Role of Angiotensin II Type 1A Receptors in Cardiovascular Reactivity and Neuronal Activation After Aversive Stress in Mice

Davern, Pamela J.; Chen, Daian; Head, Geoffrey A.; Chavez, Carolina; Walther, Thomas; Mayorov, Dmitry N.

doi:10.1161/hypertensionaha.109.139741

Cited by 44 publications

(54 citation statements)

References 34 publications

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“…For example, in the CVLM, ANG II and AT 1 Rs mediate depressor and bradycardic responses (2,8,9,27,38), inhibition of the baroreflex (3,32,35,39), stress responses (13,32), and vasopressin release (1). In this report, we showed that microinjections of ANG-(1-12) elicit cardiovascular responses, which are mediated via its conversion to ANG II and ANG-(1-7).…”

Section: Perspectivesmentioning

confidence: 66%

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

Kawabe

Sapru

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Kawabe T, Kawabe K, Sapru HN. Cardiovascular effect of angiotensin-(1-12) in the caudal ventrolateral medullary depressor area of the rat. Am J Physiol Heart Circ Physiol 306: H438 -H449, 2014. First published November 27, 2013 doi:10.1152/ajpheart.00628.2013.-Angiotensin (ANG)-(1-12) excites neurons via ANG II type 1 receptors (AT 1Rs), which are present in the caudal ventrolateral medullary depressor area (CVLM). We hypothesized that microinjections of ANG-(1-12) into the CVLM may elicit decreases in mean arterial pressure (MAP), heart rate (HR), and sympathetic nerve activity. This hypothesis was tested in urethane-anesthetized adult male Wistar rats. Microinjections of ANG-(1-12) into the CVLM elicited decreases in MAP, HR, and greater splanchnic nerve activity (GSNA). ANG-(1-12)-induced responses consisted of initial (first 1-8 min) and delayed (8 -24 min) phases. Prior microinjections of losartan, A-779, and captopril into the CVLM blocked initial, delayed, and both phases of ANG-(1-12) responses, respectively. Blockade of GABA receptors in the rostral ventrolateral medullary pressor area (RVLM) attenuated cardiovascular responses elicited by microinjections of ANG-(1-12) into the ipsilateral CVLM. Microinjections of ANG-(1-12) into the CVLM potentiated the reflex decreases and attenuated the reflex increases in GSNA elicited by intravenous injections of phenylephrine and sodium nitroprusside, respectively. These results indicate that microinjections of ANG-(1-12) into the CVLM elicit decreases in MAP, HR, and GSNA. Initial and delayed phases of these responses are mediated via ANG II and ANG-(1-7), respectively; the effects of ANG II and ANG-(1-7) are mediated via AT 1Rs and Mas receptors, respectively. Captopril blocked both phases of ANG-(1-12) responses, indicating that angiotensin-converting enzyme is important in mediating these responses. GABA receptors in the RVLM partly mediate the cardiovascular responses to microinjections of ANG-(1-12) into the CVLM. Microinjections of ANG-(1-12) into the CVLM modulate baroreflex responses.angiotensin II receptors; baroreflex; GABAergic neurons; Mas receptors; sympathetic nerve activity ANGIOTENSIN (ANG)-(1-12), a new ANG, has been recently identified (29). In brain tissue, the concentration of ANG-(1-12) is about five times greater than ANG II (29). Unlike ANG II, renin is not involved in the formation of ANG-(1-12) (15, 40), prompting the suggestion that ANG-(1-12) may act as a renin-independent alternative substrate for the formation of ANG II in several organs (40). In the periphery, ANG-(1-12) may exert its actions via a rapid conversion to ANG II because pressor responses elicited by intravenous injections of ANG-(1-12) in the rat were blocked by prior injections of an ANG type 1 receptor (AT 1 R) antagonist (29). Because it is known that ANG I and ANG II can be converted into ANG-(1-7) (41), there is a possibility that ANG-(1-7) may be formed from ANG-(1-12) in the brain. The receptors via which ANG-(1-7) exerts its actions [Mas receptors (MasRs)] have ...

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Section: Perspectivesmentioning

confidence: 66%

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

Kawabe

Sapru

2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Further investigations have found that NO,45 IL‐6,25 and corticotrophin‐releasing hormone and activation of the hypothalamic‐pituitary‐adrenal axis46 are directly involved in the physiological responses to CSS. The renin‐angiotensin system plays a complex role in the pressor response to CSS, with AT 1A receptors having both prohypertensive and antihypertensive roles, depending on their location 3, 33, 34, 47, 48, 49. Future research is needed to determine whether endothelium‐derived ET‐1 interacts with these other pathways or vice versa to mediate the acute pressor response.…”

Section: Discussionmentioning

confidence: 99%

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Fox

Becker

Loria

et al. 2018

JAHA

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BackgroundAcute psychosocial stress provokes increases in circulating endothelin‐1 (ET‐1) levels in humans and animal models. However, key questions about the physiological function and cellular source of stress‐induced ET‐1 remain unanswered. We hypothesized that endothelium‐derived ET‐1 contributes to the acute pressor response to stress via activation of the endothelin A receptor.Methods and ResultsAdult male vascular endothelium‐specific ET‐1 knockout mice and control mice that were homozygous for the floxed allele were exposed to acute psychosocial stress in the form of cage switch stress (CSS), with blood pressure measured by telemetry. An acute pressor response was elicited by CSS in both genotypes; however, this response was significantly blunted in vascular endothelium‐specific ET‐1 knockout mice compared with control mice that were homozygous for the floxed allele. In mice pretreated for 3 days with the endothelin A antagonist, ABT‐627, or the dual endothelin A/B receptor antagonist, A‐182086, the pressor response to CSS was similar between genotypes. CSS significantly increased plasma ET‐1 levels in control mice that were homozygous for the floxed allele. CSS failed to elicit an increase in plasma ET‐1 in vascular endothelium‐specific ET‐1 knockout mice. Telemetry frequency domain analyses suggested similar autonomic responses to stress between genotypes, and isolated resistance arteries demonstrated similar sensitivity to α1‐adrenergic receptor‐mediated vasoconstriction.ConclusionsThese findings specify that acute stress‐induced activation of endothelium‐derived ET‐1 and subsequent endothelin A receptor activation is a novel mediator of the blood pressure response to acute psychosocial stress.

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“…ANG II exerts its sympathoexcitatory and pressor effects by activating AT 1 Rs, increasing NADPH oxidase-mediated production of ROS leading to ROS-mediated inhibition of delayed rectifier potassium channels and increased neuronal firing rate (14,15). Besides their effect on neuronal activity, ROS also upregulate MIF in PVN neurons (27).…”

Section: Discussionmentioning

confidence: 99%

“…The paraventricular nucleus of the hypothalamus (PVN) plays a central role in integrating the physiological response to stress, and angiotensin II (ANG II) signaling within the PVN has been shown to contribute to both the activation of the hypothalamic-pituitary-adrenal (HPA) axis and elevations in blood pressure and heart rate during stress (1,6,14,31,51). Previous work from our laboratory demonstrated that within the brain macrophage migration inhibitory factor (MIF) is an important intracellular counterregulator of ANG II in PVN neurons and that this action is mediated by the intrinsic thiol-protein oxidoreductase (TPOR) activity that is exerted by a C-A-L-C motif at residues 57-60 of MIF (40,57,58).…”

Section: Exaggerated Activation Of the Sympathetic Nervous System Andmentioning

confidence: 99%

“…Stress also activates the hypothalamic-pituitary-adrenal (HPA) axis, leading to elevated plasma glucocorticoid concentrations (cortisol in humans, corticosterone in rats), and elevated glucocorticoids confer additional risk for hypertension and related cardiovascular disease (49, 61,62). Despite the important influence stress-induced increases in blood pressure and HPA axis activity have on cardiovascular health, the central mechanisms influencing the magnitude of these responses are incompletely understood.The paraventricular nucleus of the hypothalamus (PVN) plays a central role in integrating the physiological response to stress, and angiotensin II (ANG II) signaling within the PVN has been shown to contribute to both the activation of the hypothalamic-pituitary-adrenal (HPA) axis and elevations in blood pressure and heart rate during stress (1,6,14,31,51). Previous work from our laboratory demonstrated that within the brain macrophage migration inhibitory factor (MIF) is an important intracellular counterregulator of ANG II in PVN neurons and that this action is mediated by the intrinsic thiol-protein oxidoreductase (TPOR) activity that is exerted by a C-A-L-C motif at residues 57-60 of MIF (40,57,58).…”

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confidence: 99%

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Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress

Erdös

Clifton

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Erdos B, Clifton RR, Liu M, Li H, McCowan ML, Sumners C, Scheuer DA. Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress. Am J Physiol Heart Circ Physiol 309: H634-H645, 2015. First published June 12, 2015 doi:10.1152/ajpheart.00207.2015.-Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stressinduced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN. Cardiovascular responses to a 15-min water stress (1-cm deep, 25°C) and a 60-min restraint stress were evaluated 3-4 wk later. MIF treatment in the PVN attenuated average restraintinduced increases in blood pressure (37.4 Ϯ 2.0 and 27.6 Ϯ 3.5 mmHg in GFP and MIF groups, respectively, P Ͻ 0.05) and corticosterone (42 Ϯ 2 and 36 Ϯ 3 g/dl in GFP and MIF groups, respectively, P Ͻ 0.05). MIF treatment in the PVN also reduced stress-induced elevations in the number of c-Fos-positive cells in the rostral ventrolateral medulla (71 Ϯ 5 in GFP and 47 Ϯ 5 in MIF SHRs, P Ͻ 0.01) and corticotropin-releasing factor mRNA expression in the PVN. However, MIF had no significant effects on the cardiovascular responses to water stress in SHRs or to either stress in Sprague-Dawley rats. Therefore, viral vector-mediated restoration of MIF in PVN neurons of SHRs attenuates blood pressure and hypothalamic pituitary adrenal axis responses to stress. psychological stress; blood pressure; brain; angiotensin ii; hypertension NEW & NOTEWORTHY Exaggerated activation of the sympathetic nervous system and/or the hypothalamic-pituitary-adrenal (HPA) axis increases cardiovascular disease risk. The present study demonstrates that macrophage migration inhibitory factor (MIF) in paraventricular nucleus (PVN) neurons is a novel mechanism mediating attenuation of both the sympathetic and HPA axis responses to acute stress.SEVERAL LINES OF EVIDENCE suggest that the amplitude of blood pressure increases in response to psychological or physical stressors in young and middle-aged normotensive adults elevates the risk of developing hypertension and other cardiovascular diseases such as coronary artery disease, myocardial ischemia, and stroke later in their life (8,20,39,41,42,44,50,60). Larger variations in blood pressure in response to repeated everyday stressors may lead to accelerated damage of the kidneys and vasculature. Altered central mechanisms that mediate augmented...

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Role of Angiotensin II Type 1A Receptors in Cardiovascular Reactivity and Neuronal Activation After Aversive Stress in Mice

Cited by 44 publications

References 34 publications

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

Cardiovascular effect of angiotensin-(1–12) in the caudal ventrolateral medullary depressor area of the rat

Acute Pressor Response to Psychosocial Stress Is Dependent on Endothelium‐Derived Endothelin‐1

Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress

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