Attenuation of Salt-Induced Cardiac Remodeling and Diastolic Dysfunction by the GPER Agonist G-1 in Female mRen2.Lewis Rats

The G protein-coupled estrogen receptor (GPER) is expressed in various tissues including the heart. Since the mRen2.Lewis strain exhibits salt-dependent hypertension and early diastolic dysfunction, we assessed the effects of the GPER agonist (G-1, 40 nmol/kg/hr for 14 days) or vehicle (VEH, DMSO/EtOH) on cardiac function and structure.Intact female mRen2.Lewis rats were fed a normal salt (0.5% sodium; NS) diet or a high salt (4% sodium; HS) diet for 10 weeks beginning at 5 weeks of age.Prolonged intake of HS in mRen2.Lewis females resulted in significantly increased blood pressure, mildly reduced systolic function, and left ventricular (LV) diastolic compliance (as signified by a reduced E deceleration time and E deceleration slope), increased relative wall thickness, myocyte size, and mid-myocardial interstitial and perivascular fibrosis. G-1 administration attenuated wall thickness and myocyte hypertrophy, with nominal effects on blood pressure, LV systolic function, LV compliance and cardiac fibrosis in the HS group. G-1 treatment significantly increased LV lusitropy [early mitral annular descent (e')] independent of prevailing salt, and improved the e'/a' ratio in HS versus NS rats (P<0.05) as determined by tissue Doppler.Activation of GPER improved myocardial relaxation in the hypertensive female mRen2.Lewis rat and reduced cardiac myocyte hypertrophy and wall thickness in those rats fed a high salt diet. Moreover, these advantageous effects of the GPER agonist on ventricular lusitropy and remodeling do not appear to be associated with overt changes in blood pressure

Cardiac Geometry and Systolic Parameters.

<p>Data are expressed as mean ± SEM. LV mass  =  left ventricular mass; LVEDd  =  left ventricular end-diastolic dimension; LVESd  =  left ventricular end-systolic dimension; RWT  =  relative wall thickness; %FS  =  percent fractional shortening.</p

G1 treatment for two weeks does not affect salt-associated increases in blood pressure.

<p>Tail-cuff systolic blood pressure in conscious female mRen2.Lewis rats fed a normal salt (NS) or high salt (HS) diet over the course of the experiment. Arrow indicates time of pump insertion for 14-day delivery of either G-1 or vehicle (VEH). Values are mean ± SEM; * P<0.05 compared to NS (Salt effect).</p

Heart Rate and Diastolic Parameters.

<p>Data are expressed as mean ± SEM. Emax  =  maximum early transmitral filling velocity; E dec time  =  early-filling deceleration time; E dec slope  =  early-filling deceleration slope; e' =  early mitral annular velocity; E/e'  =  early transmitral filling velocity-to-mitral annular velocity ratio.</p

Sequence of PCR Primers.

<p>S16; GPER, G protein-coupled estrogen receptor; BNP, brain natriuretic peptide.</p

G1 treatment for two weeks does not alter salt-induced increases in collagen deposition.

<p>Quantification of cardiac perivascular collagen content using polarized dark field images. Data represent mean ± SEM. *** P<0.001 (Salt effect).</p