Insulin sensitivity and big ET-1 conversion to ET-1 after ETA- or ETB-receptor blockade in humans.
Cardiovascular diseases are characterized by insulin resistance and elevated endothelin (ET)-1 levels. Furthermore, ET-1 induces insulin resistance. To elucidate this mechanism, six healthy subjects were studied during a hyperinsulinemic euglycemic clamp during infusion of (the ET-1 precursor) big ET-1 alone or after ET(A)- or ET(B)-receptor blockade. Insulin levels rose after big ET-1 with or without the ET(B) antagonist BQ-788 (P < 0.05) but were unchanged after the ET(A) antagonist BQ-123 + big ET-1. Infused glucose divided by insulin fell after big ET-1 with or without BQ-788 (P < 0.05). Insulin and infused glucose divided by insulin values were normalized by ET(A) blockade. Mean arterial blood pressure rose during big ET-1 with or without BQ-788 (P < 0.001) but was unchanged after BQ-123. Skeletal muscle, splanchnic, and renal blood flow responses to big ET-1 were abolished by BQ-123. ET-1 levels rose after big ET-1 (P < 0.01) in a similar way after BQ-123 or BQ-788, despite higher elimination capacity after ET(A) blockade. In conclusion, ET-1-induced reduction in insulin sensitivity and clearance as well as splanchnic and renal vasoconstriction are ET(A) mediated. ET(A)-receptor stimulation seems to inhibit the conversion of big ET-1 to ET-1.
Ahlborg
Gunvor
G
Division of Clinical Physiology, Department of Medical Laboratory Sciences and Technology, Karolinska Institutet, Huddinge University Hospital, SE-141 86 Stockholm, Sweden. gunvor.ahlborg@labtek.ki.se
Lindström
Jonas
J
D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage; D001158:Arteries; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood*; D016232:Endothelins / Q000008:administration & dosage*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006503:Hepatic Veins; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D010100:Oxygen / Q000097:blood; D010456:Peptides, Cyclic / Q000008:administration & dosage; D011498:Protein Precursors / Q000008:administration & dosage*; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000378:metabolism; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology
D000959:Antihypertensive Agents; D001786:Blood Glucose; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010456:Peptides, Cyclic; D011498:Protein Precursors; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D010100:Oxygen