Targeting sigma-1 receptor with fluvoxamine ameliorates pressure-overload-induced hypertrophy and dysfunctions.
OBJECTIVE
We here investigated the effect of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy, cardiac functional recovery and defined mechanisms underlying its cardioprotective action.


METHODS
Wistar rats subjected to bilateral ovariectomy (OVX) were treated with abdominal aortic banding between the right and left renal arteries. To confirm the cardioprotective role of Sig-1R stimulation, we treated the rats with Sig-1R agonist (fluvoxamine, 0.5 and 1 mg/kg) orally once a day for 4 weeks after the onset of aortic banding.


RESULTS
Interestingly, the expression of Sig-1R in the left ventricle (LV) decreased significantly 4 weeks after pressure overload (PO)-induced hypertrophy in OVX rats. The fluvoxamine administration significantly attenuated PO-induced myocardial hypertrophy with concomitant increase in the expression of Sig-1R in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV functions. The cardioprotective effect of fluvoxamine was nullified by treatment with Sig-1R antagonist (NE-100; 1 mg/kg). Fluvoxamine treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV.


CONCLUSIONS
We here found, for the first time, the potential role of Sig-1R expression in the heart in attenuating PO-induced hypertrophy in OVX rats. Fluvoxamine treatment protects PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in ovariectomized rats.
Bhuiyan
Md Shenuarin
MS
Tohoku University, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan.
Tagashira
Hideaki
H
Shioda
Norifumi
N
Fukunaga
Kohji
K
D000818:Animals; D000840:Anisoles / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D016666:Fluvoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D010052:Ovariectomy; D011437:Propylamines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D017480:Receptors, sigma / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D015398:Signal Transduction; D015854:Up-Regulation; D000097605:Sigma-1 Receptor
D000840:Anisoles; D002316:Cardiotonic Agents; D016666:Fluvoxamine; D011437:Propylamines; D018009:Receptors, Glycine; D017480:Receptors, sigma; D017367:Selective Serotonin Reuptake Inhibitors; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride