Effect of atorvastatin on endothelium-dependent constrictor factors in dyslipidemic rabbits

Gen Pharmacol. 2000 Apr;34(4):263-72. doi: 10.1016/s0306-3623(00)00074-4.

Abstract

Relaxations to acetylcholine and contractions to acetylcholine in the presence of the nitric oxide (NO) synthesis inhibitor (L-N(G)-nitroarginine methyl ester, L-NAME) were studied in aortic rings from rabbits fed either a control or a diet containing 0.5% cholesterol+14% coconut oil for 14 weeks and treated or not with atorvastatin (2.5 mg kg(-1) day(-1)). Rings were incubated with the endothelin (ET(A)) receptor antagonist BQ123, and/or the thromboxane A(2) (TXA(2))/prostaglandin H(2) (PGH(2)) receptor antagonist ifetroban. In rabbits, high cholesterol and triglyceride plasma levels were associated with intimal thickening and blunted acetylcholine-relaxation as compared with controls. By contrast, acetylcholine+L-NAME response was higher. Incubation with either ifetroban or BQ123 increased acetylcholine-relaxation in both diet groups and it reduced the constrictor response only in dyslipidemic rabbits. Removal of endothelium reduced acetylcholine+L-NAME contraction in dyslipidemic rabbits, although increased it in control animals. Atorvastatin treatment reduced plasma lipid levels and lesion size in dyslipidemic animals. Likewise, it prevented acetylcholine-relaxation reduction. In addition, atorvastatin reduced constrictor response in dyslipidemic rabbits but only in rings with endothelium. Incubation with either ifetroban or BQ123 did not further modify these responses in atorvastatin-treated animals in any group. These data suggest that ET and TXA(2) availabilities seem to participate in the endothelial dysfunction associated with dyslipidemia. Atorvastatin treatment reduces intimal thickening and improves endothelial dysfunction in rabbits. This effect seems to be a consequence of its ability to act on ET and TXA(2) systems.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticholesteremic Agents / pharmacology
  • Aorta / drug effects
  • Aorta / physiopathology
  • Atorvastatin
  • Drug Interactions
  • Endothelins / drug effects
  • Endothelins / metabolism*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology
  • Enzyme Inhibitors / pharmacology
  • Heptanoic Acids / pharmacology*
  • Hyperlipidemias / metabolism*
  • Hyperlipidemias / physiopathology
  • Male
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Pyrroles / pharmacology*
  • Rabbits
  • Receptor, Endothelin A
  • Receptors, Endothelin / agonists
  • Receptors, Prostaglandin / agonists
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Vasoconstriction / drug effects*

Substances

  • Anticholesteremic Agents
  • Endothelins
  • Enzyme Inhibitors
  • Heptanoic Acids
  • Pyrroles
  • Receptor, Endothelin A
  • Receptors, Endothelin
  • Receptors, Prostaglandin
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Atorvastatin
  • NG-Nitroarginine Methyl Ester