title: Cardiovascular effects of chloroethylclonidine, an irreversible alpha 1B-adrenoceptor antagonist, in the unanesthetized rat: a pharmacological analysis in vivo and in vitro.
abstract: The role of vascular alpha 1B-adrenergic receptors in the regulation of arterial pressure (MAP) and heart rate (HR) was examined by assessing the effect of i.v. chloroethylclonidine (CEC; irreversible alpha 1B antagonist) in unanesthetized, normotensive Long-Evans rats. MAP, HR and the pressor response to i.v. phenylephrine (PE) were monitored for 24 hr after saline or CEC (15 mg/kg and 25 mg/kg) injection. Neither i.v. saline nor CEC affected MAP or HR throughout the course of the study, yet the PE response was maximally inhibited (> 75% at 15 min) by both doses of CEC. The PE response recovered by 2 hr at the 15-mg/kg dose but remained inhibited up to 4 hr at 25 mg/kg. At 24 hr, all cardiovascular parameters returned to control levels. CEC (100 microM, 30 min) produced irreversible blockade of norepinephrine-induced contractions in rat aortic rings; prazosin (10 nM) and sodium thiosulphate (1 mM, a reagent that inactivates aziridinium ions) reversed CEC's inhibitory effect. Precyclized CEC and its hydrolysis product beta-hydroxyethylclonidine (beta-HEC) poorly antagonized aortic alpha 1B-receptors. Ex vivo analysis of aortic rings from saline and CEC-treated rats showed that PE-induced contractions were shifted to the right and maximally depressed in a dose-dependent manner after 24 hr. These results suggest that 1) CEC produces long lasting blockade of alpha 1B-adrenoceptors in vitro and in vivo via formation of an aziridinium ion intermediate and 2) vascular alpha 1B-adrenoceptors are not coupled to the tonic physiological regulation of MAP in the rat.
authors.affiliation: Hoechst-Roussel Pharmaceuticals, Inc., Neuroscience Business Unit, Somerville, New Jersey.
authors.forename: H M
authors.initials: HM
authors.lastname: Vargas
authors.forename: D
authors.initials: D
authors.lastname: Cunningham
authors.forename: L
authors.initials: L
authors.lastname: Zhou
authors.forename: H B
authors.initials: HB
authors.lastname: Hartman
authors.forename: A J
authors.initials: AJ
authors.lastname: Gorman
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; C051731:chlorethylclonidine; D003000:Clonidine