Beta 1-selectivity of bisoprolol, a new beta-adrenoceptor antagonist, in anesthetized dogs and guinea pigs

The beta-adrenoceptor activity of the newly synthesized antagonist bisoprolol [+/-)-1-[4-(2-isopropoxyethoxymethyl)-phenoxy]-3-isopropylamino-2- propranol, hemifumarate), has been compared with the effect of several reference compounds in anesthetized dogs and guinea pigs. In anesthetized, bivagotomized dogs, isoprenaline dose-response relations for increase in heart rate and decrease in diastolic blood pressure were established. Bisoprolol had the largest beta 1/beta 2 ratio, i.e., 147 (102-292). Practolol showed a beta 1/beta 2 ratio greater than 17; betaxolol 6-15; acebutolol, atenolol, and metoprolol 1.1-3.2; mepindolol 0.6-1 and propranolol 0.2. In artificially ventilated guinea pigs, the activity of bisoprolol on histamine-induced increase in tracheal lateral pressure (TLP) and basal heart rate (HR) was tested: using doses taken at TLP (30 mm Hg) and HR (250 beats/min), bisoprolol exhibited the most pronounced ratio TLP/HR of 124 +/- 59, followed by atenolol 33 +/- 23, metoprolol 25 +/- 15, betaxolol 12 +/- 4, propranolol 1 +/- 0.3, and celiprolol 0.23 +/- 0.19. These experiments indicate that bisoprolol possesses a pronounced beta 1-selectivity, which seems to be superior to that of known beta 1-selective antagonists.     

The selectivity of the beta-adrenoceptor for ventilation in man.

1 Minute ventilation, alveolar PCO2, CO2 production and heart rate were measured in eight normal subjects before and during infusions of noradrenaline 0.2, 1.0 and 5.0 micrograms min-1 and isoprenaline 0.04, 0.2 and 1.0 microgram min-1. 2 These measurements were repeated after propranolol 3.5 mg, atenolol 8 mg or metoprolol 7 mg by intravenous injection. 3 Noradrenaline 5.0 micrograms min-1 and isoprenaline 1.0 microgram min-1 significantly increased ventilation and CO2 production and decreased alveolar PCO2. These changes were attenuated by propranolol, atenolol and metoprolol. There was no significant difference between the blocking effects of the three beta-adrenoceptor blockers for these three variables but propranolol was more effective than atenolol or metoprolol in blocking isoprenaline induced tachycardia (P less than 0.001). 4 The hyperventilatory response to catecholamines is predominantly a beta1-effect.     

Biochemical characterization of a new highly cardioselective beta-adrenoceptor antagonist

P0160 (1-phenyl-3-(2-(3-(2-cyanophenoxy)-2-hydroxypropyl)amino) ethylhydantoin HCl) is an aryloxypropanolamine which contains a ureido group as part of the hydantoin ring. This molecule was synthesized to obtain a more cardioselective beta-adrenoceptor blocker. Preliminary data have shown that it is as potent as propranolol and four times more cardioselective than atenolol in pharmacological tests in-vitro and in the conscious rat. In the present study we evaluated the interaction of P0160 with beta-adrenoceptors by radioreceptor binding studies and by measuring adenylate cyclase activity coupled to beta-adrenoceptors. The data indicate that P0160 binds with nanomolar affinity to beta-adrenoceptors labelled with [3H]DHA in the rat heart, but with micromolar affinity in the rat lung. Its binding is stereospecific, the S-(-)isomer being 200 times more active than the R-(+) form. P0160's selectivity between cardiac beta 1- and beta 2-receptors was 1388, about 60 times that for metoprolol. Analysis of the thermodynamic characteristics of P0160's interaction with rat heart beta-adrenoceptors indicated antagonist properties of the same order of magnitude as propranolol, as confirmed by adenylate cyclase studies. These data indicate that P0160 is a potent, specific and selective beta 1-adrenoceptor antagonist, and give a molecular explanation for the cardioselective activity found in pharmacological tests.     

Pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist.

The pharmacodynamic profile of bisoprolol, a new beta 1-selective adrenoceptor antagonist, was investigated in four independent studies including 36 healthy male volunteers. Using the model of exercise-induced tachycardia (ET) the beta-adrenoceptor blocking properties of bisoprolol (2.5-40 mg) were examined in comparison to metoprolol (50 and 100 mg), propranolol (40 and 80 mg) and atenolol (50 and 100 mg). The maximal reduction of ET was achieved between 1 and 4 h following single oral administration. The dose-response relationship using individual maximal reduction of ET showed, on a molar basis, that bisoprolol is about 5, 7 and 10 times more effective than propranolol, atenolol and metoprolol, respectively. In the model of insulin-induced hypoglycaemia bisoprolol behaved as a beta 1-selective adrenoceptor antagonist. There was a good correlation (r = 0.94) between the log bisoprolol concentration and the reduction in exercise-induced tachycardia. Bisoprolol is a potent new cardioselective beta-adrenoceptor antagonist with a competitive action at beta 1-adrenoceptors.     

Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist

The basic pharmacokinetics of bisoprolol were investigated in three independent studies involving 23 healthy volunteers. After administering 20 mg of 14C-bisoprolol orally, mean elimination half-lives of 11 hours for the unchanged drug and 12 hours for total radioactivity were observed. The enteral absorption of bisoprolol was nearly complete. Fifty percent of the dose was eliminated renally as unchanged bisoprolol and the other 50% metabolically, with subsequent renal excretion of the metabolites. Less than 2% of the dose was recovered from the feces. Intraindividual comparison of the pharmacokinetic data measured after oral and intravenous administration of 10 mg bisoprolol to 12 subjects yielded an absolute bioavailability of 90%. Total and renal clearance were calculated as 15.6 L/hr and 9.6 L/hr, respectively. The volume of distribution was 226 L. Concomitant food intake did not influence the bioavailability of bisoprolol.     

Pharmacokinetics of a new beta-adrenoceptor blocking agent, LF 17-895, in man.

The pharmacokinetics of a new potent beta-adrenoceptor blocking drug, bis-4-(2-hydroxy-3-isopropylamino-propoxy)-2-methyl indole sulphate (LF 17-895), have been studied in 5 volunteers after single oral (10 mg) and intravenous (4 mg) doses in a cross-over design. Following oral administration adsorption was rapid with peak plasma concentrations recorded after 3 h. Following the intravenous dose a biphasic decline of the plasma level curve was observed. The half-life of plasma elimination during beta-phase was 4.6 +/- 0.7 (p.o.) and 4.7 +/- 0.3 (i.v.) h, respectively. Absorption of the drug was 88.3 +/- 9.6% comparing the areas under the curve. 28.4 +/- 2.2% of the dose given i.v. was excreted in urine unchanged. When the pharmacokinetic data obtained with LF 17-895 were compared with those of pindolol, which differs only in lacking one methyl group in position 2 at the indole ring, only minor differences were seen: absorption of pindolol as well as plasma elimination were slightly faster.     

General pharmacological profiles of the new beta-adrenoceptor antagonist carvedilol

General pharmacological properties of carvedilol (BM 14.190) were investigated in comparison with propranolol. 1. Central nervous system: Carvedilol caused reduction of awareness, motor activity and muscle tone, and staggering gait in Irwin's test (mice). It decreased spontaneous motor activity and potentiated hexobarbital anesthesia (mice). It lacked anticonvulsant activity (mice) and did not have any effect on body temperature (rabbits). Various changes were produced in mono- and polysynaptic spinal reflex (cats). In EEG, a slight arousal pattern was observed (cats). These effects of carvedilol were weaker than those observed after propranolol administration in general. Carvedilol, however, caused potentiation of hexobarbital anesthesia at lower doses than propranolol. Carvedilol inhibited acetic acid-induced writhing syndrome, whereas it failed to show analgesic activity in the tail-pinch test (mice). Propranolol inhibited both pain reactions. 2. Respiratory and cardiovascular system (dogs): Carvedilol increased respiratory rate and decreased expiratory velocity. It produced hypotension and bradycardia. Cardiac contractility was reduced and femoral blood flow was transiently increased after carvedilol administration. Propranolol induced weaker hypotension and greater bradycardia in comparison with carvedilol. It decreased femoral blood flow. 3. Autonomic nervous system: Carvedilol had little or no effects on pupil size, whereas propranolol produced mydriasis (rabbits). Carvedilol inhibited pressor response to norepinephrine (rats), and it also reduced the nictitating membrane contraction induced by pre- and postganglionic sympathetic nerve stimulation (cats). Propranolol did not show any inhibitory effect on pressor response to norepinephrine and on the contractile response induced by preganglionic sympathetic nerve stimulation. 4. Smooth muscle: Carvedilol produced inhibitory effects on spontaneous motility, and contractile responses to acetylcholine, histamine, nicotine, serotonin and BaCl2 in isolated ileum (guinea pigs). It also inhibited contractile responses to acetylcholine and histamine in isolated trachea (guinea pigs), and spontaneous motility in isolated uterus (rats). Carvedilol reduced norepinephrine-induced contraction of isolated vas deferens at lower concentration (guinea pigs). 5. Digestive system: Decrease in intestinal motility was observed after intravenous administration of carvedilol and propranolol (rabbits). However, carvedilol failed to influence on gastric motility and tonus, whereas propranolol increased them (rabbits). Carvedilol, like propranolol, induced little or no effects on gastro-intestinal transit (mice) and gastric emptying rate (rats). Both drugs decreased gastric secretion at similar dose (rats). Carvedilol at higher doses produced lesion of gastric mucosa, whereas propranolol did not show these effects (rats). 6. Skeletal muscle: In in vitro experiment, carvedilol, like propranolol, reduced the contractile response of diaphragm to nerve and muscle stimulation (rats)...     

Vascular effects of carvedilol, a new beta-adrenoceptor antagonist with vasodilating properties, in isolated canine coronary artery

The pharmacologic properties of carvedilol, a beta-adrenoceptor antagonist with vasodilating activity, were investigated in isolated canine coronary artery ring preparations. Carvedilol competitively antagonized the relaxations caused by isoproterenol in 40 mM K+-depolarized preparations and its pA, value was 9.70 +/- 0.08. At concentrations greater than or equal to 3 x 10(-6) M, carvedilol significantly inhibited the contractile response to high [K+]o. Compared with the inhibitory effect on the KCl-induced contraction, the drug was less effective in suppressing the contraction induced by prostaglandin F2 alpha (PGF2 alpha). In addition, carvedilol (10(-7) to 3 x 10(-5) M) suppressed the contraction produced by Bay K 8644, a Ca2+ channel agonist. The concentration-response curve for Bay K 8644 was shifted downward by carvedilol in a concentration-dependent manner. The drug also produced a concentration-dependent inhibitory effect on the 4-aminopyridine-induced rhythmic contractions in a similar fashion to the Ca2+ channel antagonists. Carvedilol was ineffective in suppressing the contractions induced by PGF2 alpha in Ca2+-free solution and by A-23187. The results suggest that carvedilol exerts a vasodilating action possibly by inhibiting Ca2+ influx through potential-operated Ca2+ channels, although the concentrations required for producing the vasodilation are much higher than that for the beta-adrenoceptor antagonism in canine coronary artery.     

Adimolol, a long acting beta-adrenoceptor blocker in man.

A comparative study in eight healthy normotensive males of the effects on blood pressure, heart rate and beta-adrenoceptor function following single oral doses of adimolol (600 mg), propranolol (240 mg) and placebo. Both active treatments produced small but significant reductions in blood pressure and heart rate, supine and erect. These effects persisted for up to 7 days after adimolol. The heart rate increases following both dynamic exercise and intravenous isoprenaline were attenuated by both propranolol and adimolol. With adimolol evidence of functional beta-adrenoceptor antagonism was sustained for up to 7 days. Lymphocyte beta-adrenoceptor binding studies showed that both adimolol and propranolol significantly reduced affinity for beta-adrenoceptors. In addition, adimolol significantly reduced receptor number and even by 3 days after dosing Bmax had only returned to half the control value. In a small sub-group of subjects there was no evidence to suggest that adimolol had additional alpha-adrenoceptor antagonist properties. Adimolol was detected in plasma for up to 3 days after dosing. The mean terminal elimination half-life was 14 h, compared to 3 h for propranolol. This study confirms that adimolol has prolonged beta-adrenoceptor antagonist activity with effects persisting for up to 7 days after a single dose. The reduction in beta-adrenoceptor number following adimolol suggests that this prolonged effect may not be solely due to competitive antagonism but may additionally depend upon non-competitive antagonism at beta-adrenoceptors.     

Human pharmacokinetic and pharmacodynamic studies on Ro31-1118, a new beta-adrenoceptor antagonist.

The pharmacokinetic and pharmacodynamic effects of Ro31-1118 were examined in groups of healthy volunteers. In three subjects given 10 mg of [14C]-Ro31-1118 orally, peak levels of radioactivity (84 +/- 5 ng/ml) were 16 times those of the parent drug (approximately 5 ng/ml). Very little parent drug was recovered in the urine, although recovery of total radioactivity was nearly 80% in the urine by day 5. In five subjects studied after both oral and intravenous administration of 20 mg Ro31-1118 the average bioavailability was 57% (range 41-73%). Following intravenous infusion the apparent volume of distribution for the five subjects averaged 590 1 (range 510-700 1). The elimination half-life averaged 18 h (range 17-26 h). In eight subjects who received 40, 80, 160 and 320 mg of Ro31-1118 orally there was a linear relationship between dose and plasma concentration (r = 0.999) and between dose and AUC (r = 0.996). Ro31-1118 had no effect on resting heart rate whereas atenolol reduced resting heart rate up to 6 h after all doses. The maximum reduction of an exercise tachycardia after Ro31-1118 (320 mg) was 23.13 +/- 0.7% and compared with atenolol (100 mg) was 28.2 +/- 1.25%. At 24 h the percentage reduction after Ro31-1118 was 21.5 +/- 1.7%, while after atenolol the percentage inhibition had decreased to 11.1 +/- 1.6%. In three subjects Ro31-1118 (160 mg) orally had no effect on resting heart rate, forearm blood flow and systolic blood pressure, while atenolol (50 mg) reduced all three parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

The dose dependency of the alpha- and beta-adrenoceptor antagonist activity of carvedilol in man.

1. The alpha- and beta-adrenoceptor antagonist activity of carvedilol, a beta-adrenoceptor antagonist with vasodilating properties, and labetalol were investigated in 10 healthy male subjects. They received infusions with serially increasing concentrations of isoprenaline and phenylephrine before and after single oral doses of carvedilol 6.25, 12.5 and 25 mg, labetalol 400 mg and placebo at weekly intervals in a double-blind randomised manner. An exercise step test was performed at the end of the infusions. 2. The dose of isoprenaline required to increase heart rate by 25 beats min-1 (I25) and the dose of phenylephrine required to increase systolic and diastolic blood pressure by 20 mm Hg (PS20 and PD20) were calculated using a quadratic fit to individual dose-response curves. Comparisons were made with placebo and P < 0.05 was considered significant. 3. The I25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I25 were: carvedilol 6.25 mg 2.1 +/- 1.6, carvedilol 12.5 mg 3.1 +/- 1.9, carvedilol 25 mg 6.4 +/- 4.9 and labetalol 400 mg 8.8 +/- 4.4. 4. The PS20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: carvedilol 6.25 mg 1.0 +/- 0.2; 12.5 mg, 1.2 +/- 0.2; 25 mg, 1.3 +/- 0.4 and labetalol 400 mg 2.2 +/- 0.8. 5. The PD20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PD20 were: carvedilol 6.25 mg 1.1 +/- 0.3; 12.5 mg, 1.3 +/- 0.3; carvedilol 25 mg 1.3 +/- 0.4 and labetalol 400 mg 2.1 +/- 0.8.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic profile of nebivolol, a beta-adrenoceptor antagonist with unique characteristics

beta-Adrenoceptor antagonists (beta-blockers) have historically been considered an effective and safe option for first-line treatment of hypertension. However, very recently, it has been proposed that beta-blockers should no longer be considered suitable for first-line therapy in the patient with uncomplicated hypertension because of unfavourable morbidity and mortality data. New evidence from recent clinical studies of nebivolol, a third-generation highly selective beta(1)-blocker with additional endothelial nitric oxide (NO)-mediated vasodilating activity, confirms previous findings that this drug differs from other beta-blockers. The combined mechanisms of beta-adrenoceptor antagonism and NO-mediated vasodilation may potentiate the blood pressure-lowering effect of this agent, and confer a broader favourable metabolic profile, which may be clinically relevant for hypertensive patients. The antioxidant properties of nebivolol and its neutral or even favourable effects on both carbohydrate and lipid metabolism are well documented. These properties consistently differentiate nebivolol from nonvasodilating beta-blockers such as atenolol, metoprolol or bisoprolol. Therapeutic indications for beta-blockers include a wide range of co-morbidities found in hypertensive patients, including ischaemic heart disease, tachyarrhythmias and heart failure. Given that the majority of hypertensive patients require more than one drug to control blood pressure, the multiple mechanisms of action and favourable metabolic profile of nebivolol could make it an alternative therapeutic option for hypertensive patients requiring beta-adrenoceptor therapy.     

Betaxolol, a cardioselective beta-adrenoceptor antagonist, attenuates ischemic myocardial acidosis in dogs

The effects of betaxolol, a cardioselective beta-adrenoceptor antagonist, on ischemic myocardial acidosis were studied in dog hearts, in which the left anterior descending coronary artery was partially occluded for 90 min, and were compared with those of atenolol and propranolol. Myocardial ischemia produced a decrease in myocardial pH (measured by a micro glass pH electrode) and an elevation of the ST segment of epicardial ECG (assessed by a surface electrode). Betaxolol (0.01, 0.03 or 0.1 mg/kg), atenolol (0.03 or 0.1 mg/kg) or propranolol (0.03 or 0.1 mg/kg), when injected i.v. 30 min after ischemia, restored myocardial pH and the ST segment of ECG that had been altered by partial occlusion. However, the effect of betaxolol on myocardial acidosis was more potent than that of atenolol or propranolol. The decrease in (+)dp/dt by betaxolol (0.03 mg/kg) was less potent than that by atenolol (0.1 mg/kg) and equivalent to that by propranolol (0.1 mg/kg), although the restorations of myocardial acidosis by the drugs were almost equivalent. These results have confirmed that beta-adrenoceptor antagonists attenuate the ischemia-induced myocardial acidosis and have shown that among three beta-adrenoceptor antagonists, betaxolol is the most effective in improving myocardial acidosis with a relatively weak effect on myocardial contractile function.     

Comparison of the new beta-adrenoceptor antagonist,nadolol, and propranolol in the treatment of angina pectoris

Summary

A randomized, double-blind study was carried out in 24 patients with stable angina pectoris to compare the efficacy of nadolol, a new beta-adrenoceptor antagonist, and propranolol. After a period on placebo, 14 patients received nadolol once daily and 10 patients propranolol 4-times daily over a 10-week dose-ranging period followed by a maintenance period of 4 weeks. Optimal daily dosage for nadolol was 100?mg, and 112?mg for propranolol. Parameters used for evaluation of therapeutic effects included the number of anginal attacks, number of nitroglycerine tablets needed, time before onset of chest pain during exercise test, exercise time, and overall clinical impression of response. The results indicated that nadolol given once daily was equally as effective as propranolol 4-times daily in treating angina pectoris.     

Antihypertensive effect of betaxolol, a cardioselective beta-adrenoceptor antagonist, in renal hypertensive dogs

The antihypertensive effect of betaxolol, a highly selective beta 1-adrenoceptor antagonist, was investigated in renal hypertensive dogs, and the mechanism was also studied. A single oral administration of betaxolol (1 and 10 mg/kg) lowered blood pressure dose-dependently. The hypotensive effect of betaxolol was enhanced by daily oral administration for 10 days. In anesthetized dogs, intraarterial injection of betaxolol produced a dose-dependent increase in femoral artery flow; and in this test, betaxolol was 3 times less potent than papaverine. The increase in blood flow with betaxolol was not affected by pretreatment with propranolol. These findings indicate that a certain vasodilating activity may contribute to the antihypertensive mechanism of betaxolol.     

Carvedilol, a new beta-adrenoceptor antagonist and vasodilator antihypertensive drug, inhibits superoxide release from human neutrophils.

Carvedilol produced a dose-dependent inhibition of superoxide (O2-) release from human neutrophils (PMNs) (IC50 = 28 microM) and scavenged O2- generated during dihydroxyfumaric acid (DHF) autooxidation (IC50 = 41 microM). Other beta-blockers, such as celiprolol, labetalol and atenolol, or the antioxidant, 'lazaroid', U74500A had no effect on O2- either released from PMNs or generated during DHF autooxidation. Propranolol, at 0.3 mM, inhibited O2- release from PMNs (73%) but failed to scavenge O2- generated from DHF. The novel free radical-scavenging effect of carvedilol may contribute to the cardioprotective activity of the compound.     

Antiarrhythmic activity of flestolol, a novel ultra-short-acting beta-adrenoceptor antagonist, in the dog

The antiarrhythmic activity of flestolol, an ultra-short acting beta-adrenergic blocker lacking appreciable local anesthetic activity, was examined in several different canine ventricular arrhythmia models. Flestolol, at steady state infusions of 1-1,000 micrograms/kg per min, was generally ineffective in reversing either ouabain-induced or delayed ischemia-induced (24 h Harris dog) ventricular tachycardia. However, flestolol (1, 10 and 100 micrograms/kg per min) produced a dose-dependent decrease in l-norepinephrine (5 micrograms/kg i.v.)-induced ventricular tachycardia in the 5-6 day old Harris dog; the effect of 100 micrograms/kg per min flestolol, 94% suppression of norepinephrine-induced ventricular tachycardia, was completely reversed 60 min after termination of flestolol infusion. In pentobarbital-anesthetized open-chest dogs with pretreatment heart rates greater than or equal to 145 beats/min, flestolol (10 micrograms/kg per min) reduced the incidence of ventricular fibrillation resulting from abrupt coronary artery occlusion compared to placebo-treated controls (15% or 2/13 vs. 70% or 7/10, respectively). These results demonstrate that flestolol has an antiarrhythmic profile consistent with its lack of local anesthetic activity and its ultra-short duration of beta-blockade.