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PubMed1982

Characteristics of the lipolytic beta-adrenergic receptors in hamster adipocytes.

Hamster adipocyte beta-adrenergic receptors were characterized by the effect on the lipolysis rate of several selective beta-adrenergic agonists and antagonists. Prenalterol and procaterol, selective beta 1- and beta 2-agonists, respectively, both stimulated the lipolysis rate half-maximally at 1-2 microM, a concentration approximately 100-fold higher than that needed for half-maximal stimulation by isoprenaline. The maximal procaterol effect was similar to that of isoprenaline, while the effect of prenalterol was 40% lower. Submaximally isoprenaline-stimulated lipolysis was half-maximally inhibited by propranolol at 0.2 microM and by atenolol and H 35/25, selective beta 1- and beta 2-antagonists, at 23 and 6 microM concentration, respectively. Highly specific beta 1 and beta 2 stimulation was induced by incubation with prenalterol or procaterol, with simultaneous maximal selective beta 2 or beta 1 inhibition, respectively. The maximal beta 2 stimulation was approximately twice the corresponding beta 1 effect under these conditions, the sum of both effects closely approaching that of maximal nonselective beta-adrenergic stimulation with isoprenaline. Similar results were obtained with the selective beta 2-antagonist, ICI 118,551, or the beta 1-antagonists, pamatolol and practolol. The findings are most easily explained by the existence of a heterogeneous beta 1- and beta 2-adrenergic receptor population on hamster adipocytes.

Adipose Tissue↗
PubMed1987

Inhibition of purified bovine milk lipoprotein lipase by propranolol and other beta-adrenergic blockers in vitro.

Numerous clinical studies have shown that propranolol administration causes hypertriglyceridemia and a decrease in high-density lipoprotein in man. Although these findings have been attributed to diminution of triacylglycerol-rich lipoprotein catabolism by lipoprotein lipase, biochemical studies of the effects of propranolol on lipoprotein lipase activity in vitro have not been previously reported. We purified lipoprotein lipase from raw bovine skimmed milk and examined the effect of propranolol using as substrate phospholipid-stabilized, triolein emulsions containing purified human apolipoprotein C-II. These studies demonstrate that propranolol inhibits lipoprotein lipase activity. The inhibition was found to be noncompetitive with a Ki for propranolol of 0.55 mM. In addition, propranolol was shown to bind to phospholipid-stabilized triolein emulsions reaching local concentrations at the particle surface many times higher than its bulk concentration. Metoprolol, timolol and practolol, which are less hydrophobic than propranolol, were less inhibitory. Atenolol was the weakest inhibitor of purified bovine lipoprotein lipase in vitro.

Adrenergic beta-Antagonists↗
PubMed1990

Beta-adrenergic regulation of cyclic GMP in rat pinealocytes.

Stimulation of rat pinealocyte cyclic GMP by beta-adrenergic agonists (in the presence of prazosin to block alpha 1-adrenoceptors) showed an identical potency order (isoproterenol greater than epinephrine = norepinephrine much greater than salbutamol greater than terbutaline) to the stimulation of pinealocyte cyclic AMP. The increase in cyclic AMP and cyclic GMP produced by norepinephrine was inhibited by various subtype-selective beta-adrenergic antagonists with the same potency order (propranolol greater than atenolol = ICI 118,551 greater than practolol). These results indicate that pinealocytes have a single beta-adrenoceptor, of the beta 1-subtype. Activation of this beta 1-adrenoceptor mediates adrenergic stimulation of not only cyclic AMP but also cyclic GMP.

Adrenergic alpha-Agonists↗
PubMed1982

Homogeneous class of beta-1 adrenergic receptors in rat kidney. Identification by (+/-)-125 iodocyanopindolol binding.

The highly specific beta-adrenergic radio-ligand (+/-)-125 iodocyanopindolol (ICYP) was used to characterize the beta-adrenergic receptor subtype present in rat kidney. Binding of ICYP to membranes from rat kidney was of high affinity (KD = 68.9 pM) and saturable with 1.06 pmoles ICYP bound/g tissue wet wt at maximal occupancy of the sites. Analysis of inhibition of ICYP binding by beta 1- and beta 2-selective adrenergic drugs via pseudo-Scatchard ("Hoifstee') plots resulted in linear plots indicating the existence of a homogeneous population of beta-adrenergic receptors. From the resulting KD-values for practolol (2.2 microM), metoprolol (0.21 microM), zinterol (0.4 microM) and IPS 339 (0.046 microM) it is concluded that the beta-adrenergic receptor in rat kidney is of the beta 1-subtype. This subclassification is further supported by the fact that (-)-noradrenaline and (-)-adrenaline were equipotent in inhibiting ICYP binding. The beta-adrenergic agonists (-)-isoprenaline and zinterol bind to two distinct states of this beta 1-receptor, a high and low affinity state. GTP (10(-4) M) converts this heterogeneous binding into a homogeneous low affinity binding.

Animals↗
PubMed1983

Effects of full and partial beta-adrenergic agonists and antagonists on human lung adenylate cyclase.

The beta-adrenergic stimulation of adenylate cyclase in membranes from human lung was compared to that of adenylate cyclase in membranes with a majority of beta 2-adrenergic receptors (from rat lung) and in membranes with a homogeneous population of beta 2-adrenergic receptors (from rat erythrocytes and reticulocytes). In terms of adenylate cyclase stimulation, three full agonists (isoproterenol, epinephrine and norepinephrine), four partial agonists (procaterol, salbutamol, fenoterol and zinterol), and four antagonists (propranolol, metoprolol, atenolol and practolol) were tested. The potency (Kact or Ki) of the eleven beta-adrenergic agents, and the Hill coefficient (of 1) for the four antagonists tested indicated that the activation of human lung adenylate cyclase occurred through receptors of the beta 2-subtype only. Partial beta-adrenergic agonists were efficiently discriminated by the human lung preparation, as shown by distinct intrinsic activities. The mediocre efficacy and the relatively low potency of all beta-adrenergic agonists on adenylate cyclase suggested a relatively low density of beta 2-adrenergic receptors, as compared to the enzyme density.

Adenylyl Cyclase Inhibitors↗
PubMed1983

Beta-adrenergic receptors of human leukocytes. Studies with intact mononuclear and polymorphonuclear cells and membranes comparing two radioligands in the presence and absence of chloroquine.

Owing to the large differences in reported values for beta-adrenergic receptor numbers and binding affinity in normal leukocytes, we undertook a systematic re-examination of the binding of two widely used beta antagonists, (-)-[3H]dihydroalprenolol (DHA) and (+/-)-[125I]iodohydroxybenzylpindolol (HYP), to intact normal mononuclear (MN) leukocytes and polymorphonuclear (PMN) leukocytes and membrane preparations. Assays were conducted in the presence and absence of chloroquine, which has been proposed recently to eliminate ligand uptake into a non-receptor cell compartment such as lysosomes. The binding curves relating radioligand concentration to specific sitesper intact cell were biphasic. At high (10-24 nM) (-)-DHA ligand concentration in the absence of chloroquine, a large number (20,000-60,000 sites/cell) of low affinity (Kd 12-15 nM) stereospecific binding sites were detected in both cell types. This class of binding sites was eliminated by 10 microM chloroquine not only in PMN cells but also in the lysome-poor MN cells (greater than or equal to 90% lymphocytes), leaving 2000-3000 specific high affinity (-)-DHA sites/cell. In the absence of chloroquine, comparably low numbers of specific high affinity binding sites/cell were also obtained by the use of appropriately low concentrations of (-)-DHA or (+/-)-HYP (800 pM or less). However, even at these low radioligand concentrations chosen to measure high affinity specific binding, the addition of 10 microM chloroquine produced a moderate reduction in the number of sites/cell, without a detectable change in the apparent Kd. Mean (+/- S.E.M.) site numbers obtained in the presence of chloroquine were: 1331 +/- 100 sites/MN cell and 1135 +/- 129 sites/PMN cell (Kd 143-153 pM) using (-)-DHA; and 1487 +/- 210 sites/MN cell and 1065 +/- 69 sites/PMN cell [avg. Kd(+/-) 224-274 pM] using (+/-)-HYP. Chloroquine had no effect on agonist-stimulated cAMP production but produced an apparent increase in the effectiveness of (-)-propranolol as an inhibitor of DHA binding. Competition studies on the binding of DHA and HYP with zinterol and practolol confirmed that the receptor was of the beta 2-subtype for both MN and PMN cells. The detection of a moderately larger number of high affinity binding sites at saturation (Scatchard analysis) by (+/-)-HYP than by (-)-DHA was a consistent finding with either intact cells or membranes, with or without chloroquine. The possible overestimation of receptor numbers by a racemic ligand such as (+/-)-HYP is discussed and leads us to favor the use of a pure stereoisomer such as (-)-DHA. A system employing 800 pM (-)-[3H]DHA, 1 microM (-)-propranolol and 10 microM chloroquine with intact MN and PMN cells yielded reproducible and plausible results. Our values for beta-adrenergic receptor numbers of intact MN and PMN cells and membranes are compared to others in the literature.

Adult↗
PubMed1984

Beta-adrenoceptor antagonists and human platelets: relationship of effects to lipid solubility.

Six beta-adrenoceptor antagonists (propranolol (+ and - isomers); ICI-118,551; oxprenolol; timolol; metoprolol; and practolol (+ and - isomers), chosen to represent a spectrum of physicochemical and pharmacological properties, inhibited the response of human platelets to all aggregating agents tested. For any given aggregating agent the extent of inhibition correlated with the lipid solubility of the beta-adrenoceptor antagonist and showed no relation to other properties of these compounds. Inhibition of aggregation by the beta-adrenoceptor antagonists was manifested as a parallel shift to the right in the dose-response curve. Analysis of these data according to Arunlakshana and Schild (Br. J. Pharmac. 14, 48-58 (1969] showed a dependence of the apparent pA2 on the agonist employed and gave a slope approximating unity when ADP, 9,11-epoxymethanoprostaglandin H2 (U-46619), adrenaline, 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (PAF) or arachidonate were used as agonists. Slopes significantly greater than unity, and approaching a value of 2, were obtained when this analysis was applied to data obtained using collagen in the presence or absence of aspirin, 12-O-tetradecanoylphorbol-13-acetate (TPA), or a divalent cation ionophore (A-23187) as agonists. Inhibition by (+/-) propranolol of secretion induced by collagen was manifested as a parallel shift to the right in the dose-response curve for collagen. The Schild plot of these data has a slope of unity. (+/-)-Propranolol inhibited thromboxane B2 production induced by collagen but over a similar concentration range had little effect on conversion of arachidonate to thromboxane B2. (+/-)Propranolol had no significant effect on the level of cyclic-3',5'-AMP (cAMP) in unstimulated platelets or on the increase in the level caused by addition of forskolin, but caused partial inhibition of the increase in platelet cAMP induced by prostaglandin E1. It also completely abolished inhibition by ADP of the increase in [cyclic-3',5'-AMP] induced by prostaglandin E1. These data are interpreted on the basis of a model in which interaction of propranolol with phosphatidylserine and phosphatidylinositol causes inhibition of phospholipases C and A2, inhibition of protein kinase C and alteration of membrane receptor properties as a consequence of distortion of their microenvironment.

Adenosine Diphosphate↗
PubMed1984

Effects of (-)-(R)-1-(p-hydroxyphenyl)-2-[3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat.

Effects of the new cardiotonic and selective beta 1-adrenergic agonist TA-064, (-)-(R)-1-(p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino] ethanol, on circulating concentrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg (ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective beta-adrenergic antagonist) and practolol (a selective beta 1-adrenergic antagonist). The non-selective beta-adrenergic agonist isoproterenol and the selective beta 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective beta 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the beta-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.

Adrenergic beta-Agonists↗
PubMed1986

Selective lysosomal uptake and accumulation of the beta-adrenergic antagonist propranolol in cultured and isolated cell systems.

The beta adrenoreceptor antagonist propranolol is rapidly taken up and accumulated in various cultured cell lines. When incubated in the presence of low concentrations of propranolol (10(-9) M), Hela (non-differentiated epithelia), BC3H1 (smooth muscle) and MDCK (differentiated kidney epithelia) cell cultures take up (t1/2 = 4-10 min) and accumulate the drug such that the intracellular concentration is over 1000 times that in the incubation medium. The release of propranolol from the cells was slower (t1/2 = 22 min) than the rate of uptake but the dissociation was stimulated by the addition of 1 microM propranolol to the external medium (t1/2 = 9 min). Uptake, which is non-stereoselective, is dependent on pH and is inhibited by the lysosomotropic agents, NH4Cl, methylamine and chloroquine. At higher concentrations (greater than 10(6) M), uptake is accompanied by a visual swelling of intracellular acidic vesicles staining with acridine orange. These results suggest that propranolol, a basic amphiphilic amine, is accumulated within the lysosomes of these cells. Uptake was confined to these cultured cell systems with no chloroquine-sensitive propranolol uptake, being found in isolated rabbit ventricular myocytes, red blood cells or blood platelets. Although alprenolol and cyanopindolol competed with propranolol for uptake, isoprenaline, adrenaline, noradrenaline, phenylephrine, atenolol, practolol and salbutamol were not effective inhibitors. The possible consequences of this uptake and accumulation of propranolol by certain tissues is discussed in relation to the known actions of the drug, particularly during or after abrupt withdrawal from chronic applications.

Animals↗
PubMed1986

Classification of beta-adrenergic subtypes in immature rabbit bone marrow erythroblasts.

The beta-adrenergic receptors of immature rabbit bone marrow erythroid cells (proerythroblasts and basophilic erythroblasts) were identified. [125I]iodocyanopindolol bound to membrane preparations derived from these erythroblasts in a rapid, reversible and saturable manner. Scatchard analysis of binding data revealed a single class of binding sites (Hill coefficient of 0.954) with an apparent equilibrium dissociation constant (Kd) of 8 pM, and a density of binding sites (Bmax) of 1.53 pM/10(6) cells, corresponding to 920 receptors per cell. The binding of [125I]iodocyanopindolol was inhibited stereospecifically by concentrations of (-)-propranolol 2 orders of magnitude lower than by the (+)-isomer. Only L-isoprenaline and L-adrenaline activated the adenylate cyclase of immature rabbit erythroblasts, while L-noradrenaline, a beta 1-adrenergic agonist, was inactive. The order of potency of different agonists for displacement of bound [125I]iodocyanopindolol was: isoprenaline greater than adrenaline greater than noradrenaline with respective EC50 (concentration required for half maximal inhibition of binding) of 7.9 X 10(-7) M, 1.5 X 10(-5) M and 7.9 X 10(-5) M. This agonist potency series did not change with differentiation of rabbit bone marrow erythroblasts. The inhibition of specific [125I]iodocyanopindolol binding to immature cells by beta 1- and beta 2-selective drugs (noradrenaline, practolol, procaterol and butoxamine) resulted in linear Hofstee plots. The inhibition curves obtained with procaterol and butoxamine, with apparent Kd values of 3.1 X 10(-9) M and 4.9 X 10(-9) M, further evidence that the high-affinity binding sites correspond to a homogeneous beta 2-receptor subtype.

Adenylyl Cyclases↗
PubMed1994

The role of intracellular calcium in A-23187 stimulated and beta-adrenoceptor blocking drug treated blood platelets.

A significant concentration-dependent difference was found between beta-adrenoceptor blocking drugs in their ability to inhibit A23187-induced isolated platelet aggregation. In the absence of extracellular calcium ions the following rank order of potency to inhibit calcium ionophore stimulated platelet aggregation was shown: propranolol > bevantolol > alprenolol > metipranolol > oxprenolol > atenolol > pindolol > metoprolol approximately sotalol approximately practolol. The interruption of induced aggregation, as well as inhibition of aggregation, in the absence of extracellular calcium ions indicated interference of inhibitory beta-adrenoceptor blocking drugs with intramembrane or intraplatelet calcium pools activated with A23187. This suggestion was supported by the reversal of the inhibitory effect of beta-adrenoceptor blocking drugs in the presence of extracellular calcium ions. The effect was dose dependent and occurred within 30 sec after calcium administration. The results indicated that inhibitory beta-adrenoceptor blocking drugs, possessing a cationic amphiphilic structure, suppressed calcium mobilization in A23187-stimulated platelets, most probably after entering platelets. This explains why lipophilic drugs are more effective than hydrophilic ones in calcium ionophore A23187-stimulated platelets.

Adrenergic beta-Antagonists↗
PubMed1979

The resolution of dopamine and beta 1- and beta 2-adrenergic-sensitive adenylate cyclase activities in homogenates of cat cerebellum, hippocampus and cerebral cortex.

The stimulation of adenylate cyclase by dopamine and various beta-adrenergic agonists has been investigated in homogenates from 3 areas of cat brain: the cerebral cortex, cerebellum and hippocampus. The purpose of the study was to determine whether the beta-arenergic receptors coupled to adenylate cyclase could be classified as either beta 1 and beta 2 subtypes in the different regions studied. The stimulation of adenylate cyclase by the beta-adrenergic agonist, (-)isoproterenol (5 X 10(-6) M), was completely blocked by the specific beta-adrenergic antagonist, (p)alprenolol (1-(-5) M), but not by the dopaminergic antagonist, fluphenazine (10(-5) M), whereas the stimulation of adenylate cyclase by (-)epinephrine (10(-4) M) was blocked to varying extents by these two drugs in each of the 3 regions studied. The (-)epinephrine effect was always blocked in the combined presence of (p)alprenolol and fluphenazine. The adenylate cyclase stimulation by (p)epinephrine which is not blocked by (p)alprenolol was due to interaction of (p)epinephrine with a dopaminergic-sensitive adenylate cyclase which has been characterized in cerebral cortex, hippocampus and cerebellum. Regional differences in the affinity of beta-adrenergic-sensitive adenylate cyclase for various agonists were investigated in the presence of fluphenazine (10(-5) M). In the cerebellum the potency order was (+/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (+/-)isoproterenol greater than (-)epinephrine greater than (+/-)salbutamol greater than (-)norepinephrine, indicating the presence of a beta 2-adrenergic receptor. In the cerebral cortex the potency order was (-)isoproterenol greater than +/-)protokylol greater than (+/-)hydroxybenzylisoproterenol greater than (-)epinephrine = (-)norepinephrine ((+/-)salbutamol being inactive). A similar pattern was found in the hippocampus indicating the presence of a beta 1-adrenergic receptor in these two regions. (+/-)Salbutamol was a partial agonist in the cerebellum and a competitive antagonist in the cerebral cortex. The ratio of the antagonist potencies of (+/-)practolol and (+/-)butoxamine preferential beta 1- and beta 2-adrenergic antagonists respectively, to block the stimulation of adenylate cyclase was 25 in the cerebellum, compared to 0.5 in the cerebral cortex and 1.6 in the hippocampus. These results confirm the presence of a beta 2 subtype of receptor coupled to adenylate cyclase in the former and beta 1 subtypes in the latter two regions. The comparison between the affinities of a series of beta-adrenergic agonists and antagonists for the beta-adrenergic receptors coupled with an adenylate cyclase in cerebral cortex and cerebellum with their affinities for well characterized beta 2-adrenergic receptors in lung and beta 1-adrenergic receptor in heart substantiated this conclusion.

Adenylyl Cyclases↗
PubMed1980

Some electrophysiological and pharmacological properties of the cortical, noradrenergic projection of the locus coeruleus in the rat.

The effect of repetitive stimulation of the locus coeruleus (LC) on the discharge rate of spontaneously active neurons of the visual, rostral and cingulate cortex was investigated in untreated and catecholamine-depleted rats under chloral hydrate anesthesia. In untreated animals, the inhibitory transsynaptic effects predominated over the excitatory ones. In catecholamine-depleted rats, the percentage of inhibited cells was significantly reducted in all areas. The vast majority of spontaneously active neurons in all cortical regions was depressed by microiontophoretically applied noradrenaline (NA). A few cells were resistant to NA; no excitatory effects were noticed on any cell. The transsynaptically mediated depression of the discharge rate of cells in all three cortical areas was reversibly antagonized by the iontophoretically administered beta-receptor blocking drug practolol. On the contrary the a-receptor blocking drugs piperoxane and WB4101 were ineffective in this respect. Thus, we tentatively conclude from these data that the NA-elicited depression of cells in the cortex is mediated by a receptor of the beta-type. Repetitive stimulation of the reticular formation elicited a desynchronizing effect on the EEG of chloral hydrate anaesthetized rats. LC stimulation, in contrast, hardly produced any modification of the EEG as judged by visual examination of the recordings.

Adrenergic alpha-Antagonists↗
PubMed1981

Selective survival of beta 1-adenergic receptors in rat cerebellum following neonatal x-irradiation.

Although beta 2-adrenergic receptors predominate in adult rat cerebellum, a small number of beta 1-receptors are also present. To investigate the cellular localization of beta 1- and beta 2-adrenergic receptors, the effects of intermittent neonatal X-irradiation focused on the cerebellum were determined on the densities of the two subtypes of beta-adrenergic receptor. This treatment destroys the late-maturing cerebellar interneurons including the granule, basket and stellate cells. A 60--70% loss of cerebellar mass was observed in 2-, 6- and 12-week-old animals. The large early-maturing Purkinje cells are resistant to the effects of X-irradiation. The total number of beta-adrenergic receptors per cerebellum, measured by Scatchard analysis of saturation isotherms of specific [125I]iodohydroxybenzylpindolol (IHYP) binding, was reduced by 70--80% in 2-, 6- and 12-week-old animals. The relative proportion of beta 1- and beta 2-receptors was determined by analyzing the inhibition of specific IHYP binding by the beta 1 selective antagonist practolol. The total number of beta 2-adrenergic receptors per cerebellum was reduced by 81--83% in 6- and 12-week-old X-irradiated rats. However, the number of beta 1-adrenergic receptors per cerebellum in 6- and 12-week-old X-irradiated rats was not significantly different from that in control animals. The results suggest that beta 2 receptors in the rat cerebellum are primarily associated with the small interneurons destroyed by neonatal X-irradiation. The beta 1 receptors may be located on a cell population which is unaffected by this treatment, possibly on cerebellar Purkinje cells.

Animals↗
PubMed1976

Hypotensive responses following oral adminstration of beta-adrenoceptor blocking drugs to the conscious cat.

On oral administration, the non-selective beta-adrenoceptor blocking drugs (+/-)-bufuralol, (-)-bufuralol, propanolol, oxprenolol, pindolol and alprenolol produced hypotensive responses in the conscious cat; (+)-bufuralol was without effect. The selective beta-adrenoceptor blocking drugs practolol and atenolol had no effect on blood pressure but tolamolol elicited a hypotensive response. All the drugs tested reduced the tachycardia due to intravenous isoprenaline in the conscious cat; however, not all doses of these drugs reduced blood pressure. (+)-Bufuralol was devoid to beta-adrenoceptive blocking activity. Only tolamolol reduced the pressor response to i.v. phenylephrine in the conscious cat, indicating that alpha-adrenoceptive blocking activity may contribute to its hypotensive action. The results suggest that beta-adrenoceptive blocking activity is necessary for the hypotensive responses of these drugs. However, for the different drugs, there was no correlation between peripheral beta-adrenoceptive blocking activity and hypotensive response.

Adrenergic alpha-Antagonists↗
PubMed1978

Effects of ionophores A23187 and X537A on vascular smooth muscle activity.

The ionophore A23187 initiated contractions in both dog coronary artery and rabbit aortic strips in a dose-dependent manner whereas X537A contracted rabbit aortic strips and relaxed KCl-induced contractions in dog coronary artery. Diphenylhydantoin (DPH) and verapamil ccompletely abolished KCl-induced responses in both vascular tissues. DPH (10(-4) M) partially prevented A23187-induced responses in both tissues and verapamil (33 micrometer) partially prevented A23187-induced responses in dog coronary artery but not in rabbit aorta. Phenoxybenzamine (10(-5) M), but not practolol, significantly reduced X537A-induced contractions in rabbit aortic strips but did not affect A23187-induced contractions in either tissue. The inability of DPH and verapamil to completely block the A23187 contractions leads one to conclude that these agents do not completely block calcium influx, or that A23187 does not work solely by increasing the permeability of the cell membrane to calcium. The effect of X537A on rabbit aorta, however, may be mediated at least partially, via release of catecholamines.

Animals↗
PubMed1978

Beta-adrenoceptors modulate noradrenaline release from axonal sprouts in cultured rat superior cervical ganglia.

Superior cervical ganglia of rats grown in organ culture were used to study the effect of beta-receptor stimulants and antagonists on 3H-noradrenaline release in response to stimulation by KC1 (75 mM). (--)-Isoprenaline 1X 10(-9)--1 X 10(-7) M) increased 20--25% the release of 3H-noradrenaline from cultured ganglia exposed to KC1. Isoprenaline did not modify either the spontaneous (non-calcium dependent) release of 3H-noradrenaline from cultured ganglia, or the KC1-stimulated release from fresh ganglia. The effect of (--)-isoprenaline was blocked by (--)-propranolol 5 X 10(-9) -- 1 X 10(-8) M and by butoxamine 10(-6) M, but not by (+)-propranolol (1 -- 5 X 10(-8) M), practolol (1 X 10(-8) -- 1 X 10(-6) M), or sotalol (1 X 10(-7) -- 1 X 10(-6) M). Isoprenaline induced augmentation of 3H-noradrenaline release and its antagonism by (--)-propranolol still occurred in the presence of DMI. It is suggested that presynaptic beta-receptors in sympathetic nerve terminals may be involved in a positive feedback of noradrenaline release.

Adrenergic beta-Antagonists↗
PubMed1978

Antidiuresis induced by beta1- and beta2-adrenergic agonists in ethanol-anesthetized rats.

The beta1- and beta2-components in antidiuresis and sodium retention induced by beta-adrenergic agonists were analysed in ethanol-anesthetized, water-diuretic rats. Intravenous infusions of isoprenaline, salbutamol and carbuterol did not affect insulin clearance but increased plasma renin concentration to the same same extent. Propranolol completely blocked the decreases in urine volume (V) and urinary sodium excretion (UNaV) induced by isoprenaline; practolol (beta1-blocker) inhibited only the decrease in UNaV and butaxamine (beta2-blocker) inhibited only the decrease in V. The ratios of doses of beta-agonists which decreased UNaV and by 50% (ED50 UNaV decrease/ED50 V decrease) were 0.34, 0.68, 1.56 and 2.36 for isoprenaline, tretoquinol, salbutamol and carbuterol, respectively. This increasing order of the ratios coincided with the order reported for the preponderance of the beta2- over beta1-component of these agonists. These results indicate that the decrease in UNaV induced by beta-agonists is related to beta1 stimulation, while the decrease in V is related to beta2 stimulation.

Adrenergic beta-Agonists↗