We recently reported decreased σ1 receptor expression in the heart after abdominal aortic stenosis in bilateral ovariectomized rats. Here, we use ovariectomized female rats to investigate the distinct cardioprotective effects of 17β-estradiol (E2) and dehydroepiandrosterone (DHEA) in pressure overload (PO)–induced cardiac dysfunction.
E2 (0.1 mg/kg) and DHEA (30 mg/kg) were administered to rats subcutaneously and orally, respectively, for 14 days starting 2 weeks after aortic banding.
Both E2 and DHEA treatments significantly inhibited PO-induced increases both in heart weight/body weight ratio and lung weight/body weight ratios. Both E2 and DHEA also ameliorated hypertrophy-induced impairment of left ventricular end-diastolic pressure, left ventricular–developed pressure, left ventricular contraction and relaxation (±dp/dt) rates, heart rate, and mean arterial blood pressure. Notably, DHEA but not E2 administration rescued decreased PO-induced σ1 receptor reduction in the heart. Coadministration with N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy) phenyl]-ethylamine monohydrochloride, an σ1 receptor antagonist, inhibited DHEA-induced amelioration of heart dysfunction without altering E2-induced cardioprotection. Mechanistically, both E2 and DHEA treatments significantly restored PO-induced decreases in protein kinase B (Akt) phosphorylation and Akt-mediated endothelial nitric oxide synthase (eNOS) phosphorylation (Ser1179). N,N-Dipropyl-2-[4-methoxy-3-(2-phenylethoxy) phenyl]-ethylamine monohydrochloride treatment totally abolished DHEA-induced Akt and eNOS phosphorylation without altering E2-induced Akt-eNOS activation.
Taken together, these results from an ovariectomized rat model of PO-induced cardiac dysfunction show that DHEA but not E2 elicits a cardioprotective action through σ1 receptor activation. DHEA-induced Akt-eNOS activation through σ1 receptors is probably associated with its cardioprotective activity.
From the Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Received January 5, 2011; revised and accepted April 13, 2011.
Funding/support: This work was supported in part by grants-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan (22390109 to K.F.).
Financial disclosure/conflicts of interest: None reported.
Address correspondence to: Kohji Fukunaga, PhD, Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba, Aoba-ku, Sendai 980-8578, Japan. E-mail: firstname.lastname@example.org