Telmisartan inhibits vasoconstriction via PPARγ-dependent expression and activation of endothelial nitric oxide synthase.

AIMS

Telmisartan activates peroxisome proliferator-activated receptor-γ (PPARγ) in addition to serving as an angiotensin II type 1 receptor (AT(1)R) blocker. The PPARγ activity of telmisartan on resistance arteries has remained largely unknown. The present study investigated the hypothesis that telmisartan inhibited vascular tension in mouse mesenteric resistance arteries, which was attributed to an increased nitric oxide (NO) production through the PPARγ-dependent augmentation of expression and activity of endothelial nitric oxide synthase (eNOS).

METHODS AND RESULTS

Second-order mesenteric arteries were isolated from male C57BL/6J, eNOS knockout and PPARγ knockout mice and changes in vascular tension were determined by isometric force measurement with a myograph. Expression and activation of relevant proteins were analysed by Western blotting. Real-time NO production was measured by confocal microscopy using the dye DAF. Telmisartan inhibited 9,11-dideoxy-11α,9α-epoxymethanoprostaglandin F(2α) (U46619)- or endothelin-1-induced contractions. An NOS inhibitor, N(G)-nitro-L-arginine methyl ester (l-NAME), or an inhibitor of soluble guanylate cyclase, 1H-[1,2,4]-oxadizolo[4,3-a]quinoxalin-1-one (ODQ), prevented telmisartan-induced inhibition of U46619 contractions. A PPARγ antagonist, GW9662, abolished telmisartan-induced inhibition. Likewise, the PPARγ antagonist rosiglitazone attenuated U46619-induced contractions. The effects of telmisartan and rosiglitazone were prevented by actinomycin-D, a transcription inhibitor. In contrast, losartan, olmesartan, and irbesartan did not inhibit contractions. The inhibition was absent in mesenteric arteries from eNOS knockout or PPARγ knockout mice. Telmisartan augmented eNOS expression, phosphorylation, and NO production, which were reversed by the co-treatment with GW9662.

CONCLUSIONS

The present results suggest that telmisartan-induced inhibition of vasoconstriction in resistance arteries is mediated through a PPARγ-dependent increase in eNOS expression and activity that is unrelated to AT₁R blockade.