Angiotensin Type 1A Receptors in C1 Neurons of the Rostral Ventrolateral Medulla Modulate the Pressor Response to Aversive Stress (original) (raw)
Related papers
Cardiovascular Research, 2012
The caudal ventrolateral medulla (CVLM) is important for autonomic regulation and is rich in angiotensin II type 1A receptors (AT 1A R). To determine their function, we examined whether the expression of AT 1A R in the CVLM of mice lacking AT 1A R (AT 1A 2/2) alters baroreflex sensitivity and cardiovascular responses to stress. Methods and results Bilateral microinjections into the CVLM of AT 1A 2/2 mice of lentivirus with the phox-2 selective promoter (PRSx8) were made to express either AT 1A R (Lv-PRSx8-AT 1A) or green fluorescent protein (Lv-PRSx8-GFP) as a control. Radiotelemetry was used to record mean arterial pressure (MAP), heart rate (HR), and locomotor activity. Following injection of Lv-PRSx8-GFP, robust neuronal expression of GFP was observed with 60% of the GFP-positive cells also expressing the catecholamine-synthetic enzyme tyrosine hydroxylase. After 5 weeks, there were no differences in MAP or HR between groups, but the Lv-PRSx8-AT 1A-injected mice showed reduced baroreflex sensitivity (225%, P ¼ 0.003) and attenuated pressor responses to cage-switch and restraint stress compared with the Lv-PRSx8-GFPinjected mice. Reduced MAP mid-frequency power during cage-switch stress reflected attenuated sympathetic activation (Pgroup × stress ¼ 0.04). Fos-immunohistochemistry indicated greater activation of forebrain and hypothalamic neurons in the Lv-PRSx8-AT 1A mice compared with the control. Conclusion The expression of AT 1A R in CVLM neurons, including A1 neurons, while having little influence on the basal blood pressure or HR, may play a tonic role in inhibiting cardiac vagal baroreflex sensitivity. However, they strongly facilitate the forebrain response to aversive stress, yet reduce the pressor response presumably through greater sympathoinhibition. These findings outline novel and specific roles for angiotensin II in the CVLM in autonomic regulation.
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...
Hypertension, 2006
Angiotensin type 1A (AT 1A ) receptors are expressed within the rostral ventrolateral medulla, and microinjections of angiotensin II into this region increase sympathetic vasomotor tone. To determine the effect of sustained increases in AT 1A receptor density or activity in rostral ventrolateral medulla, we used radiotelemetry to monitor blood pressure in conscious rats before and after bilateral microinjection into the rostral ventrolateral medulla of adenoviruses encoding the wild-type AT 1A receptor or a constitutively active version of the receptor (Asn 111 Gly, [N111G]AT 1A ). The constitutively active receptor signals in the absence of angiotensin II. Adenovirus-directed receptor expression was extensively characterized both in vitro and in vivo. We established that adenoviral infection was limited to the rostral ventrolateral medulla and that receptor expression was sustained for Ն10 days; we also observed that adenoviral transgene expression occurs in glia, with no transgene expression observed in neurons of the rostral ventrolateral medulla. Rats receiving the wild-type AT 1A receptor showed no change in blood pressure, whereas animals receiving the [N111G]AT 1A receptor displayed an increase in blood pressure that persisted for 3 to 4 days before returning to basal levels. These data indicate that increased AT 1A receptor activity (not just overexpression) is a primary determinant of efferent drive from rostral ventrolateral medulla and reveal counterregulatory processes that moderate AT 1A receptor actions at this crucial relay point. More importantly, they imply that constitutive receptor signaling in glia of the rostral ventrolateral medulla can modulate the activity of adjacent neurons to change blood pressure.
American journal of physiology. Regulatory, integrative and comparative physiology, 2017
Angiotensin II acts via two main receptors within the CNS, with the type 1A receptor (AT1AR) most widely expressed in adult neurons. Activation of the AT1R in the nucleus of the solitary tract (NTS), the principal nucleus receiving central synapses of viscerosensory afferents, modulates cardiovascular reflexes. Expression of the AT1R occurs in high density within the NTS of most mammals, including humans, but the fundamental electrophysiological and neurochemical characteristics of the AT1AR-expressing NTS neurons are not known. To address this, we have used a transgenic mouse, in which the AT1AR promoter drives expression of green fluorescent protein (GFP). Approximately one third of AT1AR-expressing neurons express the catecholamine-synthetic enzyme, tyrosine hydroxylase (TH) and a sub-population of these stained for the transcription factor Phox2b. A third group, comprising approximately two thirds of the AT1AR-expressing NTS neurons showed Phox 2b-immunoreactivity alone. A fourt...
Cardiovascular role of angiotensin type1A receptors in the nucleus of the solitary tract of mice
Cardiovascular Research, 2013
Bilateral microinjections of lentivirus expressing AT 1A receptors (AT 1A v mice, n ¼ 6) or green fluorescent protein (GFPv, n ¼ 8, control) under the control of the PRSx8 promotor were made into the NTS of AT 1A receptors null mice (AT 1A 2/2 ). Telemetry devices recorded blood pressure (BP), heart rate (HR), and locomotor activity. Expression of AT 1A receptors in the NTS increased BP by 11.2 + 4 mmHg (P , 0.05) at 2 and 3 weeks, whereas GFPv mice remained at pre-injection BP. Ganglion blockade reduced BP to similar levels pre-and post-transfection in GFPv and AT 1A v mice.
Angiotensin-(3–7) pressor effect at the rostral ventrolateral medulla
Regulatory Peptides, 2007
Ang-(3-7) is a fragment of the renin-angiotensin system that can be derived both from Ang II or Ang-(1-7). In the present study we determined the cardiovascular effects produced by angiotensin-(3-7) [Ang-(3-7)] microinjection into the rostral ventrolateral medulla (RVLM), a key region for the control of sympathetic drive to the periphery. RVLM microinjection of Ang-(3-7) (20, 40 or 80 ng) in male Wistar rats anesthetized with urethane produced significant increases in MAP (19 ± 3.8 mm Hg, n = 5; 16 ± 1.6 mm Hg, n = 15 and 11 ± 1.2 mm Hg, n = 4, respectively) as compared to saline (4 ± 0.7 mm Hg, n = 6). These alterations were similar to that induced by Ang-(1-7) (14 ± 1.3 mm Hg, 40 ng; n = 12) and Ang II (17 ± 2.3 mm Hg, 40 ng; n = 7). Microinjection of losartan (AT 1 receptor antagonist, 100 pmol) or A779 (selective Mas receptor antagonist, 100 pmol) did not alter the pressor effect caused by Ang- . Microinjection of an Ang-(3-7) analogue, D-Ala 7 -Ang-(3-7) (100 pmol), completely abolished the pressor effect caused by Ang- . These results suggest that Ang-(3-7) may be an additional peptide of the RAS to act as neuromodulator, at least at the RVLM. Further, the Ang-(3-7) pressor effect is not mediated by the interaction with AT 1 or the Ang-(1-7), Mas, receptors.
tensin peptides acting at rostral ventrolateral medulla contribute to hypertension of TGR(mREN2)27 rats. Physiol Genom-ics 2: 137-142, 2000.-We have previously demonstrated that microinjections of the selective angiotensin-(1-7) [ANG-(1-7)] antagonist, A-779, into the rostral ventrolateral medulla (RVLM) produces a significant fall in mean arterial pressure (MAP) and heart rate (HR) in both anesthetized and conscious rats. In contrast, microinjection of angiotensin II (ANG II) AT 1 receptor antagonists did not change MAP in anesthe-tized rats and produced dose-dependent increases in MAP when microinjected into the RVLM of conscious rats. In the present study, we evaluated whether endogenous ANG-(1-7) and ANG II acting at the RVLM contribute to the hyperten-sion of transgenic rats harboring the mouse renin Ren-2 gene, TGR(mREN2)27. Unilateral microinjection of A-779 (0.1 nmol) produced a significant fall in MAP (Ϫ25 Ϯ 5 mmHg) and HR (Ϫ57 Ϯ 20 beats/min) of awake TGR rats. The hypotensive effect was greater than that observed in Sprague-Dawley (SD) rats (Ϫ9 Ϯ 2 mmHg). Microinjection of the AT 1 antagonist CV-11974 (0.2 nmol) produced a fall in MAP in TGR rats (Ϫ14 Ϯ 4 mmHg), contrasting with the pressor effect observed in SD rats (33 Ϯ 9 mmHg). These results indicate that endogenous ANG-(1-7) exerts a significant pressor action in the RVLM, contributing to the hypertension of TGR(m-REN2)27 transgenic rats. The role of ANG II at the RVLM seems to be dependent on its endogenous level in this area. rostral ventrolateral medulla; angiotensin II; angiotensin-(1-7); AT 1 antagonists; angiotensin-(1-7) antagonist; transgenic hypertensive rats SEVERAL STUDIES HAVE SHOWN that the neurons of the rostral ventrolateral medulla (RVLM), a key region in the central regulation of blood pressure (10, 14), can be influenced by angiotensin peptides including ANG II (3, 16, 17), ANG III (36), and ANG-(1-7) (11, 12, 34). The findings that topical application or local microinjection of ANG II into the RVLM produces increases in blood pressure and renal nerve activity (3, 16, 17) are consistent with a high expression of AT 1 receptors in this region as demonstrated by autoradiography (2, 13, 24). A physiological role for endogenous ANG II in this region has been suggested by the demonstration of a significant drop in mean arterial pressure (MAP) following topical application or microinjection of the nonselec-tive ANG II receptor antagonist [Sar 1 ,Thr 8 ]ANG II (3, 17, 31). We have recently uncovered a possible role for ANG-(1-7) in this region by showing that microinjection of this heptapeptide into the RVLM increases MAP (34), whereas microinjection of its selective antagonist, A-779, produces the opposite effect (12, 29). These data, obtained first in anesthetized rats (12, 29, 34), have been confirmed in awake animals (11). It is now well accepted that the biological effects elicited by ANG II are mediated through the interaction with AT 1 and AT 2 receptor subtypes. Several pharmacological evidences indicate that the actions of ANG-(1-7) can be mediated by different receptor or receptor sub-type (29, 35). AT 1 receptor antagonists are capable of abolishing the pressor effect of ANG II at the RVLM (4, 16). However, microinjection of these antagonists alone did not change blood pressure or produce a slight increase in MAP in anesthetized animals (4, 12, 16, 29) and produced a dose-dependent increase in MAP in freely moving rats (11). These observations, especially in awake rats (11), suggest a primary inhibitory role for ANG II in this region, in normotensive animals. However , the role of angiotensin peptides in the RVLM of freely moving hypertensive animals has not been studied. The generation of the genetic model of hypertension by insertion of the mouse Ren-2 renin gene into the genome of the Sprague-Dawley (SD) rat (26) created an important tool for investigating the pathophysiological consequences of enhanced activity of the brain renin-angiotensin system (RAS), particularly activated in this model of hypertension, TGR(mREN2)27 (8, 18, 26, 33). The finding that the circulating RAS activity is normal in TGR(mREN2) rats and the effectiveness of drugs interfering with the RAS to lower blood pressure in these animals (25) indicate a major role for tissue RAS in the pathogenesis of this genetic model of hypertension. Interference with the brain RAS by intracerebroventricular administration of ANG II anti