Β-blocker Atenolol Research Articles

Complexes of copper(II) with the β-blocker atenolol

Mono- and binuclear copper(II) complexes with atenolol (HAt) can be obtained, depending on the reaction conditions. The mononuclear violet complex cation has the general formula Cu(HAt)42+ with an elongated octahedral geometry. The two ligands in the equatorial plane are bound in a bidentate fashion through the hydroxyl oxygen and amino nitrogen, while the other two atenolol molecules in axial position are coordinated in a monodentate way. The binuclear green complex Cu2At2Cl2, is neutral, where atenolol acts as a bidentate (O−, NH) bridging ligand. The bridge between the two Cu atoms is realized by the deprotonated oxygen of the alcohol group.

ATENOLOL DEPRESSES POST-ISCHAEMIC RECOVERY IN THE ISOLATED RAT HEART

Metabolic events during ischaemia are probably important in determining post-ischaemic myocardial recovery. The aim of this study was to assess the effects of the β-blocker atenolol and the high energy demand in an ischaemia-reperfusion model free of neurohormonal and vascular factors. We exposed Langendorff-perfused isolated rat hearts to low-flow ischaemia (30 min) and reflow (20 min). Three groups of hearts were used: control hearts (n =11), hearts that were perfused with 2.5 μg l−1atenolol (n =9), and hearts electrically paced during ischaemia to distinguish the effect of heart rate from that of the drug (n =9). The hearts were freeze-clamped at the end of reflow to determine high-energy phosphates and their metabolites. During ischaemia, the pressure-rate product was 2.3±0.2, 5.2±1.1, and 3.3±0.3 mmHg 103min in the control, atenolol and paced hearts, respectively. In addition, the ATP turnover rate, calculated from venous (lactate), oxygen uptake and flow, was higher in atenolol (11.2±1.7 μmol min−1) and paced (8.1±0.8 μmol min−1) hearts than in control (6.2±0.8 μmol min−1). At the end of reflow, the pressure×rate product recovered 75.1±6.4% of baseline in control vs 54.1±9.1 and 48.8±4.4% in atenolol and paced hearts (P<0.05). In addition, the tissue content of ATP was higher in the control hearts (15.8±1.0 μmol gdw−1) than in atenolol (10.5±2.6 μmol gdw−1) and paced (10.9±1.3 μmol gdw−1) hearts. Thus, by suppressing the protective effects of down-regulation, both atenolol and pacing apparently depress myocardial recovery in this model. 1999 Academic Press@p$hr

Angiotensin II Antagonism and the Heart: Valsartan in Left Ventricular Hypertrophy

Summary: Left ventricular hypertrophy (LVH) represents an independent risk factor for cardiovascular morbidity and mortality, and normalization of left ventricular mass has become a desirable goal of antihypertensive treatment. In a randomized, double-blind study, the angiotensin II (AT1-receptor) antagonist valsartan (Diovan®; 80-160 mg q.d.) was compared with the β-blocker atenolol (50-100 mg q.d.) over 8 months in previously untreated patients with essential hypertension and LVH. Sixty-nine patients were randomized, of whom 58 were evaluated by echocardiography. After 8 months of treatment in the atenolol group [n = 8 with additional hydrochlorothiazide (HCTZ)], initial blood pressure was reduced from 160/103 to 147/92 mm Hg (p < 0.0001). In the valsartan group (n = 9 with HCTZ), blood pressure decreased from 163/101 to 146/90 mm Hg (p < 0.0001). Left ventricular mass index decreased from 127 to 117 g/m2 in the atenolol group and from 127 to 106 g/m2 in the valsartan group. Long-term treatment with valsartan resulted in a significant reduction of LVH in patients with essential hypertension.

A Comparison of the Effects of Mibefradil and Atenolol on Regression of Left Ventricular Hypertrophy in Hypertensive Patients

Objective: This study was designed to compare the effect of mibefradil, a selective T-type calcium channel antagonist, with the β-blocker atenolol on regression of left ventricular (LV) hypertrophy in hypertensive patients. Methods: In this multicenter, double-blind, active-controlled, randomized, parallel-group comparison, 66 patients with mild-to-moderate hypertension (sitting diastolic blood pressure, SDBP, 95–114 mm Hg) and LV mass index >102 g/m² for males and >88 g/m² for females were randomized to an initial treatment with 50 mg of either mibefradil or atenolol for 4 weeks. Doses were increased to 100 mg/day if blood pressure was not normalized to ≤90 mm Hg, and, if needed, 25 mg of hydrochlorothiazide was added. Treatment continued for a total of 24 weeks. LV hypertrophy was assessed by echocardiography, and trough SDBP and adverse events were recorded. Results: Treatment with mibefradil or atenolol resulted in decreases from baseline in LV mass index of 11.1% (p < 0.001) and 9.1% (p < 0.001), respectively. The treatment difference (mibefradil vs. atenolol) was not statistically significant. Reductions in SDBP with mibefradil and atenolol were 14.3 and 10.7 mm Hg, respectively, again not statistically significant. Both drugs were well tolerated; however, overall there were more potentially drug-related adverse events reported with atenolol (48.5%) than with mibefradil (24.2%). Conclusions: The reductions in LV hypertrophy and blood pressure achieved with mibefradil were larger but statistically equivalent to those with atenolol, but a lower overall incidence of treatment-related adverse events was seen in the mibefradil-treated patients.

Capillary Zone Electrophoretic Method for the Quantitative Determination of the β-Blocker Atenolol in Human Urine

A simple capillary zone electrophoresis method was developed for the quantitation of the β-blocker 4-[2-hydroxy-3-[(l-methylethyl)amino]propoxy] benzeneacetamide, atenolol. The electrophoretic separation was performed using a 78 cm × 75 μm I. D. fused silica capillary. The electrolyte consisted of a buffer Na2HPO4 (25mM)-Na2B4O7 (25 mM) (50−50; V/V), pH 9.7. The introduction of the sample was made hydrostatically for 25 s and the running voltage was 20 KV at the injector end of the capillary. Photometric detection was used and a wavelength of 214 nm. The method was applied to the determination of atenolol in urine samples obtained from a hypertensive patient under medical treatment with the pharmaceutical formulation “Tenormin 100 mg” (atenolol 100 mg), another patient under treatment with the pharmaceutical combination “Tenoretic” (atenolol 100 mg + chlorthalidone 25 mg), and also in urine samples obtained from a healthy volunteer after the ingestion of a 100 mg atenolol tablet, “Tenormin 100 mg”. Using a simple solid phase extraction, a recovery of 70.69±3.27% and a very good separation from the urine matrix are achieved. A good reproducibility, linearity, and accuracy are obtained, and a quantitation limit of 0.1 μg/mL in urine, allows the method to be applied to pharmacokinetic studies of the compound.

D37 Comparison of the angiotensin II antagonist valsartan with the β-blocker atenolol in patients with severe essential hypertension

D37 Comparison of the angiotensin II antagonist valsartan with the β-blocker atenolol in patients with severe essential hypertension

Nifedipine gastrointestinal therapeutic system versus atenolol in stable angina pectoris

The gastrointestinal therapeutic system formulation of nifedipine enables a once-daily dosing resulting in predictable, relatively constant plasma concentrations. To evaluate the efficacy and safety of this formulation and to compare this with the β-blocker atenolol, we conducted a double-blind, randomised, multi-centre study in 129 male patients with documented exercise induced angina pectoris. After 4 weeks' treatment, nifedipine (60 mg), improved time to onset of 0.1 mV ST-segment depression from 536 s by 72 ± 117 s, time to onset of pain from 619 s by 56 ± 120 s, and total exercise time from 685 s by 40 ± 88 s. Atenolol 100 mg, had a comparable effect, time to onset of 0.1 mV ST-segment depression improved from 496 s by 53 ± 129 s, time to onset of pain from 572 s by 57 ± 118 s, and total exercise time from 653 s by 33 ± 99 s. Between group analysis revealed no statistically significant differences for these exercise parameters. Atenolol, but not nifedipine, significantly reduced heart rate and systolic blood pressure at rest and during exercise ( P < 0.001 between groups), indicating different modes of action of the drugs. With regard to safety, both drugs were generally well tolerated. There were significantly ( P = 0.01) more vasodilation related side effects with nifedipine. These data demonstrate that gastrointestinal therapeutic system formulation of nifedipine and atenolol as once-daily monotherapy are equally effective and safe, but with different effects on exercise parameters.

Development and validation of liquid chromatography methods for the quantitation of propranolol, metoprolol, atenolol and bisoprolol: Application in solution stability studies

Four analytical methods have been developed and validated for the quantitation of β-blockers (propranolol, metoprolol, atenolol and bisoprolol) using high-performance liquid chromatography (HPLC) with UV detection. Excellent proportionality, precision and accuracy were achieved by the assays. The use of only one kind of reverse-phase column and a mobile phase for all β-blockers permitted the analysis of a large number of samples in a short time. Their stability in solution was also studied. The results show that the β-blockers assayed are stable for at least 84 h at 90°C.

Comparison of Effects of Angiotensin I– Converting Enzyme Inhibition and β-Blockade for 2 Years on Function of Small Arteries From Hypertensive Patients

The effect of treatment with two different antihypertensive agents on the function of small arteries from 17 patients with essential hypertension randomly assigned to receive either the angiotensin I-converting enzyme inhibitor cilazapril or the beta-blocker atenolol was investigated. Subcutaneous small arteries obtained from gluteal fat biopsies were studied on a wire myograph before treatment and at 1 and 2 years of treatment. Blood pressure was mildly elevated in both groups of patients (mean, 150/100 mm Hg) and was well controlled throughout the 2 years of treatment (mean, 130/85 mm Hg). We previously reported, in arteries from patients treated with cilazapril, an improvement at 1 year of treatment of the vasoconstrictor effect of endothelin-1, which had been significantly attenuated in the untreated hypertensive patients compared with normotensive subjects. After 2 years of treatment, this normalization of endothelin-1 response was still present in small arteries of patients treated with the angiotensin I-converting enzyme inhibitor, whereas in patients treated with atenolol, responses were still unchanged after 2 years of treatment. Endothelial function was tested by examining the response of norepinephrine-precontracted arteries to acetylcholine. Untreated hypertensive patients exhibited a slightly but significantly blunted vasorelaxation in response to 10 mumol/L acetylcholine compared with normotensive subjects. After 1 and 2 years of effective antihypertensive treatment, cilazapril-treated patients exhibited responses to acetylcholine that were not different from those of normotensive subjects, whereas atenolol-treated patients still had impaired responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of Cardiac β 2 -Receptors in Cardiac Responses to Exercise in Cardiac Transplant Patients

In healthy human hearts, beta 2-receptor-mediated chronotropic and inotropic responses contribute to the cardiac responses to beta-agonists. A (patho)physiological relevance for beta 2-receptor-mediated responses has so far not been demonstrated, in part because beta 1-receptor-mediated responses to cardiac neuronally released norepinephrine can mask beta 2-receptor-mediated responses. In the present study, we evaluated the blood pressure and heart rate responses to bicycle exercise in cardiac transplant patients (n = 7) compared with patients with essential hypertension (n = 8) on placebo and two doses of the beta 1-selective beta-blocker atenolol (25 and 50 mg/d) and the nonselective beta-blocker nadolol (20 and 40 mg/d), each dose for 1 week using a double-blind, randomized, crossover design. Exercise was performed 3 hours after dosing, using a stepwise increase in load until exhaustion. Exercise performance was less in the transplant patients and significantly further (25%) decreased by nadolol. Exercise caused equivalent increases in plasma norepinephrine in the two groups, but more marked increases in plasma epinephrine in the transplant patients despite less exercise. In the essential hypertension patients, systolic blood pressure increased by 80 mm Hg on placebo and 60 mm Hg on either blocker. The increase in heart rate (by about 75 beats per minute) was inhibited by 10% and 20% by the lower and higher doses, respectively, similar for the two blockers. In contrast, in the transplant patients, systolic blood pressure increased by 60 mm Hg on placebo, but this increase was totally blocked by either blocker. The heart rate increase (by 50 beats per minute on placebo) was blunted (dose related) by either blocker but 50% more by nadolol versus atenolol. The present study shows that cardiac beta 2-receptors contribute to a clear extent to the heart rate responses to endogenous circulating catecholamines in the absence of cardiac neuronally released norepinephrine. Nonselective beta-blockade probably is less well tolerated in cardiac transplant patients compared with beta 1-selective blockade.

Chronic β-blockade transregulates inhibitory A 1 adenosine and muscarinic M 2 receptors of the adenylyl cyclase system

Chronic β-blockade has evolved to an important therapeutic strategy in medicine. Not all its therapeutic effects may be explained by its direct action on the β-adrenergic system. We therefore investigated if chronic β-blockade in vivo or in isolated cell systems may modulate also inhibitory receptors of the adenylyl cyclase system. Chronic treatment with metoprolol for 6 days (10 mg/day) induced an increase of β-adrenergic receptors in rat cardiac plasma membranes (53 ± 8 vs 80 ± 12 fmol/mg protein). Simultaneously the density of cardiac muscarinic M 2 receptors decreased significantly from 150 ± 17 to 110 ± 12 fmol/mg protein without any change of the affinity of the receptors for their agonists or antagonists. By this mechanism chronic β-blockade leads to an unexpected impairment of the muscarinic-mediated inhibition of the adenylyl cyclase. This transregulation of inhibitory receptors by chronic β-blockade was not restricted to the heart but also reduced the muscarinic receptors of rat lung (35 ± 4 vs 24 ± 3 fmol/mg protein). Additionally, other inhibitory receptors of the adenylyl cyclase system such as the A 1 adenosine receptors of rat brain were reduced by chronic β-blockade (532 ± 32 vs 444 ± 26 fmol/mg protein). This transregulation of A 1 adenosine receptors occurred only after chronic β-blockade with the active stereoisomer (−)-metoprolol whereas the (+)-isomer was ineffective. The ability of the remaining A 1 adenosine receptors to form the agonist-promoted high affinity state was unaltered. Their reduction, however, was sufficient to abolish the phenylisopropyl-mediated inhibition of the adenylyl cyclase. To evaluate if this regulation of various inhibitory receptors in different organs may represent a general cellular regulation mechanism, we investigated whether this transregulation also occurred in isolated cells. Isolated smooth muscle cells derived from the vas deferens (DDT 1 MF-2) were cultivated in the presence of the β-blocker atenolol (10 −5 m) for 3 days. Chronic β-blockade in these isolated cells induced an increase of β-adrenergic receptors and concomitantly a significant decrease of A 1 adenosine receptors (460 ± 42 vs 368 ± 18 fmol/mg protein). The affinity of the A 1 adenosine receptors for their agonists and antagonists and the ability of the remaining receptors to form the agonist-promoted high affinity state remained unaltered. In contrast, the reduction of receptor density greatly impaired the adenosine-mediated inhibition of the adenylyl cyclase. These data demonstrate that chronic β-blockade leads to a functionally significant reduction of inhibitory receptors of the adenylyl cyclase system. This newly characterized transregulation of inhibitory receptors of the adenylyl cyclase system by chronic β-blockade represents a new regulation mechanism which involves several inhibitory receptor systems and occurs at the cellular level. This transregulation may explain some of the therapeutic effects of the little understood chronic β-blockade.

The assay and resolution of the beta-blocker atenolol from its related impurities in a tablet pharmaceutical dosage form

For the complete resolution and determination of the β-blocker atenolol and its manufacturing impurities a high-performance liquid chromatographic method is developed using structured optimization techniques. The method utilizes a 300 × 3.9 mm i.d. stainless steel column packed with μBondapak C 18 and a mobile phase containing methanol—25 mM potassium dihydrogen orthophosphate containing 0.06% (v/v) dibutylamine (20:80, v/v) (pH 3.0). The flow rate of 1.0 ml min −1 is used and a detection wavelength of 226 nm. The linearity and repeatability are good for the present compound over the range 1.5–510.0 μg ml −1 ( r > 0.99 and RSD 0.27%, n = 10). Application of the method to 50 and 100 mg tablets gave recoveries of 99% (w/w) and reproducibilities of (RSD) 1.1 and 0.52%, respectively ( n = 5). The manufacturing impurities are found to be >0.5% (w/w) of the atenolol peak.

A high-performance liquid chromatographic method for the monitoring and quantification of the synthesis of p-hydroxyphenylacetamide

p-Hydroxyphenylacetamide (HPAD) is the precursor for the synthesis of the β-blocker atenolol. A high-performance liquid method using methanol—water—tetrahydrofuran—acetic acid (35:65:1:1, v/v) as the mobile phase, a Novapak-C 18 column and detection at 254 nm was developed for the monitoring and quantification of the synthesis of HPAD. The method allows the simultaneous determination of the product, the starting material and the intermediates and thereby permits the optimization of the reaction parameters to obtain impurity-free HPAD.

Propanolol preserves ultrastructure in adult cardiocytes exposed to anoxia/reoxygenation: A morphometric analysis

The protective effective of d,l-propranolol was studied using freshly isolated canine ventricular cardiocytes (1.5 × 10 6/mL) exposed to 30 min anoxia (95% N 2 / 5% CO 2) and 0,3,20 and 45 min of reoxygenation (95% O 2 / 5% CO 2). In addition to preventing lipid peroxide formatiion, propanolol maintained cellular viability, and minimized ultrastructural alterations. In the absence of pronolol, the outer mitochondria become swollen and rounded up within the first few minutes of reoxygenation. The perinuclear mitochondrial area increased only slightly. We observed that the cellular injury process proceeded differentially from the exterior to the interior, with a mitochondrial area increase and outer membrane rupture. Sarcolemmal damage was also observed with prevalent blebbing and membrane loss. The Z-lines became wider and more diffuse with reoxygenation. Injury to the nuclear double membrane was observed. Incubation with propanolol showed significant protection during postanoxia reoxygenation. In contrast, the more water soluble β-blocker atenolol only exhibited slight protection. In addition, d-propanolol (the non β-blocking isomer) and the antioxidant enzymes, SOD and catalase, showed significant protection. These data support previous findings concerning the antioxidant properties of propanolol which appear to be independent of β-receptor blockade.

Combined α/β-blockade versus β1-selective blockade in essential hypertension in black and white patients

The purpose of this multicenter investigation was to determine the efficacy and safety of the alpha/beta-blocker labetalol versus the beta 1-selective beta-blocker atenolol in white and black patients with essential hypertension. Equal numbers of black and white patients were enlisted to form four treatment groups (white patients taking either labetalol or atenolol and black patients taking either labetalol or atenolol). Two hundred ninety-two patients (152 white and 140 black patients) with essential hypertension characterized by a standing diastolic blood pressure of 105 to 119 mm Hg (inclusive) were recruited for this trial. Patients were randomized to either labetalol (dosage titrated from 200 to 1600 mg/day) or atenolol (dosage titrated from 50 to 100 mg/day). The therapeutic goal was achievement of a standing diastolic blood pressure of 90 mm Hg or less or a fall of 15 mm Hg in diastolic pressure from baseline value at the end of the placebo run in period. At the end of the study there were no significant differences in blood pressure or heart rate changes in the supine position between the labetalol and atenolol groups. In contrast, labetalol produced greater reduction in both the standing systolic and diastolic blood pressure (-12/-13 mm Hg, respectively) compared with atenolol (-7/-9 mm Hg; p less than 0.05; p less than 0.005, respectively). The greatest decrease in blood pressure was observed in white patients receiving labetalol. In black patients the decrease in blood pressure was greater in those treated with labetalol compared with atenolol, particularly with respect to the systolic blood pressure. We conclude that the alpha 1-blocking property of labetalol provides an additional lowering of the blood pressure over that seen with beta 1-blockade alone, especially in the standing position, and this enhanced efficacy is not confined to one radical group.

The safety of amlodipine

The safety profile of amiodipine was assessed from the pooled data base of clinical research studies. This data base included 4227 subjects, 2495 of whom received amlodipine (including 2189 who received multiple-dose amlodipine); the remainder received comparative agents (placebo 1213; active comparatives 519). Amlodipine treatment was associated with a slightly higher incidence of side effects compared with placebo, but most of this difference was the result of edema, which was usually well tolerated. When compared with the β-blockers atenolol and nadolol, amlodipine had a favorable safety profile. In particular, the incidence of severe side effects in patients receiving amlodipine was approximately half that reported for patients receiving β-blockers. The data base comparing different calcium antagonists was small; in a study versus verapamil, edema was more common in patients receiving amlodipine, but constipation was more common in patients receiving verapamil. In a study versus diltiazem, both amlodipine and diltiazem were similarly well tolerated. Amlodipine was not associated with the deleterious effects of serum creatinine, urate, and fasting glucose, which was caused by hydrochlorothiazide, and in contrast to hydrochlorothiazide and nadolol, amlodipine was not associated with unfavorable changes in serum cholesterol and serum triglyceride levels. Amlodipine was well tolerated by elderly patients and is not contraindicated in patients with conduction abnormalities. Dosage modifications are unnecessary in renal impairment, but the dosage regimen for patients with hepatic impairment is not yet established. Amlodipine is an antihypertensive and antiischemic agent that has the combined advantages of a good safety profile with once-daily dosage and a smooth onset and long duration of action.

Adrenergic stimulation of sea urchin sperm cells.

The noradrenergic agonists norepinephrine and isoproterenol elicit greater stimulatory swimming responses in sea urchin spermatozoa than epinephrine. The beta-blocker atenolol induces an even greater motile rate, while the alpha-blocker phentolamine has only a moderate effect, it also causes a minimal reduction in the sperm cells' response to atenolol. Caffeine increases the motility but to a lesser degree than 8-Br-cAMP. In drug interaction assays, both caffeine and 8-Br-cAMP depress the adrenergic effects. Agents that affect access of calcium to the flagellar apparatus (verapamil and trifluoperazine) depress the motility below the level of the controls when incubated separately with the sperm suspensions and counteract the stimulation due to atenolol. Adrenergic modulation of sperm motility thus appears to be both a calcium-dependent and a cyclic nucleotide-dependent process.

Primary Prevention With Metoprolol in Patients With Hypertension

To the Editor.— The design of the Metoprolol Atherosclerosis Prevention in Hypertensives (MAPHY) Study 1 is as unorthodox as the results are surprising. How can deletion of the half of the original cohort from centers not electing to use metoprolol as the β-blocker in the Heart Attack Primary Prevention in Hypertensives (HAPPHY) trial and extension of the period of observation for only 15 months yield findings so disparate from those of the parent HAPPHY trial? If smoking men randomized to metoprolol treatment in the MAPHY Study had a significantly lower mortality rate than those randomized to diuretic treatment, yet in the HAPPHY trial there was no difference in mortality between men taking β-blocker (metoprolol or atenolol) and those taking diuretics, irrespective of smoking habits, it seems inescapable that in the atenolol group that was deleted from the MAPHY Study the mortality rate must have been significantly higher for men taking the

Atenolol and short umbilical cords

Umbillcal cord length may be a function of fetal movement. Agents that cause decreased fetal movement may cause short umbilical cords. This investigation examined the effect of the β-blocker atenolol on umbilical cord length in rabbits. Fetuses of rabbits treated with atenolol had significantly shorter cords than control animals (p ≤ 0.0005). Since short cords are associated with problems in labor, low Apgar scores, and abruption, we recommend careful surveillance of mothers and fetuses who are given β-blocking agents in the first 30 weeks of pregnancy.

BENEFITS AND POTENTIAL HARM OF LOWERING HIGH BLOOD PRESSURE

To investigate whether the lower the blood pressure (BP) the better the prognosis for the patient with moderate-to-severe hypertension, an assessment was made of 902 patients who received the β1-selective β-blocker atenolol (median dose 100 mg a day), either alone or with other antihypertensive agents, for up to 10 years (mean 6·1). 91 died, 40 from myocardial infarction, 21 from stroke, and 30 from other causes. Initial BP was a poor predictor of mortality from myocardial infarction, whereas treated systolic blood pressure (SBP) was a strong predictor. There was a J-shaped relation, confined to those with evidence of ischaemic heart disease, between frequency of death from myocardial infarction and treated DBP (phase V); the frequency was lowest at treated DBP of 85-90 mm Hg and rose with treated DBP on either side of this range.