814 ANTIHYPERTENSIVE EFFECT OF BIA 5–1058 A NEW SELECTIVE PERIPHERAL DOPAMINE β-HYDROXYLASE INHIBITOR

Abstract

Background: Sympathetic nervous system tone alters blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is reduction of biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH; EC 1.14.17.1), the enzyme that catalyses the conversion of dopamine (DA) to NE in sympathetic nerves. BIA 5-1058 is a reversible DβH inhibitor that decreases NE levels in peripheral sympathetically innervated tissues, without effect in brain tissues. Methods: In telemetry transmitter implanted SHR single administration of BIA 5-1058 demonstrates dose (3, 30 and 100 mg/Kg) and time dependent blood pressure effects with no significant effect on heart rate (HR) and total activity monitored over 96-hours. Results: The maximum reductions of systolic blood pressure (SBP) were -10.8, -21.1 and -35.2 mmHg for 3, 30 and 100 mg/Kg, respectively and diastolic blood pressure (DBP) were -9.9, -18.4 and -24.8 mmHg, respectively. Antihypertensive effects of BIA 5-1058 (30 mg/Kg) was further evaluated in combination with efficacious doses of well-known antihypertensive drugs, like the ACE inhibitor captopril, the AT1 receptor antagonist losartan, the diuretic hydrochlorothiazide, beta-blocker metoprolol, the alpha-1 receptor antagonist prazosin, and the calcium channel blocker diltiazem. All drugs were administered orally (single dose) in a cross-over design and the effect was monitored for 72 hours. Combination of BIA 5-1058 the tested antihypertensive drugs caused a stronger and prolonged blood pressure decrease than any single compound. Conclusions: In conclusion, peripheral DβH inhibitors can be used, alone or in combination with others antihypertensive drugs, to reduce blood pressure.