Fimasartan, Anti-hypertension Drug, Suppressed Inducible Nitric Oxide Synthase Expressions <i>via</i> Nuclear Factor-Kappa B and Activator Protein-1 Inactivation

Abstract

Since inhibition of angiotensin II type 1 (AT1) receptor reduces chronic inflammation associated with hypertension, we evaluated the anti-inflammatory potential and the underlying mechanism of fimasartan, a Korean Food and Drug Administration approved anti-hypertension drug, in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Fimasartan suppressed the expressions of inducible nitric oxide synthase (iNOS) by down-regulating its transcription, and subsequently inhibited the productions of nitric oxide (NO). In addition, fimasartan attenuated LPS-induced transcriptional and DNA-binding activities of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1). These reductions were accompanied by parallel reductions in the nuclear translocation of NF-κB and AP-1. Taken together, our data suggest that fimasartan down-regulates the expression of the iNOS in macrophages via NF-κB and AP-1 inactivation.Key words fimasartan; inflammation; nitric oxide; nuclear factor-kappa B; activator protein-1 Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. Hypertension patients have impaired functions of the endothelium, in which inflammation plays a key role.1) Angiotensin II is recognized as an important vascular pro-inflammatory factor in hypertension. Angiotensin II-driven vascular inflammation is considered the result of direct modulates on cytokine release and pro-inflammatory transcription factor including nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), and angiotehsin II receptor blockers (ARBs) reduce the peripheral and cerebrovascular inflammation associated with this disease. 2,3)Anti-inflammatory effects of ARBs, first established in the peripheral vasculature, 4) were later demonstrated in the cerebral vasculature 5) and in stress-induced gastric ulcerations. 6)These observations suggest that ARBs may exert general antiinflammatory effects beyond those associated with cardiovascular and metabolic disease. 7) Thus, apart from being a major vasopressor effector of the renin-angiotensin system, ARBs are probably good candidate drugs for inflammation. 8)Since the important role of macrophages in inflammation, many investigations about ARBs (e.g., candesartan, losartan, telmisartan and valsartan) were performed in lipopolysaccharide (LPS)-induced macrophages.9-11) In fact, there are several physiological roles of angiotensin II type 1 (AT1) receptor in macrophages, such as positive regulation of peroxide production 12) and shift M1/M2 polarization balance. 13) However, in macrophages AT1a receptor expression level is reportedly low and AT1b receptor is not detected at all 14) and the most important feature of macrophages is that macrophages are widely distributed in the body and provide an immediate defense against foreign agents, such as lipopolysaccharide (LPS).15) Nitric oxide (NO), a potent pro-inflammatory mediator, is mainly produced by macrophages and acts as a cytotoxic agent during immune and inflammatory responses, which is...

Angiotensin II and its receptor in activated microglia enhanced neuronal loss and cognitive impairment following pilocarpine-induced status epilepticus

“…AT1 antagonists have been shown to attenuate inflammation and oxidative stress (Sharma and Singh, 2012;Bild et al, 2013), prevent the activation of nuclear factor-kappa B, and inhibit mRNA expression of interleukin (IL)-1β, IL-6, and TNF-α in microglia (Sharma and Singh, 2012;Ryu et al, 2013). Previous study had showed that angiotensin-converting enzyme type 2 (ACE2) decreased Ang II overproduction with ischemic injury in the model of ischemic, suggesting that ACE2 can protect against the effects of Ang II, and AII is in part a pharmacological consequence of brain injury (Chen et al, 2014).…”

Angiotensin II/Angiotensin II Receptor Blockade Affects Osteoporosis via the AT1/AT2-Mediated cAMP-Dependent PKA Pathway

“…To further study the mechanism by which activating or deactivating AT receptors results in a high bone-turnover state with osteoblastic and osteoclastic activity, osteoblasts and osteoclast precursors expressing AT receptors were used for in vitro cell viability and the osteogenic and osteoclastogenic assay [Nishiya and Sugimoto, 2001;Ryu et al, 2013]. As shown in Fig.…”

Pharmacological Profiles of a Highly Potent and Long-Acting Angiotensin II Receptor Antagonist, Fimasartan, in Rats and Dogs after Oral Administration

“…When the blood pressure and heart rate were stabilized, Ang II (0.1 µg/kg) was intravenously administered to the left femoral vein of rats three times with an interval of 20 min prior to treatment of test compounds to obtain the reference. Fimasartan (0.3, 1, or 3 mg/kg), losartan (1, 3, or 10 mg/kg) or vehicle distilled water (D.W.) were administered orally and then Ang II were intravenously treated as a bolus at various time points (20,40, 60 min, 1.5, 2, 3, 4, 5,6,8,10,12,16,20, and 24 h) to determine the Ang II-induced blood pressure response.…”