Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice (original) (raw)
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American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2008
To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT1A) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT1A] with brain-restricted overexpression of AT1Areceptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT1Acompared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT1A. Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in ...
Hypertension, 2011
To examine the physiological importance of brain angiotensin II type 1 (AT 1 ) receptors, we developed a novel transgenic mouse model with rat AT 1a receptors targeted selectively to neurons of the central nervous system (CNS). A transgene consisting of 2.8 kb of the rat neuron-specific enolase (NSE) 5Ј flanking region fused to a cDNA encoding the full open-reading frame of the rat AT 1a receptor was constructed and transgenic mice (NSE-AT 1a ) were generated. Two of six transgenic founder lines exhibited brain-selective expression of the transgene at either moderate or high levels. Immunohistochemistry revealed widespread distribution of AT 1 receptors in neurons throughout the CNS. This neuron-targeted overexpression of AT 1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) angiotensin II (Ang II) injection but not to other central pressor agents, demonstrating functional overexpression of the transgene in NSE-AT 1a mice. Interestingly, baseline blood pressure (BP) was not elevated in either transgenic line. However, blockade of central AT 1 receptors with ICV losartan caused significant falls in basal BP in NSE-AT 1a mice but had no effect in nontransgenic controls. These results suggest that whereas there is an enhanced contribution of central AT 1 receptors to the maintenance of baseline BP in NSE-AT 1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT 1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT 1a receptors in cardiovascular homeostasis in health and disease. (Circ Res. 2002;90:617-624.)
Circulation Research, 2004
Angiotensin IV (Ang IV) is a metabolite of the potent vasoconstrictor angiotensin II (Ang II). Because specific binding sites for this peptide have been reported in numerous tissues including the brain, it has been suggested that a specific Ang IV receptor (AT4) might exist. Bolus injection of Ang IV in brain ventricles has been implicated in learning, memory, and localized vasodilatation. However, the functions of Ang IV in a physiological context are still unknown. In this study, we generated a transgenic (TG) mouse model that chronically releases Ang IV peptide specifically in the brain. TG mice were found to be hypertensive by the tail-cuff method as compared with control littermates. Treatment with the angiotensin-converting enzyme inhibitor captopril had no effect on blood pressure, but surprisingly treatment with the Ang II AT1 receptor antagonist candesartan normalized the blood pressure despite the fact that the levels of Ang IV in the brains of TG mice were only 4-fold ele...
Characterization and development of angiotensin II receptor subtypes (AT1 and AT2) in rat brain
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 1991
Characterization and development of angiotensin II receptor subtypes (AT1 and AT,) in rat brain. Am. J. Physiol. 261 (Regulatory Integrative Comp. Physiol. 30): R209-R216, 1991.-Angiotensin II receptor subtypes (AT1 and AT,) were characterized in rat brain by displacement with the specific angiotensin antagonists Du Pont 753 and CGP 42112A, respectively, and quantitative autoradiography. Young (2-wk-old) rats expressed AT1 receptors in selected limbic system areas, structures involved in cardiovascular and fluid regulation, parts of the hippocampal formation, and the choroid plexus. In young rats, AT, receptors were concentrated in areas involved in control and learning of motor activity, sensory areas, and selected limbic system structures. The cingulate cortex, the molecular layer of the cerebellar cortex, and the superior colliculus contained both ATI and AT, receptors. The number of ATI receptors in most areas of adult (&wk-old) rats was similar to or even higher than that present in young rats. Conversely, AT, receptors were always much lower in number in adult animals, and in some areas they were undetectable in adults. Their differential localization and development suggest different functions for the specific angiotensin II receptor subtypes. angiotensin receptor subtypes; Du Pont 753; CGP 42112A; renin-angiotensin system; receptor development IN ADULT RATS, the brain angiotensin II (ANG II) system, including specific ANG II receptors located in very select areas, is involved in the central regulation of cardiovascular function, drinking and fluid metabolism, salt appetite, vasopressin release, and stress (4, 5, 13, 14, 21, 23, 24). Peripherally formed ANG II, present in the has been proposed on the basis of the response of smooth muscle to ANG II synthetic analogues (19). More recently, terized two subtypes in peripheral of ANG II receptors were charactissues on the basis of their sensitivity to reducing agents (7, 10-12) and their displacement with newly developed specific ANG II antagonists (6, 8, 9, 30). AT, receptors are sensitive to the reducing agent dithiothreitol (DTT) (7,9-12) and to displacement by the selective ANG II antagonist Du Pont 753 (8, 9). ANG II binding to the AT, receptors is resistant to DTT and selectively displaced by the ANG II-receptor antagonist CGP 42112A (30). Q uantitative autoradiography and displacement with the selective ANG II-receptor antagonists revealed that the rat brain contains AT1 receptors lot ular nucleus ated in the s , nucleus of ubfornical organ, pa the solitary tract, raven and tricarea postrema and AT, receptors localized in the inferior olive (27). The characteristics of the brain AT1 and AT2 receptors was similar to those described in peripheral organs (27). We have in the inferior recently shown by autoradiography that, olive, parasolitary and hypoglossal nuclei, and cerebellar cortex, the brain of young rats expresses more ANG II receptors than that of adult animals (28) and that, in the inferior olive of young and adult rats, the binding is insensitive to DTT (29). These observations suggested that young rats may express more AT, receptors than their adult controls. To determine the detailed developmental pattern of the receptor subtypes throughout the brain, we studied all areas containing significant numbers of ANG II receptors and compared their distribution and sensitivity to selected ANG II general circulation, binds to brain ANG II receptors antagonists in young (2-wk-o located in circumventricular organs outside the blood-rats. brain barrier (16, 21, 22) and contributes to the central regulation of cardiovascular function and fluid homeo-MATERIALS AND METHODS
Mapping tissue angiotensin-converting enzyme and angiotensin AT1, AT2 and AT4 receptors
Journal of Hypertension, 1998
Background The renin-angiotensin system (RAS) functions as both a circulating endocrine system and a tissue paracrine/autocrine system. As a circulating peptide, angiotensin II (Ang II) plays a prominent role in blood-pressure control and body fluid and electrolyte balance by acting on the AT 1 receptor in the brain and peripheral tissues. As a paracrine/autocrine peptide, locally formed Ang II also plays additional roles in tissues involving the regulation of regional haemodynamics, cell growth and remodelling, and neurotransmitter release. Evidence is emerging that Ang II is not the only active peptide of the RAS, and other Ang II fragments may also have important biological activities.
AJP: Regulatory, Integrative and Comparative Physiology, 2010
ANG II, the main circulating effector hormone of the renin-angiotensin system, is produced by enzymatic cleavage of angiotensinogen. The present study aimed to examine whether targeted deletion of the angiotensinogen gene ( Agt) altered brain ANG II receptor density or responsiveness to ANG II. In vitro autoradiography was used to examine the distribution and density of angiotensin type 1 (AT1) and type 2 receptors. In most brain regions, the distribution and density of angiotensin receptors were similar in brains of Agt knockout mice ( Agt −/− ) and wild-type mice. In Agt −/− mice, a small increase in AT1 receptor binding was observed in the rostral ventrolateral medulla (RVLM), a region that plays a critical role in blood pressure regulation. To examine whether Agt −/− mice showed altered responses to ANG II, blood pressure responses to intravenous injection (0.01–0.1 μg/kg) or RVLM microinjection (50 pmol in 50 nl) of ANG II were recorded in anesthetized Agt −/− and wild-type mic...
Emerging features of brain angiotensin receptors
Regulatory Peptides, 1999
In mammalian brain, angiotensin II AT and AT receptor subtypes are apparently expressed only in neurons and not in glia. AT and 1 2 1 AT receptor subtypes are sometimes closely associated, but apparently expressed in different neurons. Brain AT /AT interactions may 2 1 2 occur in selective cases as inter-neuron cross talk. There are two AT isoforms in rodents, AT , which predominates, and AT. There 1 1 A 1 B are also important inter-species differences in receptor expression. Relative lack of amino acid conservation in the gerbil gAT receptor 1A substantially decreases affinity for the AT antagonists. AT receptors are expressed in brain areas regulating autonomic and hormonal 1 1 responses. AT receptors are heterogeneously regulated in a number of experimental conditions. In specific areas, AT receptors are not 1A 1A normally expressed, but are induced under influence of reproductive hormones in dopaminergic neurons. There are AT and AT 1 2 receptors also in areas related to limbic, sensory and motor functions and their expression is developmentally regulated. A picture is emerging of widespread, neuronally localized, heterogeneously regulated, closely associated brain angiotensin receptor subtypes, modulating multiple functions including neuroendocrine and autonomic responses, stress, cerebrovascular flow, and perhaps brain maturation, neuronal plasticity, memory and behavior.
Down-regulation of aortic and cardiac AT1receptor gene expression in transgenic (mRen-2) 27 rats
British Journal of Pharmacology, 1997
Transgenic(TG) (mRen-2) rats overexpressing the mouse renin gene develop fulminant hypertension and cardiac hypertrophy. Since the activation of AT 1 receptor by angiotensin II is involved in blood pressure regulation, cardiac performance and myocardial growth, we investigated the biological eects of angiotensin II and the regulation of the AT 1 receptor in the heart and aorta of TGR (mRen-2)27 rats in comparison to control animals. 2 Contraction studies on isolated cardiac muscle strips reveal that angiotensin II exerts no positive inotropic eect on the left ventricular myocardium of both, transgenic and control rats. In contrast, angiotensin II leads via AT 1 receptor activation in the left atrium of control rats to a signi®cant contraction (130+5% of basal contraction) which is not detectable in left atrium preparations of the transgenic animals. Furthermore, AT 1 receptor activation causes a profound contraction of aortic rings isolated from control rats amounting to 1.39+0.2 mN mg 71 wet weight, whereas aortic rings from TGR (mRen-2)27 rats contract only minimally upon angiotensin II stimulation (0.2+0.02 mN mg 71 wet weight). 3 These altered physiological responses of angiotensin II in the transgenic rats are in part due to a marked down-regulation of the AT 1 receptor in atrial, ventricular and aortic tissue of these transgenic animals in comparison to control Sprague-Dawley rats, as shown by radioligand binding assays and quantitative polymerase chain reaction (PCR) experiments. The AT 1 receptor density B max in the left atrium was 1.3+0.08 fmol mg 71 protein in control rats (K D 1.1+0.18 nmol l 71) and 0.94+0.15 fmol mg 71 protein (K D 2.1+0.3 nmol l 71. In the aorta B max values were 15.1+0.5 fmol mg 71 protein (K D 1.9+0.27 nmol l 71) for control rats and 11.3+0.76 fmol mg 71 protein (K D 1.9+0.27 nmol l 71) for the TGR(mRen-2)27 rats AT 1 receptor mRNA was reduced in the transgenic animals to 46+3% in the left atrium, 50+11% in the left ventricle and 40+3% in the aorta, respectively. 4 Together, the AT 1 receptor is down-regulated in TGR (mRen-2)27 rats in comparison to wildtype Sprague Dawley rats leading to a profoundly decreased response of cardiac and aortic tissue upon stimulation with angiotensin II.