title: Cardiovascular effects of nepicastat (RS-25560-197), a novel dopamine beta-hydroxylase inhibitor.
abstract: 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.
authors.affiliation: Neurobiology Unit, Center for Biological Research, Roche Bioscience, Palo Alto, California 94304, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Stanley
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.forename: L G
authors.initials: LG
authors.lastname: Johnson
authors.forename: R L
authors.initials: RL
authors.lastname: Whiting
authors.forename: R M
authors.initials: RM
authors.lastname: Eglen
authors.forename: S S
authors.initials: SS
authors.lastname: Hegde
mesh_terms: D000818:Animals; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004558:Electric Stimulation; D004656:Enalapril / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013871:Thiones / Q000494:pharmacology*; D014439:Tyramine / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D013871:Thiones; D004656:Enalapril; D004299:Dopamine beta-Hydroxylase; C109487:nepicastat; D014439:Tyramine