G protein-coupled receptor (GPR) 30 is a novel estrogen receptor. Recent studies suggest that activation of the GPR30 confers rapid cardioprotection in isolated rat heart. It is unknown whether chronic activation of GPR30 is beneficial or not for heart failure. In this study we investigated the cardiac effect of sustained activation or inhibition of GPR30. Female Sprague–Dawley rats were divided into 7 groups #2Q1: sham surgery (Sham), bilateral ovariectomy (OVX), OVX+estrogen (E2), OVX+isoproterenol (ISO), OVX+ISO+G-1, OVX+ISO+E2+G15, OVX+ISO+E2. ISO (85 mg/kg×17 day, sc) was given to make the heart failure models. G-1(120 µg/kg·d×14 day) was used to activate GPR30 and G15 (190 µg/kg·d×14 day) was used to inhibit GPR30. Concentration of brain natriuretic peptide in serum, masson staining in isolated heart, contractile function and the expression of β1 and β2- adrenergic receptor (AR) of ventricular myocytes were also determined. Our data showed that ISO treatment led to heart failure in OVX rats. G-1 or E2 treatment decreased concentration of brain natriuretic peptide, reduced cardiac fibrosis, and enhanced contraction of the heart. Combined treatment with β1 (CGP20712A) and β2-AR (ICI118551) antagonist abolished the improvement of myocardial function induced by G-1. We also found that chronic treatment with G-1 normalized the expression of β1-AR and increased the expression of β2-AR. Our results indicate that chronic activation of the GPR30 with its agonist G-1 attenuates heart failure by normalizing the expression of β1-AR and increasing the expression of β2-AR.

After menopause, the development of cardiovascular disease (CVD) is due not only to estrogen decline but also to androgen decline. This study examined the effects of either estradiol (E 2 ) or testosterone replacement alone or E 2 -testosterone combination on isolated myocytes in ovariectomized (Ovx) rats subjected to ischemia/reperfusion (I/R). Furthermore, we determined whether the effects are associated with b 2 -adrenoceptor (b 2 -AR). Five groups of adult female Sprague-Dawley rats were used: Sham operation (Sham) rats, bilateral Ovx rats, Ovx rats with E 2 40 mg/kg per day (OvxCE), Ovx rats with testosterone 150 mg/kg per day (OvxCT), and Ovx rats with E 2 40 mg/kg per dayC testosterone 150 mg/kg per day (OvxCE/T). We determined the lactate dehydrogenase (LDH) release, percentage of rod-shaped cells and apoptosis of ventricular myocytes from rats of all groups subjected to I/R. Then, we determined the above indices and contractile function with or without a selective b 2 -AR antagonist ICI 118 551. We also determined the expression of b 2 -AR. Our data show that either E 2 or testosterone replacement alone or E 2 and testosterone in combination decreased the LDH release, increased the percentage of rod-shaped cells, reduced apoptotic cells (%), and combination treatment appeared to be more effective than either E 2 or testosterone replacement alone. ICI 118 551 abolished the effects of the three. Combination supplementation also enhanced the expression of b 2 -AR. We concluded that in Ovx rats, testosterone enhances E 2 's cardioprotection, while E 2 and testosterone in combination was more effective and the protective effects may be associated with b 2 -AR. The study highlights the potential therapeutic application for CVD in postmenopausal women.

Increased plasma catecholamine levels are associated with a high risk of perioperative cardiac events in aged individuals undergoing non-cardiac surgical interventions. Given the different effects of β1-adrenoreceptor (β1AR) and β2-adrenoreceptor (β2AR) stimulation by catecholamine in cardiomyocytes, this study evaluated whether simultaneous inhibition of β1AR and activation of β2AR is better than separate application in reducing the risk of perioperative cardiac events in aged rats undergoing non-cardiac surgery. Male aged Sprague-Dawley (SD) rats were divided into five groups. Normal group received no treatment. Surgery group received an abdominal surgery with hypoxia. β1- group, β2+ group, β2+ group and β1+β2+ group received surgery and hypoxia with metoprolol (100 mg/kg·d), fenoterol (250 μg/kg·d) or both, respectively. The drugs were given three days before surgery with treatment continued through post-surgical day 7. The results showed that simultaneous activation of β2AR with a β2AR agonist and inhibition of β1AR with a selective β1AR blocker normalized myocardial oxygen consumption, decreased myocardial damage, augmented cardiomyocyte survival, improved cardiac function, reduced the incidence of arrhythmia, thus decreasing the occurrence of cardiac events in perioperative aged rats undergoing non-cardiac surgery. The results demonstrated that combined use of β2AR agonist and β1AR blocker achieved better general effects than use of either one alone. Our results provide a new insight into preventing perioperative cardiac events for elderly patients undergoing surgical stress.