Role of AT1 receptors in the resetting of the baroreflex control of heart rate by angiotensin II in the rabbit.

Wong, Julie; Chou, Li-Shan; Reid, Ian A.

doi:10.1172/jci116357

Cited by 48 publications

(39 citation statements)

References 32 publications

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“…She demonstrated that angiotensin-induced baroreflex resetting was partially reversed soon after angiotension II infusion was stopped despite maintenance of the hypertensive state with infusions of phenylephrine or methoxamine. Although the exact mechanism of baroreflex resetting by angiotension II is unknown, it is thought to involve central nervous system actions via AT-1 receptors at the level of the area postrema (43,44).…”

Section: Discussionmentioning

confidence: 99%

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Merrill¹,

Thompson²,

Carney³

et al. 1996

J. Clin. Invest.

170

192

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We have generated a transgenic model consisting of both the human renin and human angiotensinogen genes to study further the role played by the renin-angiotensin system in regulating arterial pressure. Transgenic mice containing either gene alone were normotensive, whereas mice containing both genes were chronically hypertensive. Plasma renin activity and plasma angiotensin II levels were both markedly elevated in the double transgenic mice compared with either single transgenic or nontransgenic controls. The elevation in blood pressure caused by the human transgenes was independent of the genotype at the endogenous renin locus and was equal in mice homozygous for the Ren-1 c allele or in mice containing one copy each of Ren-1 c , Ren-1 d , or Ren-2. Chronic overproduction of angiotensin II in the double transgenic mice resulted in a resetting of the baroreflex control of heart rate to a higher pressure without significantly changing the gain or sensitivity of the reflex. Moreover, this change was not due to the effects of elevated pressure itself since angiotensin-converting enzyme inhibition had minimal effects on the baroreflex in spontaneously hypertensive BPH-2 control mice, which exhibit non-renindependent hypertension. This double transgenic model should provide an excellent tool for further studies on the mechanisms of hypertension initiated by the renin-angiotensin system. ( J. Clin. Invest. 1996. 97:1047-1055.)

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Section: Discussionmentioning

confidence: 99%

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Merrill¹,

Thompson²,

Carney³

et al. 1996

J. Clin. Invest.

170

192

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“…Moreover, intravenous administration of losartan (10 mg/kg/d) to normal rats for 10 d blocked Ang II action and lowered the blood pressure (7). Dizziness was reported as a side effect of losartan in clinical treatment (25,26). However, the mechanism of the losartan-induced lowering effect on normal blood pressure was not elucidated in these studies.…”

Section: Discussionmentioning

confidence: 99%

Diverse Effects of AT1 Receptor Antagonists on Normal Blood Pressure and Regulatory System.

1999

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An AT1 receptor antagonist, losartan, has been reported to improve survival and quality of life in patients with congestive heart failure as angiotensin converting enzyme inhibitors do. Since many of the patients are normotensive, it may be a drawback if the compound decreases normal blood pressure. In this study, we investigated whether a novel AT1 receptor antagonist, TA-606, which is more potent than losartan, affects normal blood pressure and its regulatory system in comparison with losartan. TA-606 (30 and 100 mg/kg, p.o.) did not change normal blood pressure, whereas losartan (100 mg/kg, p.o.) tended to decrease it. Although EXP3174 (1 and 10 mg/kg, i.v.), an active metabolite of losartan, suppressed the baroreceptor-heart rate (HR) reflex, 606A (1 and 10 mg/kg, i.v.), an active metabolite of TA-606, did not affect it. Since losartan is known to affect the L-glutamate receptor which is part of the central blood pressure regulatory system, we also investigated whether 606A affects L-glutamate receptor binding. We found that 606A did not affect the binding of the L-glutamate receptor, but EXP3174 inhibited the binding with IC50 values of 13.3 tuM. These findings suggest that, even having the same AT1 receptor antagonist properties as losartan and EXP3174, TA-606 and its active metabolite do not influence normal blood pressure or its regulatory system. (Hypertens Res 1999; 22: 121-127) Key Words: TA-606, losartan, AT1 receptor antagonist, baroreceptor-heart rate reflex, blood pressure regulation An AT1 receptor antagonist, losartan, has been reported to improve survival and quality of life of patients with congestive heart failure (1) as angiotensin converting enzyme inhibitors (2, 3) do, which are considered to be good treatments for patients with hypertension. However, hypotensive action of these agents may limit their usage in heart failure patients. Excessively low blood pressure may induce ischemia in multiple organs, and it was reported that blood pressure excessively lowered by antihypertensive agents (< 85 mmHg in diastolic blood pressure) was related to poor prognosis in patients with ischemic heart disease; i. e. , J curve phenomenon (4).Losartan is known as the first nonpeptide AT1 receptor antagonist developed for clinical use (5), and was reported to affect normal blood pressure; by lowering it even at regular clinical doses (6, 7) . In addition to AT1 receptor antagonism, losartan was reported to affect the glutamate receptor which is involved in the central blood pressure regulatory system, including the baroreflex (8, 16). L-glutamate is known as an important neurotransmitter in the medulla oblongata in the central blood pressure regulatory system (9-11). It is also known that this area lacks a blood-brain barrier despite dense vascular supply (12,16). Therefore, humoral factors in blood can be detected by this area, and it is considered to be ideally suited to the integration of both neural and humoral signals essential for normal autonomic regulation (13,14) . It is possible that the low...

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“…Each drug was administered once daily for 6 days either alone or in combination in a crossover fashion. Blood samples for concentration measurements were taken before the first dose and the fifth dose and at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3,4,5,6,8,12,16,24,48 and 72 hr after the last dose. Cardiovascular observations consisting of systolic and diastolic blood pressure and HR were measured using digital blood pressure cuffs before dosing from the first to the fifth dose and at 0, 2, 4, 8, 12, 24, 48 and 72 hr after the last dose.…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the proposed model uses a concept of a set point, a reference value of MAP that can be lowered by a drug through TPR and assumes that a difference between current MAP and the set point acts as the driving force of exerting negative feedback to PP and HR. This idea of the set point being lowered by a drug is found in the literature in the case of losartan which has the same angiotensin II AT1 receptor-blocking mechanism as telmisartan [8] and enalapril which is an angiotensin-converting enzyme inhibitor [9].The objective of the current report was to improve upon empirical models to achieve better predictive capabilities using non-invasive markers with known physiological and drug action mechanisms, which can be readily applicable in real clinical situations. …”

mentioning

confidence: 99%

Mechanistic Model for Blood Pressure and Heart Rate Changes Produced by Telmisartan in Human Beings

Chae

Son

Kim

et al. 2017

Basic Clin Pharma Tox

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Telmisartan, an angiotensin receptor blocker (ARB), is indicated for the treatment of essential hypertension. This study aimed to develop a mechanistic model of telmisartan drug effect in human beings using non-invasive markers. Data were acquired from a previous study where telmisartan 80 mg was given once daily for 6 days. Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) were measured before dosing for days 1-5 and serially after the last dose. Mean arterial pressure (MAP) and pulse pressure (PP) were calculated from SBP and DBP. Relationships between MAP, PP, HR and total peripheral resistance (TPR) were developed. Circadian variation was incorporated into PP and HR, and TPR was assumed to adjust itself in response to changes in PP and HR based on baroreflex mechanism. Drug effects were then described as lowering the set point of MAP through TPR with a physiological feedback effect stimulating HR and PP. Drug concentrations were described by a two-compartment disposition model with first-order absorption and lag time, and first-order elimination. Circadian variation was described by cosine functions, having periods of 12 and 24 hr. A log-linear model was used to describe drug effect, with estimated drug effect parameter of 0.051/hr. Estimated fractional turnover rate of PP, HR and TPR was 11.2 hr. The model successfully described the time courses of these cardiovascular variables. This work demonstrated the feasibility of using non-invasive cardiovascular measurements to derive a mechanistic model for telmisartan in human beings. The model may be suitable for other ARBs.Telmisartan is an antagonist of the angiotensin II type 1 (AT1) receptor that is used for the treatment of hypertension. It selectively inhibits stimulation of the AT1 receptor by angiotensin II. It has a high volume of distribution and is eliminated mainly by the kidneys which results in a long terminal elimination half-life. The compound is not metabolized by cytochrome P450 isoenzymes and has a low risk for P450-based drug interactions [1,2].The action of telmisartan is known to lead to inhibition of aldosterone secretion and reduced vasoconstriction. The time course of its effect involves both rapid and slow responses. The rapid response is mainly due to antagonizing angiotensin II vasoconstriction. The slow response is due to antagonizing angiotensin-mediated aldosterone secretion which leads to a natriuretic effect, followed by decreased plasma volume and consequent decrease in cardiac stroke volume. Both the rapid and slow effects contribute to lowering of blood pressure [1].A population pharmacokinetic (PK) model for telmisartan was first published in 2003 [3] and reported that a two-compartment disposition model with first-order absorption and elimination described the data. A PKPD model of telmisartan has been published [4] in spontaneously hypertensive rats. To the authors' knowledge, no PKPD model of telmisartan has been published in human beings. Previous PKPD models used either an empirical modelli...

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Role of AT1 receptors in the resetting of the baroreflex control of heart rate by angiotensin II in the rabbit.

Cited by 48 publications

References 32 publications

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Chronic hypertension and altered baroreflex responses in transgenic mice containing the human renin and human angiotensinogen genes.

Diverse Effects of AT1 Receptor Antagonists on Normal Blood Pressure and Regulatory System.

Mechanistic Model for Blood Pressure and Heart Rate Changes Produced by Telmisartan in Human Beings

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