The importance of endothelin-1 for vascular function in patients with atherosclerosis and healthy controls

Abstract: Background: Atherosclerosis is associated with endothelial dysfunction, which is an early sign with prognostic implications in patients with coronary artery disease. Atherosclerosis is also associated with enhanced expression of the vasoconstrictor peptide endothelin-1 (ET-1). The enhanced production of ET-1 in atherosclerotic arteries may be related to increased activity of the endothelin converting enzyme (ECE) which converts big ET-1 to ET-1. ET-1 causes vasoconstriction via ETA and ETB receptors located on vascular smooth muscle cells and vasodilatation via ETB receptors on endothelial cells. In vitro studies indicate that ETB receptors are upregulated in atherosclerosis. The purpose of the thesis was to investigate the pathophysiological consequences of this altered ET-system in patients with atherosclerosis. Results, study I: The ETB receptor agonist sarafotoxin 6c evoked significantly larger reduction in forearm blood flow (FBF) in patients with atherosclerosis (n=7) than in age-matched healthy controls (n=6), whereas the non-selective ETA and ETB receptor agonist ET-1 induced a similar vasoconstrictor response in the two groups. These findings suggest an upregulation of vascular smooth muscle ETB receptors in atherosclerosis. Study II: ETB receptor blockade evoked a significant increase in FBF in patients with atherosclerosis (n= 10) whereas a small reduction was observed in age-matched controls (n=10). Combined ETA and ETB receptor antagonism evoked a marked increase in FBF in the patients whereas there was no effect in the controls. ETA receptor blockade alone increased FBF to a similar degree in patients and in controls. These observations suggest an enhanced ET-1-mediated vascular tone in atherosclerotic patients, which at least partly is mediated via the ETB receptors. Study III: Intra-arterial infusion of ET-1 significantly blunted endothelium-dependent vasodilatation (EDV) in young healthy males (n=10). Selective ETA receptor blockade significantly increased in patients with atherosclerosis (n=10), whereas no significant change was observed in healthy age-matched controls (n=9). These observations demonstrate that elevated levels of ET-1 impair EDV. Furthermore, ETA receptor blockade improves EDV in patients with atherosclerosis indicating that ET-1 attenuates EDV via an ETA receptormediated mechanism. Study IV: Big ET-1 evoked a more pronounced reduction in FBF in patients with atherosclerosis (n=9) than in age-matched controls (n=9). The elevation of local venous plasma ET-1 and the net formation of ET-1 during administration of big ET-1 was more pronounced in the patients than in the controls. These findings suggest an increased ECE activity in the patients. Study V: Systemic ETA receptor blockade inhibited the increase in splanchnic and renal vascular resistance induced by ET-1 in healthy men (n=6). ETB receptor blockade alone increased basal splanchnic and renal vascular resistance, and enhanced ET-1- induced vasoconstriction. Plasma ET-1 increased more following ETB receptor blockade as compared to control conditions and following ETA receptor blockade. These findings suggest that ETA receptors mediate the splanchnic and renal vasoconstriction induced by ET-1 in healthy humans. The ETB receptor seems to function as a clearance receptor and may modulate vascular tone by altering the plasma concentration of ET-1. Conclusions: These findings suggest that ET-1 may play an important role in the enhanced vasoconstriction and endothelial dysfunction seen in patients with atherosclerosis. ET receptor blockade may be of therapeutic value by improving blood flow and endothelial function in these patients.