Long-term administration of
vasodilators increases shear stress, which is thought to be important for vascular growth in the heart.
Nicorandil, an activator of
ATP-sensitive potassium channels with a
nitrate-like action, is a potent
vasodilator. We have now investigated the effects of
nicorandil on vascular growth and gene expression in the failing heart of Dahl
salt-sensitive (DS) hypertensive rats. DS rats fed a high-
salt diet from 6 weeks of age develop concentric
cardiac hypertrophy secondary to
hypertension at 11 weeks, followed by
heart failure at 18 weeks. DS rats on such a diet were treated with a nonantihypertensive oral dose of
nicorandil (6 mg/kg per day) or vehicle from 11 to 18 weeks of age. Treatment of DS rats with
nicorandil improved cardiac function and attenuated the development of
heart failure. Myocardial capillary and arteriolar densities did not differ between vehicle-treated DS rats and age-matched controls. The abundance of mRNAs for endothelial
NO synthase (eNOS),
vascular endothelial growth factor (
VEGF), the
VEGF receptor Flt-1, and
basic fibroblast growth factor (bFGF) in the myocardium was markedly reduced in vehicle-treated DS rats compared with controls. Treatment of DS rats with
nicorandil greatly increased capillary and arteriolar densities and inhibited the downregulation of eNOS,
VEGF, fms-like tyrosin kinase-1, and bFGF gene expression. This,
nicorandil stimulates coronary capillary and arteriolar growth and thereby likely suppresses the development of
heart failure in DS rats.
Nicorandil may prove beneficial for the treatment of hypertensive
heart failure as well as of
ischemic heart disease.