Nepicastat, a dopamine-beta-hydroxylase inhibitor decreases blood pressure and induces the infiltration of macrophages and B cells in the heart of spontaneous hypertensive rats

Abstract

AbstractNepicastat is a potent dopamine-beta-hydroxylase inhibitor that modulates the sympathetic nervous system by inhibiting the synthesis of norepinephrine. Nepicastat is a potential drug for the treatment of congestive heart failure. We sought to investigate the mechanistic role of Nepicastsat in the heart of Spontaneous Hypertensive Rats (SHR) rats. Here, we investigated if Nepicastat at both acute (7 days) and chronic administration (14 days) decrease blood pressure and echocardiography parameters in SHR rats. SHR 3-4 months male rats were administered either Nepicastsat (30mg/kg, orally), Enalapril (10 mg/kg, orally), or vehicle for 7 days or 14 days. Blood pressure and echocardiography parameters were recorded on day 0, day 3, day 7, and day 14 of drug administration. The animals were sacrificed, and tissues are collected for histology, qRTPCR, and flow cytometry analysis. At both acute and chronic administration, Nepicastat decreased systolic blood pressure and intraventricular septal thickness of SHR rats compared to vehicle groups. The decrease in blood pressure was comparable to Enalapril treated rats. Interestingly, Nepicastat also decreased the infiltrating macrophages and B cells in the hearts of SHR rats. In conclusion, Nepicastsat consistently decreased the systolic blood pressure but increased the macrophages and B cell infiltration in the heart of SHR rats.