Angiotensin-converting Enzyme Inhibition, but Not AT(1) Receptor Blockade, in the Solitary Tract Nucleus Improves Baroreflex Sensitivity in Anesthetized Transgenic Hypertensive (mRen2)27 Rats

Overview

Journal Hypertens Res

Specialty Cardiology & Vascular Diseases

Date 2011 Sep 23

PMID 21937997

Citations 15

Authors

Katsunori Isa

Amy C Arnold

Brian M Westwood

Mark C Chappell

Debra I Diz

Affiliations

Soon will be listed here.

Abstract

Transgenic hypertensive (mRen2)27 rats overexpress the murine Ren2 gene and have impaired baroreflex sensitivity (BRS) for control of the heart rate. Removal of endogenous angiotensin (Ang)-(1-7) tone using a receptor blocker does not further lower BRS. Therefore, we assessed whether blockade of Ang II with a receptor antagonist or combined reduction in Ang II and restoration of endogenous Ang-(1-7) levels with Ang-converting enzyme (ACE) inhibition will improve BRS in these animals. Bilateral solitary tract nucleus (nTS) microinjections of the AT(1) receptor blocker, candesartan (CAN, 24 pmol in 120 nl, n=9), or a peptidic ACE inhibitor, bradykinin (BK) potentiating nonapeptide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro; BPP9α, 9 nmol in 60 nl, n=12), in anesthetized male (mRen2)27 rats (15-25 weeks of age) show that AT(1) receptor blockade had no significant effect on BRS, whereas microinjection of BPP9α improved BRS over 60-120 min. To determine whether Ang-(1-7) or BK contribute to the increase in BRS, separate experiments using the Ang-(1-7) receptor antagonist D-Ala(7)-Ang-(1-7) or the BK antagonist HOE-140 showed that only the Ang-(1-7) receptor blocker completely reversed the BRS improvement. Thus, acute AT(1) blockade is unable to reverse the effects of long-term Ang II overexpression on BRS, whereas ACE inhibition restores BRS over this same time frame. As the BPP9α potentiation of BK actions is a rapid phenomenon, the likely mechanism for the observed delayed increase in BRS is through ACE inhibition and elevation of endogenous Ang-(1-7).

Citing Articles

Angiotensin II and the Cardiac Parasympathetic Nervous System in Hypertension.

Shanks J, Ramchandra R Int J Mol Sci. 2021; 22(22).

PMID: 34830184 PMC: 8624735. DOI: 10.3390/ijms222212305.

Both central sympathoexcitation and peripheral angiotensin II-dependent vasoconstriction contribute to hypertension development in immature heterozygous Ren-2 transgenic rats.

rezacova L, Vaneckova I, Hojna S, Vavrinova A, Valovic P, Rauchova H Hypertens Res. 2021; 45(3):414-423.

PMID: 34621032 DOI: 10.1038/s41440-021-00775-2.

Comparison of Candesartan and Angiotensin-(1-7) Combination to Mito-TEMPO Treatment for Normalizing Blood Pressure and Sympathovagal Balance in (mREN2)27 Rats.

Nautiyal M, Shaltout H, Chappell M, Diz D J Cardiovasc Pharmacol. 2018; 73(3):143-148.

PMID: 30540685 PMC: 8427515. DOI: 10.1097/FJC.0000000000000645.

The ACE2/Angiotensin-(1-7)/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7).

Santos R, Sampaio W, Alzamora A, Motta-Santos D, Alenina N, Bader M Physiol Rev. 2018; 98(1):505-553.

PMID: 29351514 PMC: 7203574. DOI: 10.1152/physrev.00023.2016.

Novel role of aminopeptidase-A in angiotensin-(1-7) metabolism post myocardial infarction.

Alghamri M, Morris M, Meszaros J, Elased K, Grobe N Am J Physiol Heart Circ Physiol. 2014; 306(7):H1032-40.

PMID: 24464749 PMC: 3962633. DOI: 10.1152/ajpheart.00911.2013.

References

PATCHETT A, Harris E, Tristram E, Wyvratt M, Wu M, Taub D . A new class of angiotensin-converting enzyme inhibitors. Nature. 1980; 288(5788):280-3. DOI: 10.1038/288280a0. View

Arnold A, Shaltout H, Gallagher P, Diz D . Leptin impairs cardiovagal baroreflex function at the level of the solitary tract nucleus. Hypertension. 2009; 54(5):1001-8. PMC: 2789663. DOI: 10.1161/HYPERTENSIONAHA.109.138065. View

Dobruch J, Paczwa P, Lon S, Khosla M, Szczepanska-Sadowska E . Hypotensive function of the brain angiotensin-(1-7) in Sprague Dawley and renin transgenic rats. J Physiol Pharmacol. 2003; 54(3):371-81. View

Diz D, Garcia-Espinosa M, Gegick S, Tommasi E, Ferrario C, Tallant E . Injections of angiotensin-converting enzyme 2 inhibitor MLN4760 into nucleus tractus solitarii reduce baroreceptor reflex sensitivity for heart rate control in rats. Exp Physiol. 2008; 93(5):694-700. PMC: 2704611. DOI: 10.1113/expphysiol.2007.040261. View

Diz D, Jacobowitz D . Cardiovascular effects of discrete intrahypothalamic and preoptic injections of bradykinin. Brain Res Bull. 1984; 12(4):409-17. DOI: 10.1016/0361-9230(84)90113-8. View

Yamamoto K, Chappell M, Brosnihan K, Ferrario C . In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. Hypertension. 1992; 19(6 Pt 2):692-6. DOI: 10.1161/01.hyp.19.6.692. View

Gallagher P, Ferrario C, Tallant E . MAP kinase/phosphatase pathway mediates the regulation of ACE2 by angiotensin peptides. Am J Physiol Cell Physiol. 2008; 295(5):C1169-74. PMC: 2585001. DOI: 10.1152/ajpcell.00145.2008. View

Arnold A, Sakima A, Ganten D, Ferrario C, Diz D . Modulation of reflex function by endogenous angiotensins in older transgenic rats with low glial angiotensinogen. Hypertension. 2008; 51(5):1326-31. PMC: 2483961. DOI: 10.1161/HYPERTENSIONAHA.107.106005. View

Sakima A, Averill D, Kasper S, Jackson L, Ganten D, Ferrario C . Baroreceptor reflex regulation in anesthetized transgenic rats with low glia-derived angiotensinogen. Am J Physiol Heart Circ Physiol. 2006; 292(3):H1412-9. DOI: 10.1152/ajpheart.00984.2006. View

10.

Caligiorne S, Santos R, Campagnole-Santos M . Cardiovascular effects produced by bradykinin microinjection into the nucleus tractus solitarii of anesthetized rats. Brain Res. 1996; 720(1-2):183-90. DOI: 10.1016/0006-8993(95)01498-5. View

11.

Paula R, Lima C, Khosla M, Santos R . Angiotensin-(1-7) potentiates the hypotensive effect of bradykinin in conscious rats. Hypertension. 1995; 26(6 Pt 2):1154-9. DOI: 10.1161/01.hyp.26.6.1154. View

12.

Reid I . The use of saralasin to evaluate the function of the brain renin-angiotensin system. Prog Biochem Pharmacol. 1976; 12:117-34. View

13.

Tan P, Killinger S, Horiuchi J, Dampney R . Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1 receptors in the nucleus tractus solitarius. Am J Physiol Regul Integr Comp Physiol. 2007; 293(6):R2267-78. DOI: 10.1152/ajpregu.00267.2007. View

14.

Chappell M . Emerging evidence for a functional angiotensin-converting enzyme 2-angiotensin-(1-7)-MAS receptor axis: more than regulation of blood pressure?. Hypertension. 2007; 50(4):596-9. DOI: 10.1161/HYPERTENSIONAHA.106.076216. View

15.

Kohara K, Brosnihan K, Chappell M, Khosla M, Ferrario C . Angiotensin-(1-7). A member of circulating angiotensin peptides. Hypertension. 1991; 17(2):131-8. DOI: 10.1161/01.hyp.17.2.131. View

16.

Krob H, Vinsant S, Ferrario C, Friedman D . Angiotensin-(1-7) immunoreactivity in the hypothalamus of the (mRen-2d)27 transgenic rat. Brain Res. 1998; 798(1-2):36-45. DOI: 10.1016/s0006-8993(98)00384-9. View

17.

Sakima A, Averill D, Gallagher P, Kasper S, Tommasi E, Ferrario C . Impaired heart rate baroreflex in older rats: role of endogenous angiotensin-(1-7) at the nucleus tractus solitarii. Hypertension. 2005; 46(2):333-40. DOI: 10.1161/01.HYP.0000178157.70142.33. View

18.

Deddish P, Marcic B, Jackman H, Wang H, Skidgel R, Erdos E . N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. Hypertension. 1998; 31(4):912-7. DOI: 10.1161/01.hyp.31.4.912. View

19.

Oliveira M, Fortes Z, Santos R, Kosla M, de Carvalho M . Synergistic effect of angiotensin-(1-7) on bradykinin arteriolar dilation in vivo. Peptides. 1999; 20(10):1195-201. DOI: 10.1016/s0196-9781(99)00123-0. View

20.

Diz D, Garcia-Espinosa M, Gallagher P, Ganten D, Ferrario C, Averill D . Angiotensin-(1-7) and baroreflex function in nucleus tractus solitarii of (mRen2)27 transgenic rats. J Cardiovasc Pharmacol. 2008; 51(6):542-8. PMC: 2676577. DOI: 10.1097/FJC.0b013e3181734a54. View