Abstract Body: Estrogen loss contributes to the development of heart failure (HF) in women because of the lack of its cardioprotective effect. New intervention using Rho-kinase inhibitor (iROCK) could interfere with ventricular dysfunction progression, and improve the quality of life of women after menopause. iROCK could exert anti-inflammatory and anti-oxidant effects in animal model of HF after estrogen depletion. This work evaluated HF with reduced ejection fraction (HFrEF) in spontaneously hypertensive rats (SHR) submitted to oophorectomy (OVX) after treatment with a novel synthetic iROCK.
Methods. Experimental protocols were approved Animal Care and Use Committee at Universidade Federal do Rio de Janeiro, Brazil. Under anesthesia with ketamine (80 mg/kg, i.p.) and xylazine (15 mg/kg, i.p.), SHR were submitted to OVX and randomly divided in groups treated orally with either vehicle (DMSO) or iROCK (30 mg/kg) during 2 weeks. Transthoracic echocardiography and cardiac catheterization used to obtain hemodynamic parameters after ten weeks of OVX and after oral administration of iROCK.
Results. LV catheterization demonstrated increased systolic pressure of 151.1 ± 13.4 mmHg and recovery to 106.5 ± 3.0 mmHg (P<0.05) after treatment with iROCK. LV end diastolic pressure increased from 9.7 ± 0.6 to 16.4 ± 2.8 in SHR after 10 weeks post-OVX, and iROCK reduced to 6.8 ± 0.7 mmHg (P<0.05). Treatment with iROCK improved LV dysfunction, but did not alter heart rate in SHR submitted to OVX with 211.0 ± 18.5 and 114.2.± 28.8 bpm before and after treatment. Mean arterial pressure decreased from 131.4.± 10.4 to 123.7 ± 14.7 mm Hg (P<0.05), possibly mediated by iROCK-induced vasodilation. HFrEF detected through the reduction of ejection fraction from 70.7 ± 2.5 to 51.5 ± 1.3%, returned to 69.7 ± 3.3% after treatment with iROCK. Ratio of early transmitral flow velocity to mitral annular velocity (E/e') increased from 12.1 ± 1.3 in SHR-Sham to 19.3 ± 0.5 (after OVX), reinforcing LV dysfunction. However, oral treatment with iROCK reduced filling pressure to 17.3 ± 0.6 (P<0.05).
In conclusion, targeting the anti-inflammatory and antioxidant effects resulting from ROCK inhibition attenuates LV dysfunction induced by estrogen depletion in SHR.