts with the apoptosis effect in vitro. [3] Ramipril inhibits systolic blood pressure (SBP) with IC50 of 1.97 mg/kg in spontaneously hypertensive rats (SHR). When in combination with AT1-receptor blockade by candesartan–cilexetil increases SBP reduction synergistically rather than additively. [4] Administration of Ramipril to spontaneously hypertensive rats (SHR) produces significant inhibition of aorta ACE and lung ACE with IC50 ~5 mg/kg, but shows little effect for brain ACE ex vivo. [5] Ramipril prevents beta cell dysfunction in osteoprotegerin treated mice through decreasing islet monocyte/macrophage infiltration, fibrosis and apoptosis involving decreasing RAS, growth factor genes and inflammatory molecules expressions. [6] |
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Clinical Trials
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Phase IV trails for evaluating the efficacy and safety of Aliskiren versus Ramipril in patients with moderate systolic essential hypertension have been completed. |
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Features
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Ramipril is a pro-drug converted to its active metabolite ramiprilat by liver esterase enzymes. |
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Protocol
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Cell Assay
[3]
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| Cell Lines |
Human umbilical vein endothelial cells (HUVECs) |
| Concentrations |
~1 μM |
| Incubation Time |
24 hours |
| Methods |
The HUVECs are pretreated with the active metabolites of Ramipril for 24 hours. A serum deprivation method is used to induce apoptosis in the presence of Ramipril for an additional 24 hours. The rate of apoptosis is then determined using flow cytometry with two makers annexinV fluorescein isothiocyanate (FITC+) and propidium iodide (PI). |
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Animal Study
[4]
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| Animal Models |
Male spontaneously hypertensive rats |
| Formulation |
Dissolved in distilled water by using gum arabic (10% w/v) |
| Doses |
0.03-10 mg/kg |
| Administration |
Gavage, every day |
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References |
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[1] Stevens BR, et al. Comp Biochem Physiol C, 1988, 91(2), 493-497.
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[2] Kohlstedt K, et al. Circ Res, 2004, 94(1), 60-67.
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[3] Ceconi C, et al. Cardiovasc Drugs Ther, 2007, 21(6), 423-429.
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[4] Raasch W, et al. J Hypertens, 2004, 22(3), 611-618.
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[5] Cushman DW, et al. Br J Clin Pharmacol, 1989, 28, 115S-131S.
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[6] Toffoli B, et al. Mol Cell Endocrinol, 2011, 331(1), 136-142.
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