Frequency- and train length-dependent variation in the roles of postjunctional α₁- and α₂-adrenoceptors for the field stimulation-induced neurogenic contraction of rat tail artery

Summary

The present paper examines the roles of postjunctional α₁- and α₂-adrenoceptors for the noradrenaline (NA)-induced neurogenic contractile response to field stimulation mainly with 1–100 pulses at 2 or 20 Hz, in the tail artery of adult normotensive rats. Pharmacological tools were employed to isolate and characterize the α₁- and α₂-adrenoceptor-mediated components of this response. The degree to which the drugs influenced NA release or reuptake was assessed by their effects on the electrochemically determined, stimulation-induced rise in the NA concentration at the innervated outer surface of the media. This response was unaffected by α,β-methylene ATP (10 μM) or suramin (500 μM), added to desensitize or block P₂-purinoceptors, respectively prazosin (0.1 μM) or SK&amp;F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxyl]-3-methyl-1H-2, 3, 4, 5-tetrohydro-3-benzazepine, 0.1 μM), used to block postjunctional α₁- and α₂-adrenoceptors respectively, nifedipine (10 μM), blocker of Ca²⁺ influx through L-type channels, and ryanodine (10 μM), which blocks mobilization of Ca²⁺ from intracellular stores; it was moderately enhanced by yohimbine (0.1 μM), blocker of pre- and postjunctional α₂-adrenoceptors, and strongly enhanced by cocaine (3 μM) or desipramine (1 μM), blockers of NA reuptake. Judging from their inhibitory effects on the contractile responses to the α₁- and α₂-adrenoceptor agonists, phenylephrine andxylazine, prazosin (0.1 μM)and SK & F 104078 (0.1 μM) could be used to selectively block α₁- and α₂-adrenoceptors respectively, while yohimbine (0.1 μM) was less selective, strongly depressing α₂- and slightly depressing α₁-adrenoceptor-mediated responses. The α₁-adrenoceptor-mediated component of the contractile response to short trains at 20 Hz was fast in onset, brief in duration and abolished by ryanodine; that mediated by α₂-adrenoceptors was more delayed, prolonged and insensitive to ryanodine. Both components were dose-dependently depressed by nifedipine (0.1–10 μM). The small contractile responses to single pulses, or up to 50 pulses at 2 Hz, or short train (< 4 pulses) at 20 Hz, were more markedly depressed by 0.1 μM yohimbine or SK & F 104078 than by 0.1 μM prazosin and, hence, mediated mainly by α₂-adrenoceptors. The reverse was true of the much larger response to longer trains at 20 Hz, which thus probably was mediated mainly by α₁-adrenoceptors. Cocaine or desipramine, as well as α,β-methylene ATP or suramin, amplified both components of the NA induced contractile response especially that mediated via a₁-adrenoceptors and caused by single pulses or short trains.

The main conclusions are (i) that the small NA-induced contractile responses of this artery to single pulses, or pulses at low frequency, or in short trains at high frequency, are mediated mainly via α₂-, and the larger responses to longer trains at high frequency increasingly via α₁-adrenoceptors, (ii) that the α₁- and α₂-adrenoceptor-mediated components interact cooperatively, probably at least in part by utilizing two different pathways to increase the intracellular Ca²⁺, (iii) that neuronal reuptake of NA strongly restricts both components of the NA-induced contraction, especially the α₁-adrenoceptor-mediated response to single pulses or short trains, and (iv) that both components of the NA-induced contraction, especially that mediated by α₁-adrenoceptors, may be depressed by ATP released by field stimulation and acting via P_2x-purinoceptors on smooth muscle. Based on these results a novel working hypothesis is proposed, in which it is assumed that the geometry of NA-mediated neuromuscular transmission in this vessel varies with the frequency and number of impulses in a stimulus train.