The Brain Renin-Angiotensin System Contributes to the Hypertension in Mice Containing Both the Human Renin and Human Angiotensinogen Transgenes

Davisson, Robin L.; Yang, Ge; Beltz, Terry G.; Cassell, Martin D.; Johnson, Alan Kim; Sigmund, Curt D.

doi:10.1161/01.res.83.10.1047

Cited by 136 publications

(165 citation statements)

References 61 publications

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“…These mice exhibited a marked elevation in BP and a resetting of the baroreflex control of HR to a higher pressure without significantly changing the gain of the reflex (25). ICV administration of losartan in these mice lowered BP acutely, demonstrating the functional importance of brain ANG II even when systemically overexpressed (6). To examine the mechanisms regulating production of ANG II in the brain, we generated double transgenic mice carrying both the hREN and hAGT genes under the control of the neuron-specific synapsin-I promoter (N-AII mice) or the glia-specific GFAP promoter (G-AII mice).…”

Section: Discussionmentioning

confidence: 85%

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

Sakai

Chapleau

Morimoto

et al. 2004

Physiological Genomics

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. Differential modulation of baroreflex control of heart rate by neuron-vs. glia-derived angiotensin II. Physiol Genomics 20: 66-72, 2004. First published October 5, 2004 doi: 10.1152/physiolgenomics.00168.2004.-We developed transgenic mice with targeted expression of human renin (hREN) and human angiotensinogen (hAGT) to either neurons (N-AII mice) or glia (G-AII mice) to test the hypothesis that neuronal and glial ANG II may have differential function. Since baseline blood pressure (BP) did not differ between the models (109 Ϯ 3 vs. 114 Ϯ 4 mmHg), we stressed the BP regulatory pathway by measuring the heart rate (HR) (baroreflex) response to phenylephrine-and nitroprusside-induced changes in arterial BP. The midpoint of the baroreflex curve (BP50) was reset to a significantly higher BP in N-AII mice (131 Ϯ 5 mmHg) compared with littermate controls (115 Ϯ 3 mmHg). Baroreflex gain (slope of BP-HR relation) was similar in N-AII and control mice (12 Ϯ 1 vs. 14 Ϯ 2 beats⅐min Ϫ1 ⅐mmHg Ϫ1 ). In contrast, G-AII mice exhibited less of an increase in BP50 (125 Ϯ 5 mmHg) but a larger decrease in baroreflex gain (8 Ϯ 1 beats⅐min Ϫ1 ⅐mmHg Ϫ1 ) compared with both control and N-AII mice. Differences in BP50 and gain between N-AII, G-AII, and control mice persisted after parasympathetic blockade with atropine but were eliminated after sympathetic blockade with propranolol, indicating the effects of ANG II were selective for cardiosympathetic arm of the reflex. ANG II-like immunoreactivity was observed more prominently around the paraventricular nucleus and nucleus tractus solitarii in G-AII mice but more prominently in the ventrolateral medulla in N-AII mice. We conclude that ANG II differentially modulates baroreflex control of HR in mice producing ANG II in neurons vs. glia, and its differential function may reflect regional differences in the production of ANG II in cardiovascular control nuclei of the brain. renin-angiotensin system; brain; transgenic animal; sympathetic nervous system THE ARTERIAL BAROREFLEX is a major regulator of arterial pressure (AP) and cardiovascular function and acts to buffer changes in AP in part by changing heart rate (HR). The baroreflex has been studied extensively in animal models and humans. Clinical studies have demonstrated that hypertension is accompanied by a modulation of baroreflex function (3,4,11,23,32); and it is known that this modulation occurs by one of two mechanisms. In the first, the baroreflex curve is shifted or reset to a higher pressure, whereas in the second there is a decreased sensitivity of the reflex as measured by a decreased slope (or attenuated gain) of the baroreflex curve. These mechanisms have been documented in many experimental animal models of hypertension (10,17,25,26).There is considerable evidence that circulating ANG II plays a critical role in the baroreflex control of HR by modulating either the set point or sensitivity of the reflex (7,24,25,34). For example, chronic intracerebroventricular (ICV) infusion of ANG II decreased baroreflex gain and bloc...

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Section: Discussionmentioning

confidence: 85%

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

Sakai

Chapleau

Morimoto

et al. 2004

Physiological Genomics

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“…Mice were implanted with intracerebroventricular (ICV) cannulae and carotid arterial catheters for brain microinjection of drugs and for direct measurement of pulsatile and mean arterial pressure (MAP), respectively, as described by us in detail previously (17). All experiments were performed in conscious, freely moving mice.…”

Section: Animalsmentioning

confidence: 99%

“…Animals were allowed 4 days' recovery before in vivo testing for proper ICV cannula placement by intraventricular injection of the muscarinic agonist carbachol (50 ng). Carbachol elicits a characteristic pressor and bradycardic response in rodents when injected intraventricularly (17). Mice that did not respond to carbachol were not used in the studies (n = 2).…”

Section: Animalsmentioning

confidence: 99%

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Divergent functions of angiotensin II receptor isoforms in the brain

Davisson¹,

Oliverio²,

Coffman³

et al. 2000

J. Clin. Invest.

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IntroductionThe renin angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. In addition to its importance in regulating normal physiology, enhanced activity or dysregulation of the RAS can lead to maladaptive responses and significant cardiovascular disease. The RAS is an ancient system that is present in lower organisms including amphibians, and many of its features have been conserved across evolution. The major biologically active peptide of the RAS is angiotensin II, and its major actions are mediated by G protein-coupled angiotensin receptors. These receptors can be divided into two pharmacological classes, AT 1 and AT 2 (1). Most of the classically recognized actions of the RAS in fluid and blood pressure homeostasis are mediated by AT 1 receptors. AT 1 receptors are expressed in brain and peripheral tissues. The central nervous system (CNS) receptors play a key role in blood pressure regulation and in regulation of drinking and water balance (2).The discovery of two AT 1 receptor isoforms in rats and mice, termed AT 1A and AT 1B receptors, uncovered an additional level of complexity of the system (3-5). These receptors are highly homologous with indistinguishable binding profiles, but are products of distinct genes (Agtr1a and Agtr1b) that are differentially expressed and regulated (6-8). Although a single report has suggested the existence of AT 1B receptors in humans (9), most investigators believe that humans have only a single AT 1 receptor gene. Despite this apparent genetic difference, the physiological actions of AT 1 receptors in humans and rodents are virtually identical. Because pharmacological AT 1 receptor antagonists cause equivalent inhibition of both AT 1 isoforms, the relative physiological roles of AT 1A and AT 1B and their relationship to human AT 1 receptor functions have been difficult to identify. Recent gene-targeting experiments have clarified the relative role of the AT 1A and AT 1B receptors in the periphery, demonstrating a predominant role for AT 1A receptors in regulation of vascular tone (10, 11). In the brain as in the periphery, expression of AT 1A exceeds that of AT 1B , with the exception of the pituitary gland, where AT 1B expression predominates (12)(13)(14). AT 1A expression is especially prominent in major forebrain cardiovascular and fluid regulatory centers (12). AT 1B expression is highest in the anterior pituitary (12-14). However, the relative contributions of these AT 1 receptor subtypes to central angiotensin II responses are not known. We used gene targeting in combination with a unique system for maintaining catheters in the cerebral ventricles of conscious mice to test whether there are differential roles for AT 1A and AT 1B receptors in responses elicited by angiotensin II in the CNS. The renin-angiotensin system (RAS) plays a critical role in cardiovascular and fluid homeostasis. The major biologically active peptide of the RAS is angiotensin II, which acts through G protein-coupled receptors of two pharmacological classes...

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“…Following the delivery of adenovirus, the catheter was trimmed, sealed, and enclosed inside the mouse. For mice in which the pressor response to infused human renin was tested, the catheter was tunneled subcutaneously and exteriorized between the scapulae as described (28). No differences in the overall efficiency or tissue specificity of infection were observed between the two methods of delivery (data not shown).…”

Section: Generation Of Transgenic Mice-mentioning

confidence: 99%

Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

Stec¹,

Davisson²,

Haskell

et al. 1999

Journal of Biological Chemistry

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Tissue-specific ablation of gene function is possible in vivo by the Cre-loxP recombinase system. We generated transgenic mice containing a human angiotensinogen gene flanked by loxP sites (hAGT flox ). To examine the physiologic consequences of tissue-specific loss of angiotensinogen gene function in vivo, we constructed an adenovirus expressing Cre recombinase. Studies were performed in several independent lines of hAGT flox mice before and after intravenous administration of either Adcre or Ad␤Gal as a control. Systemic administration of Adcre caused a significant decrease in circulating human angiotensinogen and markedly blunted the pressor response to administration of purified recombinant human renin. Southern blot analysis of genomic DNA from various organs revealed that the Cre-mediated deletion was liver-specific. Further analysis revealed the absence of full-length human angiotensinogen mRNA and protein in the liver but not the kidney of Adcre mice, consistent with the liver being the target for adenoviruses administered intravenously. These studies demonstrate that extra-hepatic sources of angiotensinogen do not contribute significantly to the circulating pool of angiotensinogen and provide proof-of-principle that the Cre-loxP system can be used effectively to examine the contribution of the systemic and tissue reninangiotensin system to normal and pathological regulation of blood pressure.

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The Brain Renin-Angiotensin System Contributes to the Hypertension in Mice Containing Both the Human Renin and Human Angiotensinogen Transgenes

Cited by 136 publications

References 61 publications

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

Differential modulation of baroreflex control of heart rate by neuron- vs. glia-derived angiotensin II

Divergent functions of angiotensin II receptor isoforms in the brain

Efficient Liver-specific Deletion of a Floxed Human Angiotensinogen Transgene by Adenoviral Delivery of Cre Recombinasein Vivo

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