Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension

Abstract

Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.

The Role of Cyclooxygenase Enzymes in the Effects of Losartan and Lisinopril on the Contractions of Rat Thoracic Aorta

“…In our study, we also observed that losartan inhibited Ang II-induced contractions. Santuzzi et al [27] observed that losartan reduced Phe-induced contractions, similar to the results of our study. Accorsi-Mendonça et al [28] observed that the ACE inhibitor trandolapril treatment decreased the Ang II-and Phe-induced but not KCl-induced contractions on isolated carotid arteries in rats.…”

Aliskiren protects against myocardial ischaemia‐reperfusion injury via an endothelial nitric oxide synthase dependent manner

“…In ischaemic muscles, aliskiren significantly increased vascular density, enhanced expression of eNOS and reduced oxidative stress levels, which is not dependant on blood pressure lowering effect . In Hypertensive rats induced by clipping the left renal artery, aliskiren was effective in preventing endothelial dysfunction and reduction endothelial oxidative stress . In hypertensive dTGR (double‐transgenic rat) harbouring human renin and angiotensinogen genes, aliskiren improved the remodelling of resistance arteries, which might be ascribed to the enhanced expression of eNOS and reduced oxidative stress by aliskiren .…”

“…However, the potential mechanisms of aliskiren have not been well elucidated. Combination of aliskiren and l ‐arginine (a precursor of nitric oxide, NO) reduced contractile response to phenylephrine and improved acetylcholine relaxation in aortic rings 2‐kidney, 1‐clip (2K1C) hypertension . Associated with the fact that NO plays an important role in the pathogenesis of myocardial I/R injury, enhancing bioactivity of NO has emerged as an attractive target of novel drugs to attenuate I/R injury and improve endothelial dysfunction .…”

Effects Of The Direct Renin Inhibitor Aliskiren On Oxidative Stress In Isolated Rat Heart

“…One recent addition to the family of RAAS blockers was Aliskiren, which is a DRI that is indicated for the treatment of hypertension. Several studies demonstrated that Aliskiren, as first orally active DRI, could be used as a monotherapy and in combination with other agents to lower blood pressure (24). Some studies estimated that once daily Aliskiren administration reduced hypertension compared with ACEI, ARB, and diuretics (25)(26)(27)(28)(29).…”