title: Specific endothelin ET(A) receptor antagonism does not modulate insulin-induced hemodynamic effects in the human kidney, eye, or forearm.
abstract: There is evidence that hyperinsulinemia may stimulate endothelin-1 (ET-1) generation or release, which may affect diabetic vascular complications. BQ-123, a specific ET(A) receptor antagonist, was used to investigate if insulin-induced vascular effects are influenced by an acute ET-1 release. Two randomized, placebo-controlled, double-blind, cross-over studies were performed. In protocol 1, 12 healthy subjects received, on separate study days, infusions of BQ-123 (60 microg/min for 30 min) during placebo clamp conditions, BQ-123 during euglycemic hyperinsulinemia (3 mU/kg/min for 390 min), or placebo during euglycemic hyperinsulinemia. Fundus pulsation amplitude (FPA) was measured to assess pulsatile choroidal blood flow, and mean flow velocity (MFV) of the ophtalmic artery was measured by color Doppler imaging. In protocol 2, eight healthy subjects received, on separate study days, intra-arterial infusions of BQ-123 (32 microg/min for 120 min) during placebo or insulin clamp. Forearm blood flow was measured with bilateral plethysmography, expressing the ratio of responses in the intervention arm and in the control arm. Insulin alone increased FPA (+10%, p < 0.001) and forearm blood flow (+19%). BQ-123 increased FPA, MFV, and forearm blood flow ratio in the absence and presence of exogenous insulin, but this effect was not different between normo- and hyperinsulinemic conditions. ET-1 plasma concentrations were not affected by insulin. In conclusion, these data do not support the concept that hyperinsulinemia increases ET-1 generation in healthy subjects. Our results, however, cannot necessarily be extrapolated to diabetic and obese subjects.
authors.affiliation: Department of Clinical Pharmacology, Institute of Medical Physics, Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Rab
authors.forename: Susanne
authors.initials: S
authors.lastname: Dallinger
authors.forename: Kaija
authors.initials: K
authors.lastname: Polak
authors.forename: Johannes
authors.initials: J
authors.lastname: Pleiner
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Polska
authors.forename: Michael
authors.initials: M
authors.lastname: Wolzt
authors.forename: Leopold
authors.initials: L
authors.lastname: Schmetterer
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism; D005123:Eye / Q000187:drug effects*; D005542:Forearm / Q000502:physiology*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D012039:Regional Blood Flow / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D007328:Insulin; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)