ABSTRACT
PURPOSE: Dexmedetomidine, a full agonist of alpha2B-adrenoceptors, is used for analgesia and sedation in the intensive care units. Dexmedetomidine produces an initial transient hypertension due to the activation of post-junctional alpha2B-adrenoceptors on vascular smooth muscle cells (SMCs). The aims of this in vitro study were to identify mitogen-activated protein kinase (MAPK) isoforms that are primarily involved in full, alpha2B-adrenoceptor agonist, dexmedetomidine-induced contraction of isolated rat aortic SMCs. MATERIALS AND METHODS: Rat thoracic aortic rings without endothelium were isolated and suspended for isometric tension recording. Cumulative dexmedetomidine (10(-9) to 10(-6) M) dose-response curves were generated in the presence or absence of extracellular signal-regulated kinase (ERK) inhibitor PD 98059, p38 MAPK inhibitor SB 203580, c-Jun NH2-terminal kinase (JNK) inhibitor SP 600125, L-type calcium channel blocker (verapamil and nifedipine), and alpha2-adrenoceptor inhibitor atipamezole. Dexmedetomidine-induced phosphorylation of ERK, JNK, and p38 MAPK in rat aortic SMCs was detected using Western blotting. RESULTS: SP 600125 (10(-6) to 10(-5) M) attenuated dexmedetomidine-evoked contraction in a concentration-dependent manner, whereas PD 98059 had no effect on dexmedetomidine-induced contraction. SB 203580 (10(-5) M) attenuated dexmedetomidine-induced contraction. Dexmedetomidine-evoked contractions were both abolished by atipamezole and attenuated by verapamil and nifedipine. Dexmedetomidine induced phosphorylation of JNK and p38 MAPK in rat aortic SMCs, but did not induce phosphorylation of ERK. CONCLUSION: Dexmedetomidine-induced contraction involves a JNK- and p38 MAPK-mediated pathway downstream of alpha2-adrenoceptor stimulation in rat aortic SMCs. In addition, dexmedetomidine-induced contractions are primarily dependent on calcium influx via L-type calcium channels.
Subject(s)
Animals , Male , Rats , Adrenergic alpha-2 Receptor Agonists/pharmacology , Anthracenes/pharmacology , Aorta/cytology , Dexmedetomidine/pharmacology , Enzyme Inhibitors/pharmacology , Extracellular Signal-Regulated MAP Kinases/antagonists & inhibitors , Flavonoids/pharmacology , Imidazoles/pharmacology , JNK Mitogen-Activated Protein Kinases/antagonists & inhibitors , Muscle Contraction , Muscle, Smooth, Vascular/drug effects , Protein Isoforms/antagonists & inhibitors , Pyridines/pharmacology , Rats, Sprague-Dawley , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is a complex multigenic disorder, with significant inheritable elements having important roles relating to environmental factors. Recently, the alpha 2 adrenoceptor (alpha(2)-AR) gene has been reported to be involved in the development of coronary artery disease (CAD). The aim of this study was to investigate the relationships between an insertion/deletion (I/D) in alpha(2B)-AR and CAD in Korean subjects. SUBJECTS AND METHODS: The alpha(2B)-AR I/D polymorphism, which was located in the third intracellular loop of the receptor polypeptide, was examined in 292 patients (M:F=219:73) with CAD and 151 healthy control subjects (M:F=70:81) who visited the Cardiovascular Genome Center in Yonsei Cardiovascular Hospital. RESULTS: In the patient group, 77 men (35.1%) and 26 women (35.6%) had the I/I genotype; 105 men (47.9%) and 39 women (53.4%) a heterozygous genotype and 37 (17.0%) and 8 (11.0%) the D/D genotype. In the controls, 23 men (32.8%) and 29 women (35.8%) had the I/I genotype; 38 (54.3%) and 39 (48.1%) the I/D genotype and 9 (12.9%) and 13 (16.1%) the D/D genotype. There were no differences in the genotype frequencies between the patient and control groups, either in men or women. From a logistical regression analysis, the alpha(2B)-AR genotype was not significantly associated with CAD in our study group. CONCLUSION: The alpha(2B)-AR I/D polymorphism is not a risk factor for CAD in the Korean population.