UPREGULATION OF ANGIOTENSIN AT₁ RECEPTOR AND INTRACELLULAR KINASE GENE EXPRESSION IN HYPERTENSIVE RATS

Abstract

1. Activation of angiotensin II AT1 receptors (AT1R) stimulates catecholamine systems within both central and peripheral tissues that are associated with blood pressure control. In the present study, we sought to determine whether the hypertensive phenotype of the spontaneously hypertensive rat (SHR) is associated with changes in AT1R gene expression and whether gene expression of downstream signalling molecules was coupled to catecholamine gene expression, both in key brainstem nuclei and in peripheral sites implicated in cardiovascular control. 2. Gene expression levels of AT1R, extracellular signal-regulated kinase (ERK) 1 and 2 and phosphatidylinositol 3-kinase (PI3-K) were quantified in Wistar-Kyoto (WKY) rats and SHR. Messenger RNA expression levels were quantified using real time reverse transcription-polymerase chain reaction. In addition, we investigated whether there was a relationship between gene expression and systolic blood pressure. 3. The gene expression levels of AT1R, ERK2 and PI3-K were significantly higher in the paraventricular nucleus of the hypothalamus (4.12-, 1.40- and 1.38-fold, respectively), rostral ventrolateral medulla (2.71-, 1.33- and 2.73-fold, respectively), spinal cord (30.5-, 2.72- and 1.53-fold, respectively), adrenal medulla (1.68-, 1.55- and 1.76-fold, respectively) and coeliac ganglion (1.39-, 1.35- and 1.12-fold, respectively) in SHR compared with WKY rats. There was no significant difference in the level of ERK1 gene expression between the two strains. The gene expression levels of AT1R and ERK2 were positively correlated with blood pressure in all central nervous tissues investigated in the SHR, but not in WKY rats. Gene expression levels of the AT1R in the coeliac ganglion and adrenal medulla were also positively correlated with increased systolic blood pressure. 4. The present data suggest that a defect in AT1R expression (that may further alter downstream signalling pathways) in the SHR may be responsible, at least in part, for the hypertensive phenotype.

Sympathoinhibition caused by orally administered telmisartan through inhibition of the AT1 receptor in the rostral ventrolateral medulla of hypertensive rats

“…6 AT 1 R is rich in the specific brain nuclei that regulate SNS activation, such as the anteroventral third ventricle, paraventricular nucleus of the hypothalamus, nucleus tractus solitarii and RVLM. [48][49][50] Moreover, a high density of AT 1 R is present in the brain regions involved in the regulation of SNS activation, such as the circumventricular organs outside of the bloodbrain barrier, where peripherally administered ARBs are able to effect change without consideration of the blood-brain barrier, as well as inside of the blood-brain barrier. 50 The reduction of oxidative stress via inhibition of AT 1 R caused by orally administered TLM may not be a phenomenon unique to the RVLM.…”

Oxidative stress in the cardiovascular center has a pivotal role in the sympathetic activation in hypertension

“…22,24,42 It is interesting to note that AT1 receptors are rich in the specific brain nuclei that regulate the sympathetic activity such as the anteroventral third ventricle, paraventricular nucleus of the hypothalamus, NTS and the RVLM in the brainstem. 46,47,76 It has been demonstrated that the peripheral administration of the AT1 receptor blockers penetrate the blood-brain barrier and blocks the AT1 receptors within the brain as well as outside of the brain, although the extent of the blocking action within the brain varies among the AT1 receptor blockers when they are administered peripherally. 77 There are two important observations in this regard.…”

“…41 The brain renin-angiotensin system is upregulated in chronic disease states such as hypertension and heart failure with enhanced central sympathetic outflow. [42][43][44][45][46][47] We also determined whether mitochondria-derived ROS mediates sympathoexcitation induced by angiotensin II in the RVLM. 19 It is well established that exogenously administered angiotensin II into the RVLM elicits the pressor response via the activation of the sympathetic nervous system.…”

Artificial microRNA interference targeting AT1a receptors in paraventricular nucleus attenuates hypertension in rats

“…It has been found that the angiotensin II type 1 receptors (AT 1 R) in the PVN are increased in SHR 11 and renovascular hypertensive rats. 12 Our recent studies have shown that angiotensin II (Ang II) in the PVN increases sympathetic activity and arterial pressure, and antagonist of AT 1 R in the PVN attenuates the enhanced sympathetic activity in renovascular hypertensive rats.…”