Injections of angiotensin‐converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats

Diz, Debra I.; Garcı́a-Espinosa, Marı́a A.; Gegick, Stephen; Tommasi, Ellen N.; Ferrario, Carlos M.; Tallant, E. Ann; Chappell, Mark C.; Gallagher, Patricia E.

doi:10.1113/expphysiol.2007.040261

Cited by 72 publications

(84 citation statements)

References 47 publications

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“…Overexpression of ACE2 in the brain reduces hypertension by improving the arterial baroreflex and autonomic function in hypertensive animals (37,38). Injection of the ACE2 inhibitor MLN-4760 into the NTS reduces the baroreceptor reflex sensitivity for HR control in rats (6). Our data show that the basal RSNA in CHF rats is significantly higher than that in sham rats.…”

Section: Discussionsupporting

confidence: 52%

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure

Zheng

Liu

Patel

2011

American Journal of Physiology-Heart and Circulatory Physiology

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Angiotensin (ANG)-converting enzyme (ACE)2 in brain regions such as the paraventricular nucleus (PVN) controlling cardiovascular function may be involved in the regulation of sympathetic outflow in chronic heart failure (CHF). The purpose of this study was to determine if ACE2 plays a role in the central regulation of sympathetic outflow by regulating neuronal nitric oxide (NO) synthase (nNOS) in the PVN. We investigated ACE2 and nNOS expression within the PVN of rats with CHF. We then determined the effects of ACE2 gene transfer in the PVN on the contribution of NO-mediated sympathoinhibition in rats with CHF. The results showed that there were decreased expressions for ACE2, the ANG-(1-7) receptor, and nNOS within the PVN of rats with CHF. After the application of adenovirus vectors encoding ACE2 (AdACE2) into the PVN, the increased expression of ACE2 in the PVN was confirmed by Western blot analysis. AdACE2 transfection significantly increased nNOS protein levels (change of 50 ± 5%) in the PVN of CHF rats. In anesthetized rats, AdACE2 treatment attenuated the responses of renal sympathetic nerve activity (RSNA), mean arterial pressure, and heart rate to the NOS inhibitor N-monomethyl-L-arginine in rats with CHF (RSNA: 28 ± 3% vs. 16 ± 3%, P < 0.05) compared with CHF + AdEGFP group. Furthermore, neuronal NG-108 cells incubated with increasing doses of AdACE2 showed a dose-dependent increase in nNOS protein expression (60% at the highest dose). Taken together, our data highlight the importance of increased expression and subsequent interaction of ACE2 and nNOS within the PVN, leading to a reduction in sympathetic outflow in the CHF condition.

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Section: Discussionsupporting

confidence: 52%

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure

Zheng

Liu

Patel

2011

American Journal of Physiology-Heart and Circulatory Physiology

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“…ACE2 and neprilysin mRNAs were significantly higher in the old treated group compared with the old group, while ACE mRNA declined with age but was restored with the AT 1 receptor blockade. We previously showed that ACE2 is the major ANG-(1-7) processing enzyme in dorsomedial medulla (9). There was no difference in AT 1a receptor mRNA expression between the groups, but AT 1b mRNA was significantly increased in the old treated group.…”

Section: Discussionmentioning

confidence: 84%

Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components

Gilliam-Davis¹,

Gallagher²,

Payne

et al. 2011

Physiological Genomics

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Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components. Physiol Genomics 43: 829 -835, 2011. First published May 3, 2011 doi:10.1152/physiolgenomics.00167.2010 rats, renin-angiotensin system (RAS) blockade for 1 yr with the angiotensin II type 1 (AT1) receptor blocker L-158,809 prevents age-related impairments in metabolic function, similar to transgenic rats with low glial angiotensinogen (Aogen). Brain RAS regulation may contribute to the benefits of long-term systemic AT1 antagonism. We assessed the mRNA of RAS components in the dorsomedial medulla of F344 rats at 3 (young; n ϭ 8) or 15 mo of age (old; n ϭ 7) and in rats treated from 3 to 15 mo of age with 20 mg/l of the AT1 receptor antagonist L-158,809 (OldϩL; n ϭ 6). Aogen and renin mRNA were lower in the young compared with old group. Angiotensin-converting enzyme (ACE) mRNA was lower in the old and OldϩL compared with the young group. ACE2 and neprilysin expression were significantly higher in OldϩL compared with young or old rats. AT1b, AT2, and Mas receptor mRNA were higher with treatment. Leptin receptor mRNA was lower in the old rats and this was prevented by L-158,809 treatment. Dual-specificity phosphatase 1 (DUSP1) mRNA was highest in the OldϩL group. Aggregate correlate summation revealed a positive relationship for Mas receptor mRNA with food intake. The findings provide evidence for regulation of dorsomedial medullary renin and Aogen mRNA during aging. Long-term AT1 receptor blockade increases the mRNA of the enzymes ACE2 and neprilysin and the MAS receptor, which could potentially shift the balance from ANG II to ANG-(1-7) and prevent age-related declines in the leptin receptor and its signaling pathway.angiotensinogen; Fischer 344 rats; leptin; aggregate correlate summation SYSTEMIC BLOCKADE OF the renin-angiotensin system (RAS) with angiotensin II type 1 (AT 1 ) receptor blockers or angiotensinconverting enzyme (ACE) inhibitors provides beneficial effects outside of the classic hemodynamic actions. RAS blockade improves many components of aging and reduces the onset of the metabolic syndrome and Type 2 diabetes (1,8,17,43). However, the precise mechanisms underlying the beneficial effects are not entirely known. During aging, there is a decline in the circulating (systemic) RAS, including angiotensin (ANG)-(1-7) (30), suggesting that the beneficial actions of RAS blockade are partly due to the suppression of ANG II in tissues. Many tissues and organs contain their own local RAS, including the kidney, heart, vessels, adrenal gland, pancreas, and brain (4, 25). Increased brain ANG II activates sympathetic outflow, inhibits the baroreflex, stimulates thirst, and contributes to neurogenic hypertension (25,36, 38). In rats with chronic renal failure, components of the brain RAS are upregulated, resulting in sympathetic overactivity and hypertension (29). Transgenic mice with increased production of brain ANG II developed hypertension and an increase in salt ...

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“…Furthermore, we (18,51) have shown that ExT improves the sympathoexcitatory drive from the PVN by normalization of the glutamatergic and angiotensinergic drives to sympathoexcitation in rats with HF. Recently, the role of the nonclassical pathway of renin-angiotensin system genes such as angiotensin-converting enzyme 2 and the Mas receptor in the central nervous system and their participation in central sympathetic activation have been also been widely addressed (6,7,17,45). Changes in these inhibitory pathways may also be involved in the improvement of the central component of the baroreflex in rats with HF, but this remains to be examined.…”

Section: Discussionmentioning

confidence: 95%

Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN

Patel

Salgado

Liu

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Exercise training (ExT) normalizes the increased sympathetic outflow in chronic heart failure (HF). The underlying mechanisms are not clearly understood. We hypothesized that ExT normalized the blunted central component of the baroreflex control of renal sympathetic nerve activity (RSNA) in HF. Four groups of rats [sham operated (sham)-sedentary (Sed), sham-ExT, HF-Sed, and HF-ExT] were used. HF was induced by left coronary artery ligation, and ExT consisted of 3 wk of treadmill running. In anesthetized rats, the decrease in RSNA in response to aortic depressor nerve stimulation (5-40 Hz) in the HF-Sed group was significantly lower than that in the sham-Sed group (-37 ± 7% vs. -63 ± 8% at 40 Hz, P < 0.05). In the HF-ExT group, responses in RSNA, mean arterial pressure (MAP), and heart rate (HR) were not significantly different from those in the sham-Sed or sham-ExT groups. ExT normalized blunted RSNA, MAP, and HR responses to bicuculline microinjections into the paraventricular nucleus (PVN) in rats with HF. Activation of the PVN by blockade of GABA receptors with bicuculline in normal control rats blunted the centrally component of the baroreflex arc. GABAA-α1 and -β1 receptor protein expression were significantly lower (by 48% and 30%) in the HF-Sed group, but ExT normalized this difference between the HF and sham groups. These data suggest that one mechanism by which ExT alleviates elevated sympathetic outflow in HF may be through normalization of central integrative mechanisms, perhaps via improving the inhibitory GABAergic mechanism within the PVN, on the baroreflex arc.

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Injections of angiotensin‐converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats

Cited by 72 publications

References 47 publications

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure

Angiotensin-converting enzyme 2 overexpression improves central nitric oxide-mediated sympathetic outflow in chronic heart failure

Long-term systemic angiotensin II type 1 receptor blockade regulates mRNA expression of dorsomedial medulla renin-angiotensin system components

Exercise training normalizes the blunted central component of the baroreflex in rats with heart failure: role of the PVN

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