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British Journal of Pharmacology Jun 19991. Negative inotropic effects of several beta-adrenoceptor (betaAR) antagonists on electrically-stimulated right atria, left atria, right ventricles and left ventricular...
1. Negative inotropic effects of several beta-adrenoceptor (betaAR) antagonists on electrically-stimulated right atria, left atria, right ventricles and left ventricular papillary muscles from reserpine-treated rats were used as a measure of their inverse agonist activities. 2. Beta1AR antagonists acebutolol, atenolol and metoprolol, beta2AR antagonist ICI-181,551 and nonselective betaAR antagonists alprenolol, nadolol, propranolol and timolol produced negative inotropic effects, which were most marked on the right atria. 3. The nonselective betaAR antagonist pindolol did not exhibit inverse agonist activity but inhibited the negative inotropic activities of ICI-118,551, atenolol and propranolol. 4. The negative inotropic effects of lidocaine, nifedipine and pentobarbitone were similar on all the four myocardial preparations. 5. The positive inotropic efficacy of salbutamol on right and left atria but not on right ventricles and papillary muscles was comparable to that of isoprenaline. The antagonist activity of ICI-118,551 against isoprenaline was greater on right atria than on other cardiac regions. 6. Beta1AR proteins were expressed in all regions of the heart but of beta2AR were primarily localized in the right atrium. 7. It is concluded that beta2AR play a greater role in right atria than in other cardiac regions and almost all betaAR antagonists behave as inverse agonists.
Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Albuterol; Animals; Blotting, Western; In Vitro Techniques; Isoproterenol; Male; Myocardial Contraction; Pindolol; Propanolamines; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, beta-1; Receptors, Adrenergic, beta-2
PubMed: 10433496
DOI: 10.1038/sj.bjp.0702616 -
Hypertension Research : Official... Jun 1997This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical...
This study was conducted to investigate the effects of long-term administration of a calcium-channel antagonist (nifedipine) and a beta-blocker (acebutolol) on physical fitness in men with mild hypertension. All subjects underwent symptom-limited treadmill stress testing and routine echocardiographic studies. Twenty-two subjects who had either a causal diastolic blood pressure of more than 105 mmHg or a left ventricular mass index (LVMI) of 125 g/m2 or more during follow-up were assigned to receive medical therapy. The other 31 men who did not meet either criterion were continuously followed-up without medication. Among the 22 treated men, the age-adjusted treadmill time (normalized treadmill time, TMTn) significantly decreased before the initiation of medication, while 31 untreated men showed no change in TMTn throughout the study. The 22 treated subjects were subsequently divided into two groups; 13 were given nifedipine and 9 were given acebutolol. All treated subjects were followed-up for more than 3 years. After treatment, the two groups showed similar reductions in blood pressure and LVMI, but a different outcome for TMTn: TMTn increased from 104 +/- 8% to 115 +/- 16% in subjects given nifedipine (p < 0.05) and decreased from 106 +/- 12% to 99 +/- 10% (p < 0.01) in those given acebutolol. Thus, the physical fitness of subjects who required medication significantly deteriorated without medication; their physical fitness improved after treatment with a calcium-channel antagonist and deteriorated after treatment with a beta-blocker.
Topics: Acebutolol; Adrenergic beta-Antagonists; Adult; Blood Pressure; Calcium Channel Blockers; Drug Therapy, Combination; Echocardiography; Humans; Hypertension; Long-Term Care; Male; Middle Aged; Nifedipine; Physical Fitness; Retrospective Studies; Ventricular Function, Left
PubMed: 9220274
DOI: 10.1291/hypres.20.105 -
British Journal of Pharmacology Jun 19961. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the...
1. The effects of beta-adrenoceptor antagonists including (-)- and (+)-propranolol, (-)- and (+)-penbutolol, timolol, pindolol, atenolol, acebutolol and practolol on the Ca(2+)-overload induced by lysophosphatidylcholine (LPC) were examined in isolated cardiomyocytes of the rat. 2. Fura-2 was used for measurement of the intracellular calcium concentration ([Ca2+]i). LPC (15 microM) produced a rapid increase in [Ca2+]i from 72 +/- 5 to 3042 +/- 431 nM which coincided with a decrease in the percentage of rod-shaped cells from 69 +/- 2 to 5 +/- 2%. 3. Preincubation with (-)-propranolol (20 microM), (+)-propranolol (50 microM), or (-)- or (+)-penbutolol (20 microM), the lipophilicity of which is higher than other beta-adrenoceptor antagonists, significantly inhibited both the increase in [Ca2+]i and the cell-shape change induced by 15 microM LPC. The inhibitory effects of the four drugs on the LPC-induced increase in [Ca2+]i and cell-shape change were concentration-dependent. The IC50S of (-)-propranolol, (+)-propranolol, (-)- and (+)-penbutolol for the increase in [Ca2+]i were 1.28, 10.50, 0.67 and 0.76 microM, respectively. 4. Pretreatment with pindolol, timolol, acebutolol, practolol, atenolol or lignocaine did not inhibit the increase in [Ca2+]i and the morphological change induced by LPC. 5. LPC markedly increased the release of creatine phosphokinase from 9 +/- 1 to 45 +/- 2% which could be significantly reduced by (-)- or (+)-propranolol but not by acebutolol or timolol. 6. The protective effects of (-)- and (+)-propranolol, (-)- and (+)-penbutolol against the Ca(2+)-overload induced by LPC were not associated with the beta-adrenoceptor antagonistic action, but probably with an unknown action which is related to the preservation of membrane integrity. Further studies are necessary to clarify the exact mechanisms of the protective action of these beta-adrenoceptor antagonists against the Ca(2+)-overload induced by LPC.
Topics: Adrenergic beta-Antagonists; Animals; Calcium; Cell Size; Chelating Agents; Creatine Kinase; Fura-2; Heart; Lysophosphatidylcholines; Male; Myocardium; Rats; Rats, Sprague-Dawley
PubMed: 8799555
DOI: 10.1111/j.1476-5381.1996.tb15479.x -
Dermatology (Basel, Switzerland) 1995
Topics: Acebutolol; Adrenergic beta-Antagonists; Adult; Humans; Hyperhidrosis; Male; Middle Aged; Sotalol
PubMed: 7894107
DOI: 10.1159/000246645 -
BMJ (Clinical Research Ed.) Oct 1994To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVE
To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure.
DESIGN
Open randomised multicentre trial with three year follow up.
SETTING
Outpatient departments of six French hospitals.
PATIENTS
100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment).
INTERVENTIONS
Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg.
RESULTS
17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups.
CONCLUSION
In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.
Topics: Acebutolol; Adolescent; Adult; Aged; Atenolol; Blood Pressure; Body Weight; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Proteinuria
PubMed: 7950612
DOI: 10.1136/bmj.309.6958.833 -
British Journal of Pharmacology Nov 19931. The transepithelial transport of the beta-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal...
1. The transepithelial transport of the beta-adrenoceptor blocking drug, celiprolol, was investigated in monolayers of the well differentiated human intestinal epithelial cell line, Caco-2. 2. The basal-to-apical transport (secretion) of [14C]-celiprolol (50 microM) was 5 times higher than apical-to-basal transport (absorption). In the presence of an excess (5 mM) of unlabelled celiprolol the basal-to-apical transport was reduced by more than 80%, whereas the apical-to-basal transport remained unchanged. 3. Net celiprolol secretion obtained in the concentration range 0.01 to 5 mM displayed saturable kinetics with an apparent Km of 1.00 +/- 0.23 mM and Vmax of 113 +/- 11 pmol/10(6) cells min-1. These results are consistent with saturable active secretion and provide an explanation for the dose-dependent bioavailability of celiprolol. 4. The secretion of celiprolol was sensitive to pH, and decreased in the absence of sodium and in the presence of ouabain, suggesting that transport was coupled to proton and sodium gradients. 5. The secretion of celiprolol was inhibited by substrates for P-glycoprotein (vinblastine, verapamil and nifedipine) and either inhibited or stimulated by typical substrates for the renal organic cation-H+ exchanger (cimetidine, N1-methylnicotinamide, tetraethylammonium and choline), suggesting that there are at least two distinct transport systems. 6. The secretion of celiprolol was also inhibited by other beta-adrenoceptor blocking drugs (acebutolol, atenolol, metoprolol, pafenolol and propranolol) and by the diuretics, acetazolamide, chlorthalidone and hydrochlorothiazide, suggesting that the clinically observed effect of chlorthalidone on the bioavailability of celiprolol occurs at the level of the intestinal epithelium.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Biological Availability; Biological Transport; Buffers; Carrier Proteins; Celiprolol; Cell Line; Choline; Dose-Response Relationship, Drug; Epithelial Cells; Epithelium; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Mucosa; Intestines; Kinetics; Membrane Glycoproteins; Tritium; Vinblastine
PubMed: 7905337
DOI: 10.1111/j.1476-5381.1993.tb13914.x -
British Journal of Pharmacology May 19931. The effects of tienoxolol, (ethyl 2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-5- [(2-thienylcarbonyl) amino] benzoate, hydrochloride), a novel drug exhibiting...
1. The effects of tienoxolol, (ethyl 2-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-5- [(2-thienylcarbonyl) amino] benzoate, hydrochloride), a novel drug exhibiting both diuretic and beta-adrenoceptor blocking properties, were investigated on urinary 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and PGE2 excretion in the rat and compared to those of reference diuretic (furosemide) and beta-adrenoceptor antagonists (acebutolol, propranolol). Since tienoxolol was shown to bind to A1 and A2 adenosine receptors, the action of theophylline was also evaluated. 2. Tienoxolol (8-128 mg kg-1, p.o.) induced a dose-related increase of 6-keto-PGF1 alpha excretion from 32 mg kg-1 but a significant elevation of urinary PGE2 levels was only reached after administration of 128 mg kg-1. However, renal prostaglandin concentrations were not modified by tienoxolol. 3. Furosemide (32 mg kg-1) displayed a strong diuretic activity but did not enhance 6-keto-PGF1 alpha excretion. Likewise, the latter was unaffected by acebutolol and propranolol (128 mg kg-1) and no significant diuresis was observed following administration of these two beta-blocking agents. Theophylline (64 mg kg-1), like tienoxolol, was able to induce both diuresis and urinary prostaglandin excretion. Furthermore, they bound with similar affinities to A1 and A2 adenosine receptors. This led to the suggestion that a relationship between P1-purinoceptors, prostaglandin release, diuresis and natriuresis could exist. 4. Oral co-administration of NECA (0.2 mg kg-1) with tienoxolol markedly reduced the urinary 6-keto-PGF1 alpha excretion observed when tienoxolol was administered alone. However, neither diuresis nor natriuresis were modified, demonstrating that the proposed relationship was untenable. 5. In conclusion, PGI2 probably does not participate in the diuretic and natriuretic activity oftienoxolol. The increase of urinary 6-keto-PGF1alpha excretion may result not only from the haemodynamic properties of the drug but also from the rise of the urinary flow induced by tienoxolol.
Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Adenosine-5'-(N-ethylcarboxamide); Adrenergic beta-Antagonists; Animals; Brain Chemistry; Dinoprostone; Diuresis; Epoprostenol; Furosemide; Male; Natriuresis; Propanolamines; Prostaglandins; Radioimmunoassay; Radioligand Assay; Rats; Rats, Inbred Strains; Receptors, Purinergic; Theophylline; Vasodilator Agents
PubMed: 8098641
DOI: 10.1111/j.1476-5381.1993.tb13565.x -
The American Journal of Cardiology Mar 1993Early studies of acute beta-blocking drug therapy, such as metoprolol and acebutolol, in patients with idiopathic dilated cardiomyopathy (IDC) and survivors of acute... (Review)
Review
Early studies of acute beta-blocking drug therapy, such as metoprolol and acebutolol, in patients with idiopathic dilated cardiomyopathy (IDC) and survivors of acute myocardial infarction were interpreted to have detrimental or, at best, neutral effects on cardiac and clinical hemodynamics. Subsequent trials of longer duration with metoprolol versus placebo in patients with IDC demonstrated an "exceptional response" to beta-blocker therapy in some individuals. Hemodynamics and patient demographic characteristics appear not to predict those patients who may or may not benefit. Controlled trials with newer beta-adrenoceptor modulating drugs--such as xamoterol, bucindolol, and carvedilol--have been equivocal in some situations. Xamoterol has been associated with progressive heart failure and increased sudden cardiac deaths, whereas bucindolol improved clinical heart failure symptoms and testing hemodynamic parameters, as did treatment with carvedilol, in patients with ischemic cardiomyopathy. The success of these agents in patients with congestive heart failure may be in their ability to modulate the excessive myocardial stimulation of the beta-adrenergic nervous system while benefitting the dynamics of the peripheral system.
Topics: Adrenergic beta-Antagonists; Cardiomyopathy, Dilated; Female; Hemodynamics; Humans; Male; Metoprolol; Middle Aged
PubMed: 8096675
DOI: 10.1016/0002-9149(93)90086-r -
British Journal of Pharmacology Dec 19921. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes...
1. The outward K+ current induced by KRN2391 (K+ channel opener) in Xenopus oocytes is blocked by glibenclamide. We have investigated the effects of various classes (I-IV) of antiarrhythmic drugs on this KRN2391-induced response. 2. All class I antiarrhythmic drugs (Na+ channel blockers) tested concentration-dependently suppressed KRN2391-induced responses with the rank order of potency (IC50 in microM), disopyramide (17.8) > aprindine (29.5) > propafenone (63.1) > ajmaline (145) > quinidine (151). Flecainide, SUN1165, lignocaine, mexiletine and procainamide were much less potent (IC50, 450- > 1000 microM) than quinidine. 3. The class II antiarrhythmic drugs (beta-blockers), timolol, (-)- and (+/-)- propranolol, and (+)- propranolol (a non-beta-blocker) inhibited KRN2391-induced K+ currents in a concentration-dependent manner with values for IC50 (microM) of 79, 131, 151 and 129, respectively, whilst butoxamine, oxprenolol, alprenolol, pindolol, nadolol, metoprolol and acebutolol were either weak (IC50, 300 microM-600 microM) or virtually inactive (IC50, > 1000 microM). 4. The class III antiarrhythmic drugs, amiodarone and (+)-sotalol scarcely affected KRN2391 responses. 5. All class IV drugs (Ca2+ antagonists) tested suppressed KRN2391-induced responses in a concentration-dependent manner with an IC50 of 6.3 microM for bepridil, 38 microM for prenylamine, 85 microM for verapamil and 135 microM for diltiazem. 6. In conclusion, antiarrhythmic drugs of classes I, II and IV potently blocked glibenclamide-sensitive K+ channels in Xenopus oocytes.
Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Calcium Channel Blockers; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiology; Female; Glyburide; Oocytes; Potassium Channels; Pyridines; Sodium Channels; Xenopus laevis
PubMed: 1361399
DOI: 10.1111/j.1476-5381.1992.tb13407.x -
The Journal of Clinical Investigation Jul 1992IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the...
IgG reactivity with the (H2A-H2B)-DNA complex, a subunit of the nucleosome, has been detected in many patients with lupus induced by procainamide and quinidine, but the similarity among the epitopes targeted by these antibodies in this heterogeneous patient group as well as the prevalence of this specificity in lupus induced by other drugs is unknown. Studies with histone-DNA complexes formed by sequential addition on a solid phase demonstrated that complexes containing single histones had negligible antigenicity, indicating that DNA stabilizes a protein epitope in the H2A-H2B dimer or that the complete epitope is generated by a surface feature involving H2A-H2B and DNA. F(ab')2 isolated from a patient with procainamide-induced lupus blocked greater than 90% of the anti-[(H2A-H2B)-DNA] reactivity in six of six sera from patients with lupus induced by procainamide, four of four quinidine-induced patients and in sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid, but not methyldopa or auto-antibodies to the component macromolecules. Fab fragments purified from the IgG of two quinidine-induced lupus patients and patients with isoniazid- and procainamide-induced lupus retained 39% +/- 8% of their original IgG reactivity compared to 34 +/- 28% of the original anti-tetanus toxoid activity of Fab fragments in two of the same sera and two normal sera. These results indicate that anti-[(H2A-H2B)-DNA] does not require divalent antigen-antibody complexes for stability, and that the complete epitope is created by the monomeric, trimolecular histone-DNA complex. We conclude that despite their pharmacologic and chemical heterogeneity, many lupus-inducing drugs elicit near identical autoantibodies.
Topics: Antibodies, Antinuclear; Autoantibodies; DNA; Epitopes; Female; Histones; Humans; Immunoglobulin G; Lupus Vulgaris; Middle Aged; Procainamide; Quinidine
PubMed: 1378852
DOI: 10.1172/JCI115832