Allisartan ameliorates vascular remodeling through regulation of voltage-gated potassium channels in hypertensive rats

Abstract

Background The objective of the present study was to determine the effect of allisartan, a new angiotensin II type 1 receptor antagonist on vascular remodeling through voltage gated potassium channels (Kv7) in hypertensive rats. Methods The study included a total of 47 Sprague Dawley (SD) rats. The animals were randomized to sham operation (n = 14), untreated hypertensive control group (n = 18) and allisartan treatment group (n = 15). Using renal artery stenosis, hypertension was induced in animals. Single dose of allisartan was administered intra-gastrically to animals in the allisartan treatment group and match placebo in the other 2 groups. Wire myography was used to measure the muscle tension in isolated mesenteric arteries from the animals. Real-time polymerase chain reaction was used to quantify the expression of Kv7 channel mRNA subunits. Results After 4 weeks of treatment, a significant decrease in mean arterial, systolic and diastolic blood pressure (SBP and DBP) was observed in allisartan treatment group compared to hypertension control group. The median arterial wall thickness and area/diameter ratio reduced significantly in treatment group compared to untreated hypertension group (P < 0.05). Wire myography demonstrated increased relaxation of mesenteric artery with increase in concentration of ML213. A significant up-regulation in the expression of all Kv7 mRNA subunits was observed in allisartan group compared to untreated hypertension group. Conclusions From the results, allisartan was found to lower BP and preserve vascular remodeling through Kv7 channels.

Transcriptome and proteome analyses reveal that upregulation of GSTM2 by allisartan improves cardiac remodeling and dysfunction in hypertensive rats

“…Furthermore, allisartan can reduce the risk of stroke-related death in hypertensive rats, which may be related to its inhibition of NAD(P)H oxidase expression to alleviate oxidative stress ( 4 ). Allisartan can also activate SIRT1/Nrf2, inhibit NF-κB, and alleviate oxidative stress and inflammation in diabetic rats ( 6 ), and it can regulate voltage-gated potassium channels in hypertensive rats to alleviate cardiac and vascular remodeling ( 8 , 9 ).…”

“…There is also evidence that the antioxidative and anti-inflammatory effects of allisartan may be related to the SIRT1/Nrf2/NF-κB signaling pathway ( 6 ). Allisartan can also regulate the expression of voltage-gated potassium channels, Kv7( 8 ) and Kv1.5( 9 ), in hypertensive rats. Therefore, in-depth exploration of the mechanisms of action of allisartan may improve understanding of the pathogenesis of hypertensive heart disease and result in the identification of new therapeutic targets.…”

Pharmacokinetics and Drug–Drug Interaction of Allisartan Isoproxil and Indapamide Sustained‐Release Formulation

“…The World Health Organization's Essential Medicines recommends medication including angiotensin‐converting enzyme inhibitors, calcium channel blockers, angiotensin receptor blockers, and thiazide diuretics for management of hypertension. Because AI can be metabolized to EXP3174 in the gastrointestinal tract, it has a low incidence of drug interactions, adverse drug reactions, and good safety and tolerability 14 . A Phase II prospective multicenter trial comparing the effects of AI (240 mg) versus placebo in patients with hypertension at low to medium risk in China showed a strong control of BP and few AEs 15 …”

“…Because AI can be metabolized to EXP3174 in the gastrointestinal tract, it has a low incidence of drug interactions, adverse drug reactions, and good safety and tolerability. 14 A Phase II prospective multicenter trial comparing the effects of AI (240 mg) versus placebo in patients with hypertension at low to medium risk in China showed a strong control of BP and few AEs. 15 Thiazide-like diuretics are recommended as firstline agents for uncomplicated primary hypertension.…”