Effects of zamicastat treatment in a genetic model of salt-sensitive hypertension and heart failure

• Published in: European journal of pharmacology 2019-01, Vol.842, p.125-132
• Main Authors: Igreja, Bruno, Pires, Nuno M., Wright, Lyndon C., Soares-da-Silva, Patrício
• Format: Article
• Language: English
• Subjects: Animals; Benzopyrans - pharmacology; Benzopyrans - therapeutic use; Blood Pressure - drug effects; Dahl SS rat; Disease Models, Animal; Dose-Response Relationship, Drug; Heart Failure - drug therapy; Heart Failure - genetics; Hypertension - drug therapy; Hypertension - genetics; Hypertension - physiopathology; Imidazoles - pharmacology; Imidazoles - therapeutic use; Inflammation; Male; Rats; Rats, Inbred Dahl; Salt sensitivity; Survival; Sympathetic activity; Zamicastat
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2018.10.030

Hyperactivity of sympathetic nervous system plays an important role in the development and progression of cardiovascular diseases. An approach to mitigate the enhanced sympathetic nervous system drive is restricting the biosynthesis of noradrenaline via inhibition of the enzyme dopamine β-hydroxylase (DβH), that catalyzes the hydroxylation of dopamine to noradrenaline in sympathetic nerves. The aim of the present study was to evaluate the effects of zamicastat, a novel DβH inhibitor that decreases noradrenaline and increases dopamine levels in peripheral sympathetically innervated tissues, on the hemodynamic and cardiometabolic parameters in salt-induced hypertension and heart failure in the Dahl salt-sensitive (SS) rat. Zamicastat (10, 30 and 100 mg/kg body weight) was tested acutely against salt-induced hypertension in the Dahl SS rat. Chronic zamicastat treatment (30 mg/kg/day) was evaluated against salt-induced cardiac hypertrophy and biomarkers of cardiometabolic risk and inflammation in Dahl SS rats and upon the survival rate in aged Dahl SS rats fed a high-salt diet. The reduction in the sympathetic tone attained with zamicastat shaped a dose- and time-dependent effect on blood pressure. Prolonged treatment with zamicastat ameliorated end-organ damage, metabolic syndrome and inflammation hallmarks in hypertensive Dahl SS rats. Survival rate of Dahl SS rats fed a high-salt diet demonstrated that zamicastat increased median survival of Dahl SS rats fed a high-salt diet. The use of DβH inhibitors, like zamicastat, is a promising approach to treat hypertension, heart failure and cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.