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

J Clin Invest. 2021 Sep 15;131(18):e149029. doi: 10.1172/JCI149029.


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.

Keywords: Hypertension; Microcirculation; Mouse models; Neuroscience; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amlodipine / therapeutic use
  • Angiotensin II Type 1 Receptor Blockers / administration & dosage
  • Angiotensin II Type 1 Receptor Blockers / therapeutic use
  • Animals
  • Antihypertensive Agents / administration & dosage
  • Antihypertensive Agents / therapeutic use*
  • Cerebral Small Vessel Diseases / drug therapy*
  • Cerebral Small Vessel Diseases / etiology*
  • Cerebral Small Vessel Diseases / physiopathology
  • Cerebrovascular Circulation / drug effects
  • Cerebrovascular Circulation / physiology
  • Dementia, Vascular / drug therapy
  • Dementia, Vascular / etiology
  • Dementia, Vascular / physiopathology
  • Disease Models, Animal
  • Drug Therapy, Combination
  • Eplerenone / administration & dosage
  • Eplerenone / therapeutic use
  • Heart Disease Risk Factors
  • Humans
  • Hyperemia / drug therapy*
  • Hyperemia / physiopathology
  • Hypertension / complications*
  • Hypertension / drug therapy*
  • Losartan / administration & dosage
  • Losartan / therapeutic use
  • Male
  • Mice
  • Microvessels / drug effects
  • Microvessels / physiopathology
  • Potassium Channels, Inwardly Rectifying / drug effects
  • Potassium Channels, Inwardly Rectifying / physiology
  • Renin-Angiotensin System / drug effects
  • Renin-Angiotensin System / physiology


  • Angiotensin II Type 1 Receptor Blockers
  • Antihypertensive Agents
  • Kir2.1 channel
  • Potassium Channels, Inwardly Rectifying
  • Amlodipine
  • Eplerenone
  • Losartan