Long-term lowering of blood pressure levels in the SHR by selective peripheral inhibition of dopamine-ß-hydroxylase with BIA 5-453

Bruno Igreja, Lyndon Wright, Patrício Soares-da-Silva

BIAL – Portela & Cº, S.A, S. Mamede do Coronado, Portugal

BIA 5-453 ((R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride) is a reversible dopamine-ß-hydroxylase (DβH) inhibitor that decreases norepinephrine (NE) levels in sympathetically innervated tissues and slows down the drive of sympathetic nervous system. Its design was intended to act as a reversible inhibitor of peripheral DβH with limited access to the brain (Beliaev A. et al., 2006).

In order to assess the extent of changes in blood pressure resulting from inhibition of DßH, systolic (SBP) and diastolic (DBP) blood pressure and heart rate (HR) were evaluated in male normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) orally administered with BIA 5-453. The WKY and SHR received BIA 5-453 (10 mg/kg/day) for 35 weeks (from 5 to 40 weeks of age) in drinking water and cardiovascular assessments were performed on a weekly basis.

BIA 5-453 significantly reduced SBP (mean decreases of 37 mm Hg, p<0.001) and DBP (mean decreases of 32 mm Hg, p<0.01) in SHR without changes in WKY. The blood pressure lowering effect of BIA 5-453 in the SHR was not accompanied by changes in heart rate; in the WKY, BIA 5-453 also failed to affect heart rate. SBP and DBP in SHRs after 100 mg/kg BIA 5-453 was normalized to levels observed in WKYs. BIA 5-453 (10 mg/kg/day) reduced (p<0.01) to a similar extent the urinary excretion of NE in WKY and SHR. The decrease in NE urinary excretion by BIA 5-453 was accompanied by a significant increase (p<0.001) in the urinary excretion of dopamine in the SHR but not in the WKY. The increases (p<0.001) in the urinary excretion of DOPAC and HVA by BIA 5-453 in the SHR were greater than in the WKY. The administration of BIA 5-453 (10 mg/kg/day) for 35 weeks was found to produce no adverse effects and did not alter bodyweight or food consumption.

It is concluded that BIA 5-453 produces sustained lowering blood pressure effects in the SHR being devoid of reflex tachycardia.

Beliaev A. et al. J. Med. Chem 2006; 49(3): 1191-1197