The rabbit pulmonary artery contains postsynaptic alpha-adrenoceptors which meidate smooth muscle contraction; its noradrenergic nerves contain presynaptic alpha-adrenoceptors which mediate inhibition of the release of the transmitter evoked by nerve impulses. Dose-response curves for the pre- and postsynaptic effects of eight alpha-receptor agonists were determined on superfused strips of the artery in the presence of cocaine, corticosterone and propranolo. 1. According to the concentrations which caused 20% of the maximal contraction (EC20 post), the postsynaptic rank order of potency was: adrenaline greater than noradrenaline greater than oxymetazoline greater than naphazoline greater than phenylephrine greater than tramazoline greater than alpha-methylnoradrenaline greater than methoxamine. The pA2 values of phentolamine againstoxymethazoline, phenylephrine, alpha-methylnoradrenaline and methoxamine were 7.43, 7.48, 7.59 and 7.69, respectively. 2. For the investigation of presynaptic effects, the arteries were preincubated with 3H-noradrenaline. All agonists inhibited the overflow of tritium evoked by transmural sympathetic nerve stimulation. According to the concentrations which reduced the stimulation-induced overflow by 20% (EC20 pre), the rank order of potency was: adrenaline greater than oxymetazoline greater than tramazoline greater than alpha-methylnoradrenaline greater than noradrenaline greater than naphazoline greater than phenylephrine greater than methoxamine. 10(-5) M phentolamine shifted the presynaptic dose-response curves for moradrenaline and oxymethazoline to the right. 3. The ratio EC20 pre/EC20 post was calculated for each agonist as an index of its relative post- and presynaptic potency. According to the ratios, the agonists were arbitrarily classified into three groups. Group 1 (ratio about 30: preferentially postsynaptic agonists) comprised methoxamine and phenylephrine; group 2 (ratio near 1; similar pre- and postsynaptic potencies) comprised noradrenaline, adrenaline and naphazoline; group 3 (ratio below 0.2; preferentially presynaptic agonists) comprised oxymetazoline, alpha-methylnoradrenaline and tramazoline (as well as clonidine). 4. Preferentially presynaptic and preferentially postsynaptic agonists had opposite effects on the basoconstrictor response to nerve stimulation. Methoxamine and phenylephrine either did not change or enhanced, but never reduced, the response. In contrast, oxymetazoline, alpha-methylnoradrenaline and tramazoline at low concentrations selectively inhibited the response to stimulation at low frequency (0.25-2Hz). 5. It is concluded that alpha-adrenoceptor agonists vary widely in their relative pre- and postsynaptic potencies, possibly because of structural differences between pre- and postsynaptic alpha-receptors. Pre- and postsynaptic components contribute to their overll postsynaptic effec in actively transmitting synapses. The preferential activation of presynaptic alpha-receptors results in alpha-adrenergic inhibition of synaptic transmission.

A search was performed for presynaptic, release-modulating receptor systems on the post-ganglionic sympathetic nerves of rabbit pulmonary artery. Strips of the artery were preincubated with (-)-3H-noradrenaline and then superfused and stimulated transmurally. 1. Tetrodotoxin, guanethidine, and omission of calcium all suppressed the stimulation-evoked overflow of tritium, thus confirming selective release from noradrenergic neurones. 49% of the stimulation-evoked overflow of total consisted of 3H-noradrenaline, 22% of 3H-3,4-dihydroxyphenyglycol (DOPEG), and 9% of 3H-normetanephrine. Cocaine virtually abolished the evoked overflow of 3H-DOPEG; further addition of corticosterone also abolished that of 3H-normetanephrine. In the presence of cocaine plus corticosterone, unmetabolized 3H-noradrenaline accounted for 86% of the stimulation-evoked overflow of total tritium. The overflow evoked per pulse was 2.2 X 10(-5) of the tritium content of the tissue (1 Hz); it increased 2-fold when the frequency was raised to 8 Hz. 2. Presynaptic alpha-adrenoceptors have previously been demonstrated in this tissue (Starke et al., 1975b). High concentrations of isoprenaline reduced the stimulation-evoked overflow of tritium, presumably by alpha-adrenergic inhibiton. No presynaptic effect of up to 10(-5) M normetanephrine and metanephrine was found. 3. Dopamine slightly diminished the stimulation-evoked overflow of tritium, but only at 100 times the inhibitory threshold concentration of noradrenaline (which is 10(-8) M; Starke et al., 1975b), probably through activation of presynaptic alpha-adrenoceptors. Apomorphine failed to reduce the evoked overflow whether the superfusion medium contained cocaine and corticosterone or not. 4. Isoprenaline (10(-9) -10(-6) M) did not change the evoked overflow whether the medium contained cocaine and corticosterone or not, and whether the frequency was 1 or 2 Hz. Propranolol also had no effect. 5. Angiotensin II increased the stimulation-evoked overflow both in the absence and in the presence of cocaine and corticosterone. Equieffective concentrations of angiotensin I were 10 times higher. Saralasin had no effect, whereas 1-Sar,8-Ile-angiotensin produced a small increase. Both of the latter peptides behaved as presynaptic antagonists of angiotensin II. A presynaptically supramaximal concentration of the alpha-adrenergic agonist oxymetazoline prevented the facilitatory action of yohimbine, but not that of angiotensin II. Separation of 3H-compounds showed that angiotensin II caused a proportionate increase in stimulation-evoked overflow of 3H-noradrenaline, 3H-DOPEG, and 3H-normetanephrine; this finding rules out any inhibition of noradrenaline uptake mechanisms. 6. 10(-4) -10(-3) M acetylcholine caused hexamethonium-sensitive acceleration of basal tritium outflow. Much lower concentrations (10(-7) M and higher) reduced the overflow evoked by electrical stimulation. The evoked overflow of 3H-noradrenaline, 3H-DOPEG, and 3H-normetanephrine was proportionately decreased...

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