Inhibition of the Angiotensin II Type 1 Receptor by TCV-116: Quantitation by In Vitro Autoradiography

Song, Keifu; Kanehara, H; Shiota, Naotaka; Wada, Takeo; Inada, Yuji; Miyazaki, Mizuo

doi:10.1254/jjp.79.131

Cited by 10 publications

(7 citation statements)

References 22 publications

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“…The central actions of angiotensin II appear to be mediated through the circumventricular organs such as the area postrema and subfornicular organ, which contain angiotensin II-sensitive neurons and which, lacking a blood-brain barrier, are accessible to circulating angiotensin II [6]. It is not known whether candesartan, or indeed any of the AT " receptor blockers, penetrates the blood-brain barrier in humans, although there is evidence of partial penetration into the central nervous system in rats at high doses [32,33]. Conversely, AT " receptor blockers do not reduce, and may even increase, circulating levels of angiotensin II [31], and require access to the AT " receptor to exert their effect.…”

Section: Discussionmentioning

confidence: 99%

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure

et al. 2001

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The objective of the present study was to determine the autonomic effects of angiotensin II (AT(1)) receptor blocker therapy in heart failure. In a randomized double-blind cross-over study, we compared the effects of candesartan and placebo on baroreflex sensitivity and on heart rate variability at rest, during stress and during 24 h monitoring. Acute effects were assessed 4 h after oral candesartan (8 mg) and chronic effects after 4 weeks of treatment (dose titrated to 16 mg daily). The study group comprised 21 patients with heart failure [mean (S.E.M.) ejection fraction 33% (1%)], in the absence of angiotensin-converting enzyme (ACE) inhibitor therapy. We found that acute candesartan was not different from placebo in its effects on blood pressure or mean RR interval. Chronic candesartan significantly reduced blood pressure [placebo, 137 (3)/82 (3) mmHg; candesartan, 121 (4)/75 (2) mmHg; P<0.001; values are mean (S.E.M.)], but had no effect on mean RR interval [placebo, 857 (25) ms; candesartan, 857 (21) ms]. Compared with placebo there were no significant effects of acute or chronic candesartan on heart rate variability in the time domain and no consistent effects in the frequency domain. Baroreflex sensitivity assessed by the phenylephrine bolus method was significantly increased after chronic candesartan [placebo, 3.5 (0.5) ms/mmHg; candesartan, 4.8 (0.7) ms/mmHg; P<0.05], although there were no changes in cross-spectral baroreflex sensitivity. Thus, in contrast with previous results with ACE inhibitors, angiotensin II receptor blockade in heart failure did not increase heart rate variability, and there was no consistent effect on baroreflex sensitivity.

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Section: Discussionmentioning

confidence: 99%

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure

et al. 2001

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“…Candesartan, administered systemically by osmotic minipump (Nishimura et al, 2000) or orally (Song et al, 1999) . After chronic subcutaneous (but not acute i.v.)…”

Section: Penetration Into Brainmentioning

confidence: 99%

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

et al. 2013

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“…Because the RVLM area contains a moderate density of AT 1 receptors, 12,22,26 endogenous Ang II can stimulate RVLM neurons through AT 1 receptors. A quantitative autoradiographic study found that the nucleus tractus solitarius and the dorsal motor nucleus of the vagus possess a higher density of AT 1 receptors in adult SHR than in WKY, 28 suggesting the number of AT 1 receptors per neuron being increased in SHR compared with WKY.…”

Section: Matsuura Et Al Ang II and Candesartan To Rvlm Neurons 563mentioning

confidence: 99%

Rostral Ventrolateral Medulla Neurons of Neonatal Wistar-Kyoto and Spontaneously Hypertensive Rats

et al. 2002

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Abstract-We compared the electrophysiological properties of neurons in the rostral ventrolateral medulla (RVLM) of neonatal Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and responses to angiotensin II and its type 1 receptor antagonist candesartan. Using the whole-cell patch-clamp technique, we examined the characteristics of RVLM neurons in brainstem-spinal cord preparations with a preserved sympathetic neuronal network. The baseline membrane potential of irregularly firing neurons was less negative (Ϫ50.1Ϯ0.6 versus Ϫ52.0Ϯ0.6 mV) and the firing rate was faster (3.0Ϯ0.2 versus 2.0Ϯ0. Key Words: brain Ⅲ rostral ventrolateral medulla Ⅲ angiotensin II Ⅲ receptors, angiotensin Ⅲ candesartan Ⅲ hyperpolarization R ostral ventrolateral medulla (RVLM) neurons are located at a pivotal site involved in the baroreflex pathway and play a key role in controlling peripheral sympathetic nerve activity (SNA) and blood pressure (BP). [1][2][3] We have reported impairment of the baroreflex function in hypertension based on recordings of renal SNA (RSNA) in conscious rabbits and rats and on vagal afferent nerve activity. 4,5 We have also confirmed that the angiotensin (Ang) II type 1 (AT 1 ) receptor antagonist candesartan improves the impaired baroreflex in conscious rats with congestive heart failure. 6 Earlier studies examined the responses of BP and SNA to Ang II and Ang II antagonists microinjected into the RVLM of normotensive and hypertensive animals, 7-11 because the RVLM area contains Ang II-immunoreactive nerve terminals and a moderately high density of AT 1 receptors. 12 Microinjection of Ang II increased BP and SNA, 7-10 whereas candesartan reduced BP, RSNA, and heart rate (HR). 11 However, the precise neuronal mechanisms by which RVLM neurons regulate SNA and BP and how these neurons are involved in the development of hypertension have not been fully elucidated. The firing rate of extracellular units in RVLM neurons was faster in adult spontaneously hypertensive rats (SHR) than in Wistar-Kyoto rats (WKY) in vivo. 13 Iontophoretic application of Ang II increased the extracellular activity of 30% of RVLM neurons in both strains, and the increase was greater in SHR. 14 However, very few studies have compared the intracellular properties of RVLM neurons and responses to Ang II and its antagonist between WKY and SHR. Recently, we determined the intracellular electrophysiological characteristics of RVLM bulbospinal neurons in neonatal WKY using brainstem-spinal cord preparation, in which the neuronal network is preserved from the vagal afferents to the sympathetic efferents exiting the intermediolateral cell column. 15 In the present study, we performed intracellular recordings (whole-cell patch-clamp technique) of RVLM neurons in WKY and SHR during superfusion rather than microinjection of Ang II or candesartan to precisely understand the role of the RVLM neurons. Although BP of SHR increases above that of WKY sometime between 3 and 4 weeks of age, 16 RVLM neuron activity cannot be assumed to be iden...

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Inhibition of the Angiotensin II Type 1 Receptor by TCV-116: Quantitation by In Vitro Autoradiography

Cited by 10 publications

References 22 publications

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure

Effects of angiotensin II (AT1) receptor blockade on cardiac vagal control in heart failure

A Systematic Comparison of the Properties of Clinically Used Angiotensin II Type 1 Receptor Antagonists

Rostral Ventrolateral Medulla Neurons of Neonatal Wistar-Kyoto and Spontaneously Hypertensive Rats

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