Glitazones have blood pressure lowering effects, which are independent of their insulin-sensitizing action. The vascular action of these drugs is not well understood. We have studied the effects of pioglitazone (10-5 M) on endothelial function in microvessels and aorta using the Mulvany myograph. We measured isometric responses of mesenteric resistance vessels and aortic segments obtained from spontaneously hypertensive rats. We found that pioglitazone increased contractile responses to phenylephrine in intact, but not deendothelialized vessels and were markedly diminished by the addition of indomethacin and the sensitivity enhanced by the addition of L-NAME (10-5 M). This suggests that glitazones stimulate the endothelial release of vasoconstrictor prostanoids and NO. Concentration-dependent contractions to L-NAME (10-6-3x10-4 M) were enhanced by both glitazones suggesting that basal NO release may be augmented. Glitazones lowered the sensitivity to acetylcholine. We conclude that glitazones alter vascular function differentially and through endothelium-dependent and -independent mechanisms. These drugs suppress smooth muscle contraction and have a dual action on the endothelium, increasing the production of NO and also of vasoconstrictor prostanoids. Despite the fact that glitazones have pro-relaxing properties, neither the effects of these drugs on the smooth muscle or on endothelial NO release can stop the actions of the endothelial prostanoids, which remarkably enhance phenylephrine-induced contractions.

This work was supported by: National I+D+i Plan from the Spanish Ministry of Science (SAF2005-02157) and Junta de Comunidades de Castilla-La Mancha (06016-00, IE-02-004 and GC-04-005.