1-(4-(6-bromobenzo(1-3)dioxol-5-yl)-3a-4-5-9b-tetrahydro-3h-cyclopenta(c)quinolin-8-yl)ethanone and Ventricular-Dysfunction--Left

This study was aimed to clarify differences in how specific agonists of the 3 estrogen receptors (ERs) influence diastolic function and the renin-angiotensin system (RAS) after ovariectomy (OVX) in 24 female spontaneously hypertensive rat (SHR) undergoing bilateral OVX at 12 weeks of age. Eight weeks after surgery, rats were randomized (n = 6/group) to receive equipotent, daily treatments of one of the ER agonists (ERα agonist, propyl pyrazole trisphenol 94 μg/kg; ERβ agonist, diarylpropionitrile 58 μg/kg; G-protein-coupled estrogen receptor [GPER] agonist, G1 100 μg/kg), or vehicle (peanut oil). After 4 weeks of treatment, left ventricular function/structure and systemic/intracardiac pressure measurements were obtained by echocardiography and a fluid-filled catheter attached to a pressure transducer, respectively. Selective ER agonist treatment with G1 or propyl pyrazole trisphenol led to improvements in diastolic function after estrogen loss when compared with vehicle-treated OVX rats. Although mean arterial blood pressure was not overtly different among groups, chronic G1, but not the other ER ligands, enhanced the in vitro vasorelaxant responsiveness to acetylcholine in aortic rings. These favorable effects of G1 were further linked to reductions in cardiac angiotensin-converting enzyme activity, AT1R protein expression, and Ang II immunoreactivity. Activation of ERβ had no effect on cardiac function and did not alter components of the canonical cardiac RAS in comparison with vehicle-treated OVX SHR. These data imply that of the 3 ERs, GPER has a unique role in preserving diastolic function and favorably modulating the cardiac RAS independent of arterial pressure. Specifically, if GPER is pharmacologically activated, it could provide a therapeutic opportunity to limit the development and/or progression of diastolic dysfunction in hypertensive women after estrogen loss.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Cyclopentanes; Diastole; Disease Models, Animal; Estrogens; Female; Hypertension; Myocardium; Ovariectomy; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Quinolines; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction; Ventricular Dysfunction, Left; Ventricular Function, Left

GPR30 is a novel oestrogen receptor expressed in various tissues, including the heart. We determined the role of GPR30 in the maintenance of left ventricular (LV) structure and diastolic function after the surgical loss of ovarian hormones in the female mRen2.Lewis rat, a model emulating the cardiac phenotype of the post-menopausal woman.. Bilateral oophorectomy (OVX) or sham surgery was performed in study rats; the selective GPR30 agonist, G-1 (50 µg/kg/day), or vehicle was given subcutaneously to OVX rats from 13-15 weeks of age. Similar to the cardiac phenotype of sham rats, G-1 preserved diastolic function and structure relative to vehicle-treated OVX littermates independent of changes in blood pressure. G-1 limited the OVX-induced increase in LV filling pressure, LV mass, wall thickness, interstitial collagen deposition, atrial natriuretic factor and brain natriuretic peptide mRNA levels, and cardiac NAD(P)H oxidase 4 (NOX4) expression. In vitro studies showed that G-1 inhibited angiotensin II-induced hypertrophy in H9c2 cardiomyocytes, evidenced by reductions in cell size, protein content per cell, and atrial natriuretic factor mRNA levels. The GPR30 antagonist, G15, inhibited the protective effects of both oestradiol and G-1 on this hypertrophy.. These data show that the GPR30 agonist G-1 mitigates the adverse effects of oestrogen loss on LV remodelling and the development of diastolic dysfunction in the study rats. This expands our knowledge of the sex-specific mechanisms underlying diastolic dysfunction and provides a potential therapeutic target for reducing the progression of this cardiovascular disease process in post-menopausal women.

Topics: Angiotensin II; Animals; Atrial Natriuretic Factor; Blood Pressure; Calcium; Cardiotonic Agents; Cell Line; Collagen; Cyclopentanes; Echocardiography, Doppler; Estrogens; Female; Gene Expression Regulation; Genotype; Hypertrophy, Left Ventricular; Injections, Subcutaneous; Mice; Myocytes, Cardiac; NADPH Oxidase 4; NADPH Oxidases; Natriuretic Peptide, Brain; Ovariectomy; Phenotype; Quinolines; Rats; Rats, Inbred Lew; Rats, Transgenic; Receptors, G-Protein-Coupled; Renin; RNA, Messenger; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Ventricular Remodeling