Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats

Klett, Christoph; Anderson, D R; Sholook, Myssara; Granger, Joey P.

doi:10.1152/ajpregu.00140.2004

Cited by 7 publications

(5 citation statements)

References 29 publications

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“…Importantly, antihypertensive effects after blockade of Aogen mRNA synthesis were similar to those observed after inhibition of the RAS by converting enzyme inhibitor or AT 1 receptor blockade. 32 These observations, together with those of the present study, showed clearly that training caused a similar antihypertensive effect as the pharmacological therapies and strongly suggest that reduced Aogen expression within brain stem areas controlling cardiovascular function is involved in the mediation of the response. If a similar deactivation also occurs in other brain areas, such as the hypothalamic integrative centers, it remains to be determined.…”

Section: Felix and Michelini Exercise Training And Brain Ras 783supporting

confidence: 85%

“…Together these observations reinforce the importance of an overactive brain RAS to condition elevated blood pressure in hypertension and the proposition that blockade of brain and/or plasma Aogen is essential for pressure fall in hypertensive individuals. 30,32 The present experimental evidence, showing positive significant correlations between NTS Aogen mRNA expression and MAP levels in the SHR (but not in the WKY group) and in the sedentary rats (not trained; Figure 2A and 3A, respectively), reinforces the association between blood pressure and brain Aogen content, suggesting additionally an important effect of training on them. Previous studies have already shown that hypertension coexists with high Ang II levels in brain areas involved in cardiovascular control.…”

Section: Discussionsupporting

confidence: 70%

“…14 In addition, in the vehicle-treated groups (similar to the present observation in sedentary versus trained groups; Figure 3) there was a positive correlation between Aogen mRNA expression and basal MAP, which was significantly reduced in the presence of chronic AT 1 receptor blockade with losartan. 14 Klett et al 32 also showed that administration of antisense oligodeoxynucleotide against mRNA-stabilizing protein in SHRs reduced both tissue and plasma Aogen expression and caused significant blood pressure fall. Importantly, antihypertensive effects after blockade of Aogen mRNA synthesis were similar to those observed after inhibition of the RAS by converting enzyme inhibitor or AT 1 receptor blockade.…”

Section: Felix and Michelini Exercise Training And Brain Ras 783mentioning

confidence: 99%

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Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii

Félix

Michelini

2007

Hypertension

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Abstract-Knowing that exercise training reduces arterial pressure in hypertensive individuals and that pressure fall is accompanied by blockade of brain renin-angiotensin system, we sought to investigate whether training (T) affects central renin-angiotensin system. Spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto controls (WKY) were submitted to training or kept sedentary (S) for 3 months. After functional recordings, brain was removed and processed for autoradiography (brain stem sequential slices hybridized with 35 S-oligodeoxynucleotide probes for angiotensinogen [Aogen] and angiotensin II type 1 [AT 1A ] receptors). Resting arterial pressure and heart rate were higher in SHR S (177Ϯ2 mm Hg, 357Ϯ12 bpm versus 121Ϯ1 mm Hg, 320Ϯ9 bpm in WKY S ; PϽ0.05). Training was equally effective to enhance treadmill performance and to cause resting bradycardia (Ϫ10%) in both groups. Training-induced blood pressure fall (Ϫ6.3%) was observed only in SHR T . In SHR S (versus WKY S ) AT 1A and Aogen mRNA expression were significantly increased within the NTS and area postrema (average of ϩ67% and ϩ41% for AT 1A and Aogen, respectively; PϽ0.05) but unchanged in the gracilis nucleus. Training did not change AT 1A expression but reduced NTS and area postrema Aogen mRNA densities specifically in SHR T (PϽ0.05 versus SHR S , with values within the range of WKY groups). In SHRs, NTS Aogen mRNA expression was correlated with resting pressure (yϭ5.95x ϩ41; rϭ0.55; PϽ0.05), with no significant correlation in the WKY group. Concurrent training-induced reductions of both Aogen mRNA expression in brain stem cardiovascular-controlling areas and mean arterial pressure only in SHRs suggest that training is as efficient as the renin-angiotensin blockers to reduce brain renin-angiotensin system overactivity and to decrease arterial pressure. Key Words: angiotensin II Ⅲ angiotensin receptors Ⅲ blood pressure Ⅲ heart rate Ⅲ hypertension Ⅲ experimental Ⅲ rats T he renin-angiotensin system (RAS) is a widely distributed regulatory system with hormonal, paracrine, and intracrine functions in many tissues. 1-4 Brain RAS has been implicated in the pathogenesis (development/maintenance) of several forms of hypertension. 2,4 -6 All of the components of the RAS (precursor, enzymes, peptides, and receptors) are present in brain areas involved in cardiovascular control as the hypothalamic paraventricular nucleus and dorsal brain stem areas including the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus nerve, and the area postrema. 4,[7][8][9][10][11] It is important to notice that angiotensinogen (Aogen), angiotensin II (Ang II), and Ang II type 1 (AT 1A ) receptors are densely expressed within the NTS, indicating the importance of local RAS on cardiovascular control. 4,8,10 -14 In previous studies we showed both the close relationship between increased Aogen and Ang II AT 1A receptor mRNA expression in brain stem areas and elevated blood pressure 14 and the permissive role of Ang II to orchestrate, via AT 1 rec...

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Section: Felix and Michelini Exercise Training And Brain Ras 783supporting

confidence: 85%

Section: Discussionsupporting

confidence: 70%

Section: Felix and Michelini Exercise Training And Brain Ras 783mentioning

confidence: 99%

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Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii

Félix

Michelini

2007

Hypertension

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“…It has also been shown that converting enzyme inhibitors, as well as angiotensin receptor blockers, reduced the collagen/elastin ratio in treated SHR while attenuating the expression of integrin in the arteries [12,14,36]. Indeed, exercise training by reducing either the activity of the renin-angiotensin system [37,38], mean pressure and pulsatility (present set of data) was able to decrease aortic stress and the stress-sensing mechanism. Future experiments might explore these possibilities.…”

Section: Discussionmentioning

confidence: 61%

Exercise Training Restores Hypertension-Induced Changes in the Elastic Tissue of the Thoracic Aorta

et al. 2011

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Background/Aims: Pharmacological antihypertensive therapies decrease both wall hypertrophy and collagen, but are unable to diminish the elastic content in the thoracic aorta. We investigated the effects of exercise training on aortic structure and function. Methods: Spontaneously hypertensive rats (SHR) and normotensive rats (WKY), submitted to low-intensity training (T) or kept sedentary (S), were subjected to haemodynamic analyses. The thoracic aorta was processed for real-time PCR, light (morphometric/stereological evaluations) and electron microscopy. Results: SHR_S versus WKY_S exhibited a higher heart rate, pressure and pulse pressure, increased α-actin, elastin and collagen mRNA expression, augmented wall volume and cross-sectional area (marked elastin/collagen content). In the SHR, training reduced pressure and heart rate, with slight reduction in pulse pressure. SHR_T aortas exhibited small morphometric changes, reduced α-actin, elastin and collagen mRNA expression, normalization of increased elastic content, reduction in collagen/connective tissue and a decrease in smooth muscle cell volume (p < 0.05 for all comparisons). SHR_T aortas showed improved circumferential orientation of smooth muscle cells and prevention of rupture/duplication of internal elastic lamina. No effects were observed in trained WKY aortas. Conclusions: Training effectively corrects elastic, collagen and smooth muscle content in SHR aortas. These changes, by reducing aortic pulsatility, facilitate a buffering function and reduce the cardiovascular risk.

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“…Although the modulation of plasma renin is generally considered to be the primary regulator of the renin–angiotensin system (RAS), experiments in laboratory animals have demonstrated that the circulating or tissue level of AGT may also be important in the regulation of the RAS. Studies in the spontaneously hypertensive rat demonstrated that antisense inhibition of an AGT mRNA‐stabilizing protein leads to a reduction in arterial blood pressure (Klett et al 2004). Moreover, intrarenal AGT mRNA and protein (Kobori et al 2001 a ; Kobori et al 2001 b ) levels are increased in experimental angiotensin (ANG) II‐induced hypertension in rats, indicating both a role of AGT in hypertension and a potential feed‐forward effect of ANG II on AGT.…”

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confidence: 99%

Influence of elevated renin substrate on angiotensin II and arterial blood pressure in conscious mice

Cholewa

Mattson

2005

Experimental Physiology

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The present experiments were performed to determine the influence of intravenous administration of renin substrate on plasma angiotensin II levels and mean arterial blood pressure in conscious C57BL/6J mice. Mice with chronic indwelling femoral arterial and venous catheters were acutely or chronically administered intravenous doses of a synthetic peptide corresponding to the 14 amino acids on the N-terminal of angiotensinogen. A dosedependent increase in arterial blood pressure was observed as the intravenous bolus dose of the renin substrate was increased from 0.18 to 180 nmol kg −1 with a maximal increase in pressure of 40 ± 3 mmHg achieved following administration of the 18 nmol kg −1 bolus (n = 11). Additional experiments demonstrated that a sustained intravenous infusion of the renin substrate led to a long-term increase in arterial blood pressure. The continuous infusion of renin substrate at 0.05 nmol kg −1 min −1 for 3 days did not alter arterial blood pressure from the control level of 119 ± 5 mmHg (n = 5); however, arterial blood pressure significantly increased to 129 ± 6 mmHg with an infusion rate of 0.5 nmol kg −1 min −1 and further increased to 141 ± 3 mmHg when the renin substrate infusion was increased to 5.0 nmol kg −1 min −1 . Finally, the infusion of renin substrate at 5.0 nmol kg −1 min −1 resulted in a significant increase in plasma angiotensin II concentration from 34 ± 6 pg ml −1 in vehicle-infused mice to 288 ± 109 pg ml −1 . These results demonstrate that modulation of the circulating level of angiotensinogen can alter the plasma angiotensin II level and arterial blood pressure in normal animals.

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Antisense oligodeoxynucleotides directed against a novel angiotensinogen mRNA-stabilizing protein reduce blood pressure in spontaneously hypertensive rats

Cited by 7 publications

References 29 publications

Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii

Training-Induced Pressure Fall in Spontaneously Hypertensive Rats Is Associated With Reduced Angiotensinogen mRNA Expression Within the Nucleus Tractus Solitarii

Exercise Training Restores Hypertension-Induced Changes in the Elastic Tissue of the Thoracic Aorta

Influence of elevated renin substrate on angiotensin II and arterial blood pressure in conscious mice

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