Central Sympathoinhibition by Moxonidine Improves Prognosis in Rats with Hypertensive Heart Failure

Aim: Excessive sympathetic activity is associated with pathologies such as hypertension and heart failure (HF) 1. Central sympathetic nervous system activity is an indicator of the prognosis of HF 2. Although the central sympatholytic drug, moxonidine, is an established therapeutic strategy for hypertension 3, its benefits for hypertensive HF are poorly understood. The present study investigated the effects of central sympathoinhibition by moxonidine on hypertensive HF. Methods: As the model of hypertension-induced HF, we fed Dahl salt-sensitive (DS) rats with 8% NaCl diet from the age of 7 weeks 4. Intracerebroventricular (ICV) infusion of moxonidine (Mox-ICV) or vehicle (Veh-ICV) was performed from 14 to 20 week-old, during the increased HF phase. We examined survival first of all, measured systolic blood pressure and heart rate with tail-cuff system and left ventricular (LV) function and remodeling by echocardiography every 2 weeks. And we measured 24-hour urinary norepinephrine excretion (uNE) as an index of sympathetic activity before and after the treatment. We also investigated LV performance by Millar catheter and pathological changes in LV at the end of the treatment. Results: Hypertension and pressure-overload LV hypertrophy were established by 13 week-old. At about 20 weeks of age, DS rats-treated with Veh-ICV experienced overt heart failure associated with sympathetic hyperactivity (Fig. 1). Mox-ICV treatment decreased uNE, suppressed LV dysfunction, remodeling and pathological changes compared with Veh-ICV treatment. Survival at 21weeks of age was significantly improved in DS rats-treated with Mox-ICV compared to Veh-ICV (76 vs. 23 %; p<0.05, n=17 and 28, respectively) (Fig. 2). Conclusion: Moxonidine-induced central sympathoinhibition prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive HF. Central sympathoinhibition can be effective for the treatment of hypertensive HF. References 1 Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens 2010; 23:1052-1060. 2 Francis GS. Neurohumoral activation and progression of heart failure: hypothetical and clinical considerations. J Cardiovasc Pharmacol 1998; 32:S16-S21. 3 Edwards LP, Brown-Bryan TA, McLean L, Ernsberger P. Pharmacological properties of the central antihypertensive agent, moxonidine. Cardiovasc Ther 2012; 30:199-208. 4 Doi R, Masuyama T, Yamamoto K, Doi Y, Mano T, Sakata Y et al. Development of different phenotypes of hypertensive heart failure: systolic versus diastolic failure in Dahl salt-sensitive rats. J Hypertens 2000; 18:111-120. Central sympathoinhibition by moxonidine improves prognosis in rats with hypertensive