Angiotensin 1A receptors transfected into caudal ventrolateral medulla inhibit baroreflex gain and stress responses (original) (raw)
Related papers
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012
The rise in blood pressure during an acute aversive stress has been suggested to involve activation of angiotensin type 1A receptors (AT 1A Rs) at various sites within the brain, including the rostral ventrolateral medulla. In this study we examine the involvement of AT 1A Rs associated with a subclass of sympathetic premotor neurons of the rostral ventrolateral medulla, the C1 neurons. The distribution of putative AT 1A R-expressing cells was mapped throughout the brains of three transgenic mice with a bacterial artificial chromosomeexpressing green fluorescent protein under the control of the AT 1A R promoter. The overall distribution correlated with that of the AT 1A Rs mapped by other methods and demonstrated that the majority of C1 neurons express the AT 1A R. Cre-recombinase expression in C1 neurons of AT 1A R-floxed mice enabled demonstration that the pressor response to microinjection of angiotensin II into the rostral ventrolateral medulla is dependent upon expression of the AT 1A R in these neurons. Lentiviral-induced expression of wild-type AT 1A Rs in C1 neurons of global AT 1A R knock-out mice, implanted with radiotelemeter devices for recording blood pressure, modulated the pressor response to aversive stress. During prolonged cage-switch stress, expression of AT 1A Rs in C1 neurons induced a greater sustained pressor response when compared to the control viral-injected group (22 Ϯ 4 mmHg for AT 1A R vs 10 Ϯ 1 mmHg for GFP; p Ͻ 0.001), which was restored toward that of the wild-type group (28 Ϯ 2 mmHg). This study demonstrates that AT 1A R expression by C1 neurons is essential for the pressor response to angiotensin II and that this pathway plays an important role in the pressor response to aversive stress.
2007
Chronic intravenous angiotensin II (Ang II) has been widely used to establish centrally mediated hypertension in experimental animals, and disruption of Ang II activity is a frontline treatment for hypertensive disease. However, the acute central actions of circulating Ang II are poorly understood. We examined the effects of intravenous pressor doses of Ang II on autonomic activity in anaesthetized rats under neuromuscular blockade, and compared baroinhibition evoked by Ang II pressor ramps to equipressor responses evoked by phenylephrine (PE). Baroinhibition of splanchnic sympathetic nerve activity was attenuated during Ang II trials compared with PE, and rats remained sensitive to electrical stimulation of the aortic depressor nerve at higher arterial pressures during Ang II trials. This was not due to a direct effect of Ang II on aortic nerve baroreceptors. In a separate series of experiments, we provide direct evidence that bulbospinal barosensitive neurones in the rostral ventrolateral medulla are differentially sensitive to pressure ramps evoked by Ang II or PE vasoconstriction. Nineteen out of 41 units were equally sensitive to increased arterial pressure evoked by Ang II or PE. In 17 of 41 units, barosensitivity was attenuated during Ang II trials, and in five of 41 cases units that had previously been barosensitive increased their firing rate during Ang II trials. These results show, for the first time, that circulating Ang II acutely modulates central cardiovascular control mechanisms. We suggest that this results from activation by Ang II of a central pathway originating at the circumventricular organs.
Hypertension, 2011
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. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT 1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT 1a receptors in cardiovascular homeostasis in health and disease. (Circ Res. 2002;90:617-624.)
The Role of AT(1A) Receptors in Cardiovascular Reactivity to Acute Aversive Stress
Hypertension
We determined whether genetic deficiency of angiotensin II Type 1A (AT 1A ) receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate, and activity. Before stress, lower resting mean arterial pressure was recorded in AT 1A
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.
Hypertension
We determined whether genetic deficiency of AT1A-receptors in mice results in altered neuronal responsiveness and reduced cardiovascular reactivity to stress. Telemetry devices were used to measure mean arterial pressure, heart rate and activity. Before stress, lower resting mean arterial pressure was recorded in AT1A-/- (85±2 mmHg) than in AT1A+/+ mice (112±2 mmHg); heart rate was not different between groups. Cage-switch stress for 90-minutes elevated blood pressure by +24±2 mmHg in AT1A+/+ and +17±2 mmHg in AT1A-/- mice (P<0.01) and heart rate increased by +203±9 bpm in AT1A+/+ and +121±9 bpm in AT1A-/- mice (P<0.001). Locomotor activation was less in AT1A-/- (3.0±0.4 units) than in AT1A+/+ animals (6.0±0.4 units), but differences in blood pressure and heart rate persisted during non-active periods. In contrast to wild-types, spontaneous baroreflex sensitivity was not inhibited by stress in AT1A-/- mice. Following cage-switch stress, c-Fos-immunoreactivity was less in the p...
American Journal of Physiology-Heart and Circulatory Physiology, 2010
The novel peptide, angiotensin (ANG)-(1–12), elicits a systemic pressor response and vasoconstriction. These effects are blocked by ANG converting enzyme (ACE) inhibitors or AT1 receptor antagonists, suggesting a role as an ANG II precursor. However, ANG-(1–12) can serve as a substrate for either ANG II or ANG-(1–7) formation, depending on the local tissue enzymes. Although levels of ANG-(1–12) are higher than ANG I or ANG II in brain, the role and processing of this peptide for autonomic control of heart rate (HR) has yet to be considered. Thus we examined the effects of nucleus tractus solitarii (NTS) microinjection of ANG-(1–12) on baroreflex sensitivity for control of HR, resting arterial pressure (AP) and HR, and indexes of sympathovagal balance in urethane/chloralose anesthetized Sprague-Dawley rats. NTS injection of ANG-(1–12) (144 fmol/120 nl) significantly impaired the evoked baroreflex sensitivity to increases in AP [ n = 7; 1.06 ± 0.06 baseline vs. 0.44 ± 0.07 ms/mmHg aft...
Hypertension, 2010
Calcitonin gene-related peptide (CGRP) is a powerful vasodilator that interacts with the autonomic nervous system. A subunit of the CGRP receptor complex, receptor activity-modifying protein 1 (RAMP1), is required for trafficking of the receptor to the cell surface and high-affinity binding to CGRP. We hypothesized that upregulation of RAMP1 would favorably enhance autonomic regulation and attenuate hypertension. Blood pressure, heart rate, and locomotor activity were measured by radiotelemetry in transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1) and littermate controls. Compared with control mice, hRAMP1 mice exhibited similar mean arterial pressure, a lower mean heart rate, increased heart rate variability, reduced blood pressure variability, and increased baroreflex sensitivity (2.83+/-0.20 versus 1.49+/-0.10 ms/mm Hg in controls; P<0.05). In control mice, infusion of angiotensin II (Ang-II) increased mean arterial pressure from 118+/-2 mm Hg to 153+/-4 and 17...
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.