Chronic infusion of angiotensin-(1-7) into the lateral ventricle of the brain attenuates hypertension in DOCA-salt rats (original) (raw)
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Hypothalamic cardiovascular effects of angiotensin-(1–7) in spontaneously hypertensive rats
Regulatory Peptides, 2006
The objective of the present work was to study the cardiovascular actions of the intrahypothalamic injection of Ang-(1-7) and its effects on the pressor response to Ang II in spontaneously hypertensive (SH) rats and Wistar Kyoto (WKY) animals. In anaesthetized SH and WKY rats, a carotid artery was cannulated for mean arterial pressure (MAP) measurement and a stainless-steel needle was inserted into the anterior hypothalamus for drug administration. The cardiovascular effects of the intrahypothalamic administration of Ang-(1-7) were determined in SH and WKY rats. In SH rats, the effect of irbesartan and D-Ala-Ang-(1-7) on Ang-(1-7) cardiovascular effect was also evaluated. Ang II was administered in the hypothalamus of SH and WKY rats and changes in blood pressure and heart rate were measured followed by the administration of Ang II, Ang II + Ang-(1-7) or Ang II + D-Ala-Ang-(1-7). Ang-(1-7) did not the change basal MAP in WKY rats, but induced a pressor response in SH animals. Whilst the coadministration of D-Ala-Ang-(1-7) did not affect the response to Ang-(1-7), the previous administration of irbesartan prevented the effect of the peptide. The intrahypothalamic injection of Ang II induced a significantly greater pressor response in SH animals compared to normotensive rats. The co-administration of Ang-(1-7) with Ang II did not affect the pressor response to Ang II in the WKY group. In SH rats, whilst the co-administration of Ang-(1-7) with Ang II reduced the pressor response to Ang II, the concomitant application of D-Ala-Ang-(1-7) with Ang II increased the pressor response to the octapeptide after 5 and 10 min of intrahypothalamic administration. In conclusion, our result demonstrated that the biologically active peptide Ang-(1-7) did not participate in the hypothalamic blood pressure regulation of WKY animals. In SH rats, Ang-(1-7) exerted pleiotropic effects on blood pressure regulation. High dose of the heptapeptide produced a pressor response because of an unspecific action by activation of AT 1 receptors. The concomitant administration of lower doses of Ang-(1-7) with Ang II reduced the pressor response to the octapeptide. Finally, the effect of AT 1-7 antagonist on Ang II pressor response suggested that hypothalamic formed Ang-(1-7) are implicated in the regulation of the cardiovascular effects of Ang II.
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
Hypertension, 2012
Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity for heart rate control and high nicotinamide adenine dinucleotide phosphate oxidase and kinase-tophosphatase signaling activity in medullary tissue compared with normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin II actions, supplementing angiotensin-(1-7), or scavenging reactive oxygen species in brain differentially alters mean arterial pressure, baroreflex sensitivity, or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular infusions of the angiotensin II type 1 receptor antagonist candesartan (4 μg/5 μL/h), angiotensin-(1-7) (0.1 μg/5 μL/h), a reactive oxygen species scavenger tempol (25 μg/5 μL/h), or artificial cerebrospinal fluid (5 μL/h) for 2 weeks. Mean arterial pressure was reduced in candesartan-treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, angiotensin-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower mean arterial pressure. Tempol significantly reduced nicotinamide adenine dinucleotide phosphate oxidase activity in brain dorsal medullary tissue but had no effect on mean arterial pressure or autonomic function. Candesartan tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase signaling pathways in dorsal medulla. Although additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary nicotinamide adenine dinucleotide phosphate oxidase or mitogen-activated protein kinase in hypertensive 27 rats. (Hypertension. 2012;60:1257-1265.) The dorsal medulla was homogenized in a lysis buffer containing protease and phosphatase inhibitors (250.0 mmol/L of sucrose, 0.5 mmol/L of EDTA, 50.0 mmol/L of NaF, and 10.0 mmol/L of Tris [pH by guest on July 19, 2017 http://hyper.ahajournals.org/ Downloaded from
Brain Angiotensin: Receptors, Actions and Possible Role in Hypertension
Pharmacology & Toxicology, 1992
The brain is one of the organs where an intrinsic reninangiotensin system (RAS) has been described (Ganten et al. 1984; Campbell 1987). Stimulation of circumventricular or brainstem angiotensin I1 (ANG 11) receptors engenders a distinct pattern of cardiovascular, endocrine and behavioural responses featuring blood pressure increase, attenuation of the baroreceptor reflex, drinking, natriuresis, and release of pituitary hormones such as vasopressin, oxytocin and ACTH (Unger et al. 1988). Biochemical characterization of ANG II receptor subtypes. Recently, two receptor subtypes for ANG I1 have been identified which differ in their binding properties as well as in their signal transduction mechanisms (Whitebread et al.
Hypertension, 2000
The potential involvement of the brain renin-angiotensin system in the hypertension induced by subpressor doses of angiotensin II was tested by the use of newly developed transgenic rats with permanent inhibition of brain angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague-Dawley rats (parent strain) (122.5Ϯ1.5 versus 128.9Ϯ1.9 mm Hg, respectively; PϽ0.05). The increase in systolic blood pressure induced by 7 days of chronic angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in comparison with control rats (29.8Ϯ4.2 versus 46.3Ϯ2.5 mm Hg, respectively; PϽ0.005). Moreover, an increase in heart/body weight ratio was evident only in Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle measured by ribonuclease protection assay were similarly increased in both TGR(ASrAOGEN) (ANP, ϫ2.5; collagen III, ϫ1.8) and Sprague-Dawley rats (ANP, ϫ2.4; collagen III, ϫ2) as a consequence of angiotensin II infusion. Thus, the expression of these genes in the left ventricle seems to be directly stimulated by angiotensin II. However, the hypertensive and hypertrophic effects of subpressor angiotensin II are at least in part mediated by the brain renin-angiotensin system. (Hypertension. 2000;35[part 2]:409-412.
Journal of Cardiovascular Pharmacology, 2012
Transgenic (mRen2)27 rats are hypertensive with impaired baroreflex sensitivity for control of heart rate compared to Hannover Sprague-Dawley rats. We assessed blood pressure and baroreflex function in male hemizygous (mRen2)27 rats (30-40 wks of age) instrumented for arterial pressure recordings and receiving into the cisterna magna either an Ang-(1-7) fusion protein or a control fusion protein (CTL-FP). The maximum reduction in mean arterial pressure achieved was -38 ± 7 mm Hg on day 3, accompanied by a 55% enhancement in baroreflex sensitivity in Ang-(1-7) fusion protein-treated rats. Both the high frequency alpha index (HF-α) and heart rate variability increased, suggesting increased parasympathetic tone for cardiac control. The mRNA levels of several components of the renin-angiotensin system in the dorsal medulla were markedly reduced including renin (-80%), neprilysin (-40%) and the AT 1a receptor (-40%). However, there was 2 to 3 increase in the mRNA levels of the phosphatases PTP-1b and DUSP1 in the medulla of Ang-(1-7) fusion protein-treated rats. Our finding that replacement of Ang-(1-7) in the brain of (mRen2)27 rats reverses in part the hypertension and baroreflex impairment is consistent with a functional deficit of Ang-(1-7) in this hypertensive strain. We conclude that the increased mRNA expression of phosphatases known to counteract the phosphoinositol 3 kinase (PI3K) and mitogenactivated protein kinases (MAPK), as well as the reduction of renin and AT 1a receptor mRNA levels may contribute to the reduction in arterial pressure and improvement in baroreflex sensitivity in response to Ang-(1-7).
Region‐specific changes in sympathetic nerve activity in angiotensin II–salt hypertension in the rat
Experimental Physiology, 2010
It is now well accepted that many forms of experimental hypertension and human essential hypertension are caused by increased activity of the sympathetic nervous system. However, the role of region-specific changes in sympathetic nerve activity (SNA) in the pathogenesis of hypertension has been difficult to determine because methods for chronic measurement of SNA in conscious animals have not been available. We have recently combined indirect, and continuous and chronic direct, assessment of region-specific SNA to characterize hypertension produced by administration of angiotensin II (Ang II) to rats consuming a high-salt diet (Ang II-salt hypertension). Angiotensin II increases whole-body noradrenaline (NA) spillover and depressor responses to ganglionic blockade in rats consuming a high-salt diet, but not in rats on a normal-salt diet. Despite this evidence for increased 'whole-body SNA' in Ang II-salt hypertensive rats, renal SNA is decreased in this model and renal denervation does not attenuate the steady-state level of arterial pressure. In addition, neither lumbar SNA, which largely targets skeletal muscle, nor hindlimb NA spillover is changed from control levels in Ang II-salt hypertensive rats. However, surgical denervation of the splanchnic vascular bed attenuates/abolishes the increase in arterial pressure and total peripheral resistance, as well as the decrease in vascular capacitance, observed in Ang II-salt hypertensive rats. We hypothesize that the 'sympathetic signature' of Ang II-salt hypertension is characterized by increased splanchnic SNA, no change in skeletal muscle SNA and decreased renal SNA, and this sympathetic signature creates unique haemodynamic changes capable of producing sustained hypertension.