Pre- and postsynaptic alpha-adrenoceptor antagonism by neuroleptics in vivo.
Different types of neuroleptics were studied for pre- and postsynaptic alpha-adrenoceptor antagonism in pithed rats using the blood pressure effect of clonidine as a measure of postsynaptic alpha-adrenoceptor activation and the depression of the heart rate response to electrical stimulation as a measure of presynaptic alpha-adrenoceptor activation. Yohimbine (0.1 mg/kg) was more active at pre- than postsynaptic alpha-adrenoceptors while the reverse was found with prazosin (0.02-5 mg/kg). Phentolamine (1-5 mg/kg) on the other hand was very active at both receptors. Cocaine 1-5 mg/kg had no effect on these responses indicating that noradrenaline uptake inhibition presumably does not interfere with the revaluation of the alpha-adrenoceptor antagonistic effect of the neuroleptics. Melperone, haloperidol, thioridazine and flupenthixol (0.15 mg/kg) were more selective antagonists at postsynaptic alpha-adrenoceptors than prazosin. Clozapine, chlorprothixene showed preferential presynaptic (0.15 mg/kg) were antagonists at both types of receptors. Chlorprothixene showed preferential presynaptic alpha-antagonism of high potency. Chlorprothixene was the only neuroleptic drug which like phentolamine (1-5 mg/kg) gave complete presynaptic alpha-antagonism. These results indicate widely different selectivity of neuroleptics for pre- and postsynaptic alpha-adrenoceptors on peripheral sympathetic nerves. It is suggested that neuroleptics with presynaptic alpha-adrenoceptor antagonism may enhance the activity of Beta-adrenergic systems indirectly both in peripheral organs like the heart, and within the central nervous system.
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D003000:Clonidine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D010646:Phentolamine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D011941:Receptors, Adrenergic / Q000187:drug effects*; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D014150:Antipsychotic Agents; D011941:Receptors, Adrenergic; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D003042:Cocaine; D003000:Clonidine; D011224:Prazosin; D010646:Phentolamine