The present study was undertaken to investigate vascular function in hypercholesterolemic rabbits and also to characterize the effects of
pioglitazone on it. Rabbits were fed normal, 0.5%
cholesterol chow, or 0.5%
cholesterol chow plus 300 ppm
pioglitazone for 5 or 10 weeks. The tension of isolated renal artery rings was measured isometrically, and morphometric analysis was performed. The
cholesterol chow diet administered for 5 weeks did not affect
acetylcholine-induced relaxation in the renal artery but that for 10 weeks decreased it. The N(G)-nitro-
L-arginine (L-
NOARG)- and
indomethacin-resistant endothelium-dependent relaxation induced by
acetylcholine in the renal artery was enhanced in rabbits receiving the
cholesterol chow for 5 or 10 weeks, as compared to rabbits receiving the control diet, and the percentage of plaque area formation was increased in the renal artery by the
cholesterol chow for 10 weeks.
Pioglitazone normalized them without lowering serum
lipid levels. The resistant parts of
acetylcholine-induced relaxation was significantly inhibited when the renal artery was treated with
charybdotoxin, an inhibitor of large and intermediate conductance Ca(2+)-activated K(+) channels, or N,N-diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF 525a), a
cytochrome P-450 monooxygenase inhibitor. Results indicate that
hypercholesterolemia enhances endothelium-derived hyperpolarizing factor (
EDHF)-mediated relaxation in the rabbit renal artery and pioglitazon normalizes it without lowering serum
lipid levels, and suggest that the maintenance of endothelial function by pioglitazon is related to the mechanisms for its anti-atheromatous activity.