title: Blood pressure-decreasing effect of etamicastat alone and in combination with antihypertensive drugs in the spontaneously hypertensive rat.
abstract: Hyperactivation of the sympathetic nervous system has an important role in the development and progression of arterial hypertension. This study evaluated the efficacy of etamicastat, a dopamine-β-hydroxylase (DβH) inhibitor, in controlling high blood pressure in the spontaneously hypertensive rat (SHR), either alone or in combination with other classes of antihypertensives. SHRs were administered with etamicastat by gavage, and its pharmacodynamic and pharmacokinetic properties were evaluated. Etamicastat induced a time-dependent decrease in noradrenaline-to-dopamine ratios in the heart and kidney, and had no effect on catecholamine levels in the frontal cortex of SHRs. Cardiovascular pharmacodynamic effects following administration of etamicastat alone or in combination with other classes of antihypertensive drugs were assessed by telemetry. Etamicastat was evaluated in combination with captopril, losartan, hydrochlorothiazide, metoprolol, prazosin and/or diltiazem. Etamicastat monotherapy induced a dose-dependent reduction in blood pressure without reflex tachycardia. Combination therapy amplified the antihypertensive effects of all tested drugs. In conclusion, inhibition of peripheral DβH with etamicastat, as a monotherapy or combination therapy, may constitute a valid alternative treatment for high blood pressure.
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Bruno
authors.initials: B
authors.lastname: Igreja
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Nuno Miguel
authors.initials: NM
authors.lastname: Pires
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Bonifácio
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Loureiro
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernandes-Lopes
authors.affiliation: Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal.
authors.forename: Lyndon Christopher
authors.initials: LC
authors.lastname: Wright
authors.affiliation: 1] Department of Research and Development, BIAL-Portela & Cª, S.A., S. Mamede do Coronado, Portugal [2] Department of Pharmacology and Therapeutics, Faculty of Medicine, University Porto, Porto, Portugal [3] MedInUP-Center for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal.
authors.forename: Patrício
authors.initials: P
authors.lastname: Soares-da-Silva
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001578:Benzopyrans / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects*; D002395:Catecholamines / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006973:Hypertension / Q000097:blood / Q000188:drug therapy*; D007093:Imidazoles / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects; D008297:Male; D011918:Rats, Inbred SHR
chemical_list: D000959:Antihypertensive Agents; D001578:Benzopyrans; D002395:Catecholamines; D007093:Imidazoles; C509002:etamicastat