Abstract P477: Effect of Zamicastat on Blood Pressure and Heart Rate - Comparison Between Acute and Repeated Dosing in the SHR

Abstract

The sympathetic nervous system (SNS) can alter blood pressure by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for the modulation of sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH), the enzyme that catalyses the conversion of dopamine to NE in sympathetic nerves. Zamicastat is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS. In order to compare the effect of zamicastat on blood pressure and heart rate after acute and repeated dosing in spontaneously hypertensive rats (SHR), male adult SHR were implanted with telemetry devices (TA11PA-C40, DSI). Zamicastat (30 mg/kg p.o.) was given either as a single dose (n=8) or once a day for five days (n=6). On day 1, the maximal effect (E max ) of zamicastat on systolic blood pressure (SBP) was attained 15h after dosing. E max was similar in the acute and repeated dosing groups: -21.1±3.9 and -22.0±8.2 mmHg, respectively. In the acute treatment group, a gradual return of the SBP to the high baseline levels was observed over time. On the other hand, in the repeat dosing group the E max were consistent across the five administrations -22.0±8.2, -25.2±7.9, -22.0±7.5, -20.0±6.0 and -16.1±2.8 mmHg, respectively day 1 to 5. On day 5, after reaching E max a gradual return of SBP to baseline levels was also observed. The effect of zamicastat on diastolic blood pressure was similar with an E max of -18.4±3.5 mmHg in the acute dosing group and -18.8±8.7, -19.2±7.2, -18.2±6.6, -19.6±6.6 and -15.7±4.7 mmHg over the five days of administration in the repeated dosing group. Zamicastat did not affect heart rate under each dosing regimen. In conclusion, there is no tachyphylaxis or sensitization to the cardiovascular effects of zamicastat in this model and blood pressure returns to basal levels after zamicastat treatment discontinuation.