Endothelin Receptor Antagonism Increases Cerebral Perfusion in Humans

Abstract

Microvascular cerebral perfusion (CP) is critical for adequate oxygenation of neuronal tissue in the brain. However, the mechanisms underlying proper CP regulation in humans have yet to be fully defined. Endothelin is a potent endogenous vasoconstrictor and appears to have a modest role in blood flow regulation in many peripheral vascular beds in healthy individuals. We tested the hypothesis that endothelin receptor antagonism will not influence CP in healthy young adults. Six male subjects (age: 24±4 yrs; BMI: 23±2 kg/m2) participated in the single‐blind study in which endothelin receptor antagonist (Ambrisentan, 10 mg) or placebo was administered orally. Only males participated in the current study due to potential teratogenic effects of Ambrisentan. Resting CP was quantified via 3T MRI using pseudo‐continuous arterial spin labeling (ASL) normalized to gray matter volume approximately 120 minutes following dosing. Blood pressure, heart rate, and end‐tidal CO2 were monitored. Data were analyzed via paired t‐tests and reported as mean±SD. Significance was taken as p≤0.05. Heart rate (57±8 vs. 59±7 bpm), mean arterial pressure (81±7 vs. 79±8 mmHg) and end‐tidal CO2 (34±6 vs. 37±3 mmHg) was not different between placebo and Ambrisentan, respectively (all p>0.05). Compared to placebo, Ambrisentan increased cerebral perfusion (31±3 vs. 34±2 mL/100g/min; p<0.05), representing a 8±5% increase. Regionally, Ambrisentan demonstrated a tendency to increase CP in brain regions supplied by the anterior cerebral circulation (frontal lobe: 36±11 vs. 45±5 mL/100g/min, p=0.05; parietal lobe: 35±10 vs. 43±5 mL/100g/min, p=0.08; temporal lobe: 35±10 vs. 43±6 mL/100g/min, p=0.07; basal ganglia: 35±9 vs. 41±5, p=0.09; cingulate: 39±10 vs. 47±5 mL/100g/min, p=0.08). In contrast, CP in regions supplied by the posterior circulation did not increase to a similar extent (occipital lobe: 37±9 vs. 43±7 mL/100g/min, p=0.13; cerebellum 30±16 vs. 38±6 mL/100g/min, p=0.27). Contrary to our hypothesis, these data suggest endothelin contributes to resting CP by increasing microvascular tone, an effect that may be more pronounced in the anterior brain regions. These preliminary findings contribute to resolving potential mechanisms mediating normal CP in healthy individuals and form the basis of future studies exploring the influence of elevated endothelin signaling in conditions like diabetes or heart failure.Support or Funding InformationADA 1‐16‐ICTS‐099