Analysis of α(1L)-adrenoceptor pharmacology in rat small mesenteric artery

Abstract

1. To illuminate the controversy on α(1A)- or α(1L)-adrenoceptor involvement in noradrenaline-mediated contractions of rat small mesenteric artery (SMA), we have studied the effects of subtype-selective α1-adrenoceptor agonists and antagonists under different experimental conditions. 2. The agonist potency order in rat SMA was: A61603 >> SKF89748-A > cirazoline > noradrenaline > ST-587 > methoxamine. Prazosin antagonized all agonists with a low potency (pA2: 8.29-8.80) indicating the involvement of α(1L)- rather than α(1A)-adrenoceptors. 3. The putative α(1L)-adrenoceptor antagonist JTH-601, but not the α(1B)-adrenoceptor antagonist chloroethylclonidine (10 μM) antagonized noradrenaline-induced contractions of SMA. The potency of the selective α(1D)-adrenoceptor antagonist BMY 7378 against noradrenaline (pA2 = 6.16 ± 0.13) and of the selective α(1A)-adrenoceptor antagonist RS-17053 against noradrenaline (pK(B) = 8.35 ± 0.10) and against the selective α(1A)-adrenoceptor agonist A-61603 (pK(B) = 8.40 ± 0.09) were too low to account for α(1D)- and α(1A)-adrenoceptor involvement. 4. The potency of RS-17053 (pK(B)/pA2(')s = 7.72-8.46) was not affected by lowering temperature, changing experimental protocol or inducing myogenic tone via KCl or U46619. 5. Selective protection of a putative α(1A)-adrenoceptor population against the irreversible action of phenoxybenzamine also failed to increase the potency of RS-17053 (pA2= 8.25 ± 0.06 against A61603). 6. Combined concentration-ratio analysis demonstrated that tamsulosin, which does not discriminate between α(1A)- and α(1L)-adrenoceptors, and RS-17053 competed for binding at the same site in the SMA. 7. In summary, data obtained in our experiments in rat SMA indicate that the α1-adrenoceptor mediating noradrenaline-induced contraction displays a distinct α(1L)-adrenoceptor pharmacology. This study does not provide evidence for the hypothesis that α(1L)-adrenoceptors represent an affinity state of the α(1A)-adrenoceptor in functional assays. Furthermore, there is no co-existing α(1A)-adrenoceptor in the SMA.