Modeling the metabolic effects of terbutaline in beta2-adrenergic receptor diplotypes

OBJECTIVE: Our objective was to determine whether beta(2)-adrenergic receptor polymorphisms influence terbutaline-stimulated changes in glucose, insulin, and potassium concentrations in healthy adults. METHODS: Seven healthy adults homozygous for the Arg-19/Gly16/Glu27 haplotype (RGE) and seven homozygous for the Cys-19/Arg16/Gln27 haplotype (CRQ) volunteered to receive a 1-hour infusion of terbutaline (0.01 mg/kg). A 2-compartment pharmacokinetic model was fitted to the terbutaline concentrations. Concentrations of glucose and insulin were fitted simultaneously by use of a coupled feedback indirect response model. An indirect response model was also fitted to the plasma potassium concentration versus time data. The -2 log-likelihood ratio test was used to determine whether estimates of the covariates of diplotype and sex improved the model fittings. RESULTS: Demographic variables, anthropometric characteristics, and pharmacokinetics did not differ by diplotype. The coupled feedback model fitted the glucose and insulin concentration data well with excellent precision. Terbutaline stimulated production of glucose (S(1)) to a greater extent in RGE compared with CRQ diplotypes, as follows: S(1) = 0.039 +/- 0.007 (mean +/- SD) versus 0.0276 +/- 0.01, respectively (P <.05, -2 log-likelihood criterion). The baseline values, disposition rate constants for glucose (k(out1)) and insulin (k(out2)), production rate of insulin (S(2)), feedback effect of insulin on glucose (S(3)), and pharmacodynamic parameters for potassium did not differ by diplotype or sex. CONCLUSIONS: The beta(2) receptor diplotype influences receptor-stimulated glucose production in healthy, nonobese individuals, which is consistent with beta(2) receptor-mediated hepatic glycogenolysis. Future metabolic studies of this system should consider beta(2) receptor genetic variants.     

CARDIOVASCULAR AND METABOLIC EFFECTS OF TERBUTALINE

Terbutaline is a selective beta 2 agonist used predominantly in the treatment of asthma. Since beta-mediated responses increase heart rate, dilate peripheral arteries, modify carbohydrate metabolism and the uptake of electrolytes into cells, the administration of terbutaline might be expected to produce widespread effects. In this study the intravenous administration of 0.5 mg terbutaline over 60 min has been shown to produce marked changes without upsetting the volunteers. Heart rate, systolic blood pressure and plasma glucose all increase; diastolic pressure and serum potassium decrease. The data suggests that the terbutaline infusion may be a useful tool for the investigator. The results also quantitate some of the side effects which may result from the intravenous administration of a therapeutic dose of terbutaline given to asthmatics or to pregnant women to reduce uterine activity and delay childbirth.     

The combination of nebivolol plus pravastatin is associated with a more beneficial metabolic profile compared to that of atenolol plus pravastatin in hypertensive patients with dyslipidemia: a pilot study

Nebivolol, a selective beta1-lipophilic blocker, achieves blood pressure control by modulating nitric oxide release in addition to b-blockade. This dual mechanism of action could result in minimum interference with lipid metabolism compared to atenolol, a classic beta1-selective blocker. Hypertensive patients commonly exhibit lipid abnormalities and frequently require statins in combination with the anti-hypertensive therapy. We conducted this trial in order to clarify the effect on the metabolic profile of beta-blocker therapy with atenolol or nebivolol alone, or in conjunction with pravastatin. Thirty hypertensive hyperlipidemic men and women (total cholesterol >240 mg/dL [6.2 mmol/L], low-density lipoprotein cholesterol >190 mg/dL [4.9 mmol/L], triglycerides <500 mg/dL [5.6 mmol/L]) were separated in two groups. One group consisted of 15 subjects on atenolol therapy (50 mg daily), and the other group included 15 subjects on nebivolol therapy (5 mg daily). After 12 weeks of beta-blocker therapy, pravastatin (40 mg daily) was added in both groups for another 12 weeks. Atenolol significantly increased triglyceride levels by 19% (P=.05), while nebivolol showed a trend to increase high-density lipoprotein cholesterol by 8% (NS) and to decrease triglyceride levels by 5% (NS). Atenolol significantly increased lipoprotein(a) by 30% (P=.028). Fibrinogen levels were equally and not significantly decreased in both groups by 9% and 7%, respectively. Furthermore, atenolol and nebivolol decreased serum high-sensitivity C-reactive protein levels by 14% (P=.05) and 15% (P=.05), respectively. On the other hand, both atenolol and nebivolol showed a trend to increase homocysteine levels (NS) by 13% and 11%, respectively. Although uric acid levels remained the same, atenolol significantly increased the fractional excretion of uric acid by 33% (P=.03). Following nebivolol administration, glucose levels remained the same, while insulin levels were reduced by 10% and the HOMA index (fasting glucose levels multiplied by fasting insulin levels and divided by 22.5) was reduced by 20% (P=.05). There were no significant differences between the two patient groups in the measured parameters after the administration of beta-blockers, except for triglycerides (P<.05) and the HOMA index (P=.05). The addition of pravastatin to all patients (n=30) decreased total cholesterol by 21% (P<.001), low-density lipoprotein cholesterol by 28% (P<.001), apolipoprotein-B by 22% (P<.001), apolipoprotein-E by 15% (P=.014) and lipoprotein(a) levels by 12% (P=.023). Moreover, homocysteine levels and C-reactive protein were reduced by 17% (P=.05) and 43% (P=.05), respectively. We conclude that nebivolol seems to be a more appropriate therapy in hypertensive patients with hyperlipidemia and carbohydrate intolerance. Finally, the addition of pravastatin could further correct the well-established predictors of cardiovascular events.     

Metabolic and antihypertensive effects of nebivolol and atenolol in normometabolic patients with mild-to-moderate hypertension.

This was a double-blind, randomized, two-center, active-controlled, prospective, parallel study designed to evaluate the effects of nebivolol at daily doses of 5 mg on lipid and carbohydrate metabolism and on blood pressure in comparison with atenolol at daily doses of 50 mg. Normometabolic subjects with mild-to-moderate essential hypertension were recruited for this study, which included a 4-week, single-blind placebo washout phase and a 12-week double-blind treatment phase. After 12 weeks of treatment, both drugs demonstrated a significant decrease from baseline in high-density lipoprotein (HDL) apolipoprotein A-I (HDL-apoA-I) (nebivolol, P <.02; atenolol, P <.05). A significant reduction in HDL cholesterol (HDL-C) from baseline was also observed with nebivolol (P <.05). There were no significant differences between the drugs for these parameters, and the ratio low-density lipoprotein cholesterol (LDL-C)-to-HDL-C did not change significantly after 12 weeks of active treatment with nebivolol or atenolol. There were no significant changes in total cholesterol, HDL (2) -C, HDL (3) -C, LDL-C, very-low-density lipoprotein cholesterol (VLDL-C), total triglycerides, HDL-triglycerides (TG), LDL-TG, VLDL-TG, total apoB, LDL-B, VLDL-B (including the ratio LDL-C-to-LDL-apoB), or Lp(a) during treatment with both drugs. No significant differences in plasma apoA-I and apoC-III as well as in apoA-I-, C-III-containing lipoprotein particles (including the apoC-III ratio) were observed between the drugs, neither before nor after each active treatment. There were no significant differences between the drugs or within each treatment group in plasma glucose, insulin, or C-peptide concentrations after a 2-hour oral glucose tolerance test. Mean clinic trough sitting systolic blood pressure (SBP)/diastolic blood pressure (DBP) significantly decreased from 150/98 mm Hg at baseline to 141/90 mm Hg at termination for nebivolol and from 160/99 mm Hg at baseline to 145/88 mm Hg at termination for atenolol. No significant between-treatment differences were observed for the mean clinic trough sitting SBP/DBP. Both drugs significantly increased the atrial natriuretic factor (ANF) N-terminal plasma levels, whereas no changes were observed in ANF C-terminal plasma concentrations. A significant decrease (P <. 05) in the plasma adrenocorticotropic hormone levels was observed after administration of both drugs. A significant decrease (P <.05) in plasma cortisol levels was observed only after atenolol treatment. The incidence of adverse events reported during nebivolol treatment was comparable to that observed during atenolol treatment. Heart rate was significantly reduced by both drugs. There were no significant changes in hematology, biochemistry, or urinalysis studies. Neither nebivolol nor atenolol adversely affected lipid or carbohydrate metabolism in normometabolic hypertensive patients. Both treatments demonstrated adequate and similar antihypertensive effects and were well tolerated.     

Effects of nebivolol, atenolol and propranolol on in vivo cardiovascular and metabolic responses to isoproterenol in dogs

Pentobarbital-anesthetized dogs were administered either dl-propranolol, atenolol or dl-nebivolol at cumulative doses of 0 (vehicle), 0.0025, 0.01, 0.04, 0.16 and 0.64 mg/kg i.v. After each dose, heart rate and diastolic blood pressure responses to isoproterenol (0.125 micrograms/kg/min i.v. for 5 min), as well as plasma glucose, insulin, lactate and free fatty acid responses, were measured. Heart rate and free fatty acid changes were taken as beta-1 adrenergic indices, with the other parameters taken as beta-2 adrenergic indices. The antagonist dose estimated to cause 50% inhibition of each isoproterenol response (ID50) was calculated. Nebivolol and atenolol had nearly identical cardiovascular profiles, which were much more beta-1 selective than that of propranolol [heart rate and blood pressure ID50 values, mg/kg: 0.034, 0.036 (propranolol); 0.058, 0.713 (nebivolol); 0.047, 0.506 (atenolol)]. Propranolol also potently inhibited isoproterenol-stimulated glucose, insulin and lactate increases (ID50S: 0.020, 0.078 and 0.007 mg/kg, respectively). Nebivolol and atenolol were much weaker inhibitors of these metabolic responses than propranolol (5-fold-35-fold and 8-fold-greater than 90-fold, respectively). Insulin responses were equivalently inhibited by both nebivolol and atenolol (ID50S greater than 0.4 mg/kg), whereas glucose and lactate ID50S for nebivolol were 0.183 and 0.243 mg/kg, respectively, with atenolol ID50S greater than 0.64 mg/kg. Free fatty acid responses were attenuated by all three antagonists with ID50 values of 0.103, 0.100 and 0.028 mg/kg for propranolol, nebivolol and atenolol, respectively. These in vivo studies demonstrate that dl-nebivolol significantly inhibited the beta-1 cardiac response at doses which did not produce either beta-2 cardiovascular or metabolic effects.     

The importance of potassium and lactate for maximal exercise performance during beta blockade

Changes in femoral vein pH, lactate, glucose and potassium were studied in a double-blind randomized, short-term, dynamic cycle ergometry exercise test on six healthy male subjects after administration of non-selective (timolol), beta-1-selective (atenolol) beta blocker or placebo. The exercise intensity was increased in steps of 200 kpm/min every 2 min until exhaustion. During submaximal exercise, potassium concentrations in blood from the exercising leg muscles increased progressively with increasing exercise intensity, and was significantly higher for any given exercise level following timolol as compared to placebo administration. The potassium concentrations following atenolol were in-between those of timolol and placebo. Despite reduced working capacity after non-selective beta blockade, almost identical potassium concentrations were reached at exhaustion irrespective of treatment regimens (placebo: 6.3, range 5.8-6.8 mmol/l; atenolol: 6.5, range 6.1-7.3 mmol/l and timolol: 6.4, range 6.2-6.8 mmol/l). The increase in s-lactate concentrations was similar across all treatments, and rose in proportion to the increase in the exercise intensity. A biphasic increase in lactate was observed with identical breaking points (anaerobic threshold) irrespective of treatment regimens. There was no difference in glucose concentrations between the treatment regimens. The marked increase in serum potassium during maximal exercise coincides with leg muscle fatigue and may, by its effect on the muscle cell membrane potential, limit the maximal working capacity following beta blockers. The rise in serum potassium may curtail the use of maximal exercise test as an index of cardiac performance in healthy young subjects.     

Pafenolol, a highly selective beta 1-adrenoceptor-antagonist, in asthmatic patients: interaction with terbutaline

Pafenolol, a new beta 1-adrenoceptor antagonist, has been shown in animals to be more selective for beta 1-adrenoceptors than metoprolol. It was studied in asthmatic patients to evaluate whether it was more selective with respect to circulatory effects and especially whether this selectivity influenced bronchial muscle tone less than metoprolol, which has been shown to have beta 1-adrenoceptor selectivity similar to that of atenolol. Intravenous pafenolol (5 mg and 7.5 mg), metoprolol (15 mg), and saline were given double-blind at random and thereafter four increasing doses of terbutaline were given intravenously to seven asthmatic patients with reproducible reversibility of airways obstruction. After the terbutaline dose-response curve was determined, terbutaline was inhaled three times in increasing doses. A separately reported exercise study in the same patients showed that 5 mg pafenolol and 15 mg metoprolol were equipotent with respect to beta 1-adrenoceptor blockade, whereas 7.5 mg pafenolol tended to increase the blockade. The reflex tachycardia on terbutaline stimulation after pafenolol was greater than after metoprolol due to less blockade of beta 2-adrenoceptors in peripheral blood vessels. The bronchial effect of pafenolol was equal to that of saline, but there was a difference between the terbutaline dose-response curves after pafenolol and metoprolol that caused a rightward shift of the dose-response curve. Thus, pafenolol was shown to be more beta 1-selective than metoprolol.     

The role of cardiac beta-1 receptors in the hemodynamic response to a beta-2 agonist

The role of beta 1-receptors in the hemodynamic response to beta 2-stimulation was assessed in seven healthy subjects by infusion of the selective beta 2-agonist terbutaline both with and without selective beta 1-blockade by atenolol (50 mg). Infusion of terbutaline increased heart rate (+28 bpm) and indices of left ventricular (LV) performance associated with a marked decrease in LV end-systolic wall stress. The LV end-diastolic dimension remained unchanged despite the tachycardia, suggesting that venous return had increased. Systolic blood pressure increased, whereas total peripheral resistance and diastolic blood pressure decreased. Atenolol pretreatment caused the hemodynamic changes expected of beta 1-blockade but did not blunt the effects of terbutaline on heart rate, peripheral resistance, or venous return. Increases after terbutaline in LV performance and systolic blood pressure were significantly blunted by atenolol. Stimulation of beta 1-receptors therefore appears to play no role in the chronotropic and only a moderate role in the inotropic response after infusion of a beta 2-agonist. Alternative mechanisms for the cardiac changes with terbutaline include (1) withdrawal of vagal tone, (2) decrease in afterload, and (3) stimulation of cardiac beta 2-receptors.     

Terbutaline-induced desensitization of human lymphocyte beta 2-adrenoceptors. Accelerated restoration of beta-adrenoceptor responsiveness by prednisone and ketotifen.

We investigated, in 36 healthy volunteers, the effects of prednisone and ketotifen on recovery of lymphocyte beta 2-adrenoceptor density (determined by (-)-125iodocyanopindolol binding) and responsiveness (assessed by lymphocyte cyclic AMP [cAMP] responses to 10 microM (-)-isoprenaline) after desensitization by the beta 2-agonist terbutaline. Terbutaline (3 X 5 mg/d) decreased lymphocyte beta 2-adrenoceptor density by approximately 40-50%; concomitantly, lymphocyte cAMP responses to 10 microM (-)-isoprenaline were significantly reduced. After withdrawal of terbutaline beta 2-adrenoceptor, density and responsiveness gradually increased, reaching predrug levels after 4 d. Prednisone (1 X 100 mg orally) accelerated beta 2-adrenoceptor recovery; only 8-10 h after administration of the steroid beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached values not significantly different from pretreatment levels. Similar effects were obtained with ketotifen (2 mg; thereafter 2 X 1 mg/d for 4 d): 24 h after application of the drug beta 2-adrenoceptor density and cAMP responses to (-)-isoprenaline had reached pretreatment levels. Furthermore, ketotifen simultaneously applied with terbutaline completely prevented terbutaline-induced decrease in lymphocyte beta 2-adrenoceptor density and responsiveness. Prednisone (1 X 100 mg orally) or ketotifen (2 mg; thereafter 2 X 1 mg/d for 2 d) had no significant influence on lymphocyte beta 2-adrenoceptor density in healthy volunteers not pretreated with terbutaline, but shifted the ratio high-to-low affinity state of the lymphocyte beta 2-adrenoceptor toward high affinity state. We conclude that glucocorticoids as well as ketotifen can accelerate recovery of density and responsiveness of lymphocyte beta 2-adrenoceptors desensitized by long-term treatment with beta 2-agonists. Such an effect may have clinical implications for preventing tachyphylaxis of asthmatic patients against therapy with beta 2-agonists.     

Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance.

Impaired glucose tolerance (IGT) is associated with defects in both insulin secretion and action and carries a high risk for conversion to non-insulin-dependent diabetes mellitus (NIDDM). Troglitazone, an insulin sensitizing agent, reduces glucose concentrations in subjects with NIDDM and IGT but is not known to affect insulin secretion. We sought to determine the role of beta cell function in mediating improved glucose tolerance. Obese subjects with IGT received 12 wk of either 400 mg daily of troglitazone (n = 14) or placebo (n = 7) in a randomized, double-blind design. Study measures at baseline and after treatment were glucose and insulin responses to a 75-g oral glucose tolerance test, insulin sensitivity index (SI) assessed by a frequently sampled intravenous glucose tolerance test, insulin secretion rates during a graded glucose infusion, and beta cell glucose-sensing ability during an oscillatory glucose infusion. Troglitazone reduced integrated glucose and insulin responses to oral glucose by 10% (P = 0.03) and 39% (P = 0.003), respectively. SI increased from 1.3+/-0.3 to 2.6+/-0.4 x 10(-)5min-1pM-1 (P = 0.005). Average insulin secretion rates adjusted for SI over the glucose interval 5-11 mmol/liter were increased by 52% (P = 0.02), and the ability of the beta cell to entrain to an exogenous oscillatory glucose infusion, as evaluated by analysis of spectral power, was improved by 49% (P = 0.04). No significant changes in these parameters were demonstrated in the placebo group. In addition to increasing insulin sensitivity, we demonstrate that troglitazone improves the reduced beta cell response to glucose characteristic of subjects with IGT. This appears to be an important factor in the observed improvement in glucose tolerance.     

Human cardiac beta1- or beta2-adrenergic receptor stimulation and the negative chronotropic effect of low-dose pirenzepine

OBJECTIVES: The M1-muscarinic receptor antagonist pirenzepine in low doses (<1 mg intravenously) decreases heart rate. We investigated whether these effects of pirenzepine differ in volunteers with activated cardiac beta1-adrenergic receptors versus activated cardiac beta2-adrenergic receptors. METHODS: In 17 male volunteers (25 +/- 1 years) we studied effects of pirenzepine infusion (0.5 mg intravenous bolus followed by continuous infusion of 0.15 microg/kg/min) on heart rate and heart rate-corrected duration of electromechanical systole (QS2c, as a measure of inotropism) that had been stimulated by activation of cardiac beta1-adrenergic receptors (bicycle exercise in the supine position for 60 minutes at 25 W) or cardiac beta2-adrenergic receptors (continuous intravenous infusion of 100 ng/kg/min terbutaline). RESULTS: Bicycle exercise and terbutaline infusion significantly increased heart rate and shortened QS2c. When pirenzepine was infused 20 minutes after the beginning of the exercise or terbutaline infusion, heart rate decreased in both settings by approximately the same extent (approximately -10 to -14 beats/min), although exercise and terbutaline infusion continued; however, QS2c was not affected. Pirenzepine (0.05 to 1 mg intravenous bolus)-induced decrease in heart rate was abolished after 6 days of transdermal scopolamine treatment of volunteers. CONCLUSIONS: Low-dose pirenzepine decreased heart rate by muscarinic receptor stimulation, because this was blocked by scopolamine. Moreover, low-dose pirenzepine did not differentiate between cardiac beta1- or beta2-adrenergic receptor stimulation; however, low-dose pirenzepine did not affect cardiac contractility as measured by QS2c. Low-dose pirenzepine therefore exerted a unique pattern of action in the human heart: it decreased heart rate (basal and beta1- and/or beta2-adrenergic receptor-stimulated) without affecting contractility.     

Human beta2-adrenergic receptor gene haplotypes and venodilation in vivo

BACKGROUND AND OBJECTIVE: beta2-Adrenergic receptors (beta2-ARs) are polymorphic. In vitro studies have shown that agonist-promoted down-regulation is enhanced for Arg16Gly and blunted for Gln27Glu beta2-AR variants; Thr164Ile beta2-ARs exhibit reduced responsiveness to agonist stimulation. Our objective was to determine whether beta2-AR polymorphisms affect beta2-AR-mediated venodilation in healthy subjects in vivo. METHODS: We studied dilation of phenylephrine-preconstricted dorsal hand veins induced by terbutaline (50-1000 ng/min) using the Aellig hand vein technique in subjects homozygous for the 3 most common beta2-AR haplotypes (group A, Arg16Gln27Thr164 [wild type (WT)] [n = 10]; group B, Gly16Gln27Thr164 [n = 8]; and group C, Gly16Glu27Thr164 [n = 9]) and in 8 subjects heterozygous for Thr164Ile beta2-AR (group D) at baseline and after 2 weeks of treatment with oral terbutaline, 5 mg 3 times daily. RESULTS: Terbutaline dose-dependently dilated hand veins; sensitivity to terbutaline was 2-fold higher in haplotype group A versus group B or C; maximal dilation, however, was not haplotype-dependent. In Thr164Ile subjects terbutaline sensitivity but not maximal dilation was 4-fold lower than in WT subjects. Long-term terbutaline treatment desensitized venous beta2-AR in a haplotype-dependent manner: The extent of desensitization (reduction in maximal venodilation) was largest for haplotype A, modest for haplotype B, and almost absent for haplotype C. Long-term terbutaline treatment also desensitized venous Thr164Ile beta2-AR; after terbutaline treatment, dose-response curves for terbutaline-induced venodilation were superimposable in WT and Thr164Ile beta2-AR subjects. CONCLUSION: beta2-AR-mediated dilation of human hand veins is influenced by the 3 most common beta2-AR haplotypes and blunted in subjects heterozygous for Thr164Ile beta2-AR. Long-term terbutaline treatment desensitizes venous beta2-AR in a haplotype-dependent manner, with haplotype A (Arg16Gln27Thr164) showing greater desensitization than haplotype B (Gly16Gln27Thr164), which shows greater desensitization than haplotype C (Gly16Glu27Thr164).     

Different effects of selective β1‐adrenoceptor antagonists,nebivolol or atenolol in acetaminophen‐induced hepatotoxicity of rats

Acetaminophen (APAP) overdose is a common cause of acute liver failure, and beta‐blockers are commonly used drugs in clinical practice. This study aimed to evaluate the effect of two different beta‐blocker agents as nebivolol and atenolol against APAP‐induced hepatotoxicity. Male Wistar rats were treated with APAP (2 g/kg/day, p.o.) to induce hepatotoxicity. Our results showed that nebivolol and atenolol reduced heart rate and blood pressure. Nebivolol (5 mg/kg/day, p.o.) for 14 days has a hepatoprotective effect shown by significant decrease in hepatic injury parameters (serum AST and ALT) with significant suppression of hepatic malondialdehyde (MDA) and nitric oxide (NO) which were elevated with APAP administration. Also, nebivolol increased reduced glutathione (GSH) which was reduced with APAP administration. Moreover, immunohistochemical examination revealed that nebivolol treatment markedly reduced inducible nitric oxide synthase (iNOS) expression, while expression of endothelial nitric oxide synthase (eNOS) was markedly enhanced, as compared to APAP group. The protective effects of nebivolol were also verified histopathologically. On the other hand, as compared to APAP group, oral administration of atenolol (50 mg/kg) increased hepatic injury parameters but did not change hepatic NO, MDA, and GSH. In conclusion, this study revealed that nebivolol not atenolol is protective against APAP‐induced hepatotoxicity possibly, in part, through its antioxidant activity, inhibition of iNOS expression, and induction of eNOS expression.     

beta-2 Adrenergic blockade evaluated with epinephrine after placebo, atenolol, and nadolol

Vascular beta 2-adrenergic blocking effects of the water-soluble drugs atenolol (beta 1-selective) and nadolol (nonselective) were evaluated. Twenty-four healthy young men were studied in three dosing groups (eight subjects per group) before and after 1 wk on placebo, atenolol (50 mg twice a day), or nadolol (40 mg twice a day). Maximal treadmill exercise heart rates were reduced to a similar degree by atenolol (-48 +/- 3 bpm) and nadolol (-48 +/- 4 bpm) but were not affected by placebo. Trough blood levels were 226 +/- 9 ng/ml for atenolol and 43 +/- 9 ng/ml for nadolol. Calf blood flow was measured with a plethysmograph and calf vascular resistance was calculated from blood pressure and flow. beta 2-Adrenergic blockade was determined at rest with epinephrine infused intravenously in graded doses from 0.001 to 0.032 micrograms/kg/min. Mean arterial pressure and calf vascular resistance rose markedly after nadolol but not after atenolol or placebo. Marked bradycardia developed after nadolol, probably by baroreceptor stimulation. Thus at an equivalent, substantial degree of beta 1-adrenergic blockade, nadolol blocks vascular beta 2-adrenergic receptors and atenolol does not. Measurement of the peripheral vascular response to epinephrine infusion is an effective means of assessing the impact of beta-adrenergic blockers on vascular beta 2-adrenergic receptors.     

Ventilatory effects of atenolol and bevantolol in asthma

The cardioequipotency of 400 mg bevantolol and 100 mg atenolol was determined by measuring the exercise heart rate in healthy subjects. The beta-blockers were then used in these doses to investigate their ventilatory effects in patients with asthma. The effects of both drugs on forced expiratory flow parameters for large and small airways were assessed at rest and during and after exercise. A dose-response curve was then plotted after inhalation of the beta 2-adrenoceptor agonist terbutaline. Bevantolol significantly decreased the forced expiratory volume in 1 second (FEV1) and the peak expiratory flow rate (PEFR) at rest, while there was no such change with placebo or atenolol. Both beta-blockers decreased the maximal expiratory flow rates at 50% of forced vital capacity (MEF50) and after expiration of 75% of the forced vital capacity (MEF25) at rest; the decrease was larger after bevantolol than after atenolol. During atenolol there was a decrease in FEV1 and in PEFR (P less than 0.01) 15 minutes after exercise in comparison with preexercise values. There was no significant difference between pre- and postexercise values of MEF50 and MEF25 during atenolol dosing. After bevantolol there was only a small change in PEFR after exercise, probably because of the low preexercise values of the ventilatory indices with this drug. Inhalation of terbutaline up to a dose of 2 mg significantly improved all ventilatory indices measured, but with bevantolol the values after 2 mg inhaled terbutaline were lower than the initial values.(ABSTRACT TRUNCATED AT 250 WORDS)     

A 1-year follow-up study on the effect of atenolol on serum beta 2-microglobulin level in hypertensive diabetic patients

Hypertensive diabetic patients are particularly prone to renal function impairment. A total of nine out-patients with diabetes and hypertension were, therefore, entered into this single-blind uncontrolled study on the effects of 50 mg/day atenolol on reducing blood pressure and preserving normal kidney functioning. Treatment and evaluations were continued for 12 months. Serum beta 2-microglobulin concentration was used as the index for measuring renal impairment. Atenolol significantly reduced heart rate, systolic and diastolic blood pressure, and serum beta 2-microglobulin concentrations compared with baseline. Plasma glucose and glycosylated haemoglobin levels were unchanged, and blood urea nitrogen levels were increased slightly (non-significant). Serum creatinine showed a tendency (non-significant) to reflect the changes in beta 2-microglobulin concentration. Ways in which atenolol may act to improve kidney functioning are suggested. It is concluded that atenolol is a favourable choice for the treatment of hypertension in diabetic patients with normally functioning kidneys since, even in long-term use, normal renal functioning is preserved.     

Effects of beta 1- and beta 2-blockade on blood pressure and sympathetic responses to flight phobia stress

Cardiovascular and sympathoadrenal effects of short-term oral treatment with beta 1-blockade (atenolol, 50 mg, administered two times) and beta 2-blockade (ICI 118,551, 50 mg, administered three times) were compared with placebo during actual flying in subjects with flight phobia (n = 34). beta 1-Blockade lowered resting blood pressure and heart rate and prevented a heart rate response but not a blood pressure response to this psychologic stress. beta 2-Blockade minimally lowered resting heart rate and prevented a heart rate response, but it failed to lower resting blood pressure or blood pressure response to the stress. Plasma epinephrine increased with all three treatments and more with beta 1-blockade than with placebo. Plasma norepinephrine decreased with administration of beta 2-blockade. Thus neither beta 1- nor beta 2-blockade prevents an increase in blood pressure during acute flight phobia stress. Increased plasma epinephrine seems to be the sympathetic variable that is closest related to this increase in blood pressure. Norepinephrine may be less consistently related to the blood pressure rise during flight phobia stress as shown by the decrease in plasma norepinephrine with administration of beta 2-blockade.     

Effects of betaxolol, propranolol, and atenolol on isoproterenol-induced beta-adrenoceptor responses

Five healthy young men received, in a double-blind fashion, single oral doses of 10 mg betaxolol, 40 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and placebo. After the dose each received serial 12-minute infusions of isoproterenol sulfate through the dose range 0.5 to 32 micrograms/min until the heart rate rose by 40 bpm or the subject could not tolerate the effects of the infusion. Heart rate, finger tremor, blood pressure, and forearm blood flow were measured after each infusion. Dose-response curves were constructed for the changes in these parameters with increasing doses of isoproterenol. The ascending order of potency of the drugs in preventing the changes in heart rate, finger tremor, diastolic blood pressure, forearm blood flow, and forearm vascular resistance induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg betaxolol, and 40 mg propranolol. The ascending order of potency of the drugs in preventing the change in systolic blood pressure induced by isoproterenol was placebo, 10 mg betaxolol, 50 mg atenolol, 40 mg propranolol, and 40 mg betaxolol. Betaxolol, 10 mg, is equally cardioselective to 50 mg atenolol and at a dose of 40 mg betaxolol also exhibits cardioselectivity.