Presence Of Beta-adrenoceptors Research Articles

Partial hindrance by beta-adrenoceptors of the antagonism of prazosin against adrenoceptor agonists in rat caecum.

The relaxation of the carbachol-contracted rat isolated caecum by noradrenaline (NA), adrenaline (A) and isoproterenol (I) was investigated, to identify the pharmacological receptors involved. The organs were pretreated with cocaine to block neuronal uptake. The relative potencies of the three agonists were I >> A > or = NA, indicating the presence of beta-adrenoceptors. However, the shift of concentration-response curves by the beta-adrenoceptor antagonist propranolol varied according to the agonist used, suggesting the presence of distorting factors. Initial attempts to verify if alpha-adrenoceptors were involved, by using the alpha-adrenoceptor antagonist prazosin, were unsuccessful, since the shifts of the concentration-response curves were small and were not concentration dependent, leading to Schild lines with slopes significantly lower than unity. When the experiments with prazosin were repeated in the presence of large concentration of propranolol (10(-5) mol/l) to block beta-adrenoceptors, the relative potencies were changed to NA > A > or = I, reflecting the presence of alpha-adrenoceptors. In addition, the shifts induced by prazosin against A lead to Schild lines with slopes not different from 1.0. It is concluded that alpha-adrenoceptors are also present in the caecum, but its presence can only be clearly disclosed after blockade of beta-adrenoceptors. The results are discussed in relation to other situations known to hinder the determination of relative potencies and competitive antagonism, as for instance the removal of agonist from the vicinity of receptors by drug uptake mechanisms.

Histoautoradiographic localization of (-)-3H-dihydroalprenolol in rabbit aorta.

The distribution pattern of (-)-3H-dihydroalprenolol (3H-DHA) binding sites within the thoracic and abdominal aorta was studied using a histoautoradiographic technique. Frozen sections of rabbit aorta were incubated with 3H-DHA in the presence or absence of 1 mumol/l (-)-propranolol and of increasing concentrations of various adrenergic agents. After washing, the same secretions were placed in scintillation vials and counted to evaluate the pharmacological characteristics of 3H-DHA binding or processed for histoautoradiography. 3H-DHA was bound by sections of the rabbit aorta in a manner consistent with the presence of beta-adrenoceptors. The binding was reversible, saturable and of high affinity, with a dissociation constant Kd of 1.0 nmol/l and a maximum binding capacity Bmax of 17 fmol/mg tissue (wet weight). It was inhibited only by beta-adrenoceptor blocking drugs. Histoautoradiographic studies revealed that beta-adrenoceptors are located primarily in the media and then in the intima. The lowest density of 3H-DHA was found in the adventitia. The distribution pattern of beta-adrenoceptors in the media suggests the possible existence of two groups of beta-adrenoceptors within this layer of the aorta. The first group was found in the outer portions of the media and may be controlled by the adrenergic nerves that supply the artery. The second group was found in the portions of the media closest to the intima and is likely under the control of catecholamines coming from the lumen of the aorta.

Presence of functionally active beta-adrenoceptors in rat mast cells. Correlation between (--)[3H]-dihydroalprenolol binding and inhibition of histamine release.

The correlation between the binding of a beta-adrenoceptor antagonist, (--)[3H]-dihydroalprenolol (DHAP), and the adrenergic inhibition of histamine release by acetylcholine and by compound 48/80 was studied with isolated purified rat mast cells and in rat mast cell crude membrane fractions. Acetylcholine-evoked histamine release was inhibited by catecholamines, in the order isoprenaline greater than adrenaline greater than noradrenaline. Pretreatment of cells with (--)alprenolol antagonized the inhibitory effect of isoprenaline on acetylcholine-induced histamine release. 40/80-evoked histamine release was blocked by isoprenaline at significantly higher concentrations than those required to inhibit cholinergic histamine release. The inhibitory effect of isoprenaline was equally antagonized by preincubating mast cells with (--)alprenolol. Specific binding sites for DHAP have been demonstrated in rat mast cell membranes. The specific binding of DHAP was inhibited by adrenoceptor agonists and antagonists according to the stereospecificity of these compounds. A close correlation between the binding-inhibitory potency of various adrenergic compounds and the data obtained in the pharmacological experiments was found, thus indicating the presence of beta-adrenoceptors in rat mast cells.

STIMULATION OF PRESYNAPTIC β‐ADRENOCEPTORS ENHANCES [3H]‐N0RADRENALINE RELEASE DURING NERVE STIMULATION IN THE PERFUSED CAT SPLEEN

1 The effects of isoprenaline, propranolol and phosphodiesterase inhibitors on (3)H-transmitter overflow elicited by low frequency nerve stimulation were determined in the isolated perfused spleen of the cat.2 (-)-Isoprenaline (0.14, 1.4, and 14 nM) produced a concentration-dependent increase in [(3)H]-transmitter overflow evoked by nerve stimulation at 1 Hz and was more effective at 1 Hz than at 2 hertz.3 A concentration of propranolol (0.1 muM), devoid of neurone blocking activity, blocked this effect of (-)-isoprenaline. These results are compatible with the presence of beta-adrenoceptors in the noradrenergic nerve endings of the cat spleen.4 (+)-Isoprenaline (140 nM) failed to increase the release of radioactivity induced by nerve stimulation, indicating that the beta-adrenoceptor mediating the facilitation of transmitter release was stereospecific.5 The increase in (3)H-transmitter overflow induced by nerve stimulation during exposure to the phosphodiesterase inhibitor, papaverine (27 muM) was more pronounced than that obtained in the presence of 3-isobutyl-1-methyl xanthine (IBMX) 0.5 mM. The facilitation in transmitter release induced by papaverine was not correlated with the granular effect produced by this drug.6 In the presence of papaverine, the concentration-effect curve for (-)-isoprenaline on transmitter release was shifted to the left and its maximum was increased. In addition, propranolol significantly reduced the enhancement in noradrenaline release obtained by exposure to papaverine under conditions in which the granular effect produced by the phosphodiesterase inhibitor was even greater than in the absence of the beta-blocker.7 It is concluded that activation of presynaptic beta-adrenoceptors in the perfused cat spleen leads to an enhancement in transmitter release which appears to be linked to an increase in cyclic adenosine 3',5'-monophosphate levels in noradrenergic nerve endings.

Effects of temperature on the responses to noradrenaline, isoprenaline and histamine on isolated rabbit mesenteric artery.

On the rabbit mesenteric artery, the elevation of temperature from 25 degrees up to 42 degrees diminished the affinity of histamine, whereas that of noradrenaline to the alpha-adrenoceptors remained unchanged. The presence of beta-adrenoceptors could not be demonstrated.