Losartan Attenuates Sex-dependent Hypertension, Neuroinflammation, and Cognitive Impairment in the Aging Male Sprague-dawley Rat

Overview

Journal Geroscience

Specialty Geriatrics

Date 2024 Dec 3

PMID 39627570

Authors

Kayla M Nist

Hannah Bard

Brannon McBride

Angela L Capriglione

Jesse D Moreira

David H Farb

Richard D Wainford

Affiliations

Soon will be listed here.

Abstract

The prevalence of hypertension increases with age and is the leading modifiable risk factor for cognitive impairment and dementia. At present, the neural mechanisms promoting hypertension across the lifespan are incompletely understood. Using the Sprague-Dawley (SD) rat as a model of normal aging, we hypothesized (1) blood brain barrier (BBB) disruption and neuroinflammation in the paraventricular nucleus (PVN) of the hypothalamus enhances sympathetic tone and contributes to age-dependent hypertension, (2) age-dependent hypertension is associated with cognitive impairment, and (3) lowering blood pressure in aged rats with established hypertension improves cognitive function. We found male, but not female, rats develop age-dependent hypertension with enhanced sympathetic tone, BBB disruption, and neuroinflammation in the PVN. Aged hypertensive male rats also showed impairments in recognition and spatial memory. Utilizing pharmacological interventions, blood pressure was lowered in male rats with established hypertension using either losartan (LOS) or hydrochlorothiazide. However, only losartan improved recognition memory. Further, LOS reduced BBB disruption, microglial activation, astrocyte reactivity, and proinflammatory cytokine expression in the PVN which we speculate contributes to a decrease in blood pressure. These data show SD rats develop age-dependent hypertension and cognitive impairment in a sex-dependent manner. However, not all antihypertensive agents improve cognitive function equally as only losartan, an angiotensin II type 1 receptor antagonist (AT1R) improved recognition memory. Thus, AT1R antagonists represent a potential therapeutic approach for treating cognitive decline in the aging population.

References

Whelton P, Carey R, Aronow W, Casey Jr D, Collins K, Himmelfarb C . 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on.... Hypertension. 2017; 71(6):e13-e115. DOI: 10.1161/HYP.0000000000000065. View

Wassertheil-Smoller S, Anderson G, Psaty B, Black H, Manson J, Wong N . Hypertension and its treatment in postmenopausal women: baseline data from the Women's Health Initiative. Hypertension. 2000; 36(5):780-9. DOI: 10.1161/01.hyp.36.5.780. View

Gorelick P, Scuteri A, Black S, DeCarli C, Greenberg S, Iadecola C . Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the american heart association/american stroke association. Stroke. 2011; 42(9):2672-713. PMC: 3778669. DOI: 10.1161/STR.0b013e3182299496. View

Frame A, Nist K, Kim K, Puleo F, Moreira J, Swaldi H . Integrated renal and sympathetic mechanisms underlying the development of sex- and age-dependent hypertension and the salt sensitivity of blood pressure. Geroscience. 2024; 46(6):6435-6458. PMC: 11494650. DOI: 10.1007/s11357-024-01266-1. View

Esler M, Hastings J, Lambert G, Kaye D, Jennings G, Seals D . The influence of aging on the human sympathetic nervous system and brain norepinephrine turnover. Am J Physiol Regul Integr Comp Physiol. 2002; 282(3):R909-16. DOI: 10.1152/ajpregu.00335.2001. View

Dampney R, Michelini L, Li D, Pan H . Regulation of sympathetic vasomotor activity by the hypothalamic paraventricular nucleus in normotensive and hypertensive states. Am J Physiol Heart Circ Physiol. 2018; 315(5):H1200-H1214. PMC: 6297824. DOI: 10.1152/ajpheart.00216.2018. View

Biancardi V, Son S, Ahmadi S, Filosa J, Stern J . Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood-brain barrier. Hypertension. 2013; 63(3):572-9. PMC: 4080808. DOI: 10.1161/HYPERTENSIONAHA.113.01743. View

Santisteban M, Ahmari N, Carvajal J, Zingler M, Qi Y, Kim S . Involvement of bone marrow cells and neuroinflammation in hypertension. Circ Res. 2015; 117(2):178-91. PMC: 4490954. DOI: 10.1161/CIRCRESAHA.117.305853. View

Shi P, Diez-Freire C, Jun J, Qi Y, Katovich M, Li Q . Brain microglial cytokines in neurogenic hypertension. Hypertension. 2010; 56(2):297-303. PMC: 2929640. DOI: 10.1161/HYPERTENSIONAHA.110.150409. View

10.

Moreira J, Chaudhary P, Frame A, Puleo F, Nist K, Abkin E . Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi protein-dependent, salt-sensitive hypertension. Exp Physiol. 2019; 104(12):1892-1910. PMC: 6884700. DOI: 10.1113/EP087924. View

11.

Knecht S, Wersching H, Lohmann H, Bruchmann M, Duning T, Dziewas R . High-normal blood pressure is associated with poor cognitive performance. Hypertension. 2008; 51(3):663-8. DOI: 10.1161/HYPERTENSIONAHA.107.105577. View

12.

Gottesman R, Schneider A, Albert M, Alonso A, Bandeen-Roche K, Coker L . Midlife hypertension and 20-year cognitive change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol. 2014; 71(10):1218-27. PMC: 4226067. DOI: 10.1001/jamaneurol.2014.1646. View

13.

Suvila K, Lima J, Yano Y, Tan Z, Cheng S, Niiranen T . Early-but Not Late-Onset Hypertension Is Related to Midlife Cognitive Function. Hypertension. 2021; 77(3):972-979. PMC: 7878356. DOI: 10.1161/HYPERTENSIONAHA.120.16556. View

14.

Yaffe K, Bahorik A, Hoang T, Forrester S, Jacobs Jr D, Lewis C . Cardiovascular risk factors and accelerated cognitive decline in midlife: The CARDIA Study. Neurology. 2020; 95(7):e839-e846. PMC: 7605504. DOI: 10.1212/WNL.0000000000010078. View

15.

Faraco G, Sugiyama Y, Lane D, Garcia-Bonilla L, Chang H, Santisteban M . Perivascular macrophages mediate the neurovascular and cognitive dysfunction associated with hypertension. J Clin Invest. 2016; 126(12):4674-4689. PMC: 5127678. DOI: 10.1172/JCI86950. View

16.

Pelisch N, Hosomi N, Ueno M, Nakano D, Hitomi H, Mogi M . Blockade of AT1 receptors protects the blood-brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats. Am J Hypertens. 2010; 24(3):362-8. PMC: 3040273. DOI: 10.1038/ajh.2010.241. View

17.

Walsh K, Kuwabara J, Shim J, Wainford R . Norepinephrine-evoked salt-sensitive hypertension requires impaired renal sodium chloride cotransporter activity in Sprague-Dawley rats. Am J Physiol Regul Integr Comp Physiol. 2015; 310(2):R115-24. PMC: 4796647. DOI: 10.1152/ajpregu.00514.2014. View

18.

Gumerlock M, Neuwelt E . The effects of anesthesia on osmotic blood-brain barrier disruption. Neurosurgery. 1990; 26(2):268-77. DOI: 10.1097/00006123-199002000-00014. View

19.

Antunes M, Biala G . The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2011; 13(2):93-110. PMC: 3332351. DOI: 10.1007/s10339-011-0430-z. View

20.

Fuentes-Santamaria V, Alvarado J, Lopez-Munoz D, Melgar-Rojas P, Gabaldon-Ull M, Juiz J . Glia-related mechanisms in the anteroventral cochlear nucleus of the adult rat in response to unilateral conductive hearing loss. Front Neurosci. 2014; 8:319. PMC: 4195288. DOI: 10.3389/fnins.2014.00319. View