Does tachyphylaxis occur to the non-pulmonary effects of salmeterol?

1. The potential for tachyphylaxis to the non-pulmonary effects of salmeterol, a long-acting selective beta 2-adrenoceptor agonist was investigated in 12 healthy male subjects in a double-blind two period crossover study design. 2. Subjects received cumulative doses of up to 400 micrograms (50 + 50 + 100 + 100 + 100 micrograms at 45 min intervals) inhaled salmeterol prior to a 13 day dosing schedule of twice-daily inhaled salmeterol 100 micrograms or placebo. Twelve hours after the last dose of salmeterol or placebo, subjects again received cumulative doses of up to 400 micrograms inhaled salmeterol. 3. Pulse rate, blood pressure, 12-lead ECG, physiological tremor and peak expiratory flow rate (PEFR) were measured before administration of cumulative doses of salmeterol, at 10, 20, 30 and 40 min after each incremental dose of salmeterol and at 4, 6 and 8 h after the first dose. Blood samples were taken for plasma potassium, magnesium, non-esterified fatty acids (NEFA) and blood glucose concentrations at 20 and 40 min after each dose and at 4, 6 and 8 h after the first dose. 4. Eleven subjects completed the study. One subject withdrew due to beta 2-adrenoceptor related adverse events. All other adverse events reported were mild in nature. 5. Dose-related changes to the effects of salmeterol on pulse rate, QTc interval, tremor, PEFR, blood glucose and plasma potassium were seen, but there was no dose-related effect of salmeterol on blood pressure, plasma magnesium and NEFA. 6. Tachyphylaxis occurred to the effects of salmeterol on tremor, QTc and blood glucose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Novel quantitative assessment of the tremorogenic effects of the beta 2-mimetics clenbuterol and salbutamol after oral administration

A pharmacodynamic study was run in 12 healthy volunteers (4 male, 8 female, mean age 33.3 years, mean body-weight 60.8 kg) to demonstrate a dose- and time-effectiveness dependency for a beta 2-mimetic drug (clenbuterol, Spiropent) versus salbutamol and placebo as reference. A newly developed 3-dimensional tremormeter was introduced in this randomised double-blind/6-way/cross-over study. The shape of the induced tremor effects (in amplitude) as well as the pulse frequency reflected highly significant dose relationships. Drug effects started 30 min after intake and lasted longer than 600 min. 10 micrograms of clenbuterol revealed no significant differences when compared to placebo, whereas the 20 micrograms dosage as usually administered in clinical routine demonstrated significant--but only slight--differences to placebo-baseline. All other dosages and the reference (salbutamol, 8 mg) could be discriminated distinctly against placebo.     

The selectivity of xamoterol, prenalterol, and salbutamol as assessed by their effects in the presence and absence of ICI 118,551

The selectivity of single oral doses of xamoterol, 200 mg, prenalterol, 50 mg, and salbutamol, 8 mg, was compared in eight healthy male volunteers by measuring their effects on sleeping heart rate, supine heart rate, blood pressure, forearm blood flow, finger tremor, and exercise heart rate in the presence and absence of the specific beta 2-adrenoceptor antagonist ICI 118,551, 25 mg. Xamoterol, 200 mg, increased sleeping heart rate and systolic blood pressure, decreased exercise heart rate, and had no effect on diastolic blood pressure, forearm blood flow, or finger tremor. The concurrent administration of ICI 118,551, 25 mg, did not alter these results. Supine heart rate was increased by xamoterol and did not differ from that for xamoterol with ICI 118,551. Prenalterol, 50 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, and finger tremor, decreased diastolic blood pressure, and had no effect on exercise tachycardia. The concurrent administration of ICI 118,551 with prenalterol reduced the increase in sleeping heart rate, supine heart rate, and forearm blood flow, and reduced the fall in diastolic blood pressure caused by prenalterol alone. The increase in finger tremor following prenalterol with ICI 118,551 tended to be less than that following prenalterol. Salbutamol, 8 mg, increased sleeping heart rate, supine heart rate, systolic blood pressure, forearm blood flow, finger tremor, and exercise heart rate, and caused a fall in diastolic blood pressure. When salbutamol, 8 mg, was administered with ICI 118,551, 25 mg, the only changes detected were a small initial increase in finger tremor and a small rise in diastolic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of cardiac beta 1-adrenergic sensitivity with dobutamine in healthy volunteers.

1. Evaluation of cardiac beta 1-adrenergic sensitivity in heart failure should provide instructive therapeutic as well as prognostic information. We set up a non-invasive test in healthy volunteers to evaluate beta 1-adrenergic reactivity using dobutamine as a preferential agonist. 2. The range of i.v. bolus doses was 3.2 to 12.2 micrograms kg-1. The test was well tolerated. The parameters that were most sensitive and best correlated to dobutamine doses were systolic blood pressure and the rate-corrected electromechanical systole (QS2i). The reproducibility of the test over 48 h and over 1 month was satisfactory for most parameters, with a mean variation coefficient ranging from 9 to 26%, and was better for QS2i than for heart rate. 3. Slope of log dose-response for heart rate and QS2i was similar with dobutamine and with isoprenaline, corresponding to stimulation of the same type of beta-adrenergic receptors (beta 1-subtype). This result was obtained despite a higher vagal stimulation with dobutamine. We conclude that the left ventricular contractile response assessed by QS2i provided the best parameter for evaluation of beta 1-adrenergic cardiac effects either with dobutamine or with isoprenaline. 4. In heart failure patients such a dobutamine test should allow separation of altered contractility and beta-adrenergic desensitization, since alteration of inotropic response to dobutamine should depend on both altered contractile function and adrenergic desensitization but heart rate response should only depend on the latter phenomenon.     

Cardiac effects of beta-adrenoceptor antagonists with intrinsic sympathomimetic activity in humans: beta1- and/or beta2-adrenoceptor mediated?

The aim of this study was to find out whether cardiac responses to the beta-adrenoceptor antagonists with intrinsic sympathomimetic activity (ISA) xamoterol and celiprolol are mediated by cardiac beta1- or beta2-adrenoceptors or both. For this purpose we assessed, in six healthy male volunteers, the effects of xamoterol (100 and 200 mg, p.o.) and celiprolol (200, 600, and 1,200 mg, p.o.) on blood pressure, heart rate, and heart rate-corrected duration of the electromechanical systole (QS2c, as a measure of inotropism). Xamoterol, in both doses, increased systolic blood pressure and heart rate, transiently decreased diastolic blood pressure, and shortened QS2c; all these effects were attenuated after pretreatment of the volunteers with the beta1-adrenoceptor antagonist bisoprolol. Celiprolol, in all three doses, increased heart rate, decreased diastolic blood pressure, and shortened QS2c but only marginally increased systolic blood pressure. Bisoprolol did not attenuate these celiprolol effects but rather enhanced celiprolol effects on systolic blood pressure and heart rate. In a further set of experiments, we studied cardiovascular effects of celiprolol in six healthy volunteers whose beta2-adrenoceptors had been desensitized by a 2-week treatment with 3x5 mg/day terbutaline. Under these conditions, celiprolol failed to increase heart rate or to shorten QS2c. We conclude that, under resting conditions, in healthy volunteers, beta-adrenoceptor antagonists with ISA can exert increases in heart rate and contractility that are mediated by either cardiac beta1-adrenoceptor (xamoterol) or cardiac beta2-adrenoceptor (celiprolol) stimulation. Thus in the human heart, the ISA of beta-adrenoceptor antagonists can be a beta1- or beta2-adrenoceptor agonistic component.     

Double-blind placebo-controlled trial of terazosin effect on blood pressure and urinary output of dopamine in hypertensive patients.

In a parallel, double-blind study, 12 untreated hypertensive patients received terazosin (2-4 mg/day for 4 weeks), and 12 received placebo during the same period. Systolic and diastolic blood pressure decreased significantly in the terazosin group, from 150 +/- 5.0 mmHg systolic and 99.6 +/- 2.0 diastolic before treatment, to 134.0 +/- 7.0 systolic and 85.6 +/- 3.0 mmHg diastolic at week 4 of treatment. No significant blood pressure changes occurred in the placebo group. Blood pressure decrease showed a positive correlation (r = .62 and r = .52 for systolic and diastolic blood pressure, respectively) with the patient's age (P less than .05). Total plasma cholesterol decreased 18% in the terazosin group (P less than .05) and 9% in the placebo group (P greater than .05). Urinary dopamine excretion decreased significantly from 692.8 +/- 180.0 to 330.5 +/- 52.0 micrograms/24 hours in the terazosin group (P less than .05) and showed a nonsignificant increase in the placebo group. Compared with 22 age- and sex-matched healthy volunteers, urinary dopamine excretion in the hypertensive group before treatment was not statistically different (779.3 +/- 83.1 micrograms/24 hours). Dopamine excretion was higher in untreated hypertensive men and in male healthy volunteers compared with women. The decrease of urinary dopamine excretion observed under terazosin treatment could be due to a decrease of kidney dopamine synthesis or release induced by blood pressure reduction, or secondarily to the blockade of kidney alpha 1-receptors, modulating dopamine excretion. No significant changes were observed in urinary excretion of noradrenaline and adrenaline.     

Selective and non-selective beta-blockade in renin release.

The effects of two beta-adrenergic receptor blocking drugs, the non-selective propranolol and the beta1selective metoprolol, were studied on hemodynamics and plasma renin activity (PRA) of healthy volunteers in an ergometric exercise test. Oral doses of 160 mg of propranolol and 200 mg of metoprolol were tested against placebo. The drug plasma concentrations were determined. Heart rate and systolic blood pressure were equal and significantly lower during treatment with both active drugs when compared to placebo. The effect of drugs on exercise heart rate was correlated with the logarithm of drug plasma concentration with both propranolol and metoprolol. Propranolol, but not metoprolol, decreased the basal level of PRA. The ergometric exercise induced a significant rise in PRA after placebo but this increase was partially inhibited by the both active drugs. On the basis of these findings it is suggested that in man the basal level of PRA could be decreased mainly by blocking the beta2-adrenoceptors. Instead the exercise induced increase of PRA could be inhibited by blocking the beta1-adrenergic receptors.     

Reducing adverse effects of inhaled fenoterol through optimization of the aerosol formulation.

We compared the adverse effects of 160 micrograms of fenoterol in the form of a 2.8-micron monodisperse aerosol with those of 800 micrograms of fenoterol as a conventional metered dose inhaler (MDI) aerosol plus spacer. Previously, a monodisperse aerosol was shown to elicit equivalent degrees of bronchodilation at an 80% lower dose using a standard MDI. A total of 12 healthy volunteers (8 women and 4 men) participated in this study and inhaled in random order a placebo, the monodisperse aerosol, and the MDI aerosol. Changes in serum potassium level, finger tremor, blood pressure, heart rate, and specific airway conductance were measured before and 15 minutes after administration. Compared with placebo, the active aerosols elicited a significant improvement in airway conductance and adverse effects. Serum potassium level decreased by 0.27 mmol/L after the monodisperse aerosol, and the MDI lowered it by 0.67 mmol/L (P = 0.001). Finger tremor also increased less: 0.07 versus 0.29 V (P = 0.029). Changes in cardiovascular parameters were not significantly different from those elicited by the placebo. There were no significant specific airway conductance differences between the two active aerosols. By changing the formulation of MDI aerosols, the occurrence of adverse effects can be reduced.     

An assessment of the partial agonist activity of Ro 31-1118, flusoxolol and pindolol in man.

1. The effects of single oral doses of three beta-adrenoceptor partial agonists (Ro 31-1118, flusoxolol and pindolol), two beta-adrenoceptor antagonists (propranolol and atenolol), two beta-adrenoceptor agonists (salbutamol and prenalterol) and placebo on sleeping heart rate, quality of sleep, supine heart rate, exercise heart rate, blood pressure, forearm blood flow and finger tremor were studied in eight healthy male volunteers. 2. Sleeping heart rate was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol and prenalterol and decreased by propranolol and atenolol. 3. None of the drugs studied affected quality of sleep. 4. Supine heart rate was increased by flusoxolol, prenalterol and salbutamol, unaffected by Ro 31-1118 and pindolol and reduced by propranolol and atenolol. 5. Exercise heart rate was reduced by both beta-adrenoceptor antagonists and the three partial agonists and unaffected by salbutamol and prenalterol. 6. Systolic blood pressure was increased by Ro 31-1118, flusoxolol, salbutamol and prenalterol, unaffected by pindolol and reduced by propranolol and atenolol. Diastolic blood pressure was reduced by salbutamol and prenalterol. 7. Forearm blood flow was increased by Ro 31-1118, salbutamol and prenalterol, unchanged by pindolol and flusoxolol and decreased by atenolol and propranolol. 8. Finger tremor was increased by Ro 31-1118, flusoxolol, pindolol, salbutamol, and prenalterol. 9. beta-adrenoceptor partial agonists have different effects on the cardiovascular system and finger tremor to beta-adrenoceptor antagonists. 10. While Ro 31-1118 and flusoxolol are antagonists mainly at the beta 1-adrenoceptor they have agonist activity at both beta 1- and beta 2 adrenoceptors. 11. While pindolol is a non-selective antagonist its agonist activity is mainly at the beta 2-adrenoceptor.     

Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist

The pharmacological profile of nebivolol (N), a chemically novel beta-adrenergic antagonist, was assessed in investigations on isolated tissues, awake spontaneously hypertensive rats (SHR), closed-chest anesthetized dogs, and humans. In vitro, N was found to be a potent antagonist of beta 1-adrenergic receptors (A2 value, 5.8 X 10(-9) M) and only a weak beta 2-adrenergic antagonist (A2 value, 1.7 X 10(-6) M). The selectivity for the beta 1-adrenergic receptor was higher for N than for any of the reference compounds. In dogs--similarly with atenolol--N was more potent in blocking the isoprenaline (I)-induced increases in left ventricular performance than the I-induced decrease in arterial pressure. In dogs, as compared with propranolol, N (0.025 and 0.01 mg.kg-1 i.v.) increased cardiac output and stroke volume, lowered systemic vascular resistance, and had no significant effect on the variables related to left ventricular contraction. In contrast to other beta-adrenergic antagonists, N acutely lowered arterial blood pressure in SHR (1.25 mg.kg-1 i.p.) and in hypertensive patients (1 oral dose of 5 mg) for several hours. In healthy volunteers N (5 mg) lowered systemic vascular resistance during daily oral treatment and did not negatively affect left ventricular function. In conclusion, N is a potent and selective beta 1-adrenergic blocking agent with an interesting hemodynamic profile. In hypertensive subjects and SHR, a single dose lowers arterial blood pressure for substantial periods of time.     

Metipranolol and propranolol: No CNS effects of a single oral dose

Effects of single oral doses of the -blocking drugs propranolol (40 mg) and metipranolol (Disorat, Boehringer, Mannheim, FRG, 5 and 20 mg), in comparison with placebo, on mental performance and psychophysiological measures were investigated in a double-blind crossover study comprising 12 healthy volunteers. Effects were evaluated using a battery of highly reliable and sensitive computerized indices of mental performance and a comprehensive range of psychophysiological measures. Propranolol and metipranolol had no effects on mental performance, in contrast to findings in a previous study for bunitrolol (Stresson, Boehringer, Ingelheim, FRG). There were marked effects on some autonomic functions; dose-dependent for heart rate and heart rate response, and dose-independent for blood pressure and finger tremor. In the previous study bunitrolol had no effect on tremor and blood pressure and a less marked effect on heart rate. The lack of psychotropic effects for metipranolol and propranolol as compared to bunitrolol cannot be predicted from pharmacokinetic properties or peripheral effects of the three drugs, arguing for the need for systematic screening using psychometric and psychophysiological methods of current and new -blocking drugs. A comparison between the effect of propranolol given in a single oral dose and findings in a previous study with repeated administration suggested that the differences in effect profile between acute and chronic administration of the drug are small.     

Terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function in humans: attenuation by ketotifen.

Use of beta-adrenoceptor agonists in long-term treatment of patients with chronic asthma bronchiale or heart failure is of limited value because beta-adrenoceptor desensitization develops. The antiallergic drug ketotifen prevents beta-adrenoceptor agonist-induced desensitization of rat and human pulmonary and lymphocyte beta 2-adrenoceptors. In 10 healthy volunteers in a double-blind, placebo-controlled study, we investigated whether ketotifen also prevents beta-adrenoceptor agonist-induced desensitization of beta 1- and/or beta 2-adrenoceptor-mediated physiologic in vivo effects. beta 1-Adrenoceptor-mediated effects were isoprenaline (ISO) infusion-induced increase in systolic blood pressure (SBP) and bicycle exercise-induced increase in heart rate (HR); beta 2-adrenoceptor-mediated effects were ISO infusion-induced increase in plasma norepinephrine (NE) and decrease in diastolic blood pressure (DBP); ISO infusion-induced increase in HR was assessed as mixed beta 1- and beta 2-adrenoceptor-mediated effect. These parameters were assessed before and after a 14-day treatment with the beta 2-adrenoceptor agonist terbutaline (5 mg three times daily) with or without simultaneous administration of ketotifen (1 mg twice daily). Terbutaline desensitized all in vivo effects involving beta 2-adrenoceptors (ISO-induced decrease in DBP and increase in plasma NE and, to a minor extent, the mixed beta 1- and beta 2-adrenoceptor-mediated increase in HR), but did not affect beta 1-adrenoceptor-mediated in vivo effects; concomitant treatment of the volunteers with ketotifen markedly blunted terbutaline-induced desensitization of beta 2-adrenoceptor in vivo function. We conclude that ketotifen prevents, or at least attenuates, beta-adrenoceptor agonist-induced desensitization of beta 2-adrenoceptor in vivo function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypokalaemia and other non-bronchial effects of inhaled fenoterol and salbutamol: a placebo-controlled dose-response study in healthy volunteers.

1. The hypokalaemia-inducing effects of two widely used inhaled antiasthmatic beta 2-adrenoceptor agonists, fenoterol and salbutamol, were compared in six healthy male volunteers. 2. Each drug was administered in three different doses, 400, 600 and 800 micrograms, which were repeated three times with 30 min intervals (total doses 1200, 1800 and 2400 micrograms in 1 h). The treatments were given at 1 week intervals in random order in a single-blind fashion. 3. The concentration of potassium in plasma was dose-dependently reduced by both drugs with peak effects 75-90 min after the first inhalations. The hypokalaemic effect of fenoterol was significantly greater than that of equal doses of salbutamol (average +/- s.d. reductions of 1.13 +/- 0.32 and 0.67 +/- 0.25 mEq l-1, respectively, after the highest doses, P less than 0.05). Concomitantly, decreases were noted in the amplitude of the T-wave on the ECG. 4. The concentration of cyclic AMP in plasma was measured and used as an indicator of systemic beta 2-adrenoceptor agonistic effects of the drugs. Increases in cAMP were a close mirror image of the drugs' effects on potassium in plasma. 5. Plasma renin activity, noradrenaline in plasma and heart rate were also dose-dependently increased by the treatments, whereas blood pressure remained unaltered. 6. While the clinical significance of hypokalaemia induced by inhaled beta 2-adrenoceptor sympathomimetics still is a matter of debate, our results point to possible differences between therapeutically equipotent doses of fenoterol and salbutamol in their propensity to cause hypokalaemia and other acute non-bronchial effects.     

Vascular beta-adrenoceptor blocking activity of endotoxin and pertussis toxin from Bordetella pertussis in rats

Isolated and purified leucocytosis promoting factor (LPF), alternatively described as pertussis toxin, reduced the hypotension after beta 2-adrenoceptor stimulation with salbutamol as well as the negative chronotropic activity induced by the muscarinic receptor stimulant arecoline 4 days after its injection into rats. These inhibitory effects of LPF were accompanied by a reduction in basal blood pressure. No effect on autonomic responsiveness or blood pressure was observed 5 h after injection of LPF. Sublethal doses of purified B. pertussis endotoxin (LPS) elicited neither vascular beta 2-adrenergic nor cardiac cholinergic blockade 4 days following injection. Only a distinct vascular beta 2-adrenolytic effect was measured 5 h after pretreatment with the same doses of LPS. This beta 2-adrenoceptor hyporesponsiveness was accompanied by neither an anticholinergic nor a hypotensive effect, but rather by a slight but significant elevation of the blood pressure. In conclusion, both components of B. pertussis (LPS and LPF) give rise to vascular beta 2-adrenergic hyporesponsiveness irrespective of blood pressure effects. There is an important difference between both components with respect to their various kinetic profiles for this phenomenon: an early occurring and short-lasting beta 2-adrenergic blockade for LPS and a late occurring LPF-mediated beta 2-adrenergic blockade.     

Influence of hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, an ultra-short-acting beta1-blocker

OBJECTIVE: To investigate the effects of mild to moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of landiolol hydrochloride, a new ultra-short-acting beta1-adrenergic antagonist. METHODS: Six patients with hepatic impairment and six healthy volunteers were enrolled in the open-label, parallel-group study. Landiolol hydrochloride was given intravenously with a 1-minute loading infusion of 0.06 mg/kg/min, followed by a 60-minute infusion of 0.02 mg/kg/min using an automated infusion pump. Venous blood was drawn just before (predose) and 1, 2, 5, 15, 30 and 61 minutes after beginning the continuous intravenous infusion (during infusion); 2, 5, 10 and 30 minutes and 1, 4 and 8 hours after the end of the infusion (after infusion); and 24 hours after beginning the infusion (next day). Urine samples were collected up to 24 hours after beginning the infusion. Before subjects were discharged, an indocyanine green elimination test, clinical laboratory testing, physical examination and recording of ECGs and vital signs were performed. RESULTS: The geometric mean maximum plasma concentration and area under the concentration-time curve values for the patients with hepatic impairment were 42% and 44% higher, respectively, than those observed for the healthy volunteers, indicating that hepatic impairment affected the disposition of landiolol hydrochloride. There were no significant changes in the elimination half-life of the drug. There were no clinically significant differences between the two groups in terms of reductions in heart rate or blood pressure. CONCLUSION: The pharmacokinetic and pharmacodynamic characteristics of this ultra-short-acting beta1-blocker were maintained even in the patients with hepatic impairment. Although we did not observe any drug-related adverse events in these patients, hypotension or bradycardia should be considered, necessitating continuous monitoring of both heart rate and BP in patients with hepatic impairment who receive landiolol hydrochloride.     

Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta 2-adrenoceptor blockade.

1. The purpose of the study was to assess and compare the effects of inhaled salbutamol on heart rate (HR), finger tremor (Tr) and specific airways conductance (sGaw) in the measurement of beta 2-adrenoceptor blockade in normal subjects. 2. Five healthy volunteers were given oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40) or identical placebo (P1) in a single-blind crossover design. 3. Three hours after drug ingestion, dose-response curves were constructed using cumulative doses of inhaled salbutamol: 200 micrograms, 700 micrograms, 1700 micrograms, 3200 micrograms, 6200 micrograms. HR, Tr and sGaw were measured at each dose increment, made every 20 min. 4. Increasing doses of atenolol were associated with progressive reduction in salbutamol induced beta-adrenoceptor responses. The greatest attenuation occurred with propranolol. These effects on beta-adrenoceptor responses were similar for HR, Tr and sGaw. Geometric mean dose ratios (compared with placebo) for A50, A100, A200 and P40 were as follows HR: 1.98, 2.75, 4.29; Tr: 1.60, 3.78, 6.34, 80.50; sGaw: 1.08, 4.35, 12.30, 66.0 (no dose ratio was obtained for HR with P40). 5. These results showed that atenolol and propranolol attenuated the effects of salbutamol on HR to a similar degree as Tr and sGaw. Furthermore, the variability was least in the measurement of chronotropic responses, suggesting that this may be used to quantify beta 2-adrenoceptor antagonism. The beta 1-adrenoceptor selectivity of atenolol was a dose-dependent phenomenon, although the beta 2-adrenoceptor blockade of A200 was much less than with P40.     

Effect of beta-adrenergic antagonists on experimentally induced drinking in female rats

The nonspecific beta-adrenergic antagonist d,l propranolol, the specific beta 1-adrenergic antagonist atenolol, and the specific beta 2-adrenergic antagonist butoxamine were administered intraperitoneally (IP) to ovariectomized female rats in order to determine the role of beta-adrenergic receptors in drinking. D,l propranolol and atenolol administered at doses of 6, 12, and 18 mg/kg significantly attenuated the one-hour water intakes of rats administered angiotensin II (200 micrograms/kg, SC) and the water intakes of rats deprived of water for 24 hours. D propranolol, which has little beta-adrenergic blocking ability, administered at doses of 6 and 12 mg/kg, and butoxamine, administered at doses of 25 and 35 mg/kg, had no significant effects on the water intakes of angiotensin II treated or water deprived rats. Regardless of the dose, d,l propranolol, atenolol, and butoxamine failed to significantly alter the water intakes of rats administered 1.0 M NaCl (10 ml/kg, IP) The results provide evidence that beta 1-adrenergic receptors, but not beta 2-adrenergic receptors, are involved in mediating the increased water intakes induced by angiotensin II and water deprivation. On the other hand the increased water intake due to administration of hypertonic saline does not appear to mediated by beta-adrenergic receptors.     

The tremorolytic action of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is mediated by beta-adrenoceptors located in a deep peripheral compartment.

The effects of intravenous propranolol 100 micrograms kg-1, sotalol 500 micrograms kg-1, timolol 7.8 micrograms kg-1, atenolol 125 micrograms kg-1 and placebo on essential, physiological and isoprenaline-induced tremor were studied. These beta-adrenoceptor blocker doses produced equal reduction of standing-induced tachycardia in essential tremor patients. Atenolol produced significantly less reduction of essential and isoprenaline-induced tremor than the non-selective drugs, confirming the importance of beta 2-adrenoceptor blockade in these effects. Propranolol and sotalol produced equal maximal inhibition of isoprenaline-induced tremor but propranolol was significantly more effective in reducing essential tremor. The rate of development of the tremorolytic effect was similar in essential, physiological and isoprenaline-induced tremors but all tremor responses developed significantly more slowly than the heart rate responses. It is proposed that these results indicate that the tremorolytic activity of beta-adrenoceptor blockers in essential, physiological and isoprenaline-induced tremor is exerted via the same beta 2-adrenoceptors located in a deep peripheral compartment which is thought to be in the muscle spindles.     

Nebivolol decreases systemic oxidative stress in healthy volunteers

AIMS: Nebivolol is a selective, vasodilatory beta1-adrenergic receptor antagonist which has been suggested to possess additional antioxidative properties. The aim of the present study was to assess the actions of nebivolol in antihypertensive doses on systemic oxidative stress in healthy volunteers, reflected by 24 h urinary excretion of 8-iso-PGF2alpha. METHODS: In a double-blind, cross-over study, 12 healthy volunteers received 5 mg nebivolol once daily or placebo for a total of 7 days, separated by a wash out period of 2 weeks. After each treatment period 24 h urinary excretion of 8-iso-PGF2alpha was determined by gas chromatography-tandem mass spectrometry. RESULTS: After the 7 day treatment period nebivolol decreased significantly urinary excretion of 8-iso-PGF2alpha by 24% from 55.3 +/- 5.1 pmol mmol-1 creatinine during the placebo period to 42.3 +/- 4.7 pmol mmol-1 creatinine (mean +/- s.e. mean, P = 0. 01), a mean decrease of 13 pmol mmol-1 creatinine (95% CI: -22.8; -3. 1). CONCLUSIONS: Our data show for the first time that nebivolol decreases systemic oxidative stress in young healthy volunteers.     

Effect of nimodipine on cerebral blood flow in human volunteers.

The present study was undertaken to examine the effect of a clinically relevant dose of nimodipine (30 micrograms/kg/h) on the autoregulation of CBF in 12 young healthy volunteers. Mean arterial blood pressure (MABP) was measured intraarterially (i.a.), and changes in cerebral blood flow (CBF) were estimated by the arteriovenous-oxygen [(a-v)O2]-difference method. The lower limit (LL) of CBF autoregulation was calculated by a computerized program and tested for different factors for correction of the PaCO2-induced changes in CBF. MABP was increased by norepinephrine (NE) and decreased by ganglion blockade (trimethaphane camphosulfonas) in combination with lower body negative pressure. The MABP manipulations were performed 1 h after infusion of nimodipine. MABP was reduced by 13 mm Hg (8-15 mm Hg), and CBF was increased by 8% (3-12%) during nimodipine infusion. Autoregulation was preserved in 11 of the 12 volunteers. A CO2-correction factor of 1% CBF/0.1 kPa was used. The LL was 75 mm Hg (71-80 mm Hg) [SE 3 mm Hg (2-4 mm Hg)] and not significantly different from a previous control group of healthy volunteers. No side effects were observed. The present study shows a maintained autoregulation of CBF during nimodipine infusion; however, this could be obtained only by reducing the correction for changes in carbon dioxide to 1%/0.1 kPa from 3%/0.1 kPa, which was used in a similar study in healthy volunteers.