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Br J Pharmacol. 1997 Mar;120(5):819-26.

Pharmacological characterization of an alpha 1A-adrenoceptor mediating contractile responses to noradrenaline in isolated caudal artery of rat.

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Roche Bioscience, Palo Alto, CA 94304, USA.


1. The alpha 1-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 pKb of 8.9 (Schild regression slope = 1.0). RS-17053 (N-[2-(2-cyclopropyl methoxy phenoxy) ethyl]-5-chloro-alpha, alpha-dimethyl-1H-indole- 3-ethanamine hydrochloride; 10-100 nM), a selective alpha 1 A-adrenoceptor antagonist, produced non-parallel, biphasic, dextral shifts of E/[A] curves to NA, suggesting the involvement of more than one alpha 1-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 alpha 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 microM for 20 min, followed by 40 min washout), which preferentially alkylates alpha 1B- and alpha 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 alpha 1-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 alpha 1-adrenoceptor) hindered estimations of pKb for some antagonists. The antagonist affinity profile obtained reflects best that described for the alpha 1A-adrenoceptor. 5. In conclusion, caudal artery of rat contracts in response to NA via activation of at least two alpha 1-adrenoceptor subtypes. One of these subtypes displays the pharmacology of the alpha 1A-adrenoceptor, while the other remains to be defined. Use of the novel selective agonist, A-61603, allows for limited pharmacological isolation of the alpha 1A-adrenoceptor permitting characterization of the properties of selective antagonists.

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