Cardiovascular and metabolic effects of endothelins in man : an experimental and clinical study

Sammanfattning: Increased plasma concentrations of endothelin-1 (ET-1) and of its propeptide big endothelin-1 have been reported in diseases associated with endothelial dysfunction, cardiovascular remodelling and insulin resistance. In this thesis, we studied the hemodynamic effects of big ET-1 in healthy humans focusing on the mechanisms of the effects (study I-IV). We also investigated whether ET-1 and big ET-1 preserve their vasoactive potency in the presence of end-stage renal failure, since permanently increased plasma levels of ET, which are seen in this condition, do not necessarily imply an increased endothelin activity. In addition, we studied the way in which the hemodialysis procedure and ischemic heart disease affect plasma concentrations of ET-1 and big ET-1 in chronic hemodialysis patients (study V). Finally we studied the effects of ET-1 on insulin sensitivity and the vasoactive interactions between insulin and ET-1 in healthy humans (study VI). We made the following findings: II) Exogenous big ET-1 caused potent and long-lasting cardiovascular effects in healthy humans as demonstrated by an increase in mean arterial blood pressure and a decrease in heart rate, cardiac output and stroke volume and a fall in renal and splanchnic blood flow. Circulating big ET-1 was removed from the circulation in the renal and splanchnic vascular beds and probably also in the vasculature of forearm skeletal muscle with a plasma half-life that was longer than that previously shown for ET-1. The renal and splanchnic extraction of big ET-1 appeared to be accompanied by regional conversion of big ET-1. Big ET-1 itself was demonstrated to be without major intrinsic vasoactivity. The C-terminal big ET-1 (22-3 8) fragment, which is also formed during the conversion of big ET-1 to ET-1, had no intrinsic vasoactive potency or capacity to potentiate the cardiovascular effects of ET-1. II) Circulating ET-1 and big ET-1 preserved their vasoactive potency in end-stage renal failure. Thus, big ET-1 seems to be converted to ET-1 even in the presence of renal insufficiency. The plasma half-lives of both peptides were significantly prolonged compared with those of healthy subjects. Chronic hemodialysis patients with ischemic heart disease had higher plasma concentrations of ET-1 and big ET-1 than hemodialysis patients without this disorder. Hemodialysis lowered plasma levels of ET-1 and big ET-1 whereby high-flux membranes removed big ET-1 more efficiently than low-flux membranes. III) Exogenous ET-1 induced peripheral insulin resistance as demonstrated by a decrease in whole-body and leg glucose uptake without causing any changes in leg blood flow. Furthermore, ET-1 blocked not only the metabolic but also the vasoactive potency of insulin in healthy humans. In summary, we demonstrated that circulating ET-1 and big ET-1 give rise to symtoms commonly noted in cardiovascular diseases which are associated with increased plasma concentrations of ET-1 and big ET-1. Since exogenous ET-1 and big ET-1 were shown to preserve their vasoactive potency in the presence of permanently elevated plasma levels of endogenous ET-1 and big ET-1, we conclude that ET-1 and big ET-1 could conceivably contribute to the genesis of endothelial dysfunction, cardiovascular remodelling and insulin resistance in cardiovascular diseases.