Umberto Campia1, Linda A Matuskey2, Manfredi Tesauro3, Carmine Cardillo4, Julio A Panza5. 1. MedStar Cardiovascular Research Network, MedStar Heart Institute, 110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA. Electronic address: umberto.campia@medstar.net. 2. MedStar Cardiovascular Research Network, MedStar Heart Institute, 110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA. 3. System Medicine, University of Tor Vergata, Viale Oxford, 81, 00133 Rome, Italy. 4. Internal Medicine, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy. 5. Westchester Medical Center, 100 Woods Road, Macy Pavilion, Room 102, Valhalla, NY, USA.
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 = 0.003), free fatty acids (P = 0.005), and C-reactive protein (P = 0.001). However, pioglitazone did not affect the vasodilator response to BQ-123 in the whole group (P = 0.618) and in the diagnosis or insulin sensitivity subgroups. Hence, in non-diabetic patients with hypertension or hypercholesterolemia, PPARγ 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.
RCT Entities:
OBJECTIVES: This study tested the hypothesis that pioglitazone reduces endothelin-1 activity in the forearm vasculature in non-diabeticpatients 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 = 0.003), free fatty acids (P = 0.005), and C-reactive protein (P = 0.001). However, pioglitazone did not affect the vasodilator response to BQ-123 in the whole group (P = 0.618) and in the diagnosis or insulin sensitivity subgroups. Hence, in non-diabeticpatients with hypertension or hypercholesterolemia, PPARγ 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-diabeticpatients 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.