rs-79948-197 and 5-methylurapidil

This study was undertaken to identify the alpha-adrenergic receptor type responsible for sympathetically evoked mydriasis in pentobarbital-anesthetized rabbits. Frequency-response curves of pupillary dilation were generated by stimulation of the preganglionic cervical sympathetic nerve (1-64 Hz). Evoked mydriatic responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-0.3 mg/kg), as well as the selective alpha(1)-adrenergic antagonist, prazosin (0.1-1 mg/kg). The alpha(2)-adrenergic antagonist, RS 79948 (0.3 mg/kg, i.v.) was without inhibitory effect, but potentiated the mydriatic response. In addition, the selective alpha(1A)-adrenoceptor antagonist, 5-methylurapidil (0.1-1 mg/kg, i.v.), antagonized the elicited mydriasis in a dose-dependent fashion. Unlike previous observations that prazosin does not block the adrenoceptor in rabbit iris dilator muscle, our results suggest that prazosin is effective in inhibiting neuronally elicited mydriasis in this species, and that alpha(1A)-adrenoceptors appear to mediate the response.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Dose-Response Relationship, Drug; Electric Stimulation; Isoquinolines; Male; Mydriasis; Mydriatics; Naphthyridines; Phenoxybenzamine; Phentolamine; Piperazines; Prazosin; Pupil; Rabbits; Sympathetic Nervous System

In this study, alpha(1)-adrenoceptor subtypes were characterised in rat femoral resistance arteries mounted on a small vessel myograph. A-61603 was found to be more potent than noradrenaline and phenylephrine in these arteries. Brimonidine (UK 14304) could not evoke any contractile responses and the sensitivity to noradrenaline and phenylephrine was not affected by (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948), ruling out the presence of alpha(2)-adrenoceptors. Prazosin, 5-methyl-urapidil and 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB 4101) produced rightward shifts in the sensitivity to noradrenaline, giving pA(2) values of 9.6, 9.4 and 10.4, respectively, in agreement with the presence of alpha(1A)-adrenoceptors. (8-[2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378; 1 microM) produced a small shift in the sensitivity of noradrenaline giving a pK(B) of 7.2. In the presence of 300 nM 5-methyl-urapidil, sensitivity to noradrenaline was not further shifted by 1 microM BMY 7378. Responses to noradrenaline were unaffected by the alpha(1B)-adrenoceptor alkylating agent chloroethylclonidine (1 microM). These results suggest alpha(1A)-adrenoceptors mediate contractile responses to noradrenaline in rat femoral resistance arteries.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-2 Receptor Antagonists; Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Brimonidine Tartrate; Clonidine; Dioxanes; Dose-Response Relationship, Drug; Femoral Artery; Imidazoles; In Vitro Techniques; Isoquinolines; Male; Naphthyridines; Norepinephrine; Phenylephrine; Piperazines; Prazosin; Quinoxalines; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Tetrahydronaphthalenes; Vascular Resistance; Vasoconstriction