Brain angiotensin AT-2 receptor antagonism and water intake

Rowland, Neil E.; Fregly, Melvin J.

doi:10.1016/0361-9230(93)90205-p

Cited by 37 publications

(13 citation statements)

References 11 publications

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“…Previous studies have suggested that brain AT2 receptors are important in the regulation of water intake. 51,52 With regard to the cardiovascular effects of ICV Ad-AT 1a -shRNA treatment, there was no evidence of any change in BP or HR. This is also an unpredicted finding based on studies of SFO physiology.…”

Section: Discussionmentioning

confidence: 97%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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Abstract-Because of the lack of pharmacological approaches, molecular genetic methods have been required to differentiate between angiotensin type 1(AT 1 ) receptor subtypes AT 1a and AT 1b . RNA interference is a new tool for the study of gene function, producing specific downregulation of protein expression. In this study, we used the small hairpin RNA (shRNA) cassette method to screen target sites for selectively silencing AT 1a or AT 1b receptor subtypes in cultured Neuro-2a cells using real-time RT-PCR. For in vivo functional studies, we used C57BL mice with arterial telemetric probes and computerized licking monitors to test the effect of adenovirus carrying the DNA sequence coding AT 1a shRNA (Ad-AT 1a -shRNA). Ad-AT 1a -shRNA was injected into the lateral ventricle (intracerebroventricular) or the brain stem nucleus tractus solitaries/dorsal vagal nucleus (NTS/DVN) with measurement of water intake, blood pressure (BP), and heart rate (HR) for up to 20 days after injection. Tissue culture studies verified the specificity and the efficiency of the constructs. In animal studies, ␤-galactosidase staining and Ang receptor binding assays showed expression of shRNA and downregulation of Ang AT 1 receptors in the subfornical organ and NTS/DVN by Ͼ70%. Intracerebroventricular injection of Ad-AT 1a -shRNA increased water intake with no effect on BP or HR. In contrast, microinjection of Ad-AT 1a -shRNA into NTS/DVN caused a decrease in BP with no effect on HR or water intake. Results demonstrate the use of the RNA interference method in site-directed silencing of gene expression and provide a method for the in vivo study of Ang AT 1 receptor function. Key Words: blood pressure Ⅲ brain Ⅲ gene regulation Ⅲ renin-angiotensin system B rain angiotensin (Ang) has been implicated in the control of blood pressure (BP), water balance, and hormone secretion. 1-3 Ang type 1 (AT 1 ) receptors are richly expressed in several brain regions, including the subfornical organ (SFO), paraventricular nucleus (PVN), dorsal nucleus vagus (DVN), nucleus tractus solitarii (NTS), and locus coeruleus. 4,5 In rodents, 6 and perhaps in humans, 7,8 there are 2 related AT 1 receptors subtypes, AT 1a and AT 1b . Recent studies by us 4,5 and others 9 demonstrate that AT 1 receptor subtypes AT 1a and AT 1b have similar distribution patterns in the mouse brain. In addition, several lines of reports showed that AT 1a and AT 1b receptor subtypes exhibit individual regulatory functions. 10 -12 Our previous results demonstrated that AT 1a and AT 1b receptors are differentially expressed in response to increased dietary salt and fluid deprivation within mouse brain areas, such as the hypothalamus, anterior pituitary, and brain stem. 4,5,13 However, the precise functional roles of brain AT 1a and AT 1b receptors in specific brain regions remain to be determined.AT 1a and AT 1b receptors share 95% homology in mRNA and amino acid sequences and have similar Ang II binding characteristics. 14 It is difficult to differentiate the subtypes, because there are ...

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Section: Discussionmentioning

confidence: 97%

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Chen

Hoffmann

et al. 2006

Hypertension

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“…The drinking and pressure responses induced by dehydration and hypertonic NaCl are predominantly blocked not only by i.c.v. injected AT 1 receptor antagonist, but also by AT 2 receptor antagonist (31–33). Although the existence of AT 2 receptors in the SFO has yet to be confirmed by a molecular biohistochemical study, the possibility cannot be excluded.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Induces Inward Currents in Subfornical Organ Neurones of Rats

Ono

Honda

Inenaga

2001

J Neuroendocrinology

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The action of angiotensin II on subfornical organ (SFO) neurones was studied using whole-cell current and voltage-clamp recordings in rat slice preparations. In the current-clamp mode, membrane depolarization in response to angiotensin II was accompanied by an increased frequency of action potentials and an increased membrane conductance. In the voltage-clamp mode, angiotensin II elicited inward currents in a dose-dependent manner. The net angiotensin II-induced inward currents were voltage-independent, with a mean reversal potential of -29.8 +/- 6.2 mV. Amplitudes of the angiotensin II-induced inward currents were decreased during perfusion with a low sodium medium. The angiotensin II-induced inward currents were blocked by the AT1 antagonist losartan, and were partially blocked by the AT2 antagonist PD-123319. Neurones which were sensitive to angiotensin II were found in the peripheral region of the SFO, whereas neurones in the central region were less sensitive to angiotensin II. These results suggest that angiotensin II induces inward currents, with opening of nonselective cation channels through mainly AT1 receptors in a subpopulation of SFO neurones of rats.

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“…It was reported that in rats, fluid intake induced by subcutaneous hypertonic saline is attenuated by a high dose of PD123319 (administered centrally), an AT 2 R antagonist, but not by an AT 1 R antagonist (112). Similarly, intracerbroventricular injection of an AT 2 R antagonist attenuates increased drinking after 24-h fluid restriction or intravenous hypertonic saline.…”

Section: Stimulators Of the Brain Ras And Physiological Effects Of Sfmentioning

confidence: 99%

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

Coble¹,

Grobe

Johnson³

et al. 2015

American Journal of Physiology-Regulatory, Integrative and Comp

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Coble JP, Grobe JL, Johnson AK, Sigmund CD. Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ. Am J Physiol Regul Integr Comp Physiol 308: R238 -R249, 2015. First published December 17, 2014 doi:10.1152/ajpregu.00486.2014.-It is critical for cells to maintain a homeostatic balance of water and electrolytes because disturbances can disrupt cellular function, which can lead to profound effects on the physiology of an organism. Dehydration can be classified as either intra-or extracellular, and different mechanisms have developed to restore homeostasis in response to each. Whereas the renin-angiotensin system (RAS) is important for restoring homeostasis after dehydration, the pathways mediating the responses to intra-and extracellular dehydration may differ. Thirst responses mediated through the angiotensin type 1 receptor (AT 1R) and angiotensin type 2 receptors (AT 2R) respond to extracellular dehydration and intracellular dehydration, respectively. Intracellular signaling factors, such as protein kinase C (PKC), reactive oxygen species (ROS), and the mitogen-activated protein (MAP) kinase pathway, mediate the effects of central angiotensin II (ANG II). Experimental evidence also demonstrates the importance of the subfornical organ (SFO) in mediating some of the fluid intake effects of central ANG II. The purpose of this review is to highlight the importance of the SFO in mediating fluid intake responses to dehydration and ANG II.angiotensin; blood pressure; barin; fluid; renin FLUID BALANCE is crucial for the homeostasis and survival of organisms because they have to properly maintain fluid and electrolyte concentrations for the normal function of all cells. Fluid balance can go awry in pathological states such as in chronic kidney disease and diabetes. Among its many roles in maintaining homeostasis, the renin-angiotensin system (RAS) is an important regulator of fluid balance. The RAS achieves this through the actions of its main effector peptide, angiotensin II (ANG II) through the ANG II type 1 (AT 1 R) and type 2 (AT 2 R) receptors. Activation of AT 1 R by blood-borne ANG II in target tissues causes increases in sodium and water retention, arginine vasopressin (AVP), and aldosterone release, vasoconstriction, increased sympathetic nervous system activity, and increased fluid intake. ANG II is produced by the consecutive enzymatic action of renin on its substrate angiotensinogen (AGT) and by angiotensin-converting enzyme (ACE) on its substrate angiotensin I (ANG I). The renin-AGT cleavage step is generally the rate-limiting step in the production of ANG II, and this is certainly true in the brain where the amount of renin is limiting. The RAS exists in two forms: a circulatory form where ANG II acts as an endocrine factor, and a tissue-specific form, where local production of ANG II acts in an autocrine or paracrine manner to induce AT 1 R signaling on ANG II producing or nearby cells (75). Intracrine, or intracellular forms of the RAS, hav...

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Brain angiotensin AT-2 receptor antagonism and water intake

Cited by 37 publications

References 11 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Angiotensin II Induces Inward Currents in Subfornical Organ Neurones of Rats

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

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Brain angiotensin AT-2 receptor antagonism and water intake

Cited by 37 publications

References 11 publications

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT 1a Receptors in Mouse Brain

Angiotensin II Induces Inward Currents in Subfornical Organ Neurones of Rats

Mechanisms of brain renin angiotensin system-induced drinking and blood pressure: importance of the subfornical organ

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Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain

Adenovirus-Mediated Small-Interference RNA for In Vivo Silencing of Angiotensin AT _1a Receptors in Mouse Brain