PHARMACOLOGICAL CHARACTERIZATION OF AN ALPHA(1A)-ADRENOCEPTOR MEDIATING CONTRACTILE RESPONSES TO NORADRENALINE IN ISOLATED CAUDAL ARTERY OFRAT

1 The alpha(1)-adrenoceptor population mediating contraction of caudal artery of rat has been characterized by using quantitative receptor p harmacology. 2 Cumulative concentration-effect (E/[A]) curves to norad renaline (NA) yielded a p[A](50) Of 5.56+/-0.05 (n=16). Prazosin cause d 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-alpha,alpha-dimeth yl -1H-indole- 3-ethanamine hydrochloride; 10-100 nM), a selective alp ha(1A)-adrenoceptor antagonist, produced non-parallel, biphasic, dextr al shifts of E/[A] curves to NA, suggesting the involvement of more th an one alpha(1)-adrenoceptor subtype. Analysis of the high affinity co mponent yielded an apparent pA(2) value of 9.2+/-0.3. 3 A-61603, a sel ective agonist at alpha(1A) adrenoceptors behaved as a full agonist re lative to NA and yielded monophasic E/[A] curves with a p[A(50)] of 7. 59+/-0.04 (n=15). Pretreatment of tissues with chloroethylclonidine (C EC; 100 mu M for 20 min, followed by 40 min washout), which preferenti ally alkylates alpha(1B)- and alpha(1D)-adrenoceptors, did not alter E /[A] curves to A-61603. Prazosin (3-300 nM) caused concentration-depen dent, parallel, dextral shifts of E/[A] curves to A-61603 yielding a p A(2) estimate of 9.2+/-0.2. 4 Experiments with alpha(1)-adrenoceptor a ntagonists of varying subtype selectivities (RS-17053, SNAP 5089, tams ulosin, 5-methylurapidil, BMY 7378, HV 723 and REC 15/2739) revealed p arallel dextral shifts of E/[A] curves to A-61603. Schild regression a nalyses yielded pA(2) estimates of 9.2, 9.3, 11.2, 9.0, 6.3, 8.7 and 1 0.0 for RS-17053, SNAP 5089, tamsulosin, 5-methylurapidil, BMY 7378, H V 723 and REC 15/2739, respectively, although deviations from unit slo pe (possibly reflecting a secondary involvement of another alpha(1)-ad renoceptor) hindered estimations of pK(b) for some antagonists. The an tagonist affinity profile obtained reflects best that described for th e alpha(1A)-adrenoceptor. 5 In conclusion, caudal artery of rat contra cts in response to NA via activation of at least two alpha(1)-adrenoce ptor 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 pharmacologic al isolation of the alpha(1A)-adrenoceptor permitting characterization of the properties of selective antagonists.