Further investigation of the alpha-adrenoceptor-mediated actions of chloroethylclonidine in rat aorta.
We have investigated the interaction between chloroethylclonidine and alpha-adrenoceptors in rat aorta. Chloroethylclonidine has two actions on rat aorta: reduction of the contraction to low concentrations of noradrenaline by alpha1-adrenoceptor antagonism and irreversible partial agonism in combination with high concentrations of noradrenaline. The former antagonist action was found to be more marked in vessels from immature rats (1 month). We have examined further the latter agonist actions in adult rats (3 month). In the absence of chloroethylclonidine, exposure to phenoxybenzamine (10 microM for 15 min) virtually abolished contractions to subsequent noradrenaline. However, when tissues were exposed to chloroethylclonidine (100 microM) for 30 min prior to exposure to phenoxybenzamine, a large contraction was produced by subsequent noradrenaline. Receptor protection with noradrenaline or the alpha2-adrenoceptor antagonists yohimbine or methoxy-idazoxan (all 10 microM), but not the alpha1-adrenoceptor antagonist prazosin (10 microM), significantly reduced the ability of chloroethylclonidine to prevent the actions of phenoxybenzamine against noradrenaline. In ligand binding studies, pre-exposure to chloroethylclonidine (100 microM) for 30 min significantly reduced the maximum binding of [3H]prazosin (Bmax) to alpha1B-adrenoceptors in rat spleen membranes to 21.4 +/- 10.2% (n = 5) and the maximum binding of [3H]yohimbine (Bmax) to alpha2D-adrenoceptors in rat submandibular gland membranes to 34.8 +/- 6.3% (n = 4), as compared to pre-exposure to vehicle. These results suggest that chloroethylclonidine interacts irreversibly with alpha2-adrenoceptors in rat aorta to make contractions to subsequent noradrenaline resistant to alpha-adrenoceptor blockade. Chloroethylclonidine appears to act as a silent irreversible agonist (i.e., an agonist which persists following multiple washout but only produces effects in combination with a classical agonist).
O'Rourke
M
M
Department of Physiology, Royal College of Surgeons in Ireland, Dublin.
Gavin
K
K
Docherty
J R
JR
D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000367:Age Factors; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D003000:Clonidine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000378:metabolism
D058668:Adrenergic alpha-1 Receptor Antagonists; D058647:Adrenergic alpha-2 Receptor Agonists; D000317:Adrenergic alpha-Antagonists; D010643:Phenoxybenzamine; C051731:chlorethylclonidine; D003000:Clonidine; D009638:Norepinephrine