PPARγ activation does not affect endothelin activity in non-diabetic patients with hypertension or hypercholesterolemia.
OBJECTIVE
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.
MedStar Cardiovascular Research Network, MedStar Heart Institute, 110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA. Electronic address: umberto.campia@medstar.net.
Umberto
U
Campia
MedStar Cardiovascular Research Network, MedStar Heart Institute, 110 Irving Street NW, Room NA-1041, Washington, DC 20010, USA.
Linda A
LA
Matuskey
System Medicine, University of Tor Vergata, Viale Oxford, 81, 00133 Rome, Italy.
Manfredi
M
Tesauro
Internal Medicine, Catholic University, Largo A. Gemelli, 8, 00168 Rome, Italy.
Carmine
C
Cardillo
Westchester Medical Center, 100 Woods Road, Macy Pavilion, Room 102, Valhalla, NY, USA.
Julio A
JA
Panza
D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D018592:Cross-Over Studies; D004219:District of Columbia; D004311:Double-Blind Method; D065130:Endothelin A Receptor Antagonists / Q000008:administration & dosage; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005542:Forearm / Q000098:blood supply*; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006973:Hypertension / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008075:Lipoproteins, HDL / Q000097:blood; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism; D010456:Peptides, Cyclic / Q000008:administration & dosage; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
D015415:Biomarkers; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008075:Lipoproteins, HDL; D047495:PPAR gamma; D010456:Peptides, Cyclic; D045162:Thiazolidinediones; D014280:Triglycerides; D002097:C-Reactive Protein; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077205:Pioglitazone
Endothelial function; Endothelin activity; Hypercholesterolemia; Hypertension; Insulin resistance