SEARCH · Search PubMed

Results for “Practolol”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

SourceResearch connectionFrom yearThrough year

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,315 records · Page 73Linked to original sources

PubMed1983

Haemodynamic consequences of intrinsic sympathomimetic activity in relation to changes in plasma renin activity and noradrenaline during beta-blocker therapy for hypertension.

The acute and long-term haemodynamic effects of pindolol, practolol, alprenolol, oxprenolol, acebutolol, penbutolol, metoprolol, atenolol, propranolol and timolol in patients with uncomplicated hypertension as reported in the literature were analysed. The long-term effects of these beta-adrenoceptor antagonists on plasma renin activity and the concentration of noradrenaline in plasma were also reviewed. In spite of the many pharmacological and physicochemical differences the drugs appeared to have a hypotensive effect of approximately equal magnitude. The degree of cardiodepression and the suppression of plasma renin activity as exerted by the different beta-blockers were inversely correlated with their pharmacologically defined degree of intrinsic sympathomimetic activity (ISA). The increments in vascular resistance acutely after administration of a beta-blocker are proportional to the degree of cardiodepression, suggesting that increased vasoconstrictor nerve activity mediated through the baroreflex had prevented an acute fall in arterial pressure in response to a given fall in cardiac output. After long-term therapy the inverse correlation between changes in cardiac output and changes in vascular resistance is shifted to a lower level of vascular resistance. Plasma renin activity and vascular resistance are inversely correlated during long-term beta-blocker therapy for hypertension. Consequently, the fall in vascular resistance underlying the hypotensive effect of beta-blockers cannot be explained by suppression of plasma renin activity. Thus, cardiodepression and renin suppression are not essential for the hypotensive effect of beta-adrenoceptor antagonists. The accessibility of the central nervous system to the different beta-blockers neither determines the time of onset of blood pressure reduction nor the magnitude of this effect. If it is neither the blockade of postsynaptic beta-adrenoceptors in the heart or on juxtaglomerular cells, nor the blockade of central beta-receptors that can be held responsible for the blood pressure lowering efficacy of beta-adrenoceptor antagonists, one is left with the remaining possibility that blockade of presynaptic beta-receptors underlies the vasodilator and antihypertensive action of these drugs. Changes in the concentrations of noradrenaline in plasma are compatible with this supposition, provided that changes in clearance of noradrenaline from plasma are taken into account.

Adrenergic beta-Antagonists↗

PubMed1984

Alterations in cardiac alpha and beta adrenoceptors during the development of spontaneous hypertension.

To study potential cardiac receptor alterations during the development of spontaneous hypertension, specific binding of [3H]-2-N(2,6-dimethoxyphenoxyethyl)amino-methyl-1,4-benzodioxane, (-)-[3H]dihydroalprenolol and (-)-[3H]quinuclidinyl benzilate in ventricles of Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) at different ages was determined. The Kd and maximal binding for specific binding of [3H]-2-N(2,6-dimethoxyphenoxyethyl)amino-methyl-1,4-benzodioxane and (-)-[3H]dihydroalprenolol in ventricular homogenates of SHR and SHRSP at prehypertensive ages were similar to those of age-matched WKY. With the development of spontaneous hypertension in SHR and SHRSP, there was a significant decrease in the maximal binding for both ligands without a change in Kd. The decrease in maximal binding in SHR and SHRSP at 10 weeks of age was 29 to 38%, compared with age-matched WKY. There was no difference in ventricular (-)-[3H]quinuclidinyl benzilate binding between WKY and SHRSP. Hofstee analysis of the inhibition of ventricular (-)-[3H]dihydroalprenolol binding by practolol demonstrated a specific 51% decrease in ventricular beta-1 receptor density in 10-week-old SHRSP. In addition, the inotropic response to isoproterenol in isolated papillary muscles from SHRSP was significantly smaller than that in WKY. Thus, it is concluded that during the development of spontaneous hypertension in SHR and SHRSP, there is a specific loss in number of cardiac alpha and beta-1 adrenoceptors with a consequently reduced responsiveness of isolated papillary muscles to isoproterenol in SHRSP. These results are compatible with the reported increase in sympathetic outflow to the cardiovascular system in spontaneous hypertension.

Adrenergic alpha-Antagonists↗

PubMed1984

Beta-blockers in the secondary prevention of myocardial infarction: a review of clinical trials of 12 months or more duration.

Data from six placebo-controlled prevention trials studying the effect of beta-blocker therapy after myocardial infarction are reviewed for comparison. The beta-blockers chosen for this review were practolol, oxprenolol, timolol, sotalol and propranolol. All studies had a duration of at least 12 months and treatment was started not earlier than 4 days and not later than 4 months after the onset of infarction. The patient selection did not reveal marked differences concerning the pre-infarct history whereas risk factors at entry varied considerably between the trials. In spite of these differences, all of the six studies showed a reduction in overall mortality and in the rate of non-fatal reinfarctions of the treated group as compared with placebo. Based on these results, the practical implications are discussed in an attempt to draw some general guidelines concerning the management of therapy. Finally, it appears that beta-blocking activity is the common factor for improving the long-term survival of post-infarction patients.

Adrenergic beta-Antagonists↗

PubMed1984

L-3,4-(3-3,4-dimethoxyphenethylamino-2-hydroxypropoxy)-phenyl- crotonic acid nitrile.HCl (Hoe 224), a beta-blocking agent with high beta 1-selectivity.

L-3,4-(3-3,4-Dimethoxyphene-ethylamino-2-hydroxypropoxy)-phenyl-++ +crotonic acid nitrile X HCl (Hoe 224) has beta 1-blocking action. In the isolated left atrium of the guinea pig, the ED50 necessary to counteract the positive inotropic action of 2 ng/ml isoprenaline (isoproterenol) was determined as 10.3 ng/ml in comparison to the ED50 of propranolol 2.7 ng/ml. On the isolated right atrium of the same animal, the ED50 for inhibition of increased heart rate brought about by 2 ng/ml isoprenaline was 29.5 ng/ml in comparison to the ED50 of propranolol 13.5 ng/ml. On the isolated tracheal chain of the guinea pig 40 micrograms Hoe 224/ml also inhibited relaxation induced by 50 ng isoprenaline/ml only by 31%. The ED50 for propranolol in this experiment was 1.2 ng/ml. Therefore, Hoe 224 is a very specific beta 1-blocker. In the dog anaesthetized with pentobarbital the ED50 of Hoe 224 for depression of dp/dt increase by 0.1 mg isoprenaline/kg i.v. was determined as 85 micrograms/kg i.v. Under the same conditions, the ED50 for propranolol was 10 micrograms/kg i.v., for atenolol 17 micrograms/kg i.v., for practolol 56 micrograms/kg i.v. In the conscious dog, 1.6 mg Hoe 224/kg orally depressed the increase of dp/dt brought about by 0.1 microgram isoprenaline/kg i.v. by 50%. The beta 2-blocking effect of Hoe 224 intraarterially against vasodilating effect of 0.01 microgram isoprenaline/kg given intraarterially in the A. femoralis of anaesthetized dogs was very weak. 100 micrograms Hoe 224/kg reduced the effect of isoprenaline only by 23%, but 2 micrograms propranolol/kg intraarterially reduced this effect by 61%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1983

On the relationship between aggregation and cyclic nucleotides in platelets treated with betaadrenoceptor blocking drugs.

The inhibition of aggregation of rat platelets treated with betaadrenoceptor blocking drugs alprenolol, exaprolol, metipranolol, practolol and propranolol, and stimulated with adenosinediphosphate was shown to be dose-dependent. Atenolol in all concentrations potentiated the aggregation. The stimulated aggregation was potentiated by low and decreased by high concentrations of doberol. Cyclic adenosinemonophosphate was decreased in platelets treated with all the betaadrenoceptor blocking drugs used. On the other hand, a dose-dependent increase in the cyclic guanosinemonophosphate content was evident in betaadrenoceptor blocker-treated platelets. The interaction of betaadrenoceptor blocking drugs with the aggregation of blood platelets seems not to be mediated through cyclic nucleotides.

Adenosine Diphosphate↗

PubMed1984

Dopamine stimulated glycosylation of brain proteins in vitro is inhibited only partially by dopamine receptor antagonists.

Dopaminergic agonists which act on adenylate cyclase-linked dopamine receptor sites (D1-type) (dopamine, apomorphine and ADTN) induced a dose-dependent increase in the incorporation of L-fucose and D-mannose into glycoproteins of hippocampal, striatal and cortical slices of rat and mouse brain, whilst in rat liver slices dopamine failed to elicit such alterations in protein glycosylation. Testing in slices of rat hippocampus dopaminergic agonists with selective affinity to D2-receptors (bromocriptine, ergometrine) no changes in sugar incorporation into glycoproteins of rat hippocampus were observed. Dopamine stimulated L-fucose incorporation into rat hippocampal glycoproteins was inhibited to a different degree, but almost incompletely by dopamine receptor antagonists like haloperidol, D-butaclamol, promazine and alpha-flupenthixol, whilst chloropromazine and the selective D2-receptor antagonist sulpiride were without any effects. Also serotonin receptor antagonists (cinanserine) and beta-adrenergic receptor blockers (pindolol, alprenolol, practolol) failed to interfere with this dopamine action. But D,L-propranolol enhanced dopamine stimulated glycosylation of rat hippocampal proteins in an additive synergistic manner. This effect appeared to be not related to the antagonistic action of propranolol on beta-adrenergic receptor sites. From our results it is concluded that interactions with dopamine receptor sites (D1-type) is only one part of the mechanism triggering dopamine stimulated glycosylation of brain proteins in vitro.

Adrenergic beta-Antagonists↗

PubMed1984

Involvement of the vascular renin-angiotensin system in beta adrenergic receptor-mediated facilitation of vascular neurotransmission in spontaneously hypertensive rats.

This study was conducted to investigate the possible involvement of the vascular renin-angiotensin system in the isoproterenol (ISO)-induced facilitation of adrenergic neurotransmission in the mesenteric vasculature. The isolated, perfused mesenteric vascular beds from normotensive Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were used for these studies. ISO at concentrations from 10(-9) to 10(-6) M caused significantly greater enhancement of the pressor response to periarterial nerve stimulation (PNS) in preparations from SHR than in those from WKY. The pressor responses to exogenous norepinephrine (NE) were, however, inhibited by ISO to a similar degree in preparations from both WKY and SHR. The enhancement of the PNS response produced by ISO was markedly attenuated by propranolol at 5 X 10(-7) M (nonselective beta receptor blocker) and by ICI 118,551 at 5 X 10(-7) M (selective beta-2 receptor blocker), whereas practolol at 5 X 10(-6) M (selective beta-1 receptor blocker) caused a potentiation of the ISO-induced enhancement of responses to PNS in preparations from both WKY and SHR. All three beta blockers generally abolished the ISO-induced inhibition of the pressor responses to exogenous NE. The selective beta-2 adrenergic receptor agonists, salbutamol (3 X 10(-8) to 3 X 10(-7) M) and terbutaline (10(-7) to 3 X 10(-7) M), caused significantly greater enhancement of the PNS response in preparations from SHR than in those from WKY, whereas the selective beta-1 agonist, dobutamine, caused only inhibition of the PNS responses in preparations from both WKY and SHR. These three agonists all tended to reduce the pressor responses to exogenous NE. The ISO-induced enhancement of the responses to PNS was also significantly reduced by either captopril (5 X 10(-6) M) or [Sar1-Ile8]angiotensin II (5 X 10(-7) M) in preparations from SHR. Neither captopril nor [Sar1-lle8] angiotensin II had an effect on the pressor response to NE infusion or on the ISO-induced inhibition of NE responses. Angiotensin I produced an enhancement of the pressor responses to PNS and to NE infusion with the effect being greater on the response to PNS than to NE in the preparations from SHR but not in those from WKY. This enhancement of the PNS response by angiotensin I was abolished by either captopril (5 X 10(-7) M) or [Sar1-Ile8]angiotensin II (5 X 10(-7) M) in preparations from both WKY and SHR.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Sarcosine-8-Isoleucine Angiotensin II↗

PubMed1984

Effects of celiprolol (REV 5320), a new cardioselective beta-adrenoceptor antagonist, on in vitro adenylate cyclase, alpha- and beta-adrenergic receptor binding and lipolysis.

Celiprolol has been previously shown in vivo to be an effective beta-adrenergic antagonist with cardio-selectivity and weak intrinsic sympathomimetic activity but no membrane stabilizing or "quinidine-like" effects. With in vitro systems reported here, the following was observed. Against the stimulation of adenylate cyclase from dog ventricular muscle by isoproterenol, celiprolol had a Ki of 2.6 X 10(-7) M which was about 1/20 the potency of propranolol. At 100 microM, celiprolol did not affect histamine or dopamine concentration-response curves for the stimulation of adenylate cyclase from guinea-pig cerebral cortex. By itself, up to 1 mM, celiprolol did not affect basal adenylate cyclase activity from either preparation. With in vitro radioligand binding assays to directly measure beta-adrenergic receptor interactions, celiprolol had Ki values of 1.4 X 10(-7) to 8.3 X 10(-6) M. A 35-fold beta selectivity was noted with membranes from rat heart vs. rat reticulocytes, which supports previously reported in vivo data on cardioselectivity. No difference in affinity to beta-receptors was noted with frog vs. turkey erythrocyte membranes which supports the contention that these two non-mammalian systems are not predictive of beta1/beta2 specificity with mammalian systems. Celiprolol also showed some selective alpha2-adrenoceptor antagonism against (3H)-yohimbine binding vs. (3H)-prazosin binding to membranes from rat cerebral cortex. With rat adipocytes, up to 300 microM celiprolol did not stimulate basal lipolysis in the presence or absence of 10 microM 1-methyl-3-isobutyl-xanthine. Celiprolol inhibited isoproterenol-induced lipolysis with a potency about 2 times greater than practolol. Unlike propranolol, celiprolol at very high concentrations did not show non-specific inhibition of lipolysis induced with cyclic nucleotides. These and other published data would suggest the following: in vitro beta adrenergic receptor antagonist activity can be demonstrated for celiprolol, cardioselectivity is due to a combination of many factors including stereochemistry of the molecule and in vivo distribution and metabolism, celiprolol does not possess "non-specific" membrane activity, the "intrinsic-sympathomimetic activity" of celiprolol is selectively observed in some but not all in vitro test models, celiprolol has about a 10-fold selectivity for alpha 2-vs. alpha 1-receptors which is relatively unique to beta-antagonists and needs further investigations as to the potential physiological significance.

Adenylyl Cyclases↗

PubMed1983

Central hemodynamics of beta-adrenoceptor blocking drugs: beta 1 selectivity versus intrinsic sympathomimetic activity.

It was the purpose of the present study to assess the hemodynamic effects of adrenergic beta-receptor blocking drugs possessing intrinsic sympathomimetic activity (ISA) and/or beta 1 selectivity, both at rest and during exercise. The hemodynamic effects of seven different beta-blockers (propranolol, atenolol, acebutolol, ICI 72,222, ICI 89,406, and pindolol) were studied at rest in patients with ischemic heart disease. Heart rate (HR), cardiac output (CO), arterial blood pressure (BP), and pulmonary artery pressure (PP) were determined. At rest, it was possible to subdivide the various beta-blockers into three main groups according to the degree of ISA. One group without ISA, including propranolol and atenolol, reduced CO by 25% and HR by 15%. A second group with moderate ISA, represented by practolol, acebutolol and ICI 72,222, reduced CO only by 15% and HR by 10%. A third group with pronounced ISA, represented by pindolol and ICI 89,406, did not change CO and HR significantly. All three groups consisted of drugs both with and without beta 1 selectivity. During exercise, pindolol and propranolol reduced CO, HR, and BP to the same extent. In conclusion, the central hemodynamic response to beta-blockers at rest is determined by the degree of ISA, whereas beta 1 selectivity does not modify the central hemodynamic response to beta-blockade. However, the hemodynamic differences between adrenergic beta-blocking drugs with and without ISA disappear in situations with increased sympathetic drive, such as exercise.

Adrenergic beta-Antagonists↗

PubMed1984

Evidence that only one type of beta adrenergic receptor mediates inhibition of antigen-induced histamine release from guinea-pig minced lung.

Lungs obtained from guinea pigs actively sensitized to ovalbumin were minced and prepared for histamine release studies. The effects of selective beta adrenergic receptor agonists and antagonists on the ovalbumin dose-response curve for histamine release were quantified. Beta agonist dose-response curves for inhibiting histamine release evoked by low, medium and maximum antigen concentrations as well as for shifting the antigen dose-response curve to the right were obtained. All experiments were conducted in the presence of phenoxybenzamine, 5,8,11,14-eicosatetraynoic acid and tissues were taken from reserpine-pretreated animals. The beta agonists isoproterenol and sulfonterol inhibited antigen-induced histamine release, whereas the beta-1 selective agonist, ICI 118587, had no effect at concentrations up to 10(-5) M. The beta-1 selective agonist R0363 inhibited histamine release only at concentrations known to activate the beta-2-type receptor. The maximum responses and potencies of isoproterenol and sulfonterol were inversely related to the concentration of ovalbumin at which the response was measured. The -log molar ED50 values of isoproterenol and sulfonterol were decreased approximately 10- and 5-fold, respectively, by increasing the antigen concentration from 10(-3) to 1 mg/ml. Therefore, the potency of sulfonterol relative to isoproterenol changed with antigen concentration. The beta antagonists propranolol, butoxamine and practolol did not alter antigen-induced histamine release when incubated with the tissue for 60 min. Apparent dissociation constants (KB) for propranolol and butoxamine were independent of the concentration of antigen used to provoke histamine release.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗

PubMed1984

Isolated parietal cells: adrenergic response and pharmacology.

Isoproterenol (Iso), epinephrine and norepinephrine each stimulated isolated gastric mucosal parietal cells as shown by an increased accumulation of [14C]aminopyrine (AP), an indirect measure of acid secretion. The beta receptor selective agonists metaproterenol, terbutaline and zinterol stimulated AP accumulation to the same extent as Iso, whereas the beta-1 receptor selective agonist dobutamine was only 20% as effective. The general beta receptor antagonists oxprenolol and dl-propranolol and the beta-2 receptor antagonist H35/25 inhibited Iso-stimulated AP accumulation. Receptor stereoselectivity was shown by the approximately 100-fold difference in potency of the I- and d-isomers of propranolol. The alpha receptor antagonists phentolamine and phenoxybenzamine, the beta-1 receptor antagonists metoprolol and practolol and the muscarinic receptor antagonist atropine were without effect. The histamine H2-receptor antagonist cimetidine inhibited Iso-stimulated AP accumulation an average of 40% at a concentration which inhibits completely histamine-stimulated AP accumulation. The data demonstrate that cells of the rat gastric mucosa have adrenergic beta-2 receptors which when stimulated result in an increase in acid secretion. The results also show that the response is in part mediated indirectly by catecholamine-stimulated release of histamine.

1-Methyl-3-isobutylxanthine↗

PubMed1980

Demonstration of beta-2 adrenergic receptors of high coupling efficiency in human neutrophil sonicates.

Using highly purified (greater than 95%) neutrophil (PMN) sonicates, we have studied the beta adrenergic (beta 1/beta 2) pattern of adenylate cyclase activation following agonist stimulation and have assessed the coupling characteristics of the beta adrenergic receptor to the adenylate cyclase enzyme. Adenylate cyclase was highly responsive to agonist activation, with peak isoproterenol (100 microM) stimulation resulting in the generation of 119 +/- 9.5 (mean +/- S.E.M.) pmol/mg/min cyclic AMP (224% above basal levels) compared to 171.7 +/- 8.6 following NaF (10 mM) stimulation. The agonist pattern of adenylate cyclase activation suggested the presence of beta-2 adrenergic receptors, since isoproterenol with a Kact of 0.7 microM was more potent than epinephrine (Kact = 8.5 microM) or norepinephrine (Kact = 90 microM). Butoxamine (beta-2 antagonist) was approximately 25 times more potent than practolol (beta-1 antagonist), with KDs of 0.75 microM and 17.5 microM, respectively. Receptor coupling efficiency was determined by measuring isoproterenol binding and adenylate cyclase activation with the same PMN sonicates and incubation conditions for each assay. The apparent KD for isoproterenol binding was 2.82 +/- 0.53 muM, the Kact was 0.47 +/- 0.05 muM, and the mean KD/Kact ratio was 6.5. Highly coupled receptor-enzyme systems have ratios greater than or equal to 1. Using sucrose gradient-purified PMN sonicates, we found that isoproterenol required the guanine nucleotides GTP or Gpp(NH)p to activate adenylate cyclase. The GTP effect on adenylate cyclase responsivenss to isoproterenol was associated with a 10-fold decrease in the isoproterenol binding affinity. These studies suggest that the human PMN has beta-2 adrenergic receptors which are highly coupled to the adenylate cyclase enzyme. We believe that this tissue offers a suitable model for the study of beta-2 adrenergic receptors and the mechanism of hormone-induced adenylate cyclase activation in man.

Adenylyl Cyclase Inhibitors↗

PubMed1981

Modulation of the activity of endogenous protein kinase inhibitors in rat heart by the beta adrenergic receptor.

The rat heart contains a large amount of two protein kinase inhibitors. The type I inhibitor blocks the activity of cAMP-dependent protein kinase while the type II inhibitor blocks cGMP-dependent protein kinase, cAMP-dependent protein kinase and cyclic nucleotide-independent protein kinase. Isoproterenol produced a dose-dependent decrease of the type I inhibitor activity and an increase of cAMP content in rat heart. The decrease of the type I inhibitor activity is mediated through adrenergic beta receptor because propranolol and practolol but not phentolamine prevented the effects of isoproterenol. Moreover, prior treatment with aminophylline markedly enhanced isoproterenol-induced increase of cAMP content and decrease of the type I inhibitor activity. Isoproterenol did not change the activity of the type II inhibitor. These results are compatible with the hypothesis that the neurotransmitter generated cAMP modulates phosphorylation in the heart by changing the relationship between cAMP-dependent protein kinase and the type I inhibitor activity.

Aminophylline↗

PubMed1983

beta-Adrenergic receptors in rabbit liver plasma membranes. Predominance of beta 2-receptors and mediation of adrenergic regulation of hepatic glycogenolysis.

[3H]Dihydroalprenolol was used to study beta-adrenergic binding sites in plasma membranes isolated from rabbit liver. Specific binding was measured at 25 degrees C as the difference between total binding and binding in the presence of 2 microM dl-propranolol or 10 microM l-isoproterenol. Binding was saturable and stereoselective. The maximum number of binding sites (Bmax) was 434 +/- 41 fmol/mg of protein. The Kd for this binding as determined by Scatchard analysis was 1.39 +/- 0.09 nM. This value agreed well with the Kd value (1.27 +/- 0.12 nM) determined by kinetic analysis. The potency order for the displacement of bound [3H]dihydroalprenolol was isoproterenol greater than epinephrine greater than norepinephrine, indicative of beta 2-receptors. Use of beta 1- and beta 2-subtype-selective inhibitors also supported the interpretation that the binding characteristics are those of beta 2-receptors. Computer-aided analysis of this inhibition indicated that the beta-receptors in this membrane are predominantly, if not exclusively, of the beta 2-subtype. That these receptors are responsible for mediating catecholamine stimulation of hepatic glycogenolysis was deduced from the inhibition of agonist-stimulated glycogenolysis, in isolated hepatocytes, by beta-receptor subtype-selective antagonists. Thus, the hydrochloride of (t-butylamino-3-ol-2-propyl)oximino-9 fluorene, a beta-antagonist which has higher affinity at beta 2-sites than at beta 1-sites, was 3 orders of magnitude more potent in inhibiting isoproterenol-stimulated glycogenolysis than either atenolol or practolol, both of which are beta 1-selective antagonists. These results resemble the inhibition of [3H]dihydroalprenolol binding in plasma membranes. The glycogenolytic effects of catecholamines occurred with the potency order isoproterenol greater than epinephrine greater than norepinephrine. Thus, both by radioligand binding studies and by metabolic studies, the functional adrenergic receptor in the rabbit liver is shown to be of the beta 2-subtype.

Animals↗

PubMed1983

Adrenergic and serotonergic regulation of skeletal muscle metabolism in rat. I. The effects of adrenergic and serotonergic antagonists on the regulation of muscle amino acid release, glycogenolysis, and cyclic nucleotide levels.

The biochemical mechanisms of serotonergic and adrenergic action on skeletal muscle cyclic nucleotide, glycogen, and amino acid metabolism have been investigated in intact rat epitrochlaris skeletal muscle preparations. Endogenous catecholamine levels in these preparations were 28.6 +/- 2.1 pg/mg of muscle. Release of these catecholamines by tyramine produced a 25% inhibition of alanine and glutamine release. Pretreatment of animals in vivo with 6-hydroxydopamine depleted catecholamine content by 85%. On incubation, preparations from these pretreated animals showed no effect of tyramine on amino acid metabolism. Serotonin (10(-5) M) and epinephrine (10(-5) M) inhibited alanine and glutamine release equally in preparations from 6-hydroxydopamine-pretreated as compared to control rats. Adrenergic antagonists such as dl-propranolol (10(-8)-10(-6) M), oxprenolol (10(-8)-10(-6) M), and practolol (10(-6)-10(-4) M) blocked equally the inhibition of alanine and glutamine release, prevented the stimulations of muscle cAMP levels, phosphosphorylase a formation, and the depletion of muscle glycogen produced by either epinephrine or serotonin. In contrast, serotonergic antagonists such as methysergide (10(-8)-10(-6) M) and cyproheptadine (10(-8)-10(-6) M) blocked the inhibition of alanine and glutamine release, the stimulations of muscle cAMP levels and phosphorylase a formation, and the decreased muscle glycogen content effected by serotonin but not by epinephrine. Incubation of muscles with both epinephrine and serotonin together produced additive stimulation of muscle cAMP levels, but not of the inhibition of alanine and glutamine release. These data indicate that the action of these agonists on skeletal muscle protein and amino acid, glycogen, and cyclic nucleotide metabolism proceeds directly via separate and discrete serotonergic and adrenergic receptor-adenylyl cyclase mechanisms in skeletal muscle.

Alanine↗

PubMed1983

Serotonergic and adrenergic regulation of skeletal muscle metabolism in the rat. II. The use of [125I]iodolysergic acid diethylamide and [125I]iodopindolol as probes of sarcolemmal receptor function and specificity.

To evaluate serotonin receptor kinetics in skeletal muscle, we synthesized and developed 2-[125I]iodolysergic acid diethylamide [( 125I]iodoLSD) as a high affinity, high specific activity probe of serotonergic receptor function. The kinetics of binding of this probe and the profile of agonist and antagonist displacement have been compared to results obtained using [125I] iodopindolol as a probe for beta-adrenergic receptor binding. [125I]IodoLSD was prepared by chloramine-T iodination and purified by high pressure liquid chromatography. Fluorescence, ultraviolet, and nuclear magnetic resonance spectra as well as mass spectroscopy demonstrate that the iodinated compound is 2-iodoLSD. This probe bound in a concentration-dependent fashion to sarcolemma in a manner consistent with existence of a single population of specific receptors having a Kd of 1.46 nM and an abundancy of 47 fmol/mg of protein. Half-maximal binding of the probe occurred within 1.0 min and equilibrium binding was observed at 8.0 min. The apparent t 1/2 for the probe-receptor complex was 40 s; the Kd calculated from kinetic data was 1.69 nM. The IC50 for displacement of iodoLSD was 330 +/- 185 nM for methysergide, 757 +/- 309 nM for cyproheptadine, and 2,570 +/- 1,390 nM for serotonin. Adrenergic antagonists such as l-propranolol and oxprenolol also displaced [125I]iodoLSD, but did so with IC50 values of 17,800 +/- 5,100 and 23,300 +/- 5,500 nM, respectively. Using [125I]iodopindolol as a receptor probe, we found the order of potency for adrenergic antagonists to be l-propranolol greater than oxprenolol much much greater than practolol. Serotonergic antagonists, although effective in displacing [125I]iodopindolol, did so only at very high concentrations. These results are consistent with the existence of separate and discrete D-serotonergic and beta 2-adrenergic receptors in skeletal muscle and the finding that adrenergic agonists and antagonists may interact with low affinities with the serotonergic receptor, but that serotonergic agonists and antagonists interact poorly, if at all, with the beta 2-adrenergic receptor.

Animals↗

PubMed1983

Antagonism by tricyclic antidepressants of reserpine-induced hypothermia in mice. Involvement of postsynaptic alpha 2-adrenoceptors.

The effects of adrenoceptor blocking agents and cyproheptadine on the antagonism by the antidepressants imipramine, desipramine and maprotiline, of reserpine-induced hypothermia in mice were studied. The anti-reserpine effect of the antidepressants was reduced by phenoxybenzamine, prazosin, yohimbine and d,1-propranolol, the two latter drugs exhibiting the strongest effect. Practolol was ineffective, while cyproheptadine potentiated the effect of maprotiline and was inactive towards imipramine and desipramine. Furthermore, the anti-reserpine effect of desipramine (the other antidepressants not being studied) was also reduced by piperoxan and l-propranolol, but not by d-propranolol. The reserpine-induced hypothermia was antagonized by clonidine and this effect was completely blocked by yohimbine and partly reduced by prazosin. These results confirm that the antagonism by tricyclic antidepressants of reserpine-induced hypothermia depends on the activation of noradrenergic mechanisms and indicate that this effect is mediated not only by alpha 1- and beta-, but also by postsynaptic alpha 2-adrenoceptors.

Animals↗

PubMed1983

The Timolol Myocardial Infarction Study: an evaluation of selected variables.

The Timolol Myocardial Infarction Study was a completely randomized program of 1884 survivors of myocardial infarction comparing timolol maleate, 10 mg twice daily, with placebo for the secondary prevention of sudden death and reinfarction. In that study, timolol maleate reduced total mortality (152 placebo vs 98 timolol) and the incidence of first nonfatal reinfarctions (131 placebo vs 90 timolol). This report evaluates the effect of timolol in selected categories--age, sex, infarction site, heart size, transmural infarction, diabetes, smoking, multiple reinfarctions and pulse. These data document two important facts. First, the effects of timolol in the total sample were also seen in different subpopulations, and there were no major subgroups for which this positive effect would not be expected. Second, the consistency of the effects observed with respect to pulse, transmural infarction, age and infarct site are in contrast to some previous studies with practolol, propranolol, and alprenolol. Thus, beta blockers may not be identical with respect to reducing the mortality and morbidity associated with acute myocardial infarction.

Aged↗