Nicorandil promotes myocardial capillary and arteriolar growth in the failing heart of Dahl salt-sensitive hypertensive rats.
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.
Xu
Jinglan
J
Department of Cardiovascular Genome Science, Nagoya University School of Medicine, Nagoya 466-8550, Japan.
Nagata
Kohzo
K
Obata
Koji
K
Ichihara
Sahoko
S
Izawa
Hideo
H
Noda
Akiko
A
Nagasaka
Tetsuro
T
Iwase
Mitsunori
M
Naoe
Tomoki
T
Murohara
Toyoaki
T
Yokota
Mitsuhiro
M
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001158:Arteries; D002196:Capillaries; D003331:Coronary Vessels / Q000254:growth & development*; D004452:Echocardiography; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000503:physiopathology* / Q000517:prevention & control; D006439:Hemodynamics; D006973:Hypertension / Q000139:chemically induced / Q000150:complications*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D020108:Nicorandil / Q000494:pharmacology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051381:Rats; D020303:Rats, Inbred Dahl; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D012965:Sodium Chloride; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects
D000959:Antihypertensive Agents; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020108:Nicorandil; D012965:Sodium Chloride; D052250:Nitric Oxide Synthase Type III; D040262:Receptors, Vascular Endothelial Growth Factor