Investigation of the actions of chloroethylclonidine in rat aorta

1 The interaction between chloroethylclonidine (CEC) and noradrenaline (NA) has been examined at α‐ adrenoceptors mediating contractions of rat aorta. 2 In rat aorta, the competitive antagonist prazosin, over the concentration‐range 0.01–10 μm, produced concentration‐dependent shifts in the contractile potency of NA, so that there was no component of the NA contraction resistant to prazosin. 3 The irreversible α1‐adrenoceptor antagonists, phenoxybenzamine (PBZ) (1–10 μm) and benextramine (10 μm) produced shifts in potency of NA and reduced the maximum response in a concentration‐dependent manner. 4 The irreversible α1‐adrenoceptor antagonist, CEC (100 μm), produced a non‐parallel shift in the NA concentration‐response curve so that low concentrations of NA produced relatively small contractions but relatively high concentrations produced further contractions, so that the maximum response was not significantly reduced. 5 The combination of CEC pretreatment and subsequent prazosin (0.1 μm) produced a parallel shift in the potency of NA. However, prazosin (10 μm) failed to produce any further effect on the response to high concentrations of NA following CEC pretreatment. Hence, a component of the contraction to NA in the presence of CEC was resistant to subsequent prazosin. Likewise, this component was resistant to a combination of prazosin (10 μm) and yohimbine (10 μm). 6 Receptor protection experiments were carried out in which tissues were exposed to NA (100 μm), yohimbine (10 μm) or prazosin (0.1 μm) prior to and during exposure to CEC. Receptor protection with NA, yohimbine or prazosin (0.1 μm), followed by washout prevented the shift in potency of NA produced by CEC. 7 Further experiments examined the effects of prazosin (10 μm) on responses to NA following receptor protection with NA (100 μm), yohimbine (10 μm), prazosin (10 μm), or xylazine (100 μm). In receptor protection studies with NA, subsequent prazosin (10 μm) produced a shift in response to NA following CEC which was not signficantly different from the shift produced by prazosin alone in the absence of receptor protection. In receptor protection studies with prazosin, yohimbine or xylazine, subsequent prazosin (10 μm) produced shifts in the response to NA following CEC which were significantly less than the shift produced by prazosin alone in the absence of receptor protection. 8 It is concluded that CEC has two actions in the rat aorta. Firstly, it behaves as an irreversible α1 adrenoceptor antagonist, reducing the response to low concentrations of NA (up to 10 μm). However, after exposure to CEC, concentrations of NA of 10 μm and above produced contractions resistant to prazosin. This resistant component was still present following receptor protection with α1‐ or α2‐adrenoceptor antagonists, but absent following receptor protection with NA. Hence, the latter response may represent an irreversible agonist interaction between CEC, NA and α‐adrenoceptors which cannot be affected by subsequent competitive antagonism, but which can be prevented by receptor protection with the agonist NA prior to CEC.