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

Can J Physiol Pharmacol. 2007 Mar-Apr;85(3-4):422-9. doi: 10.1139/y06-088.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects
  • Bosentan
  • Cyclooxygenase 2 / metabolism*
  • Endothelin Receptor Antagonists
  • Endothelin-1 / antagonists & inhibitors*
  • Fructose*
  • Hypertension / chemically induced
  • Hypertension / metabolism*
  • Hypertension / 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

Substances

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