PPARg activation does not affect endothelin activity in non-diabetic patients with hypertension or hypercholesterolemia Umberto Campia a, * , Linda A. Matuskey a , Manfredi Tesauro b , Carmine Cardillo c , Julio A. Panza d a MedStar Cardiovascular Research Network, MedStar Heart Institute,110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA b System Medicine, University of Tor Vergata, Viale Oxford, 81, 00133 Rome, Italy c Internal Medicine, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy d Westchester Medical Center,100 Woods Road, Macy Pavilion, Room 102, Valhalla, NY, USA article info Article history: Received 11 February 2014 Received in revised form 12 March 2014 Accepted 27 March 2014 Available online 5 April 2014 Keywords: Endothelial function Endothelin activity Hypertension Hypercholesterolemia Insulin resistance abstract Objectives: This study tested the hypothesis that pioglitazone reduces endothelin-1 activity in the forearm vasculature in non-diabetic patients with hypertension or hypercholesterolemia and variable degrees of insulin resistance. Methods: We conducted a single center, randomized, double-blind, placebo controlled, cross-over trial in 80 patients with either hypertension or hypercholesterolemia and further classified as insulin-sensitive or insulin-resistant based on a published insulin sensitivity index. Participants received pioglitazone 45 mg daily or matching placebo for eight weeks. The main endpoint was the change in forearm vascular endothelin-1 activity, as assessed by intra-arterial infusion of the endothelin type A receptor blocker BQ- 123, measured at the end of each 8-week treatment period. Results: Pioglitazone lowered plasma insulin (P < 0.001), improved insulin sensitivity (P < 0.001), increased HDL (P < 0.001), and reduced triglycerides (P ¼ 0.003), free fatty acids (P ¼ 0.005), and C- reactive protein (P ¼ 0.001). However, pioglitazone did not affect the vasodilator response to BQ-123 in the whole group (P ¼ 0.618) and in the diagnosis or insulin sensitivity subgroups. Hence, in non-diabetic patients with hypertension or hypercholesterolemia, PPARg activation with pioglitazone does not affect endothelin-1 activity, despite enhancing insulin sensitivity and reducing plasma insulin and C-reactive protein levels. Conclusions: In non-diabetic patients with hypertension or hypercholesterolemia, pioglitazone improves insulin sensitivity, lipid profile, and inflammation but does not affect endothelin activity. Our data suggest that the determinants of endothelin-1 vascular activity in vivo may differ and/or be more complex than those suggested by the results of previous in vitro studies. Ó 2014 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Patients with cardiovascular risk factors have abnormal endo- thelial function, characterized by impaired endothelial nitric oxide (NO)-dependent vasodilation [1,2] and enhanced endothelin-1 (ET- 1)-mediated vasoconstrictor tone [3,4]. These pathways are inter- dependent [5] such that an increased ET-1 activity may negatively affect NO-mediated vascular relaxation [6]. Endothelin-1, the most potent endogenous vasoconstrictor [7], is synthesized by endothelial cells and acts predominantly in autocrine and paracrine fashion [8]. In vitro and animal data sug- gest that ET-1 synthesis and release may be induced by numerous stimuli such as lipoproteins [9,10], thrombin [11], C-reactive protein (CRP) [12], glucose [13], and insulin [14]. Additionally, in support of this laboratory evidence, we have demonstrated that local hyper- insulinemia, induced by direct intra-arterial insulin infusion in the forearm, increases ET-1 activity in healthy humans [15]. Further, insulin resistance (IR), defined as reduced insulin-mediated glucose disposal, and the consequent hyperinsulinemia may significantly affect the normal vascular balance between NO and ET-1 5 in favor of ET-1 synthesis [16,17], thus leading to vasoconstriction and pro- atherosclerotic actions [18,19]. * Corresponding author. Washington Hospital Center,110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA. Tel.: þ1 202 877 7615; fax: þ1 202 877 2180. E-mail addresses: umberto.campia@medstar.net, ucampia@yahoo.com, ucampia@gmail.com (U. Campia). Contents lists available at ScienceDirect Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis http://dx.doi.org/10.1016/j.atherosclerosis.2014.03.035 0021-9150/Ó 2014 Elsevier Ireland Ltd. All rights reserved. Atherosclerosis 234 (2014) 436e440