Attenuation of salt-induced cardiac remodeling and diastolic dysfunction by the GPER agonist G-1 in female mRen2.Lewis rats

PLoS One. 2010 Nov 3;5(11):e15433. doi: 10.1371/journal.pone.0015433.


Introduction: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Pressure / drug effects*
  • Cardiomegaly / etiology
  • Cardiomegaly / metabolism
  • Cardiomegaly / physiopathology
  • Cyclopentanes / pharmacology*
  • Diastole
  • Echocardiography
  • Female
  • Heart / drug effects
  • Heart / physiopathology
  • Hypertension / etiology
  • Hypertension / physiopathology
  • Hypertension / prevention & control*
  • Immunohistochemistry
  • Mice
  • Myocardium / metabolism
  • Myocardium / pathology
  • Quinolines / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Rats, Transgenic
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Renin / genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sodium Chloride, Dietary / administration & dosage


  • 1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone
  • Cyclopentanes
  • Quinolines
  • Receptors, G-Protein-Coupled
  • Ren2 protein, mouse
  • Sodium Chloride, Dietary
  • Renin