Endothelin-1 blockade prevents COX2 induction and TXA2 production in the fructose hypertensive rat.

Abstract

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.

• Authors: Jihong Jiang, Linda Tran, Harish Vasudevan, Zhengyuan Xia, Violet G Yuen, John H McNeill
• Journal: Canadian journal of physiology and pharmacology (Can J Physiol Pharmacol) 2007 Mar-Apr Vol. 85 Issue 3-4 Pg. 422-9 ISSN: 0008-4212 [Print] Canada
• PMID: 17612651 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Endothelin Receptor Antagonists
• Endothelin-1
• Imidazoles
• Insulin
• Receptors, Thromboxane
• Sulfonamides
• Fructose
• dazmegrel
• Thromboxane B2
• Thromboxane A2
• Cyclooxygenase 2
• Thromboxane-A Synthase
• Bosentan

Topics

• Animals
• Blood Pressure (drug effects)
• Bosentan
• Cyclooxygenase 2 (metabolism)
• Endothelin Receptor Antagonists
• Endothelin-1 (antagonists & inhibitors)
• Fructose
• Hypertension (chemically induced, metabolism, physiopathology)
• Imidazoles (pharmacology)
• Insulin (blood)
• Male
• Rats
• Rats, Wistar
• Receptors, Thromboxane (metabolism)
• Sulfonamides (pharmacology)
• Thromboxane A2 (metabolism)
• Thromboxane B2 (blood)
• Thromboxane-A Synthase (antagonists & inhibitors)