Endothelin-1 blockade prevents COX2 induction and TXA2 production in the fructose hypertensive rat.
Feeding rats with a high fructose diet results in insulin resistance and hypertension. Fructose-hypertensive rats (FHR) have increased vascular levels of endothelin-1 (ET-1) and thromboxane (TXA2). We have previously shown that chronic treatment with either the dual endothelin receptor blocker, bosentan, or the thromboxane synthase inhibitor, dazmegrel, prevented fructose-induced increases in blood pressure, suggesting that both ET-1 and TXA2 play important roles in the development of hyperinsulinemia/insulin resistance-associated hypertension. In this study, we investigated the potential interrelationship between ET-1 and TXA2 in the development of fructose-induced hypertension in vivo. Male Wistar rats were fed on a high fructose diet for 9 weeks. Either bosentan or dazmegrel treatment (daily by oral gavage) was initiated 3 weeks after the start of fructose feeding for a total duration of 6 weeks. At the end of drug treatment, blood and aorta were collected from each animal. Plasma thromboxane B2 (TXB2), a stable TXA2 metabolite, increased significantly in FHR and was reduced to control level by both chronic bosentan and dazmegrel treatment. Protein expression of cyclooxygenase 2 (COX2) was elevated significantly in FHR aortas and treatment with bosentan and dazmegrel corrected these changes. These results indicate that the actions of ET-1 in the aorta of FHR may be mediated through COX2-derived TXA2. Bosentan may prevent the development of hypertension in fructose-fed rats through inhibition of COX2 induction and subsequently the reduction in plasma TXA2.
Jiang
Jihong
J
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, 2146 East Mall, Vancouver, BC V6T 1Z3, Canada.
Tran
Linda
L
Vasudevan
Harish
H
Xia
Zhengyuan
Z
Yuen
Violet G
VG
McNeill
John H
JH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D000077300:Bosentan; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D005632:Fructose; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017482:Receptors, Thromboxane / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007093:Imidazoles; D007328:Insulin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D005632:Fructose; C039242:dazmegrel; D013929:Thromboxane B2; D013928:Thromboxane A2; D051546:Cyclooxygenase 2; D013930:Thromboxane-A Synthase; D000077300:Bosentan