Functional characterization of α1-adrenoceptor subtypes in the rabbit spleen
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Phenylephrine and (±)N-[5-(4,5-dihydro-1-H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl] methanesulphonamide hydrobromide (A 61603) evoked concentration-dependent contractions of the rabbit spleen. These contractions were antagonized by prazosin (10–8–10–7 M) with pA 2 values of 8.34±0.11 and 8.15±0.10 against phenylephrine and A 61603, respectively. In both cases, the slopes of the Schild plots were not significantly (P>0.05) different from 1.0, indicating competitive antagonism. The effects of subtype-selective antagonists WB 4101 [2-(2-6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane hydrochloride] and 5-methylurapidil on agonist-induced contractions were also examined. WB 4101 competitively antagonized agonist-induced contractions; pA 2 values were 8.13±0.10 and 8.10±0.03 against phenylephrine and A 61603, respectively. Corresponding values for 5-methylurapidil were 8.28±0.17 and 7.93±0.02 against phenylephrine and A 61603, respectively. Tamsulosin and Rec 15/2739 [(8-3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylcarbamoyl)-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran dihydrochloride] also antagonized phenylephrine- and A 61603-induced contractions with pA 2 values of 9.38±0.13 and 9.18±0.06 (tamsulosin) and 8.41±0.12 and 8.34±0.11 (Rec 15/2739) against phenylephrine and A 61603, respectively. HV 723 (α-ethyl-3,4,5-trimethoxy-α-(3-((2-(2-methoxyphenoxyethyl)-amino)-propyl)benzene-aceto-nitrile) fumarate) competitively antagonized phenylephrine-induced contractions with a pA 2 value of 8.57±0.06. Chloroethylclonidine (CEC; 10–4 M) shifted phenylephrine and A 61603 concentration-response curves to the right, reducing their potencies approximately two- to threefold, while the maximum response was reduced by 8% in both cases. It was therefore concluded that contractions of the rabbit spleen induced by α1-adrenergic agonists were mediated predominantly by a relatively CEC-insensitive α1-adrenoceptor subtype, possibly the α1L-subtype.
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