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 g/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 g/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 (ϩ10%, p Ͻ 0.001) and forearm blood flow (ϩ19%). 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.It has been reported that plasma endothelin-1 (ET-1) concentrations are significantly increased in some patients with type I (Takahashi et al., 1990) and type II diabetes mellitus (Laurenti et al., 1997), which may contribute to the vascular complications in diabetes. Several studies demonstrated that insulin can stimulate ET-1 release in endothelial cell cultures (Metsä rinne et al., 1994;. In addition, hyperinsulinemia elevates plasma ET-1 levels in rats (Hokanson et al., 1975), suggesting increased production and/or secretion of ET-1. This effect of insulin on circulating ET-1 levels was confirmed in obese patients (Wolpert et al., 1993) and type II diabetic patients but was not seen in healthy subjects during a standard glucose tolerance test (Leyva et al., 1997) or during mild hyperinsulinemia (Metsä rinne et al., 1994).We decided to rechallenge the question of whether insulin may stimulate ET-1 release in healthy subjects for several reasons. On the one hand, studies of the effect of hyperinsulinemia on circulating ET-1 levels may be of limited value since ET-1 is predominantly a paracrine modulator of vascular tone (Webb, 1997). Hence, ET-1 plasma concentrations do not necessarily predict the level of vascular ET-1 activity. Furthermore, ET-1 concentrations are subject to considerable within-subject variability (Jilma et al., 1997). Thus, determination of ET-1 plasma lev...

Hyperinsulinemia augments endothelin-1 protein expression and impairs vasodilation of human skeletal muscle arterioles

“…; Rab et al. ), our study is the first to demonstrate similar effects in LHCs. This paradoxical similarity in FID and ET‐1 response to insulin between LHCs and T2DM subjects suggests either absence of vascular insulin resistance in T2DM or transient development of vascular insulin resistance in LHCs under conditions of acute hyperinsulinemia.…”

Hyperinsulinemia fails to augment ET-1 action in the skeletal muscle vascular bed in vivo in humans

“…These studies unequivocally demonstrate augmented insulin-mediated vasodilation following application of BQ-123, which was not different between groups. An effect of endothelin to limit insulin-stimulated vasodilation has been reported in both animals models (10,22,32,44,45,52) and in insulin-resistant humans (2,25,42). The careful matching of insulin's actions on NO between insulin-sensitive and insulin-resistant subjects before the application of the endothelin antagonist is unique to our study.…”

Interactions of Endothelin and Insulin: Expanding Parameters of Insulin Resistance

“…In contrast, ET-1-induced reductions in insulin sensitivity, and splanchnic and skeletal muscle blood flow were prevented by ET(A) antagonism [70]. In healthy subjects, ET(A) antagonists fail to augment the vasodilation induced by systemic hyperinsulinemia in skeletal muscle vascular beds [153]. Others have reported that ET(A) antagonism revealed insulin-mediated vasodilation which was not evident at baseline [154].…”