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...

Background: Randomised controlled trials have shown diverse results for radial access in patients undergoing primary percutaneous coronary intervention (PPCI). Moreover, it is questionable whether radial access improves outcome in patients with cardiogenic shock undergoing PPCI. We aimed to investigate the outcome according to access site in patients with or without cardiogenic shock, in daily clinical practice.Methods: For the present analysis we included 9,980 patients undergoing PPCI between 2012 and 2018, registered in the multi-centre, nationwide registry on PCI for myocardial infarction (MI). In-hospital mortality, major adverse cardiovascular events (MACE), and net adverse clinical events (NACE) until discharge were compared between 4,498 patients with radial (45%) and 5,482 patients with femoral (55%) access.Results: Radial compared to femoral access was associated with lower in-hospital mortality (3.5% vs. 7.7%; P<0.01). Multivariable logistic regression analysis confirmed reduced in-hospital mortality [odds ratio (OR) 0.57, 95% confidence interval (CI): 0.43 to 0.75]. Furthermore, MACE (OR 0.60, 95% CI: 0.47 to 0.78) as well as NACE (OR 0.59, 95% CI: 0.46 to 0.75) occurred less frequently in patients with radial access.Interaction analysis with cardiogenic shock showed an effect modification, resulting in lower mortality in PCI via radial access in patients without, but no difference in those with cardiogenic shock (OR 1.78, 95% CI: 1.07 to 2.96).Conclusions: Radial access for patients with acute MI undergoing PPCI is associated with improved survival in a large contemporary cohort of daily practice. However, this beneficial effect is restricted to hemodynamically stable patients.