Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers

Abstract

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO₂) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO₂. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.

Keywords: Endothelin; cerebral haemodynamics; endothelium; human; vasoconstriction.

Figure 1.

Overview of the study design and MR sequences. Subjects received infusions of ET-1 or isotonic saline (placebo) on two separate days in a randomized, double-blind crossover design. Numbers indicate time in minutes relative to the start of infusion (T = 0). Twelve subjects completed both study days. Of these, nine subjects underwent the second post-infusion angiography starting at T = 48. ANGIO: angiography; ASL: arterial spin labelling; C: CMRO₂ sequence; ET-1: endothelin-1; PCM: phase-contrast mapping for global mean CBF measurement; Q: scanning paused for questions about symptoms.

Figure 2.

Locations of the examined segments of the superficial temporal (1), middle meningeal (2), middle cerebral (3), and internal carotid (4) arteries are marked.

Figure 3.

Vital signs (non-invasive systolic, diastolic, and mean arterial blood pressure, and heart rate) during the study. Red lines: ET-1 infusion days, blue lines: placebo infusion days Values are means of all participants. Error bars indicate the 95% confidence intervals of the mean. ET-1: endothelin-1.

Figure 4.

Combined box and dot plots of arterial circumferences of the MCA (mm, left–right average) at baseline, during scan 1 (MRA acquired from T = 16 to T = 33), and during scan 2 (MR angiography acquired from T = 48 to T = 65). (a) ET-1 infusion day and (b) placebo (isotonic saline) infusion day. MCA: middle cerebral artery.