抄録
BACKGROUND
Both endothelial cell dysfunction and vessel stiffness is associated with worsening of the prognosis in patients with cardiovascular diseases. In the present study, we investigated the effect of the antifibrotic drug, pirfenidone on vascular tone and whether it restores endothelial function in arteries from diabetic animals.
METHODS
Wild type mice and 18-20 week old normoglycaemic (db/+) and type 2 diabetic (db/db) female and male mice were sacrificed by cervical dislocation. Aorta, coronary and mesenteric small arteries were isolated and mounted in microvascular myographs for isometric tension studies.
RESULTS
In coronary arteries contracted with U46619, pirfenidone induced concentration-dependent relaxations that were reduced by an inhibitor of nitric oxide (NO) synthase, by high extracellular potassium, and blockers of voltage-gated and calcium-activated K channels, XE991, tetraethylammonium, and iberiotoxin. Body weights and blood glucose levels were doubled in male and female db/db versus db/+ mice. In aorta, coronary and mesenteric small arteries from male and female db/db mice, relaxations induced by the endothelium-dependent vasodilator, acetylcholine, were significantly reduced compared to arteries from db/+ mice. In aorta segments pirfenidone and an opener of KV7 channels, flurpirtine enhanced the relaxations induced by acetylcholine. A blocker of KV7 channels, XE991 reduced the effect of both pirfenidone and flurpirtine and further reduced acetylcholine relaxations in aorta. In contrast, in mesenteric small arteries the potentiating effect of pirfenidone was absent despite impaired endothelium-dependent vasodilation to acetylcholine in arteries from diabetic db/db mice.
CONCLUSIONS
The present findings suggest that pirfenidone is a direct vasodilator and that it improves endothelium-dependent vasodilatation by a mechanism involving K channels in large arteries from diabetic animals. Thus, at relevant therapeutic concentrations the antifibrotic drug pirfenidone may restore endothelial function.
