Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of
dopamine beta-hydroxylase, which modulates
catecholamine levels (reduces
norepinephrine and elevates
dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of
nepicastat. Acute
oral administration of
nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In
inactin-anesthetized SHRs, the
antihypertensive effects of
nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs,
nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex
tachycardia. Long-term, concurrent administration of
nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of
enalapril (1 mg/kg/day, p.o.) produced greater
antihypertensive effects than those produced by
nepicastat alone. In normal dogs,
nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to
tyramine. These findings suggest that
nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as
hypertension and
congestive heart failure.