Stimulation of Angiotensin Type 1A Receptors on Catecholaminergic Cells Contributes to Angiotensin-Dependent Hypertension

Abstract In a previous study, we had shown that activation of the AT2 (angiotensin type 2) receptor of angiotensin II (Ang II) induced morphological differentiation of the neuronal cell line NG108–15. In the present study, we investigated the nature of the possible intracellular mediators involved in the AT2 effect. We found that stimulation of AT2 receptors in NG108–15 cells resulted in time-dependent modulation of tyrosine phosphorylation of a number of cytoplasmic proteins. Stimulation of NG108–15 cells with Ang II induced a decrease in GTP-bound p21ras but a sustained increase in the activity of p42mapk and p44mapk as well as neurite outgrowth. Similarly, neurite elongation, increased polymerized tubulin levels, and increased mitogen-activated protein kinase (MAPK) activity were also observed in a stably transfected NG108–15 cell line expressing the dominant-negative mutant of p21ras, RasN17. These results support the observation that inhibition of p21ras did not impair the effect of Ang II on its ability to stimulate MAPK activity. While 10 μm of the MEK inhibitor, PD98059, only moderately affected elongation, 50 μm PD98059 completely blocked the Ang II- and the RasN17-mediated induction of neurite outgrowth. These results demonstrate that some of the events associated with the AT2 receptor-induced neuronal morphological differentiation of NG108–15 cells not only include inhibition of p21ras but an increase in MAPK activity as well, which is essential for neurite outgrowth.

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Abstract TMP58: Post Stroke Activation of Angiotensin II Type 2 Receptors Shows Sustained Neuroprotective Effects in Aged Rats

Stroke ◽

10.1161/str.47.suppl_1.tmp58 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Jacob D Isenberg ◽

Douglas M Bennion ◽

Alexander J Irwin ◽

Allison T Harmel ◽

Eduardo Candelario-Jalil ◽

...

Keyword(s):

Renin Angiotensin System ◽

Neurological Function ◽

Aged Rats ◽

Neuroprotective Effects ◽

Angiotensin System ◽

Stroke Treatment ◽

Renin Angiotensin ◽

Post Stroke ◽

Angiotensin Type ◽

Stimulation Of

Background: The renin angiotensin system is a promising target for stroke neuroprotection and therapy through activation of angiotensin type II receptors (AT2Rs). Compound 21 (C21), a selective non-peptide AT2R agonist, has been shown to exhibit neuroprotection and improve stroke outcomes in preclinical studies. Stimulation of AT2Rs is believed to counteract the negative effects of angiotensin type 1 receptor and provide distinctive beneficial anti-inflammatory and neurotropic effects. We hypothesized that C21 given after stroke through peripheral injections would have sustained neuroprotective effects in aged rats. Methods: Aged adult male SD rats (18-20 months) underwent ischemic stroke by monofilament middle cerebral artery occlusion (MCAO) and were randomly divided into two groups that received intraperitoneal (IP) injections of either 0.9% NaCl or 0.03mg/kg C21 at reperfusion (90 min), 24h, and 48h after stroke. All animals received blinded neurological exams at 4h, 24h, 72h, 7d, 14d, and 21d post-stroke. Infarct size was assessed by magnetic resonance imaging at 21 days. Results: Post-stroke treatment with C21 significantly improved neurological function, as evidenced by neurological testing using Rotarod and somatosensory dysfunction exams. At 7d and 14d after stroke, C21-treated rats had significantly increased Rotarod times versus saline-treated rats, and at 21d, the somatosensory function was significantly improved as measured by time to removal of paw adhesive. Infarct volume tended to be non-significantly decreased by C21 treatment at 21d post-stroke. Conclusions: Our findings indicate that targeting the renin-angiotensin system, specifically by stimulation of AT2Rs with C21, improves neurological function in aged rats with stroke over a sustained period of 21 days. These findings encourage further research into the renin-angiotensin system and specifically AT2Rs, and offers hope for effective alternatives for treating stroke.

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Brain angiotensinergic mediation of enhanced water consumption in lactating rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00432.2001 ◽

2002 ◽

Vol 282 (3) ◽

pp. R695-R701 ◽

Cited By ~ 3

Author(s):

Robert C. Speth ◽

M. Susan Smith ◽

Kevin L. Grove

Keyword(s):

Milk Production ◽

Water Consumption ◽

Receptor Subtype ◽

Muscarinic Agonist ◽

Fluid Consumption ◽

Ang Ii ◽

And Control ◽

Angiotensin Type ◽

Stimulation Of

The mechanism by which lactating rats increase fluid consumption to meet the demands of milk production is unknown. Because ANG II is the most potent dipsogenic stimulus known, this study examined whether angiotensinergic signaling plays a role in enhanced drinking in lactating rats. ANG II administered intracerebroventricularly caused a significantly greater dipsogenic response in lactating rats than in control rats, suggesting that dipsogenic responsivity to ANG II is enhanced in the brains of lactating rats. The angiotensin type 1 (AT1) ANG II receptor subtype antagonist SKF-108566, also given intracerebroventricularly, caused a significant reduction in water consumption in lactating rats, whereas it did not significantly affect water intake in control rats. In contrast, stimulation of drinking by the muscarinic agonist carbachol, also administered intracerebroventricularly, did not differ between lactating and control rats. Inhibition of drinking by the muscarinic antagonist atropine also did not differ significantly between lactating and control rats. These results suggest that the increased drinking in lactating rats involves an increased responsivity to ANG II in neurons that mediate dipsogenesis, as well as an enhancement in the amount of angiotensinergic input to these ANG II-responsive neurons.

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Neurohumoral interactions contributing to renal vasoconstriction and decreased renal blood flow in heart failure

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00026.2019 ◽

2019 ◽

Vol 317 (3) ◽

pp. R386-R396 ◽

Cited By ~ 2

Author(s):

Rohit Ramchandra ◽

Daniel T. Xing ◽

Marcus Matear ◽

Gavin Lambert ◽

Andrew M. Allen ◽

...

Keyword(s):

Heart Failure ◽

Plasma Renin ◽

Renal Nerves ◽

Renal Vasoconstriction ◽

Healthy Sheep ◽

Norepinephrine Spillover ◽

Renal Vascular ◽

Angiotensin Type ◽

Stimulation Of

In heart failure (HF), increases in renal sympathetic nerve activity (RSNA), renal norepinephrine spillover, and renin release cause renal vasoconstriction, which may contribute to the cardiorenal syndrome. To increase our understanding of the mechanisms causing renal vasoconstriction in HF, we investigated the interactions between the increased activity of the renal nerves and the renal release of norepinephrine and renin in an ovine pacing-induced model of HF compared with healthy sheep. In addition, we determined the level of renal angiotensin type-1 receptors and the renal vascular responsiveness to stimulation of the renal nerves and α1-adrenoceptors. In conscious sheep with mild HF (ejection fraction 35%–40%), renal blood flow (276 ± 13 to 185 ± 18 mL/min) and renal vascular conductance (3.8 ± 0.2 to 3.1 ± 0.2 mL·min−1·mmHg−1) were decreased compared with healthy sheep. There were increases in the burst frequency of RSNA (27%), renal norepinephrine spillover (377%), and plasma renin activity (141%), whereas the density of renal medullary angiotensin type-1 receptors decreased. In anesthetized sheep with HF, the renal vasoconstrictor responses to electrical stimulation of the renal nerves or to phenylephrine were attenuated. Irbesartan improved the responses to nerve stimulation, but not to phenylephrine, in HF and reduced the responses in normal sheep. In summary, in HF, the increases in renal norepinephrine spillover and plasma renin activity are augmented compared with the increase in RSNA. The vasoconstrictor effect of the increased renal norepinephrine and angiotensin II is offset by reduced levels of renal angiotensin type-1 receptors and reduced renal vasoconstrictor responsiveness to α1-adrenoceptor stimulation.

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Stimulation of ANP secretion by Angiotensin‐(1–9) via Angiotensin Type 2 Receptor

The FASEB Journal ◽

10.1096/fasebj.27.1_supplement.lb688 ◽

2013 ◽

Vol 27 (S1) ◽

Author(s):

Seung Ah Cha ◽

Byung Mun Park ◽

Young‐Bin Oh ◽

Shan Gao ◽

Suhn Hee Kim

Keyword(s):

Angiotensin Type 2 Receptor ◽

Angiotensin Type ◽

Stimulation Of

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Effects of 5-5'-Diphenyl-2-thiohydantoin (DPTH) and Thyroxine on the Ultrastructure and Chemical Composition of Rat Liver

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100066917 ◽

1971 ◽

Vol 29 ◽

pp. 570-571

Author(s):

E. A. Elfont ◽

R. B. Tobin ◽

D. G. Colton ◽

M. A. Mehlman

Keyword(s):

Chemical Composition ◽

Rat Liver ◽

Future Study ◽

Mode Of Action ◽

Liver Mitochondria ◽

Rat Liver Mitochondria ◽

Effective Inhibitor ◽

Biochemical Effects ◽

Glycerophosphate Dehydrogenase ◽

Stimulation Of

Summary5,-5'-diphenyl-2-thiohydantoin (DPTH) is an effective inhibitor of thyroxine (T4) stimulation of α-glycerophosphate dehydrogenase in rat liver mitochondria. Because this finding indicated a possible tool for future study of the mode of action of thyroxine, the ultrastructural and biochemical effects of DPTH and/or thyroxine on rat liver mere investigated.Rats were fed either standard or DPTH (0.06%) diet for 30 days before T4 (250 ug/kg/day) was injected. Injection of T4 occurred daily for 10 days prior to sacrifice. After removal of the liver and kidneys, part of the tissue was frozen at -50°C for later biocheailcal analyses, while the rest was prefixed in buffered 3.5X glutaraldehyde (390 mOs) and post-fixed in buffered 1Z OsO4 (376 mOs). Tissues were embedded in Araldlte 502 and the sections examined in a Zeiss EM 9S.Hepatocytes from hyperthyroid rats (Fig. 2) demonstrated enlarged and more numerous mitochondria than those of controls (Fig. 1). Glycogen was almost totally absent from the cytoplasm of the T4-treated rats.

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