Angiotensin II AT<sub>1A</sub>Receptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus

Jöhren, Olaf; Sanvitto, Gilberto Luiz; Egidy, Giorgia; Saavedra, Juan M.

doi:10.1523/jneurosci.17-21-08283.1997

Cited by 53 publications

(36 citation statements)

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“…Additionally, analysis of adult females also allowed an exploration of the potential role of estrogen in modulating AT 1 receptor levels in the RVLM. Consistent with findings in other systems (23), the presence of estrogen (in OVXϩE tissue vs. OVXϩV tissue) appeared to have a significant effect on AT 1 receptor-ImG labeling. Analysis of p47-ImG labeling in TH-labeled RVLM neurons in adult females (40) did not reveal any significant changes across the estrous cycle.…”

Section: Discussionsupporting

confidence: 87%

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Wang

Milner²,

Speth³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Wang G, Milner TA, Speth RC, Gore AC, Wu D, Iadecola C, Pierce JP. Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla. Am J Physiol Regul Integr Comp Physiol 295: R1149 -R1157, 2008. First published August 6, 2008 doi:10.1152/ajpregu.90485.2008.-Sex differences may play a significant role in determining the risk of hypertension. Bulbospinal neurons in the rostral ventrolateral medulla (RVLM) are involved in the tonic regulation of arterial pressure and participate in the central mechanisms of hypertension. Angiotensin II (ANG II) acting on angiotensin type 1 (AT 1) receptors in RVLM neurons is implicated in the development of hypertension by activating NADPH oxidase and producing reactive oxygen species (ROS). Therefore, we analyzed RVLM bulbospinal neurons to determine whether there are sex differences in: 1) immunolabeling for AT 1 receptors and the key NADPH oxidase subunit p47 using dual-label immunoelectron microscopy, and 2) the effects of ANG II on ROS production and Ca 2ϩ currents using, respectively, hydroethidine fluoromicrography and patch-clamping. In tyrosine hydroxylase-positive RVLM neurons, female rats displayed significantly more AT 1 receptor immunoreactivity and less p47 immunoreactivity than male rats (P Ͻ 0.05). Although ANG II (100 nM) induced comparable ROS production in dissociated RVLM bulbospinal neurons of female and male rats (P Ͼ 0.05), an effect mediated by AT 1 receptors and NADPH oxidase, it triggered significantly larger dihydropyridine-sensitive longlasting (L-type) Ca 2ϩ currents in female RVLM neurons (P Ͻ 0.05). These observations suggest that an increase in AT 1 receptors in female RVLM neurons is counterbalanced by a reduction in p47 levels, such that ANG II-induced ROS production does not differ between females and males. Since the Ca 2ϩ current activator Bay K 8644 induced larger Ca 2ϩ currents in females than in male RVLM neurons, increased ANG IIinduced L-type Ca 2ϩ currents in females may result from sex differences in calcium channel densities or dynamics. C1 neurons; reactive oxygen species; NADPH oxidase; calcium channel; estrogen THERE IS INCREASING EVIDENCE that sex differences contribute to the risk of cardiovascular disease, including hypertension (14, 44). Under the age of 45 yr, fewer women than men die from cardiovascular disease (1), a pattern which is reversed after menopause (52). Similar sex-associated differences exist in animal hypertension models: females develop hypertension later, and less severely, than males (11,35,62). Studies in humans and animal models indicate that central nervous system pathways play a critical role in the development and maintenance of hypertension (27). Specifically, increases in sympathetic nerve activity and changes in arterial baroreflex function are strongly implicated in the pathogenesis of the disorder. The rostral ventrolateral medulla (RVLM) contains tonically active presympathetic bulbospinal neurons, most of which express tyrosine hydroxylase (TH) [the C1 cell...

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Section: Discussionsupporting

confidence: 87%

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Wang

Milner²,

Speth³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Central AT 1 receptors have been implicated in a wide variety of responses that are apparently independent of BP regulation, including anxiety, 47 exploratory behavior, 48 dopamine formation and release, 49 and development, plasticity, and maturation of the brain. 50 This, coupled with the widespread distribution of AT 1 receptors in brain of NSE-AT 1a transgenics, makes these mice potentially useful models for exploring other noncardiovascular-related functions of AT 1 receptors.…”

Section: Discussionmentioning

confidence: 99%

Brain-Selective Overexpression of Angiotensin (AT ₁ ) Receptors Causes Enhanced Cardiovascular Sensitivity in Transgenic Mice

Lazartigues

Dunlay

Loihl

et al. 2002

Circulation Research

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Abstract-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. Key Words: renin-angiotensin system Ⅲ blood pressure Ⅲ hypertension Ⅲ central nervous system Ⅲ neurons I n addition to its classical role as an endocrine system, evidence suggests that all components of the renin-angiotensin system (RAS) exist in individual tissues, 1-3 resulting in the local synthesis, release, and action of angiotensin II (Ang II). The brain RAS 4 -6 is hypothesized to contribute to normal regulation of blood pressure (BP) and volume homeostasis through its effects on sympathetic outflow 7 and vasopressin synthesis and release. 8,9 Ang II type 1 (AT 1 ) receptors are densely localized in several regions of the central nervous system (CNS) involved in cardiovascular regulation, including structures of the lamina terminalis of the forebrain, 10 -12 brain stem sites such as the nucleus of the solitary tract, ventrolateral medulla, 6,13,14 and hypothalamic paraventricular and supraoptic nuclei. 12 Several AT 1 -rich sites lack a blood-brain-barrier, eg, subfornical organ, organum vasculosum of the lamina terminalis, area postrema, and median preoptic nucleus, thus allowing direct interfacing with circulating Ang II. Brain AT 1 receptor activation by both locally and systemically derived Ang II is thought to modulate normal processing of sensory input and neurohumoral outflow. 15,16 Moreover, studies showing increased density or activity of AT 1 receptors in these cardiovascular control regions in various genetic and experimental hypertension models have implicated central AT 1 receptors as causal in the development and maintenance of hypertension. [17][18...

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“…For example, ANG may directly stimulate prolactin release from the pituitary gland by acting on AT 1B receptors and inhibit pituitary prolactin indirectly by stimulating dopamine release through central AT 1A receptors. 42 Earlier studies on the pituitary hormonal system revealed higher basal prolactin in SHR 19 and enhanced growth hormone but not prolactin secretion from pituitary cells after ANG in SHR. 52 Thus, reduced pituitary mRNA levels of AT 1B receptors in SHR may reflect adaptive changes to high prolactin levels caused by other secretagogues.…”

Section: Jöhren Et Al Ang Receptors In the Hpa Axis Of Shr 987mentioning

confidence: 96%

“…42 Adrenal glands from SHR and WKY were sectioned at Ϫ20°C in a cryostat, and 20-m sections were thaw-mounted alongside on aminoalkylsilane-coated glass slides (Sigma). After fixation in 4% paraformaldehyde for 10 minutes, sections were dehydrated in ethanol and air-dried.…”

Section: In Situ Hybridization Histochemistrymentioning

confidence: 99%

Differential Expression of AT ₁ Receptors in the Pituitary and Adrenal Gland of SHR and WKY

et al. 2003

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Abstract-The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT 1A , AT 1B , and AT 2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT 1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT 1B receptor mRNA was detected in the pituitary and adrenal gland. AT 2 receptor mRNA was prominent only in the adrenal gland. A ngiotensin II (ANG), the main active peptide of the renin-angiotensin system, acts at 2 distinct receptor subtypes, namely type 1 (AT 1 ) and type 2 (AT 2 ) receptors. The role of AT 1 receptors in the regulation of cardiovascular functions, fluid homeostasis, and hormone release is well established, and several AT 1 receptor antagonists are used for the treatment of hypertension. 1 In rodents, 2 pharmacologically similar AT 1 receptor isoforms, AT 1A and AT 1B , exist, which are encoded by 2 distinct genes and are expressed and regulated differentially. 2-5 High levels of AT 1A receptor mRNA are present in the rodent brain, kidney, and vasculature, whereas AT 1B receptor mRNA is mainly expressed in the pituitary and adrenal glands. 6 -10 Although widely expressed in fetal and young rats, 11 in adult rats, the expression of AT 2 receptors is low and restricted to certain organs, such as the brain and adrenal gland. 1,12 The expression of all ANG receptor subtypes in the hypothalamo-pituitary-adrenal (HPA) axis, which is activated in response to stress, as well as the regulation of ANG receptors by restraint stress [13][14][15] implies important roles of the ANG system in the regulation of the activity of the HPA axis. Accordingly, ANG has been shown to regulate corticotropin-releasing factor, adrenocorticotropic hormone (ACTH), and corticosterone synthesis and secretion. 16 -18 Spontaneously hypertensive rats (SHR) show an impaired response and habituation to various forms of stress such as immobilization and exposure to heat or open field, and they differ in their neuroendocrine reaction to stress from normotensive Wistar-Kyoto rats (WKY). 19 -23 The ANG system has been implicated in the impaired stress response of SHR. 24 -27 There are several studies showing differences in the numbers of binding sites for radiolabeled ANG between SHR and WKY in the kidney, vasculature, heart, pituitary, adrenal gland, and brain, including the hypothalamus and neuronal cultures. 28 -32 Because AT 1A and AT 1B receptors are pharmacologically indistinguishable, the distinct expression of these AT 1 receptor isoforms was not addressed in these studies. Using a different approach, Iwai et al 33 could not detect differences of AT 1A mRNA levels in the brain and adrenal gland between WKY and SHR, whereas Raizada et a...

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Angiotensin II AT_1AReceptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus

Cited by 53 publications

References 54 publications

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Brain-Selective Overexpression of Angiotensin (AT ₁ ) Receptors Causes Enhanced Cardiovascular Sensitivity in Transgenic Mice

Differential Expression of AT ₁ Receptors in the Pituitary and Adrenal Gland of SHR and WKY

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Angiotensin II AT1AReceptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus

Cited by 53 publications

References 54 publications

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Sex differences in angiotensin signaling in bulbospinal neurons in the rat rostral ventrolateral medulla

Brain-Selective Overexpression of Angiotensin (AT 1 ) Receptors Causes Enhanced Cardiovascular Sensitivity in Transgenic Mice

Differential Expression of AT 1 Receptors in the Pituitary and Adrenal Gland of SHR and WKY

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Angiotensin II AT_1AReceptor mRNA Expression Is Induced by Estrogen–Progesterone in Dopaminergic Neurons of the Female Rat Arcuate Nucleus

Brain-Selective Overexpression of Angiotensin (AT ₁ ) Receptors Causes Enhanced Cardiovascular Sensitivity in Transgenic Mice

Differential Expression of AT ₁ Receptors in the Pituitary and Adrenal Gland of SHR and WKY