Abstract 425: Beneficial Effects of BIA 5-1058 in a Genetic Model of Salt-sensitive Hypertension and Heart Failure

Abstract

Hyperactivity of Sympathetic Nervous System (SNS) is implicated in numerous cardiovascular diseases. One strategy to slow down the SNS drive is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine-β-hydroxylase (DβH), the enzyme that catalyses the conversion of dopamine (DA) to NE in sympathetic nerves. BIA 5-1058 is a new DβH inhibitor that decreases NE and increases DA levels in peripheral sympathetically innervated tissues. It was previously shown that BIA 5-1058 dose-dependently reduces blood pressure (BP) in spontaneously hypertensive rats. The Dahl salt-sensitive (Dahl/SS) rat is known to develop systemic hypertension, over 200 mmHg, due to combined pressure and volume overload, which results in compensated left ventricle (LV) hypertrophy after five to six weeks and cardiac failure with LV dilation and contractile dysfunction after 10 to 12 weeks of high-salt (HS) diet. The aim of the present study was to evaluate the effect of BIA 5-1058 in salt-induced hypertension and heart failure in the Dahl/SS rat. To evaluate the effect of acute BIA 5-1058 treatment on hypertension, six Dahl/SS rats were implanted with telemetry device TA11PA-C40 (DSI) and fed a HS (8% NaCl) diet. Salt-induced hypertensive animals were used to evaluate two different doses (10 and 100 mg/Kg) of BIA 5-1058 on BP. Afterwards, a second cohort of rats were used to evaluate the effect of prolonged BIA 5-1058 treatment (30 mg/Kg/day) on the survival rate of Dahl/SS rats fed a HS diet. The reduction in the sympathetic tone attained by DβH inhibition with BIA 5-1058 showed a dose- and time-dependent effect on systolic (SBP) and diastolic (DBP) blood pressure. The maximum reduction on SBP was -16.1 and -22.9 mmHg for 10 and 100 mg/Kg, respectively. Likewise, the maximum reduction on DBP was -18.8 and -23.3 mmHg for 10 and 100 mg/Kg, respectively. Survival rate of Dahl/SS rats fed a HS diet demonstrated that BIA 5-1058, beyond BP reduction, shows beneficial effects to the heart of Dahl/SS rats fed a HS diet with a significant 19-day increase in median survival. In conclusion, the use of DβH inhibitors, like BIA 5-1058, is a promising approach to treat hypertension, heart failure and others cardiovascular diseases where a reduction in the sympathetic tone has beneficial effects.