Effects of Angiotensin II Type 1 Receptor Antagonist on Pressor Responses to Pulsatile Compression of the Rostral Ventrolateral Medulla in Rats

Kido, Hidenori; Sasaki, Susumu; Oguni, Atsuhiko; Harada, S.; Morimoto, Satoshi; Takeda, Kazuo; Nakagawa, Masao

doi:10.1291/hypres.27.427

Cited by 6 publications

(2 citation statements)

References 24 publications

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“…*P Ͻ 0.01 or 0.001 and †P Ͻ 0.05 compared with 0 change. when injected in the RVLM, produces blockade of AT 1 receptors (1,9,12,27) and is less than the dose (200 pmol) that has been shown to have no effect on glutamate receptors in the RVLM (27). Thus the effect of candesartan in evoking increases in MAP and RSNA is likely to be a consequence of specific blockade of AT 1 receptors rather than a nonspecific effect of the drug.…”

Section: Discussionmentioning

confidence: 90%

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Sheriff¹,

Fontes²,

Killinger³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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The role of ANG type 1 (AT1) receptors in the rostral ventrolateral medulla (RVLM) in the maintenance of sympathetic vasomotor tone in normotensive animals is unclear. In this study, we tested the hypothesis that AT 1 receptors make a significant contribution to the tonic activity of presympathetic neurons in the RVLM of normotensive rats under conditions where the excitatory input to these neurons is enhanced, such as during systemic hypoxia. In urethane-anesthetized rats, microinjections of the AT1 receptor antagonist candesartan in the RVLM during moderate hypoxia unexpectedly resulted in substantial increases in arterial pressure and renal sympathetic nerve activity (RSNA), whereas under normoxic conditions the same dose resulted in no significant change in arterial pressure and RSNA. Under hypoxic conditions, and after microinjection of the GABA A receptor antagonist bicuculline in the RVLM, subsequent microinjection of candesartan in the RVLM resulted in a significant decrease in RSNA. In control experiments, bilateral microinjections in the RVLM of the compound [Sar 1 ,Thr 8 ]ANG II (sarthran), which decreases sympathetic vasomotor activity via a mechanism that is independent of AT 1 receptors, significantly reduced arterial pressure and RSNA under both normoxic and hypoxic conditions. The results indicate that, at least under some conditions, endogenous ANG II has a tonic sympathoinhibitory effect in the RVLM, which is dependent on GABA receptors. We suggest that the net effect of endogenous ANG II in this region depends on the balance of both tonic excitatory and inhibitory actions on presympathetic neurons and that this balance is altered in different physiological or pathophysiological conditions. brain stem; angiotensin receptors; arterial pressure; chemoreceptor reflex; sympathetic vasomotor tone; angiotensin type 1 receptor THE ROSTRAL PART OF THE ventrolateral medulla (RVLM) contains a group of sympathoexcitatory neurons that play a major role in the tonic and phasic regulation of sympathetic activity and arterial blood pressure (8, 16). These neurons project directly to sympathetic preganglionic neurons in the spinal cord and are an essential component of the central pathways mediating cardiovascular reflex responses to stimulation of baroreceptors, chemoreceptors, and many other peripheral receptors (8, 16).There is considerable evidence suggesting a role for endogenous ANG peptides in the regulation of RVLM neurons. Studies using in vitro autoradiography have demonstrated a high density of ANG II receptor binding sites in the RVLM of most species studied, including humans (2). These receptors are primarily of the ANG type 1 (AT 1 ) subtype (2), and recent studies using an antibody against the AT 1 receptor has confirmed the existence of these receptors on neurons in the RVLM of the rat, including catecholamine neurons of the C1 group (19). Microinjection of ANG II in the RVLM results in an increase in arterial pressure and sympathetic activity, an effect that is mediated by AT 1 receptors (3,14...

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Section: Discussionmentioning

confidence: 90%

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Sheriff¹,

Fontes²,

Killinger³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Since the increased expression of kynureninase in SHR is thought to decrease the KYN level (Mizutani et al 2002 ) and KYN is a precursor of KYNA, a decreased KYNA level can be expected in hypertensive rats. Interestingly, both an increase of mean arterial pressure and of splanchnic sympathetic nerve activity, evoked by AT-II administration into RVLM, were reduced by local administration of candesartan as well as KYNA (Kido et al 2004 ). Considering the hypotensive activity of KYNA in the brain, the fact that all tested ARBs decreased the synthesis of this GLU antagonist is unexpected.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain—Its Possible Clinical Applications

et al. 2017

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Angiotensin II receptor blockers (ARBs) are one of the most frequently recommended antihypertensive drugs. Apart from their activity towards the circulatory system, ARBs also penetrate the blood-brain barrier and display neuroprotective effects. Kynurenic acid (KYNA) is an endogenous metabolite of tryptophan produced by kynurenine aminotransferase II (KAT II) in the brain. Antagonism towards all ionotropic glutamate (GLU) receptors is the main mechanism of KYNA action. An elevated brain level of KYNA is linked with memory impairment and psychotic symptoms. The aim of this study was to examine the influence of three ARBs: irbesartan, losartan, and telmisartan on KYNA production and KAT II activity in rat brain. The effect of ARBs on KYNA production was analyzed in rat brain cortical slices and on isolated KAT II enzyme. Irbesartan, losartan, and telmisartan decreased KYNA production and KAT II activity in a dose-dependent manner in rat brain cortex in vitro. Molecular docking suggested that the examined ARBs could bind to an active site of KAT II. In conclusion, ARBs decrease KYNA production in rat brain by direct inhibition of KAT II enzymatic activity. This novel mechanism of ARBs action may be advantageous in the treatment of cognitive impairment or the management of schizophrenia.Electronic supplementary materialThe online version of this article (doi:10.1007/s12640-017-9781-2) contains supplementary material, which is available to authorized users.

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Excitatory Responses to Microinjection of Glutamate Depend on Dose Not Volume: A Meta-Analysis of Studies in Rat RVLM

Gaede

Pilowsky

2012

Stimulation and Inhibition of Neurons

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Effects of Angiotensin II Type 1 Receptor Antagonist on Pressor Responses to Pulsatile Compression of the Rostral Ventrolateral Medulla in Rats

Cited by 6 publications

References 24 publications

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain—Its Possible Clinical Applications

Excitatory Responses to Microinjection of Glutamate Depend on Dose Not Volume: A Meta-Analysis of Studies in Rat RVLM

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Effects of Angiotensin II Type 1 Receptor Antagonist on Pressor Responses to Pulsatile Compression of the Rostral Ventrolateral Medulla in Rats

Cited by 6 publications

References 24 publications

Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Blockade of AT1 receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Angiotensin II Type 1 Receptor Blockers Inhibit KAT II Activity in the Brain—Its Possible Clinical Applications

Excitatory Responses to Microinjection of Glutamate Depend on Dose Not Volume: A Meta-Analysis of Studies in Rat RVLM

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Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions

Blockade of AT₁ receptors in the rostral ventrolateral medulla increases sympathetic activity under hypoxic conditions