title: Beta-adrenergic responses are significantly enhanced in rat carotid artery with intimal hyperplasia.
abstract: The objective of the present study was to investigate the influence of balloon injury and subsequent neointima formation in the rat carotid artery on the beta-adrenoceptor function. Rat left common carotid artery was subjected to balloon injury with an arterial embolectomy catheter; the contralateral artery was sham-operated. Immediately, and at 2, 8 and 16 weeks post-injury, both the injured and the sham-operated carotid arteries were isolated and mounted in an isometric wire-myograph set-up. Subsequently, concentration-response curves (CRCs) were constructed for the beta-adrenoceptor agonist isoprenaline after precontraction with the thromboxane A2 (TP)-receptor agonist U46619 (30 nM) of the injured and sham-operated artery preparations. To evaluate the involvement of the beta1- and the beta2-adrenoceptor subtypes, CRCs were constructed in the presence of CGP 20712A (0.1 nM, a beta1-adrenoceptor-selective antagonist) and ICI 118,551 (10 nM, a beta2-adrenoceptor-selective antagonist). L-NAME (100 microM) and indomethacine (10 microM) were used to evaluate the influence of nitric oxide (NO) or prostanoids, respectively. Immediately post-injury, isoprenaline-induced vasorelaxation was impaired in the injured carotid artery preparations: Emax=19.6 +/- 2.2% vs. 64.0 +/- 4.6%, injured vs. sham, n=8, P<0.05. However, from 2 weeks post-injury onwards, this response appeared enhanced in the injured preparations: Emax, 2 weeks= 86.4 +/- 2.2% vs. 49.7 +/- 5.7%, injured vs. sham, n=5, P<0.05. In addition, the sensitivity for isoprenaline was increased in these preparations: pD2, 2 weeks=7.48 +/- 0.08 vs. 6.88 +/- 0.10, injured vs. sham, n=5, P<0.05. The beta-adrenoceptor population in both types of preparations consisted mainly of the beta2-adrenoceptor subtype, although at 8 and 16 weeks post-injury, the beta1-adrenoceptor subtype appeared to be present as well in the injured artery preparations. Inhibition of NO synthesis led to significant decreases of beta-adrenoceptor-mediated vasorelaxation both in injured and in sham-operated artery preparations for all time points, except at 16 weeks. Cyclo-oxygenase inhibition had no influence on isoprenaline-induced vasorelaxation in injured and sham-operated preparations. From this, it is concluded that beta-adrenoceptor-mediated vasorelaxation in rat carotid artery is partially NO-dependent and occurs mainly via activation of the beta2-adrenoceptor subtype. Balloon injury and subsequent neointima formation in the rat carotid artery lead initially to an impairment, but subsequently to an enhancement of the beta-adrenoceptor-mediated vasorelaxation. The impairment is attributable to the removal of endothelium, whereas the enhanced beta-adrenoceptor-mediated function may be related to the occurrence of an NO system in the neointimal smooth muscle cells.
authors.affiliation: Department of Pharmacotherapy, Academic Medical Center, University of Amsterdam, The Netherlands. f.j.heijenbrok@int.azg.nl
authors.forename: F J
authors.initials: FJ
authors.lastname: Heijenbrok
authors.forename: M J
authors.initials: MJ
authors.lastname: Mathy
authors.forename: M
authors.initials: M
authors.lastname: Pfaffendorf
authors.forename: P A
authors.initials: PA
authors.lastname: van Zwieten
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D020212:Carotid Artery Injuries / Q000150:complications*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004576:Electromyography; D006965:Hyperplasia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D007093:Imidazoles; D011412:Propanolamines; D009569:Nitric Oxide; C026777:ICI 118551; C049763:CGP 20712A; D007545:Isoproterenol