The guinea-pig trachea O-methylating system is more effective in modulating beta 2- than beta 1-adrenoceptor-mediated responses to isoprenaline.

Assuming that responses of the guinea-pig trachea to isoprenaline in the presence of atenolol (10 mumol L-1) are exclusively, or at least predominantly, beta 2-adrenoceptor mediated and that responses to isoprenaline in the presence of ICI 118,551 (erythro-DL-1(7-methylindan-4-yloxyl)-3-isopropylaminobut an-2-ol) (1 nmol L-1) are exclusively, or at least predominantly beta 1-adrenoceptor mediated, the influence of inhibition of COMT by U-0521 (dehydroxy-2-methyl propiophenone) (50 mumol L-1) has been compared in both conditions. U-0521 enhanced beta 2-adrenoceptor mediated responses to isoprenaline 3.3-fold, while those mediated by beta 1-adrenoceptors were enhanced only 2.

Postsynaptic alpha-adrenoceptor reserve and the shift of the concentration-response curves to the right, as caused by the irreversible alpha-adrenoceptor antagonist phenoxybenzamine.

1. The effect of different concentrations of phenoxybenzamine (0.1, 0.

An unusually important role of O-methylation in the disposition of noradrenaline and adrenaline by the dog renal artery.

Using the oil immersion technique, the role of neuronal uptake, monoamine oxidase and COMT in the inactivation of 2 concentrations (0.23 and 2.3 mumol/l) of noradrenaline and adrenaline was determined by the prolongation of the inactivation time caused by cocaine (12 mumol/l), pargyline (1 mmol/l) and U-0521 (50 mumol/l), respectively.

Alpha 2-adrenoceptor-mediated responses to so-called selective alpha 1-adrenoceptor agonists after partial blockade of alpha 1-adrenoceptors.

In dog saphenous vein--a tissue possessing both postsynaptic alpha 1- and alpha 2-adrenoceptors--the effects of two selective alpha 1-adrenoceptor agonists (phenylephrine and methoxamine) were compared with that of the selective alpha 2-adrenoceptor agonist, UK-14,304, before and after phenoxybenzamine. Furthermore, the influence exerted by prazosin, yohimbine and verapamil on the effects of these agonists was also studied before and after phenoxybenzamine. In the absence of phenoxybenzamine, prazosin (56 nmol/l) caused a parallel shift of the concentration-response curves of both phenylephrine and methoxamine to the right (by 0.

Postsynaptic alpha-adrenoceptor subtypes in the internal carotid, mesenteric, splenic, renal and femoral vascular beds of the dog.

Pressor effects of noradrenaline, phenylephrine and alpha-methylnoradrenaline and the inhibition of these effects by prazosin or yohimbine (or both) were studied in vivo in the renal, splenic, femoral, anterior mesenteric and internal carotid vascular beds of the dog. In all the vascular beds noradrenaline was more potent than alpha-methylnoradrenaline and alpha-methylnoradrenaline was more potent than phenylephrine. However, the ratios between the ED50 for phenylephrine and the ED50 for alpha-methylnoradrenaline in the mesenteric, in the femoral, in the splenic and in the renal circulations was 2.

The saturability of a site of loss and the degree of supersensitivity to agonists which are substrates of this site of loss.

The present investigation was undertaken to test the hypothesis that the experimentally determined degree of supersensitivity to an agonist caused by inhibition of a site of loss depends on the ratio "Km of the site of loss/ED50 of the agonist". The influence of inhibition of neuronal uptake by cocaine on the alpha-adrenoceptor-mediated effect of noradrenaline was studied on the dog saphenous vein; the influence of inhibition of COMT by U-0521 on the beta-adrenoceptor-mediated effect of isoprenaline was studied on the dog saphenous vein and on the guinea-pig trachea; the influence of inhibition of acetylcholinesterase by physostigmine on the effect of acetylcholine was studied on the guinea-pig ileum. To further extend the range of values of the ratio "Km/ED50", several concentrations of phentolamine, propranolol or atropine were used to "increase the ED50" of the respective agonist.

Pharmacological characterization of postsynaptic alpha-adrenoceptor subtypes in five different dog arteries in-vitro.

The responses of helically cut strips of arteries isolated from five different sites in the body of dogs to relatively selective alpha 1- and alpha 2-adrenoceptor agonists and the antagonism exerted on these responses by relatively selective alpha 1- and alpha 2-adrenoceptor blockers have been studied. On all arteries (renal, splenic, cranial mesenteric, jejunal and femoral) phenylephrine was a full agonist whereas UK-14,304 was a partial agonist causing maximal contractions of 49, 30, 27, 27 and 10% of the maximum, respectively. Phenylephrine was more potent than UK-14,304, being 9 times more potent in the renal artery and up to 42 times more potent in the cranial mesenteric artery.

The kinetic characteristics of the extraneuronal Q-methylating system of the dog saphenous vein and the supersensitivity to catecholamines caused by its inhibition.

The "half-saturating outside concentration" and the Vmax of the extraneuronal O-methylating system of the dog saphenous vein were determined in vitro for 3 catecholamines: isoprenaline, adrenaline and noradrenaline. Strips pretreated with 1 mmol/l pargyline were exposed to 30 mumol/l cocaine for 30 min before and during the 30 min incubation with the amines. Two methods were used to reach our aims: a) the classical one in which the 3H-O-methylated metabolites formed from a mixture of unlabelled and labelled amine were determined by using final concentrations of the substrate ranging from 0.

Evidence for the existence of distinct biophases for alpha- and beta-adrenoceptors in the vascular tissue.

In dog mesenteric artery and saphenous vein strips, the inhibition of neuronal uptake by cocaine increased the potency of exogenous adrenaline for alpha-effects and did not change its potency for beta-effects, whereas inhibition of catechol-O-methyltransferase (COMT) by U-0521 enhanced the beta-effects more than the alpha-ones. On the other hand, cocaine prolonged the duration of adrenaline-induced contraction more than it prolonged the adrenaline-induced relaxation, while U-0521 prolonged the duration of the relaxation much more than that of the contraction. Cocaine and U-0521 also caused differential influences on alpha- and beta-effects caused by endogenous adrenaline, i.

Two different biophases for adrenaline released by electrical stimulation or tyramine from the sympathetic nerve endings of the dog saphenous vein.

To study the distribution of alpha- and beta-adrenoceptors dog saphenous vein strips were electrically stimulated (2ms, 30 V, 0.25--20 Hz). The strips either had spontaneous tone (contraction experiments) or were contracted by 0.

The role played by the extraneuronal system in the disposition of noradrenaline and adrenaline in vessels.

The role played by extraneuronal sites in the disposition of noradrenaline and adrenaline was studied in the saphenous vein and in the mesenteric artery of the dog, taking as parameters the influence of blockade of these sites on the sensitivity to and on the time for half-relaxation (t50) (both in oil and in Krebs solution) of these agonists. Preliminary experiments have shown that the t50 values are not significantly changed by the changes in the height of the contraction provided the contraction is caused by the same concentration of the agonist. The results obtained permit us to conclude that in both vessels the removal of amines depends on the concentrations used.

Further study of the adrenoceptors of the saphenous vein of the dog: influence of factors which interfere with the concentrations of agonists at the receptor level.

In the present study the affinities of some sympathomimetic amines for alpha- and beta-adrenoceptors of the dog saphenous vein tissue were determined after all known factors interfering with the concentration of these agonists at the receptor level had been assessed and excluded. It was observed that in control experiments the relative potencies of sympathomimetic agonists for inducing contractions were: adrenaline (1.6) greater than noradrenaline (1.

Relation between the amount of smooth muscle of venous tissue and the degree of supersensitivity to isoprenaline caused by inhibition of catechol-O-methyl transferase.

The relation between the smooth muscle cell mass of dog saphenous vein strips and the degree of supersensitivity to isoprenaline caused by U-0521 (3,4-dihydroxy-2-methyl propiophenone), an inhibitor of the catechol-O-methyl transferase (COMT), was studied. For the quantitative determination of smooth muscle mass, the thickness of the muscle layer as determined by light microscopy and the maximal shortening induced by supramaximal concentration of phenylephrine were used. After the strips had been contracted by 3x10-6M phenylephrine, a concentration which was able to produce an about 90% maximal contraction, dose-response curves to the relaxant effect of isoprenaline were determined in the absence and in the presence of U-0521 (10-4M).