α(1L)-Adrenoceptors in canine pulmonary artery

Abstract

The aim of this study was to characterize theα1-adrenoceptors of the canine pulmonary artery. Arterial rings from lower lung lobes were suspended for isometric-tension recording in the presence of cocaine (5 x 10-6 M), hydrocortisone (3 x 10-5 M), propranolol (5 x 10-6 M), and rauwolscine (10-7 M) to inhibit neuronal uptake, extraneuronal uptake, and β- and α2-adrenoceptors, respectively. Prazosin was more potent against contractions evoked by phenylephrine (pA2 of 9.7) compared with methoxamine (pA2 of 8.4). SZL49 (10-8 and 3 x 10-8 M), an irreversible α1- adrenergic antagonist, inhibited responses to phenylephrine but not methoxamine. With norepinephrine, low concentrations of prazosin (3 x 10- 10 M and 10-9 M) caused inhibition of the concentration-response curve; a higher concentration (3 x 10-9 M) failed to produced further inhibition, whereas increasing the concentration of the antagonist (to 10-8 and 3 x 10-8 M) caused further rightward shifts in the concentration-response curve. The Arunlakshana and Schild plot revealed two components corresponding to pA2 values of 9.8 and 8.4. After SZL49 (3 x 10-8 M), the Arunlakshana and Schild plot for the interaction between norepinephrine and prazosin was linear and generated a pA2 of 8.3. Contractions evoked by phenylephrine were inhibited by the α(1B)/α(1D)adrenoceptor antagonist, chloroethylclonidine (10-5 M), or by the α(1B)-antagonist, risperidone (pA2 value of 8.5), but were relatively resistant to inhibition by the selective α(1D)-antagonist, BMY7378 (-log K(B) of 6.1). The results suggest that two α1-adrenoceptor subtypes mediate contraction of the canine pulmonary artery. One subtype has high affinity for prazosin (α(1H), likely to be α(1B)), is activated by phenylephrine, and is inhibited by SZL49. The other subtype has lower affinity for prazosin (α(1L)), is stimulated by methoxamine, and is relatively resistant to SZL49. The physiologic agonist, norepinephrine, causes contraction by activating both subtypes.