Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease
Masayo Koide, … , Adam S. Greenstein, Mark T. Nelson
Masayo Koide, … , Adam S. Greenstein, Mark T. Nelson
Published August 5, 2021
Citation Information: J Clin Invest. 2021;131(18):e149029. https://doi.org/10.1172/JCI149029.
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Concise Communication Neuroscience Vascular biology

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease

Abstract

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Authors

Masayo Koide, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Hannah R. Ferris, George C. Wellman, David C. Hill-Eubanks, Adam S. Greenstein, Mark T. Nelson

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Figure 1

Hypertension-related decline in functional hyperemia is prevented by amlodipine but not losartan.

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Hypertension-related decline in functional hyperemia is prevented by aml...
(A) Experimental timelines. (B) Mean arterial pressure (MAP) in anesthetized male BPN and BPH mice at 1, 4, and 8 months of age, with and without treatment with amlodipine (BPH+A, ~10 mg/kg/d) or losartan (BPH+L, ~100 mg/kg/d) starting at 3 months of age. Data are presented as mean ± SEM (n = 5–9 mice/group). ††P < 0.01 vs. BPN at corresponding ages; *P < 0.05, **P < 0.01 between groups; 1-way ANOVA followed by Tukey’s test. (C) Experimental scheme for measurement of whisker stimulation–induced functional hyperemia using laser-Doppler flowmetry (LDF). (D) Functional hyperemic responses, shown as CBF increases during whisker stimulation, in male BPN and BPH mice at 1, 4, and 8 months old, and 8-month-old BPH mice with antihypertensive treatment. (E) Age-dependent progression of functional hyperemia deficits in male BPH mice, with and without antihypertensive treatment. Data are presented as mean ± SEM (n = 5–9 mice/group). ††P < 0.01 vs. BPN at corresponding ages; *P < 0.05 between groups; 1-way ANOVA followed by Tukey’s test. (F) Representative traces showing whisker stimulation–induced functional hyperemia before and after cortical superfusion of Ba2+. aCSF, artificial cerebrospinal fluid. (G) Summary data showing the Ba2+-sensitive component of whisker stimulation–induced functional hyperemia in male BPN and BPH mice, with and without antihypertensive treatment. Data are presented as mean ± SEM (n = 5–9 mice/group). ††P < 0.01 vs. BPN at corresponding ages; **P < 0.01 between groups; 1-way ANOVA followed by Tukey’s test.