ABSTRACT
AIMS: Clinical complaints on the first-line of cardiovascular medications make continuous search for new drugs a necessity. This study evaluated the cardiovascular effects and mechanism of 4-[(1-phenyl-1H-pyrazol-4-yl)methyl]1-piperazine carboxylic acid ethyl ester (LQFM008). MAIN METHODS: Normotensive male Wistar or spontaneously hypertensive rats (anesthetized or conscious) were used to evaluate the effect of LQFM008 on the mean arterial pressure (MAP), heart rate (HR), arterial blood flow (ABF), arterial vascular conductance (AVC), baroreflex effectiveness index (BI), systolic blood pressure (SBP), diastolic blood pressure (DBP) and vascular function. KEY FINDINGS: In anesthetized normotensive rats, LQFM008 (7.3, 14.3 or 28.6 µmol/kg, i.v.) reduced MAP (-21.1±2.7; -23.9±4.7 or -32.4±8.3 mmHg, respectively) and AVC (22%, 32% or 38%) in a dose-dependent manner. LQFM008 elicited a temporal reduction in the SBP and DBP without changes to the BI of conscious normotensive rats. In hypertensive rats, LQFM008 (7.3, 14.3 or 28.6 µmol/kg, i.v.) reduced MAP (-2.3±2.6; -29.3±2.7 or -38.4±2.8 mmHg, respectively) and increased HR (1.6±3.7; 15.4±4.9 or 25.5±6.2 bmp, respectively) in a dose-dependent manner. A week of oral administration of LQFM008 47.7 µmol/kg elicited a temporal reduction in SBP of hypertensive rats. Pretreatments with atropine, WAY-100635 or L-NAME blocked the effect of LQFM008. In addition, LQFM008-induced endothelium-dependent vascular relaxation was inhibited by L-NAME. SIGNIFICANCE: Our findings showed hypotensive, antihypertensive and vasorelaxant effects of LQFM008 and suggest the participation of nitric oxide, 5-HT1A and muscarinic receptors.
Subject(s)
Antihypertensive Agents/pharmacology , Aorta/drug effects , Hypertension/drug therapy , Piperazines/pharmacology , Pyrazoles/pharmacology , Administration, Oral , Animals , Aorta/physiopathology , Atropine/pharmacology , Baroreflex/drug effects , Blood Flow Velocity/drug effects , Blood Pressure/drug effects , Heart Rate/drug effects , Hypertension/physiopathology , Male , NG-Nitroarginine Methyl Ester/pharmacology , Pyridines/pharmacology , Rats , Rats, Inbred SHR , Rats, Wistar , Tissue Culture Techniques , Vasodilation/drug effectsABSTRACT
Pimenta pseudocaryophyllus popularly referred to as craveiro is considered as a calming agent in different local preparations. The present study attempted to examine antidepressant-like effect of dichloromethane fraction (DF) and role of monoamine oxidase (MAO), tryptophan, and tyrosine hydroxylase. Based on the research focus, tail suspension (TS), forced swimming (FS), and open field (OF) tests were conducted after oral administration of DF (125, 250, or 500 mg/Kg). Ex vivo assay of MAO was also conducted to evaluate inhibitory effect of DF (250 mg/Kg). Administration of DF elicits antidepressant-like response in the TS and FS. However, DF 500 mg/Kg did not alter mice performance in these models. The data obtained in the OF showed a reduction in total crossing and rearing activity; these effects suggest motor interference in TS and FS performance. Mice pretreatment with p-chlorophenylalanine methyl ester (PCPA) (100 mg/kg, i.p.-serotonin biosynthesis inhibitor) for 4 consecutive days or acute administration of α-methyl-p-tyrosine (AMPT) (100 mg/kg, i.p.-catecholamine synthesis inhibitor) blocked anti-immobility effect of DF in the FS. In ex vivo assay of MAO, DF did not inhibit catabolic activity of MAO. Our findings support antidepressant-like activity of DF and suggest an effect that depends on monoamine biosynthesis.
