Selective Adrenoceptor Antagonist Research Articles

Modulation of lipopolysaccharide-induced tumor necrosis factor-α production by selective α- and β-adrenergic drugs in mice

In a previous study we demonstrated that mice pretreated with the highly selective α 2-adrenoceptor antagonist CH-38083 showed blunting of the tumor necrosis factor-α (TNF-α) response induced by bacterial lipopolysaccharide (LPS). In the present study, the effect of a selective block of α 2-adrenoreceptor and the role of the sympathetic nervous system (SNS) in the regulation of LPS-induced TNF-α production was explored further using different selective adrenoceptor antagonists and agonists. While adrenalectomy did not prevent the effect of CH-38083, the block of the sympathetic transmission by chlorisondamine fully abolished the inhibitory effect of CH-38083 on LPS-induced TNF-α production, suggesting that the effect of the α 2-adrenoceptor blocking agent is corticosteroid-independent, but it requires intact sympathetic activity. Since the selective block of α 2-adrenoceptors results in an increased sympathetic activity and an increase of the release of noradrenaline (NA) in both the central and the peripheral nervous systems, and in our experiments propranolol, a non-selective β-adrenoceptor antagonist, and atenolol, a selective antagonist of β 1-adrenoceptors, prevented the effect of α 2-adrenoceptor blockade by CH-38083 of the TNF-α response induced by LPS, it seems likely that the excessive stimulation by NA of β 1-adrenoceptors is responsible for this action. The role of β-adrenoceptors and endogenous catecholamines is further substantiated by the finding that pretreatment of animals with propranolol alone resulted in a dose-dependent increase of the TNF-α response induced by LPS, and that isoproterenol, a non-selective β-adrenoceptor agonist, decreased it. Additionally, it was shown that prazosin, an α 1-and α 2 B -adrenoceptor antagonist, reduced LPS-induced TNF-α production. However, l-phenylephrine, a selective α 1-adrenoceptor agonist, was not able to modulate the TNF-α response following LPS challenge. Our findings that α 2-and β-adrenoceptor antagonists are able to decrease or increase, respectively, the TNF-α response elicited by LPS indicate that SNS, through release of endogenous catecholamines, is involved in vivo in the regulation of LPS-induced TNF-α production. In this process, the β-adrenoceptor-mediated events seems to play a pivotal role. Since the blockade of sympathetic activity by chlorisondamine failed to affect LPS-induced TNF-α release, it seems likely that, in vivo, the inhibitory effect of SNS on TNF-α production, mediated via β-adrenoceptors, is opposed by an effect of catecholamines on α 2-adrenoceptors. It is suggested that the fine-tuning of TNF-α release exerted by SNS in vivo might be particularly important during immunological and non-immunological stress, when the concentration of catecholamines is increased in the close proximity of TNF-α-secreting cells, which are known to possess adrenoceptors.

Characterisation of beta-adrenoceptors in equine digital veins: implications of the modes of vasodilatory action of isoxsuprine.

Isolated equine digital veins (EDVs) were used to study beta-adrenoceptor mediated vasodilation and to examine isoxsuprine's vasodilatory mechanism of action. When the blood vessel wall tension was raised with potassium chloride solution (KCl; 59 mmol/l), the order of vasodilator potency of beta-agonists was: isoprenaline > fenoterol > noradrenaline > dobutamine > isoxsuprine. The beta 2-selective adrenoceptor antagonist, ICI 118551 (1 nmol/l) caused a 6.74 and 6.65-fold parallel shift to the right in the dose response curves to fenoterol and noradrenaline respectively. Propranolol (10 nmol/l) inhibited the vasodilatory action of isoprenaline in a competitive manner (19.6 +/- 6.4-fold parallel shift to the right) but was much less effective as an inhibitor of isoxsuprine's vasodilatory action. Isoprenaline and fenoterol were just as effective as vasodilators when blood vessel wall tension was raised with KCl, the thromboxanemimetic U44069 (9, 11-dideoxy-9 alpha, 11 alpha-epoxymethano-prostaglandin F2 alpha; 30 nmol/l) or the alpha 1-adrenoceptor agonist, phenylephrine (0.3 mumol/l). In addition, fenoterol's relaxation of U44069-induced tone was competitively inhibited by the beta 2-selective adrenoceptor antagonist ICI 118551 (8.4 +/- 0.9-fold parallel shift to the right). By contrast, isoxsuprine was 81.9 times more potent as a vasorelaxant of phenylephrine-induced tone when compared with KCl-induced tone and proved completely ineffective as a vasodilator of U44069-induced tone. When dose response curves to alpha-adrenoceptor vasoconstrictor agonists were obtained in the presence of isoxsuprine (0.1 mumol/l), competitive antagonism occurred with methoxamine and noncompetitive antagonism with BHT-920. These data suggest EDVs possess beta 2-adrenoceptors mediating vasodilation. Isoxsuprine is an alpha 1-selective adrenoceptor antagonist but has very low potency and efficacy as a beta-adrenoceptor agonist in this functional bioassay. Indeed, much of the vasodilatory action of isoxsuprine may be due to a mechanism which does not involve beta-adrenoceptors.

Inhibitory action of betaxolol, a β‐selective adrenoceptor antagonist, on voltage‐dependent calcium channels in guinea‐pig artery and vein

1. The effects of betaxolol, (+/-)-1-[4-[2-(cyclopropylmethoxy) ethyl] phenoxy]-3-(isopropylamino)-2-propanol hydrochloride, a beta 1-selective adrenoceptor antagonist, on voltage-dependent Ca2+ channels were investigated in single smooth muscle cells from guinea-pig mesenteric artery and portal vein using a whole-cell variant of the patch-clamp technique. Ca2+ channel currents were recorded with bath solutions contained 10 mM Ba2+ for arterial cells and 2 mM Ca2+ for venous cells. 2. Betaxolol inhibited Ca2+ channel currents dose-dependently in both mesenteric artery cells and portal vein cells. The two isomers, (+)-betaxolol and (-)-betaxolol (relative beta-antagonistic efficacies of 0.1 and 1, respectively), had similar potencies for inhibiting Ca2+ channel currents in portal vein cells. Propranolol did not inhibit the currents. Thus the inhibitory action of betaxolol on Ca2+ channel currents was independent of the beta-adrenoceptor. 3. The inhibitory action of betaxolol on Ca2+ channel currents was compared with that of diltiazem and of nifedipine in mesenteric artery cells. The current inhibition depended on the stimulation frequency with all drugs (use-dependent block). All drugs also accelerated the current decay and shifted the voltage-dependent inactivation curve in a negative direction. 4. In conclusion, betaxolol inhibited Ca2+ channel currents in vascular smooth muscle cells. The mode of inhibitory action was similar to that of diltiazem and nifedipine. Our results suggest that betaxolol is a unique beta-adrenoceptor antagonist that has a direct inhibitory action on voltage-dependent Ca2+ channels in vascular smooth muscle cells.

α1-Adrenoceptor-mediated sympathetically dependent mechanical hyperalgesia in the rat

The model of rolipram (a type IV phosphodiesterase inhibitor) induced prolongation (> 3 days) of the mechanical hyperalgesia produced by the intradermal injection of prostaglandin E 2 in the hairy skin of the hindpaw of the rat, measured by the Randall-Selitto paw-withdrawal test, was employed to study mechanisms involved in the contribution of the sympathetic postganglionic neuron to mechanical hyperalgesia. Lumbar surgical sympathectomy prevented rolipram-induced prolongation of prostaglandin E 2 hyperalgesia. Decentralization of sympathetic postganglionic neurons innervating the hindpaw did not, however, effect rolipram-induced prolongation of prostaglandin E 2 hyperalgesia. Phentolamine, an α-adrenoceptor antagonist, and prazosin, an α 1-selective adrenoceptor antagonist, when given systemically or intradermally at the site of injection of prostaglandin E 2 and rolipram, blocked rolipram-induced prolongation of prostaglandin E 2 hyperalgesia. Intrathecal administration of phentolamine and prazosin were, however, without effect on rolipram-induced prolongation of prostaglandin E 2 hyperalgesia. Yohimbine, an α 2-adrenoceptor antagonist given systemically, intradermally or intrathecally also did not produce any alteration in rolipram-induced prolongation of prostaglandin E 2 hyperalgesia. We propose that sympathetic postganglionic neurons are involved in rolipram-induced prolongation of prostaglandin E 2 hyperalgesia and that this form of sympathetically dependent hyperalgesia, which is independent of activity in preganglionic sympathetic neurons, is mediated by a peripheral α 1-adrenergic mechanism.

Effects of BRL-47672 on growth, beta 2-adrenoceptors, and adenylyl cyclase activation in female rats

The morpholine compound BRL-47672 has a chemical structure similar to that of clenbuterol and causes similar anabolic effects in rats but has no actions on beta 2-adrenoceptors in vitro. It has been argued therefore that beta 2-adrenoceptors do not mediate the anabolic effects of this family of compounds. In the present study BRL-47672 was shown to bind to rat beta 2-adrenoceptors with low affinity (dissociation constant 16 microM) relative to clenbuterol (48 nM) and to be a very weak activator of adenylyl cyclase activity in rat skeletal muscle membranes in vitro. In contrast, acute administration of the drug to anesthetized rats in vivo caused an increase in muscle adenosine 3',5'-cyclic monophosphate output, and chronic treatment of conscious rats for > 6 days caused a significant increase in weight gain (69%) accounted for by increased muscle growth. The anabolic effects of BRL-47672 were not counteracted by daily injections of the drug ICI-118551 (2 mg/day) but were prevented when the same beta 2-antagonist was administered in the diet (200 mg/kg feed, equivalent to 4.3 mg/day). The beta 1-adrenoceptor selective antagonist CGP-20712A fed in the diet (200 mg/kg feed) failed to attenuate the response to BRL-47672. These results support the conclusion that BRL-47672 has little direct action on beta 2-adrenoceptors but suggest that the compound is metabolized rapidly in vivo to a potent beta 2-agonist. Thus the stimulation of muscle growth by BRL-47672 is via beta 2-adrenoceptors, with no contribution to this response from beta 1- or beta 3-adrenoceptor activation.

Beta-adrenoceptor-mediated facilitation of endogenous noradrenaline release from rat isolated trachea.

Overflow of endogenous noradrenaline from rat isolated trachea was evoked by electrical field stimulation (3 Hz, 540 pulses) in the presence of yohimbine, desipramine and tyrosine. Isoprenaline 100 nmol/l increased the evoked overflow of noradrenaline by about 65%. This effect was antagonized by propranolol (100 nmol/l) and the beta 2-selective adrenoceptor antagonist ICI 118,551 (100 nmol/l), but not by the beta 1-selective adrenoceptor antagonist CGP 20712 A (100 nmol/l). The beta 2-selective adrenoceptor agonist formoterol (1-100 nmol/l) also facilitated the evoked overflow of noradrenaline, but maximally by only about 25% at 10 nmol/l, i.e. formoterol behaved as a partial agonist at these facilitatory beta-adrenoceptor. This assumption is also supported by the observation that formoterol (10 nmol/l) acted as antagonist against isoprenaline (100 nmol/l). Mechanical removal of the mucosa resulted in a 30% decrease in tissue noradrenaline and a 55% reduction of the evoked overflow of noradrenaline. In mucosa-denuded preparations isoprenaline failed to facilitate noradrenaline overflow. In the presence of indomethacin (3 mumol/l) the evoked overflow of noradrenaline from mucosa containing preparations was increased by about 50%, but isoprenaline still further facilitated the evoked noradrenaline overflow by about 40%. In conclusion, the overflow of noradrenaline in the rat trachea is facilitated via beta 2-adrenoceptors, an effect which requires an intact airway mucosa.

Metoprolol: a pharmacoeconomic and quality-of-life evaluation of its use in hypertension, post-myocardial infarction and dilated cardiomyopathy.

Metoprolol is a beta 1-selective adrenoceptor antagonist that is widely used in several indications. A recent investigation has also highlighted a potential role for metoprolol in selected patients with idiopathic dilated cardiomyopathy. Pharmacoeconomic and quality-of-life data for metoprolol are limited to the areas of hypertension, post-myocardial infarction and idiopathic dilated cardiomyopathy. In these settings, metoprolol has shown beneficial effects on morbidity and mortality, or closely-related end-points. Controlled release formulations offer the potential to maximise the confirmed antihypertensive benefits of metoprolol by maintaining clinically effective plasma drug concentrations within a narrow range over a 24-hour interval between doses. Recent data support the use of controlled release metoprolol at the low dose of 50 mg/day. Metoprolol is at least as effective as many other antihypertensive drugs, although compared with thiazide diuretics at relatively high doses in the MAPHY (Metoprolol Atherosclerosis Prevention in Hypertensives) trial, metoprolol was associated with a more favourable effect on mortality. Pharmacoeconomic analysis, also based on the MAPHY trial, indicates that metoprolol is more cost effective than high dose thiazide diuretics in middle-aged men with mild to moderate hypertension. However, the advantage for beta-blockade in this trial is not supported by results of other studies, and the applicability of these data to current medical practice using lower thiazide doses is therefore questionable. Quality of life in patients with mild to moderate hypertension did not deteriorate in most investigations with metoprolol. Furthermore, quality of life was similar for controlled release metoprolol and atenolol. With conventional/matrix-based sustained release metoprolol, quality of life was less satisfactory than with lisinopril but was only marginally different from that with diltiazem (at lower than usual therapeutic doses). Nevertheless, these newer agents have no proven beneficial effect on mortality, and further studies are also warranted with controlled release metoprolol 50 mg/day. When administered post-myocardial infarction, conventional metoprolol was associated with significant improvements in quality of life and was cost saving over a 3-year period. Significant improvements in quality of life were also evident for metoprolol-treated patients with idiopathic dilated cardiomyopathy. In summary, available data support the continued extensive usage of metoprolol as treatment for hypertension and as therapy post-myocardial infarction. Pharmacoeconomic data supporting an advantage for metoprolol over high dose thiazides in hypertension needs further assessment in settings reflecting usual general practice approaches to managing patients with hypertension, while differences in quality of life between metoprolol and other antihypertensive agents appear to be marginal.(ABSTRACT TRUNCATED AT 400 WORDS)

Vasoconstrictors and Renal Protection Induced by β-Selective Adrenoceptor Antagonist Bisoprolol

We investigated the role of the vasoconstrictors endothelin-1 (ET-1) and thromboxane in renal protection by the beta 1-selective adrenoceptor antagonist, bisoprolol, in Dahl salt-sensitive rats (Dahl S) and salt-resistant rats (Dahl R). Six-week bisoprolol treatment (20 mg/kg chow) reduced systolic blood pressure (SBP) by 14% in Dahl S rats fed a high-salt (4% NaCl) diet. This BP reduction was accompanied by a decrease in aortic wall thickness. ET-1 and thromboxane released from renal cortex was significantly decreased by 17 and 30% with bisoprolol, respectively. Other prostaglandin synthesis was unaffected. Renal function such as proteinuria, N-acetyl-beta-D-glucosaminidase (NAG) excretion, and glomerular filtration rate (GFR) was not influenced by bisoprolol. Morphologic investigation showed that bisoprolol significantly improved glomerular sclerosis by 29% and attenuated arterial damage by 71%, although tubular injury was not affected. The more severe the glomerulosclerotic lesions, the greater the generation of thromboxane and ET. The arterial lesions were positively correlated to thromboxane generation. These data indicate that long-term bisoprolol treatment reduces vasoconstrictive ET-1 and thromboxane generation and that these alterations may be partly responsible for the amelioration of glomerular and arterial injury in Dahl S rats.

Characterization of noradrenaline-stimulated cyclic GMP formation in brain astrocytes in culture.

Cyclic GMP accumulation induced by noradrenaline in astrocyte-enriched primary cultures from rat cerebrum involves synthesis of NO, as evidenced by the competitive inhibition exerted by the NO synthase inhibitor NG-monomethyl-L-arginine (IC50 = 3 microM). Furthermore, the noradrenaline effect was potently inhibited by haemoglobin (IC50 = 25 nM) and potentiated by superoxide dismutase, indicating that NO synthesis and cyclic GMP formation may occur in different subsets of astrocytes. Investigation of the receptors implicated by using selective adrenoceptor agonists and antagonists indicates that about 75% of the NO-dependent noradrenaline response is mediated by alpha 1-adrenoceptors and the rest by beta-adrenoceptors, with no evidence for potentiating effects between the two receptor types. This noradrenaline effect appears to require Ca2+ entry, since it is strongly dependent on extracellular Ca2+ but is not affected by conditions that will abolish intracellular Ca2+ mobilization (incubation with neomycin or pretreatment with carbachol). Inhibition by pretreatment with pertussis toxin is in agreement with involvement of the alpha 1A-adrenoceptor subtype in this Ca(2+)-dependent effect. However, implication of an unknown alpha 1-adrenoceptor subtype cannot be disregarded, because a similar inhibition is exerted by the presumably selective alpha 1B- and alpha 1C-adrenoceptor blocking agent chloroethylclonidine. Treatment of the cultures with the protein kinase C activator phorbol 12-myristate 13-acetate inhibits to a great extent the noradrenaline-induced cyclic GMP formation.

Effects of noradrenaline on rat paratracheal neurones and localization of an endogenous source of noradrenaline.

1. Intracellular recording techniques were used to study the actions of exogenous noradrenaline (NA) on rat paratracheal neurones in situ. The receptor subtypes underlying these actions were investigated by application of selective adrenoceptor antagonists. 2. Application of NA (0.1-10 microM) by superfusion evoked a membrane depolarization in 85% (52 out of 61) of all paratracheal neurones studied. The response consisted of a slow depolarization which was sometimes accompanied by action potential discharge. In 26 out of 31 cells the response was associated with a change in input resistance of the cell membrane. In 22 out of 26 cells there was a 30% increase, whilst in a further 4 cells there was a 15% decrease in input resistance. The amplitude of the NA depolarization was concentration-dependent. 3. The depolarization evoked by NA was reversibly antagonized by prazosin (1 microM) but unaffected by yohimbine (1 microM) or propranolol (1-10 microM). 4. High performance liquid chromatography with electrochemical detection (h.p.l.c.-e.c.d.) was used to assay for NA and dopamine in samples containing mainly paratracheal ganglia and in samples of tracheal smooth muscle with mucosa. NA was present in all samples assayed at a level of 1.6 micrograms NA g-1 and 0.5 microgram NA g-1 wet weight of the two sample types respectively. Dopamine was not detected in any samples of either ganglia or smooth muscle with mucosa. 5. It is concluded that NA-evoked depolarizations of rat paratracheal neurones result from stimulation of alpha 1-adrenoceptors, and that local levels of NA may be sufficiently high to activate these receptors directly.

Action of ciguatoxin on human atrial trabeculae

This report describes the action of ciguatoxin-1, the major ciguatoxin present in fishes that cause ciguatera, on the contractile activity of human cardiac musculature. Ciguatoxin-1 caused a large, sustained and concentration-dependent positive inotropy in human atrial trabeculae that were obtained during coronary artery bypass surgery from otherwise healthy hearts. Atenolol (a β 1-adrenoceptor selective antagonist without local anaesthetic-type activity) or low concentrations of tetrodotoxin abolished the positive inotropy caused by ciguatoxin-1, indicating that ciguatoxin-1 stimulated neural elements present in this tissue to release noradrenaline. The positive inotropic action of ciguatoxin-1 did not stem from a significant direct action on myocardial voltage-dependent sodium channels, nor did it stem from significant α 1- or β 2-adrenoreceptor stimulation. Ciguatoxin-1 caused positive inotropy in preparations stimulated at between 0.02 and 2.0 Hz. Mannitol, currently the treatment of choice for ciguatera, did not significantly reverse the positive inotropy induced by ciguatoxin-1 in human atrial trabeculae.

Effects of the β-adrenoceptor antagonists atenolol and propranolol on human whole saliva flow rate and composition

The effects of β-adrenoceptor antagonists on salivary secretion have been extensively studied in animals but not in man. The aim here was to compare salivary flow rate and composition in man during 1 week of treatment with a non-selective (propranolol 80 mg b.i.d.) and a β 1-selective (atenolol 50 mg o.d.) antagonist with that of placebo. The randomized, double-blind, cross-over (“Latin square”) design was used and 42 healthy male volunteers were recruited to the study. The treatment periods were separated by a wash-out period of 2 weeks. Whole saliva was sampled on day 0 (before) and on day 7 during each treatment. The plasma concentration of propranolol and atenolol was determined from blood samples obtained on day 7. Resting saliva was assessed for flow rate, amylase activity and concentration of total protein, hexosamine and sialic acid. Stimulated saliva was assessed for flow rate, pH, buffer pH, amylase activity and concentration of total protein, Ca 2+, Mg 2+, Na +, K +, Cl − and PO 4 2−. In resting as well as stimulated whole saliva both the total protein concentration and the amylase activity were significantly decreased during the active treatment periods ( p < 0.05– p < 0.001). At lunchtime during atenolol treatment the hexosamine/total protein and the sialic acid/total protein ratios were significantly increased ( p < 0.05– p < 0.01), suggesting a possible effect on protein synthesis. In addition, the concentrations of Ca 2+, PO 4 2−, Cl − and Mg 2+ were significantly altered during the active treatment periods ( p < 0.05– p < 0.001). The results suggested that the ductal Na + and Cl − transport is under β-adrenoceptor control. Therapeutic doses of either the non-selective (propranolol) or the β 1-selective (atenolol) adrenoceptor antagonist thus significantly altered the composition of resting as well as stimulated whole saliva in healthy male volunteers, without affecting secretion rates.

Celiprolol exerts microvascular dilatation by activation of beta 2-adrenoceptors.

In order to clarify the question whether the beta 1-selective adrenoceptor antagonist celiprolol possesses vasodilating properties, isolated vascular networks were perfused with increasing concentrations of celiprolol (in a cumulative manner) ranging from 10(-8) to 10(-4) mol/l. The study was carried out using the isolated mesenteric vascular bed of the guinea pig mesenterium coli. Vascular diameters of four different vascular regions [vessels classified as G1 (585 +/- 30 microns), G2 (403 +/- 25 microns), G3 (282 +/- 27 microns) and G4 (197 +/- 13 microns)] were assessed by means of microscopic videoangiometry. Perfusion with celiprolol resulted in concentration dependent vasodilation which was more pronounced in G3 and G4 vessels. In addition, cumulative concentration-response curves were determined from responses obtained in the presence of 10(-8), 10(-7), 10(-6) and 10(-4) mol/l ICI 118,551 (a highly selective adrenoceptor antagonist). In the presence of ICI 118,551 at concentrations greater than or equal to 10(-6) mol/l, no celiprolol response could be observed. Lower concentrations of ICI 118,551 shifted the celiprolol concentration-response curve to the right in a concentration-dependent manner. Therefore, it is concluded (a) that celiprolol has a vasodilating effect, (b) that this vasodilation is produced by stimulation of beta 2-adrenoceptors and (c) that the vasodilating effect is more pronounced in smaller than in larger vessels (G3, G4 vs G1, G2).

Are circulating catecholamines involved in the control of breathing by fishes?

In this review, we have provided evidence that elevated levels of circulating catecholamines are not a significant factor in the control of ventilation in fishes, but rather that this critical physiological function is controlled primarily by the external and/or internal respiratory status. This view, which opposes the more traditional consensus (review: Randall and Taylor, 1991), is based upon numerous experimental observations, theoretical considerations, and a re-evaluation of previous studies. First, circulating catecholamine levels become elevated in fish only as a final survival strategy during severe stress, whereas hyperventilatory responses begin with very slight alterations in blood/water chemistry. Thus, except during extreme stress, plasma catecholamine levels and gill ventilation volume (V w) do not co-vary. Second, with the notable exception of the European eel (Anguilla anguilla; Peyraud-Waitzenegger, 1979), experimental elevations of circulating catecholamine levels by injection/infusion of adrenalin or noradrenalin either do not alter ventilation in a physiologically significant manner or may occasionally even depress ventilation. Further, the sudden release of endogenous catecholamines during severe stress does not appear to modify the pre-existing hyperventilatory response. Third, although treatment of fish with selective adrenoceptor antagonists has yielded conflicting results to both support and reject a role for circulating catecholamines in the control of ventilation, it is nonetheless clear that such as experimental protocol cannot adequately differentiate between central and peripheral adrenergic phenomena. We suggest that there is no basis to support a role for circulating catecholamines in the regulation of breathing in fishes, and contend that discrepancies in the literature reflect the inherent difficulties associated with separating neural and humoral adrenergic phenomena.

Beta 1- and beta 2-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart

The augmentation of cardiac inotropism induced by electrical stimulation of acutely decentralized efferent preganglionic sympathetic axons is reduced after the administration of timolol into the major ipsilateral intrathoracic ganglia. Thus it has been proposed that, in addition to nicotinic synapses, beta-adrenergic ones exist in intrathoracic ganglia that are involved in the efferent sympathetic regulation of the mammalian heart. Whether these are beta 1- as opposed to beta 2-adrenoceptor subtypes is unknown. In the present series of experiments, acutely decentralized canine efferent preganglionic sympathetic axons were stimulated before and after the administration of beta 1 (atenolol)- or beta 2 (ICI 118551)-selective adrenoceptor antagonists into the ipsilateral stellate and middle cervical ganglia to determine whether beta 1- or beta 2-adrenoceptors exist in intrathoracic ganglia that are involved in cardiac regulation. Augmentations of right and left ventricular inotropism induced by efferent preganglionic sympathetic axon stimulation were attenuated when either agent was administered into the major ipsilateral intrathoracic sympathetic ganglia. Myocardial liberation of norepinephrine evoked by these stimulations was also reduced after intraganglionic administration of either agent. These data indicate that canine intrathoracic neurons contain beta 1- and beta 2-adrenoceptors that are involved in the efferent sympathetic regulation of the heart.

Characterization of β1- and β2-adrenoceptors in rat skeletal muscles

Binding studies with (−)-[ 125I]cyanopindolol (ICYP) were conducted to characterize β-adrenoceptors in plantaris and soleus muscles of rats (male, 250–300 g). The distribution of β 1- and β 2-adrenoceptors in different muscle fiber types, identified in serial sections by succinic dehydrogenase (SDH) staining, was studied by autoradiography. The densities of binding sites (B max, mol/mg protein) were 5.4 ± 0.9 (mean ± SEM) in plantaris and 11.5 ± 2.0 in soleus muscle. In plantaris muscle, monophasic competition curves were observed when binding experiments were performed using CGP 20712A (50 pM to O.SmM), a β 1-adrenoceptor selective antagonist, or ICI 118,551 (50 pM to 20,μM), a β 2-adrenoceptor selective antagonist, to compete for ICYP binding. Analysis with LIGAND revealed a single binding site with a K D value of 2.41 ± 0.56 nM (mean ± SEM) for ICI 118,551 and 8.93 ± 3.00 μM for CGP 20712A, indicating the presence of a homogeneous population of β 2-adrenoceptors. In soleus muscle, competition curves were biphasic with 16–21% β 1-adrenoceptors. Autoradiographic studies supported the findings from binding studies with membrane homogenates. The ICYP binding pattern was associated closely with the muscle fiber types identified by SDH staining. Propranolol-resistant binding sites were observed, and these sites were associated with muscle fibers positive to SDH staining.

Effects of selective adrenoceptor agonists and antagonists on aggressive behavior elicited by apomorphine, DL-DOPA and fusaric acid in REM-sleep-deprived rats

REM sleep deprivation (REMSD) results in behavioral changes such as the appearance of affective aggression induced by apomorphine (APO) and other dopaminergic agents. REMSD modifies dopamine-mediated behavior as well as the adrenergic receptor sensitivity. This paper evaluates the interaction between these two neurotransmission systems through changes in APO-, DL-DOPA- and fusaric acid (FA)-induced aggressive behavior in REMSD rats pretreated with phentolamine, propranolol, metaraminol, prazosin, clonidine, yohimbine, isoproterenol, butoxamine and maprotiline. Only isoproterenol reduced FA-induced aggressiveness. No specific changes in aggressiveness were noticed with other treatments and not even inhibitors of norepinephrine transmission induced aggressive behavior. It is concluded that norepinephrine had a slight inhibitory action on aggressiveness elicited by dopaminomimetic agents in REMSD rats. Beta-adrenoceptors could be responsible for this effect since only beta-selective drugs reduced aggression. As REMSD reduces beta-adrenoceptor sensitivity, only minor changes in aggressiveness could be observed. It was noted that the three drugs used to induce aggressive behavior elicited different patterns of aggression.

Celiprolol

Celiprolol is a hydrophilic, beta 1-selective adrenoceptor antagonist with mild selective beta 2-agonist as well as weak vasodilator properties. Celiprolol 200 to 400mg once daily by mouth is similar in antihypertensive efficacy to usual doses of propranolol, atenolol, metoprolol and pindolol in patients with mild to moderate systemic hypertension. Similar doses of celiprolol are as efficacious as propranolol and atenolol in improving exercise tolerance and reducing the frequency of anginal attacks in patients with angina pectoris. Further clinical experience suggests that celiprolol does not produce bronchoconstriction and may have mild bronchodilating activity in asthmatic patients; it may also enhance the effects of bronchodilator drugs. Celiprolol has a slightly beneficial effect on serum lipid profiles, and does not appear to exert adverse effects on carbohydrate metabolism. If the apparent pharmacodynamic advantages of celiprolol translate into clinical benefits and are confirmed in well designed long term clinical trials, then celiprolol should represent a definite advance in beta-blocker therapy.

Behavioral and biochemical studies in rats following prenatal treatment with β-adrenoceptor antagonists

Increased motor activity and poor performance in the active avoidance test were observed in the offspring of rats treated with d1-propranolol or sotalol during pregnancy, but not with atenolol and d-propranolol. All substances were administered in drinking water from days 8–22 of gestation. A significant increase in the density of muscarinic acetylcholine receptors in the hippocampus was found for dl-propranolol and sotalol, at 35 and 20 days of age, respectively. Twenty-day-old pups bom to dl-propranolol-treated rats exhibited a non-significant decrease in the number of β-adrenoceptors in the frontal cortex. Assuming that all the β-adrenoceptor antagonists tested had access to the developing fetal brain, the effect of dl-propranolol and sotalol on behavior could stem from central β 2-adrenoceptor blockade. In view of the lack of behavioral changes after atenolol, a β 1-selective adrenoceptor antagonist, it is suggested that the clinical use of β 1-selective adrenoceptor antagonists during pregnancy might be safer for the fetus than β 2-adrenoceptor antagonists.

Central and peripheral control of sympathoadrenal activity and energy metabolism in rats

The role of adrenoceptors in the hypothalamus and the peripheral sympathetic nervous system in the regulation of sympathoadrenal activity and glucose and FFA mobilization was investigated in exercising rats. Apparent close relations within the two parts of the sympathoadrenal system and between factors that regulate glucose and FFA mobilization during exercise were completely disrupted by local hypothalamic infusions of adrenoceptor antagonists or anesthetic drugs. The experiments actually identified specific areas in the hypothalamus that integrate the information regarding the substrate levels in the blood with the “central command” from higher centers in the brain. Furthermore, the results of experiments with exercising intact and adrenodemedullated (Adm) rats, with and without administration of selective adrenoceptor agonists and antagonists, suggest that the activity of the sympathetic nervous system is also regulated at the level of the peripheral sympathetic nerve endings. In particular, presynaptic adrenergic regulatory mechanisms can markedly influence the outflow of NE from the sympathetic nerve endings. In conclusion, the data show that an organ-specific organization of sympathetic output during exercise may take place at different levels within the sympathetic nervous system.