title: Sustained high blood pressure reduction with etamicastat, a peripheral selective dopamine β-hydroxylase inhibitor.
abstract: The aim of the present study was to evaluate the influence of chronic inhibition of dopamine ß-hydroxylase by etamicastat on the development of hypertension in the spontaneously hypertensive rat (SHR) and the sustainability of effects on the systolic and diastolic blood pressure in the SHR and the normotensive Wistar-Kyoto rat (WKY). WKY and SHR received etamicastat (10 mg/kg/d) from 5 weeks of age for 35 weeks in drinking water, and cardiovascular assessments were performed on a weekly basis. Etamicastat reduced systolic and diastolic blood pressure when SHRs reached the age of 16 weeks with mean decreases of 37 and 32 mm Hg, respectively, for the subsequent for 24 weeks of treatment, but did not prevent the increase in blood pressure (BP) aged between 5 and 11 week. The BP lowering effect of etamicastat in SHR was reversible on discontinuation and quickly resumed after reinstatement of therapy and was not accompanied by changes in heart rate. Etamicastat affected neither BP nor heart rate in WKY during 36 weeks of treatment. Etamicastat reduced urinary excretion of norepinephrine to a similar extent in WKY and SHR, accompanied by significant increases in urinary dopamine in SHR. Chronic administration of etamicastat did not adversely affected development of animals. Chronic dopamine ß-hydroxylase inhibition with etamicastat effectively decreases BP, although does not prevent the development of hypertension in the SHR.
authors.affiliation: Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Igreja
authors.affiliation: Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal.
authors.forename: Lyndon C
authors.initials: LC
authors.lastname: Wright
authors.affiliation: Department of Research and Development, BIAL-Portela & C(a), S.A., Portugal; Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Portugal; MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal. Electronic address: psoares.silva@bial.com.
authors.forename: Patricio
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001578:Benzopyrans / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000517:prevention & control; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D009638:Norepinephrine / Q000652:urine; D051381:Rats; D011918:Rats, Inbred SHR / Q000652:urine; D011921:Rats, Inbred WKY / Q000652:urine
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D007093:Imidazoles; C509002:etamicastat; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine
keywords: Hypertension; dopamine; norepinephrine; sympathetic nervous system