Acute and chronic dose-response relationships for angiotensin, aldosterone, and arterial pressure at varying levels of sodium intake.

Cowley, Allen W.; McCaa, R E

doi:10.1161/01.res.39.6.788

Cited by 77 publications

(53 citation statements)

References 24 publications

(13 reference statements)

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“…For example, several studies show that long-term infusion of angiotensin II (ANG II) causes salt-dependent hypertension in experimental animals (1,7,9,11,12,16). However, the precise nature of the relationship between plasma ANG II and long-term salt sensitivity of arterial pressure remains unclear.…”

mentioning

confidence: 99%

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Osborn¹,

Ariza-Nieto²,

Collister³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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.-Infusion of angiotensin II (ANG II) causes salt-sensitive hypertension. It is unclear whether this is due to the body's inability to suppress ANG II during increased salt intake or, rather, an elevated basal level of plasma ANG II itself. To distinguish between these mechanisms, SpragueDawley rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of drugs, respectively. The sensitivity of arterial pressure to salt was measured in four groups with the following treatments: 1) saline control (Con, n ϭ 12); 2) administration of the angiotensin-converting enzyme inhibitor enalapril to block endogenous ANG II (ANG-Lo, n ϭ 10); 3) administration of enalapril and 5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II to clamp plasma ANG II at normal levels (ANG-Norm, n ϭ 10); and 4) administration of enalapril and 20 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ANG II to clamp ANG II at high levels (ANG-Hi, n ϭ 10). Rats ingested a 0.4% NaCl diet for 3 days and then a 4.0% NaCl diet for 11 days. Arterial pressure of rats fed the 0.4% NaCl diet was lower in ANG-Lo (84 Ϯ 2 mmHg) compared with Con (101 Ϯ 3 mmHg) and ANG-Norm (98 Ϯ 4 mmHg) groups, whereas ANG-Hi rats were hypertensive (145 Ϯ 4 mmHg). Salt sensitivity was expressed as the change in arterial pressure divided by the change in sodium intake on the last day of the 4.0% NaCl diet. Salt sensitivity (in mmHg/meq Na) was lowest in Con rats (0.0 Ϯ 0.1) and progressed from ANG-Lo (0.8 Ϯ 0.2) to ANG-Norm (1.5 Ϯ 0.5) to ANG-Hi (3.5 Ϯ 0.5) rats. We conclude that the major determinant of salt sensitivity of arterial pressure is the basal level of plasma ANG II rather than the responsiveness of the renin-angiotensin system.renin-angiotensin system; sympathetic nervous system LONG-TERM SALT SENSITIVITY of arterial pressure is a significant clinical problem in both the normotensive and hypertensive human populations. It is currently estimated that 25% of the normotensive population is "salt sensitive" in that their arterial pressures are abnormally sensitive to changes in dietary NaCl intake (29). This is clinically significant, because the salt sensitivity of arterial pressure may be a more accurate predictor of future cardiovascular disease and morbidity than the basal level of arterial pressure (29). Salt sensitivity is more prevalent in humans with essential hypertension; estimates are that 50-75% of these patients exhibit increased salt sensitivity of arterial pressure (28). Despite the clinical importance of salt-dependent hypertension, its pathogenesis is poorly understood.Previous studies support the idea that impaired regulation of the renin-angiotensin-aldosterone system (RAAS) increases the salt sensitivity of arterial pressure. For example, several studies show that long-term infusion of angiotensin II (ANG II) causes salt-dependent hypertension in experimental animals (1,7,9,11,12,16). However, the precise nature of the relationship between plasma ANG II and long-term salt sensitivity of arterial pressure remains unclear. It is logical to conclude that the ...

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mentioning

confidence: 99%

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Osborn¹,

Ariza-Nieto²,

Collister³

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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“…3 Previous studies have shown that blood pressure elevation after exogenous Ang II administration is dose dependent after either a single bolus or a continuous infusion. 4,5 However, termination of the Ang II infusion results in a return of mean arterial pressure to the normal levels within 10-20 seconds, an effect that is consistent with its half-life. 6 The design of non-peptide AT 1 antagonists has been pursued for the past 20 years.…”

Section: Introductionmentioning

confidence: 78%

Hypertension study in anaesthetized rabbits: protocol proposal for AT₁ antagonists screening

Politi

Zervou

Triantafyllidi

et al. 2010

J Renin Angiotensin Aldosterone Syst

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Introduction: The aim of this study was to establish an optimized fast and safe protocol for the pharmacological screening of AT 1 antagonists. Materials and methods: The pharmaceutical prototype AT 1 antagonist losartan, its active metabolite EXP3174 and the synthetic compound MMK1 were analysed in order to validate the protocol. Ang II was continuously infused while the animals received the drugs in two procedures. Results: In the post-treatment procedure drugs were administered either in a single bolus dose or in a sequential manner. When losartan was administered in a single bolus dose, efficacy was evident until the 7th min (p=0.012) whilst EXP3174 infusion extended the efficiency up to the end of the study (p=0.006). In addition, the sequential injections of losartan prolonged the inhibitory time interval until the end of the study (p=0.045). In the pre-treatment procedure, results suggested a dosedependent inhibitory effect for both antagonists. The pressor response to Ang II was unchanged after MMK1 administration either in the post-or in the pre-treatment mode. Conclusions:The proposed protocol appears to be safe, simple and fast for the pharmacological screening of AT 1 antagonists and enables the evaluation of new antagonists using lower doses than any other reported in the literature.

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“…Moreover, effects of aldosterone do not appear to contribute significantly to the findings of the current study, since values of plasma aldosterone return toward baseline within 48 hours during continuous infusion of Ang II. 27 Acute and long-term Ang II treatments are well known to differentially modulate SNA and arterial pressure through both peripheral 28 and central 17,29 actions. In the current study, 7-day peripheral Ang II infusion produced a significant and sustained increase in MAP.…”

Section: Discussionmentioning

confidence: 99%

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

2003

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Abstract-The hypothalamic paraventricular nucleus (PVN) plays an important role in the sympathoexcitatory response to elevated plasma angiotensin II (Ang II). However, the mechanism by which Ang II influences sympathetic activity is not fully understood.In this study, we tested the hypothesis that GABA(␥-aminobutyric acid)-ergic function in the PVN is reduced by peripheral infusion of Ang II. To accomplish this, rats received either intravenous Ang II (12 ng/kg per minute) or vehicle (D5W) for 7 days, and renal sympathetic nerve activity (SNA), mean arterial pressure (MAP), and heart rate (HR) responses were recorded after unilateral PVN microinjection of the GABA-A receptor antagonist bicuculline methiodide (BMI, 0.1 nmol). Results indicate that in contrast to a significant increase in renal SNA, MAP, and HR observed in vehicle-infused rats (PϽ0.05), BMI injection into the PVN of Ang II-infused animals was without effect on all recorded variables. In a separate groups of animals, ganglionic blockade produced a significantly greater fall in MAP (PϽ0.01) in Ang II-infused rats than in vehicle-infused control rats, indicating that the contribution of SNA to the maintenance of blood pressure was elevated in the Ang II-infused group. Overall, these data indicate that cardiovascular and sympathoexcitatory responses to acute GABA-A receptor antagonism in the PVN are significantly blunted in rats after 7 days of intravenous infusion of Ang II. We conclude that an Ang II-induced reduction in GABAergic inhibition within the PVN may contribute to elevated SNA observed in this study. Key Words: angiotensin II Ⅲ hypothalamus Ⅲ sympathetic nervous system Ⅲ hypertension, arterial A s the dominant inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA) 1 plays an important role in regulating cardiovascular function. 2,3 In brain regions such as the nucleus tractus solitarius 2 and rostral ventrolateral medulla 2,3 that control sympathetic nerve activity (SNA), GABA tonically suppresses neuronal activity and excitability. In the hypothalamic paraventricular nucleus (PVN), neuronal activity is also regulated by GABA 4 -6 and by a number of excitatory neurotransmitters as well. 7,8 Among the latter is the peptide angiotensin II (Ang II). Ang II-containing fibers arise from Ang II-sensitive regions of the forebrain known as circumventricular organs (CVO), which lack a complete blood-brain barrier. 9,10 Neurons in two forebrain CVOs, the subfornical organ and organum vasculosum of the lamina terminalis, express Ang II AT 1 receptors in high density 11 and appear to sense and respond to circulating Ang II. 9,12-15 Although Ang II increases SNA through these and other central actions, 16,17 the mechanism by which circulating Ang II enhances PVN neuronal excitability is not fully understood.On the basis of literature evidence, it is clear that GABA 4 -6 and Ang II 13-15 can each act individually within the PVN to influence cardiovascular function. More recently, it has been shown that local GABA-Ang II interacti...

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Acute and chronic dose-response relationships for angiotensin, aldosterone, and arterial pressure at varying levels of sodium intake.

Cited by 77 publications

References 24 publications

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Hypertension study in anaesthetized rabbits: protocol proposal for AT₁ antagonists screening

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

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Acute and chronic dose-response relationships for angiotensin, aldosterone, and arterial pressure at varying levels of sodium intake.

Cited by 77 publications

References 24 publications

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Responsiveness vs. basal activity of plasma ANG II as a determinant of arterial pressure salt sensitivity

Hypertension study in anaesthetized rabbits: protocol proposal for AT1 antagonists screening

Effect of Intravenous Angiotensin II Infusion on Responses to Hypothalamic PVN Injection of Bicuculline

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Hypertension study in anaesthetized rabbits: protocol proposal for AT₁ antagonists screening