Pharmacological characterization of an α_1A-adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat

Abstract

1. The α₁-adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor pharmacology.

2. Cumulative concentration-effect (E/[A]) curves to noradrenaline (NA) yielded a p[A]₅₀ of 5.56±0.05 (n=16). Prazosin caused concentration-dependent, parallel, dextral shifts of E/[A] curves to NA yielding a pK_b of 8.9 (Schild regression slope=1.0). RS-17053 (N-[2-(2-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-α ,α-dimethyl -1H-indole- 3-ethanamine hydrochloride; 10–100 nM), a selective α_1A-adrenoceptor antagonist, produced non-parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one α₁-adrenoceptor subtype. Analysis of the high affinity component yielded an apparent pA₂ value of 9.2±0.3.

3. A-61603, a selective agonist at α_1A adrenoceptors behaved as a full agonist relative to NA and yielded monophasic E/[A] curves with a p[A₅₀] of 7.59±0.04 (n=15). Pretreatment of tissues with chloroethylclonidine (CEC; 100 μM for 20 min, followed by 40 min washout), which preferentially alkylates α_1B- and α_1D-adrenoceptors, did not alter E/[A] curves to A-61603. Prazosin (3–300 nM) caused concentration-dependent, parallel, dextral shifts of E/[A] curves to A-61603 yielding a pA₂ estimate of 9.2±0.2.

4. Experiments with α₁-adrenoceptor antagonists of varying subtype selectivities (RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed parallel dextral shifts of E/[A] curves to A-61603. Schild regression analyses yielded pA₂ estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 10.0 for RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739, respectively, although deviations from unit slope (possibly reflecting a secondary involvement of another α₁-adrenoceptor) hindered estimations of pK_b for some antagonists. The antagonist affinity profile obtained reflects best that described for the α_1A-adrenoceptor.

5. In conclusion, caudal artery of rat contracts in response to NA via activation of at least two α₁-adrenoceptor subtypes. One of these subtypes displays the pharmacology of the α_1A-adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A-61603, allows for limited pharmacological isolation of the α_1A-adrenoceptor permitting characterization of the properties of selective antagonists.

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