Role of Endothelin‐1 in Regulating Basal Macrovascular Cerebral Blood Flow: Healthy versus Metabolic Syndrome

Abstract

Endothelin‐1 (ET‐1) is a potent vasoconstrictor that regulates vascular tone by binding to the ETA receptors on vascular smooth muscle. In healthy humans, blockade of ETA receptors increases resting forearm blood flow. ET‐1 appears to contribute to poor outcomes in animal models of cerebral ischemia, but the role of ET‐1 signaling in control of basal cerebral blood flow (CBF) in healthy adults is unknown. Interestingly, ET‐1 is upregulated in insulin resistance (IR) and resting CBF is reduced primarily in the anterior circulation, which may be due to enhanced ET‐1 signaling. We hypothesized: 1) ETA receptor blockade would increase CBF more in adults with IR, but play little to no role in regulating CBF in healthy adults and 2) ETA blockade would increase CBF more in the anterior than posterior circulation. Healthy normal weight adults (Control; n=6; BMI 23±2 kg/m2; age 24±4 yrs) and adults with Metabolic Syndrome (MetSyn; n=4; BMI 34±8 kg/m2; age 25±12 yrs) underwent magnetic resonance imaging (MRI) study visits. A subset of subjects completed a second MRI study visit (Control, n=6; MetSyn, n=2) with ETA blockade (10mg oral Ambrisentan). Phase‐contrast vastly undersampled isotropic projection reconstruction (PCVIPR) MRI was used to quantify total and regional CBF (CBF= blood velocity• artery cross sectional area). CBF in the anterior circulation was represented as the sum of CBF in the left and right internal carotid arteries (ICA) whereas CBF in the posterior circulation was represented by the basilar artery (BA). Total CBF was taken as the sum of flow in the left and right ICAs and BA. Heart rate (HR), mean arterial pressure (MAP), and end‐tidal CO2 (ETCO2) were monitored. Significance was determined using a mixed two‐way ANOVA or one‐way ANOVA and significance was set at p≤0.05. Results are mean±SD. HR, MAP, and ETCO2 were similar between Control and MetSyn (p>0.05) and did not change with Ambrisentan in either group (p>0.05). Resting total CBF was higher in Control compared to MetSyn (Control 704±87 vs. MetSyn 487±44 mL/min, p<0.05). Ambrisentan did not change total CBF (p>0.05). Resting anterior CBF was similar between groups (Control 535±82 vs. MetSyn 460±26 mL/min, p>0.05), and was unchanged by Ambrisentan (p>0.05). Resting posterior CBF was higher in Control compared to MetSyn (Control 168±33 vs. MetSyn 127±18 mL/min, p<0.05) and Ambrisentan increased posterior CBF (main effect of Ambrisentan, p=0.05); however, the absolute and relative change in posterior CBF was similar between groups (%ΔCBF Control 9±15 vs. MetSyn 11±8% p>0.05). IR adults exhibited lower resting total and posterior CBF compared to healthy adults. Contrary to our hypothesis, Ambrisentan did not increase total or anterior CBF in IR. Surprisingly, Ambrisentan increased CBF in the posterior circulation of healthy and IR adults similarly. Therefore, ET‐1 signaling appears to play a role in regulating vascular tone in the posterior region, however, IR adults do not exhibit enhanced sensitivity to ET‐1. A longer duration or increased severity of IR may be needed to alter cerebrovascular responses to ET‐1 signaling.Support or Funding InformationADA1‐16‐ICTS‐099