Cardioprotective effect of benidipine on cardiac performance and remodeling in failing rat hearts.
BACKGROUND
We have known that endothelial nitric-oxide synthase (eNOS) and oxidative stress may play a key role in cardiac performance in failing rat hearts. However, the interactions between eNOS or oxidative stress and bradykinin (BK) under treatment of calcium channel blockers (CCBs) remain unknown. To elucidate the mechanism underlying the cardioprotective effect of long-acting dihydropyridine CCBs, we evaluated the effect of benidipine on the BK-eNOS and NAD(P)H oxidase pathway in Dahl salt-sensitive (DS) rats with heart failure.


METHODS
11-week-old DS rats were treated with one of the following drug combinations for 7 weeks until the onset of the failing stage: vehicle, BK B2 receptor antagonist (FR172357 (FR)) alone, hydralazine, benidipine, and benidipine plus FR. The left ventricular end-systolic pressure-volume relationship (ESPVR) (contractility: Ees) was evaluated using a conductance catheter.


RESULTS
Downregulated Ees and per cent of fractional shortening (%FS) assessed by echocardiography and eNOS expression in the failing stage were both significantly increased by using benidipine; this result was not found, however, when using FR alone or hydralazine or benidipine plus FR. Upregulated expression of NAD(P)H oxidase p22phox and p47phox and lectin-like oxidized low-density lipoprotein receptor-1, and downregulated superoxide dismutase-1 (SOD-1) were significantly ameliorated by benidipine, but not by FR alone or by hydralazine or benidipine plus FR. Benidipine effectively inhibited vascular lesion formation and suppressed atrial natriuretic peptide (ANP) and transforming growth factor-beta1 (TGF-beta1), but this was not the case when using FR alone or hydralazine or benidipine plus FR.


CONCLUSIONS
These results suggest that benidipine may be useful for cardioprotective agents in preventing the cardiac dysfunction and remodeling associated with the BK-eNOS and oxidative stress pathway.
Ohno
Tomoyuki
T
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi, Japan.
Kobayashi
Naohiko
N
Yoshida
Kohtaro
K
Fukushima
Hiromichi
H
Matsuoka
Hiroaki
H
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology*; D024042:Collagen Type I / Q000235:genetics; D004095:Dihydropyridines / Q000494:pharmacology*; D015870:Gene Expression / Q000502:physiology; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D006977:Hypertension, Renal / Q000150:complications / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D018995:Myosin Heavy Chains / Q000235:genetics; D019255:NADPH Oxidases / Q000235:genetics; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D020303:Rats, Inbred Dahl; D051127:Scavenger Receptors, Class E / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D051996:Transcription Factor RelA / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology*; D016276:Ventricular Function; D020257:Ventricular Remodeling
D002316:Cardiotonic Agents; D024042:Collagen Type I; D004095:Dihydropyridines; C495136:OLR1 protein, rat; D051127:Scavenger Receptors, Class E; D051996:Transcription Factor RelA; D053773:Transforming Growth Factor beta1; D019010:Vascular Cell Adhesion Molecule-1; D014665:Vasodilator Agents; D018799:Intercellular Adhesion Molecule-1; C061004:benidipine; D009320:Atrial Natriuretic Factor; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; C000606292:Sod1 protein, rat; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D019255:NADPH Oxidases; C515768:Cyba protein, rat; C060505:neutrophil cytosolic factor 1; D018995:Myosin Heavy Chains