Assessment of beta-adrenoceptor selectivity of a new beta-adrenoceptor antagonist, bisoprolol, in man

Bisoprolol is a new beta-adrenoceptor antagonist which has shown beta-adrenoceptor selectivity in studies in isolated tissues. Bronchial and cardiac beta-adrenoceptor blockade were assessed in eight normal subjects before and after oral ingestion of placebo, bisoprolol 20 and 40 mg, metoprolol 200 mg and propranolol 80 mg in random order. Bronchial beta-adrenoceptor blockade was assessed as the displacement of the bronchodilator dose-response curve to inhaled isoprenaline after each beta-adrenoceptor blocking drug compared to placebo and expressed as the dose ratio. Bronchodilatation was measured as change in specific airway conductance (sGaw) in the body plethysmograph. Cardiac beta-adrenoceptor blockade was assessed as the percentage reduction in exercise heart rate during the fifth minute of exercise at 70% of the subject's maximum work rate. Bisoprolol 20 and 40 mg caused a 24 and 25% reduction in exercise heart rate respectively, compared to 26% with metoprolol 200 mg and 20% with propranolol 80 mg. The dose ratios for the airway dose-response curves for the four beta-adrenoceptor blocking drugs were 1.04 and 3.4 for bisoprolol 20 and 40 mg, 1.4 for metoprolol 200 mg and 30 for propranolol 80 mg. Both doses of bisoprolol produced considerably less bronchial beta-adrenoceptor blockade than propranolol 80 mg despite causing a greater reduction in exercise heart rate. Bisoprolol 20 mg caused a similar amount of bronchial beta-adrenoceptor blockade and a similar reduction in exercise heart rate as metoprolol 200 mg, confirming that it is cardio-selective in man.     

In vitro pharmacologic profile of the novel beta-adrenoceptor antagonist and vasodilator, carvedilol

The pharmacologic profile of the novel beta-adrenoceptor antagonist/vasodilator, carvedilol, has been investigated in vitro. Carvedilol produced competitive antagonism of the beta 1-adrenoceptor mediated positive chronotropic response to isoproterenol in guinea pig atria, and the beta 2-adrenoceptor mediated relaxation to isoproterenol in carbachol (1 mumol/l) precontracted guinea pig trachea, with a dissociation constant (KB) for beta 1-adrenoceptors of 0.8 nmol/l and beta 2-adrenoceptors of 1.3 nmol/l. At slightly higher concentrations, carvedilol produced competitive inhibition of the alpha 1-adrenoceptor mediated contractile response to norepinephrine in rabbit aorta with a KB of 11 nmol/l. Carvedilol had no significant effect on the contractile response to angiotensin II in rabbit aorta at concentrations up to 10 mumol/l, thus demonstrating the lack of nonspecific vasodilator actions in arteries. In canine saphenous vein, carvedilol produced noncompetitive blockade of alpha 2-adrenoceptor mediated vasoconstriction, indicative of some additional activity. In estrogen-primed rat uterus precontracted by depolarization with KCl (70 mmol/l), carvedilol produced concentration-dependent relaxation (IC50 of 7.6 mumol/l), consistent with the notion that carvedilol may be a calcium channel antagonist. Support for this hypothesis was obtained in KCl (70 mmol/l) depolarized rabbit aorta where carvediol (10 mumol/l) produced a 10-fold parallel rightward shift in the concentration-response curve to calcium chloride. These studies demonstrate that carvedilol is a potent beta 1-, beta 2- and alpha 1-adrenoceptor antagonist, and a moderately potent calcium channel antagonist. These multiple activities of carvedilol may contribute to the antihypertensive activity of the compound.     

Comparison of prizidilol hydrochloride (SK & F 92657), a new antihypertensive agent with beta-adrenoceptor antagonist and vasodilator activity with propranolol and hydralazine in normal volunteers.

1 Some cardiovascular pharmacology of prizidilol hydrochloride, a new antihypertensive compound with precapillary vasodilator and beta-adrenoceptor antagonist activity, in man is described. 2 To investigate further the pharmacological profile of this drug the effects of a single oral dose of 400 mg prizidilol hydrochloride were compared with propranolol 40 mg in combination with either 25 mg or 50 mg of hydralazine for up to 6 h after dosing, in a placebo controlled in eight healthy subjects. 3 Prizidolol hydrochloride significantly reduced supine and standing diastolic blood pressure and was more effective than propranolol combined with either dose of hydralazine in this respect. 4 Supine heart rate was significantly increased after prizidilol hydrochloride, but was not significantly changed after propranolol combined with either dose of hydralazine. The reasons for the increase in supine heart rate after prizidolol are discussed. 5 beta-adrenoceptor antagonism was assessed in terms of inhibition of exercise induced increases in heart rate and systolic blood pressure. At the doses used, prizidolol hydrochloride was less effective than propranolol and hydralazine combined, particularly during the first 3 h after dosing.     

Evidence against beta-adrenoceptor blocking activity of diltiazem, a drug with calcium antagonist properties.

1 The isolated spontaneously beating atria of the rat, diltiazem (0.01 to 0.1 microM) shifted the atrial rate concentration-response curves to isoprenaline to the right in a non-parallel manner and depressed their maxima. Under the same experimental conditions, (+/-)-propranolol (0.03 to 0.1 microM) behaved as a competitive beta-adrenoceptor antagonist. 2 Whereas (+/-)-propranolol (IC50 = 12 nM) and isoprenaline (IC50 = 0.9 microM) inhibited (-)-[3H]-dihydroalprenolol binding to rat brain membrane preparations, diltiazem failed to do so in concentrations up to 10 microM. 3 Diltiazem but not (+/-)-propranolol, antagonized the positive chronotropic responses to calcium in spontaneously beating rat atria. 4 It is proposed that diltiazem inhibited the tachycardia induced by isoprenaline through an effect on calcium which may be an essential modulator of the sequence of events linking the beta-adrenoceptor activation and heart rate response.     

Bile and bile salts potentiate superoxide anion release from activated, rat peritoneal neutrophils

Certain bile salts cause hepatotoxicity as well as injury to extrahepatic organs when administered to animals. Activated neutrophils (PMNs) may cause tissue injury by releasing reactive oxygen species and other products. Since PMNs may come in contact with biliary components, such as bile salts, following chemical insult to the liver or during cholestasis, we examined the capacity of bile and bile salts to stimulate superoxide anion (O2-) release from rat peritoneal PMNs in vitro. Neither bile nor bile salts, with the exception of lithocholate, could by themselves stimulate O2- release from PMNs. Lithocholate (32 microM) caused small but statistically significant release of O2- from PMNs. When PMNs were primed with a barely suprathreshold concentration of 12-O-tetradecanoyl-phorbol-13-acetate (PMA), a classic stimulus for PMNs, the addition of bile and certain bile salts markedly enhanced O2- release from PMNs. The monohydroxy bile salt, lithocholate, had the greatest stimulatory activity toward PMA-primed PMNs, causing approximately an eightfold increase in O2- release. The enhancing effect of lithocholate was maximal between 10 and 32 microM, and it also occurred with PMNs isolated from rat blood. Dihydroxy bile salts, deoxycholate and chenodeoxycholate (100 microM), caused more modest enhancement of O2- release (two- to threefold) from primed PMNs. Cholate, a trihydroxy bile salt, was not active at these concentrations. Conjugation of either lithocholate or chenodeoxycholate with either glycine or taurine markedly reduced the ability of the bile salt to enhance O2- release from primed PMNs. Structural alterations on the hydrophilic side chain or within the planar, hydrophobic portion of the bile salt molecule reduced the capacity to enhance O2- release from PMA-primed PMNs. These results indicate that bile salts can potentiate the respiratory burst in PMNs and suggest a role for this interaction in toxicoses or disease states characterized by elevated serum bile salts.     

Anaesthetised normotensive rats for the detection of hypotensive activity of a beta-adrenoceptor antagonist and other antihypertensive agents.

A simple method for the detection of antihypertensive activity in anaesthetised (66 mg/kg i. v. alpha-chloralose and 20 mg/kg i. v. aprobarbital) normotensive rats is described. Dihydralazine (0.5 to 2 mg/kg i. v.) reduced blood pressure dose-dependently but did not provoke the anticipated tachycardia. Clonidine (1 to 8 microgram/kg i.a.), guanethidine (0.5 to 5 mg/kg i.a.) and alpha-methyldopa (2.5 to 10 mg/kg i.a.) reduced blood pressure dose-dependently; the effect of reserpine (0.1 to 1.0 mg/kg i.a) was, however, not dose-dependent. Although all four drugs reduced heart rate, only clonidine and guanethidine did so in a dose-dependent manner. Phentolamine (0.5 to 2 mg/kg i. v.) and propranolol (0.01 to 1 mg/kg i. v.) elicited dose-dependent falls in blood pressure. Whereas phentolamine increased heart-rate slightly, propranolol elicited a bradycardia. It is concluded that the chloralose-aprobarbital anaesthetised rat is a suitable and economical model for the screening of potential antihypertensive agents including beta-adrenoceptor antagonists. However, reflex trachycardia provoked by peripheral vasodilators may not be apparent.     

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)     

Cardiovascular properties of medroxalol, a new antihypertensive drug

Medroxalol is a new antihypertensive agent that is presently undergoing clinical trial. Its cardiovascular properties were studied using spontaneously hypertensive rats (SHR), anesthetized dogs, and isolated tissues. Medroxalol produced a long-lasting fall in blood pressure when given by the oral route to SHR. It was more potent than phentolamine in antihypertensive effectiveness. Given intravenously to dogs, medroxalol reduced the blood pressure and heart rate of doses that did not greatly reduce cardiac output. The hypotensive effect of medroxalol was reduced but not abolished following alpha- and beta-adrenergic-receptor blockade. Medroxalol inhibited heart rate and blood pressure responses to isoproterenol and phenylephrine in dogs. In vitro medroxalol resembled a competitive antagonist at alpha-adrenergic receptors in rabbit aortic strips (pA2 6.09) and beta-adrenergic receptors in guinea pig atria (pA2 7.73). It was 0.02 as potent as phentolamine at alpha-receptors and 0.09 as potent as propranolol at beta-receptors. It was concluded that the principal action of medroxalol was to produce a fall in blood pressure by decreasing peripheral vascular resistance more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does more than cardiac output. Adrenergic alpha- and beta-receptor blockade alone does not satisfactorily explain the hypotension. A contribution by an active vasodilatory component appears likely.     

A pharmacological and biochemical examination of AHR-16462B,a novel calcium antagonist coronary vasodilator/antihypertensive

A series of pharmacological and biochemical studies were conducted to characterize AHR-16462B 4-[bis(4-fluorophenyl)methyl]-1-(2-naphthalenylmethyl)piperidine (HCI), a novel antagonist of voltage-sensitive calcium channels. AHR-16462B displaced [³H]-nimodipine binding from calcium channels on rabbit skeletal muscle membranes (IC₅₀ = 118 nM) and inhibited depolarization-induced changes in intracellular free calcium in cultured PC-12 cells (IC₅₀ = 125 nM), but had virtually no effects on binding of specific radioligands to 5-HT_1a, 5-HT₂, alpha₁, alpha₂, dopamine₂, beta₁, beta₂, muscarinic M₁, or histamine H₁ receptors. AHR-16462B antagonized CaCI₂-induced contractions of depolarized rabbit aortic strips (pA₂ = 8.83), but had no negative chronotropic, and only slight negative inotropic effects on isolated guinea pig atria. In anesthetized dogs, cumulative doses of 0.1, 0.4, and 1.4 mg/kg, i. v., AHR-16462B decreased coronary vascular resistance and blood pressure; the magnitude and duration of these effects were dose related. Heart rate and Lead 2 ECG waveforms remained unaltered at all doses. In conscious spontaneously hypertensive rats (SHR), 3 to 100 mg/kg, p. o., AHR-16462B produced marked, long-lasting, and dose-related antihypertensive actions. Heart rate remained unaltered following 3, 10, and 30 mg/kg AHR-16462B, and bradycardia was evoked by 100 mg/kg. Effective antihypertensive doses of AHR-16462B had modest natriuretic and/or chloruretic actions.     

Influence of acetylator phenotype on the pharmacokinetics of a new vasodilator antihypertensive,endralazine

Summary Five and 10 mg single oral doses of a new vasodilator antihypertensive, endralazine (E) were given on separate occasions to 17 normal male volunteers (8 slow, 7 heterozygous fast and 2 homozygous fast acetylators). The homozygous fast acetylators were excluded from statistical comparisons. Only small differences were observed in the pharmacokinetics of E between the phenotypes and there was no evidence of non-linearity at the 2 dose levels studied. Terminal half-lives ranged from 2.59 to 7.14 h with a mean of 4.30±1.08 h for the 5 mg dose and 4.25±1.09 h for the 10 mg dose. There was no significant difference in half-lives between slow and heterozygous fast acetylators. The mean area under the plasma level-time curve (AUC ₀ ) was 18.2% lower (p<0.05) in the heterozygous fast acetylators than in the slow acetylators following the 5 mg dose and 11.0% lower (p>0.05) following the 10 mg dose. Extremely rapid absorption of the drug precluded accurate estimation of absorption rates. The AUC ₀ of the acetylation metabolite (methyltriazoloendralazine) was small compared to that of E although higher in the heterozygous fast acetylators than in the slow acetylators (p<0.01).     

Valsartan: new preparation. Just a second-line antihypertensive drug

(1) Valsartan is a antihypertensive drug belonging to the family of angiotensin II receptor antagonists. (2) At a dose of 40 mg/day its antihypertensive effect is inconsistent. (3) At 80 mg/day its effect on blood pressure, its adverse effects and its contraindications (mainly pregnancy and renal artery stenosis) are similar to those of angiotensin-converting-enzyme (ACE) inhibitors, except that coughing is rarer with valsartan than with ACE inhibitors. (4) Valsartan has no demonstrated advantage over losartan, another angiotensin II antagonist. (5) Valsartan has not been shown to prevent the complications of arterial hypertension, and its use is therefore less well validated than that of diuretics and betablockers.     

Inhibition of superoxide anion and elastase release in human neutrophils by 3'-isopropoxychalcone via a cAMP-dependent pathway

1 Chalcone is abundantly present in the plant kingdom and has various biological activities such as anti-inflammatory and antioxidant. In this study, the semisynthetic chalcone derivative, 3'-isopropoxychalcone (H2O7D), was demonstrated to inhibit the generation of superoxide and the release of elastase, as well as to accelerate resequestration of cytosolic calcium in formyl-L-methionyl-L-leucyl-L-phenylalanine-activated human neutrophils. 2 H2O7D displayed no antioxidant or superoxide-scavenging ability, and it failed to alter the subcellular NADPH oxidase activity. 3 H2O7D induced a substantial increase in cAMP but not cGMP levels. The elevation of cAMP formation by H2O7D was inhibited by adenosine deaminase (ADA). Furthermore, The inhibitory effects of H2O7D were reversed by protein kinase (PK)A inhibitors, as well as ADA and a selective A2a-receptor antagonist. 4 H2O7D inhibited phosphodiesterase (PDE) activities, but it did not alter adenylyl cyclase and soluble guanylyl cyclase activities. These results show that the cAMP-elevating effect of H2O7D results from the inhibition of PDE activity and not from the stimulation of cyclase function. Consistent with this, H2O7D potentiated the PGE(1)-caused inhibitory effects and cAMP formation. 5 In summary, these results indicate that the inhibitory effect of H2O7D is cAMP/PKA dependent, and that it occurs through inhibition of cAMP PDE, which potentiates the autocrine functions of endogenous adenosine. Inhibition of respiratory burst and degranulation in human neutrophils may give this drug the potential to protect against the progression of inflammation.     

Calcium channel antagonist induced inhibition of superoxide production in human neutrophils. Mechanisms independent of antagonizing calcium influx

Three calcium channel antagonists, verapamil, diltiazem and nisoldipine, inhibited superoxide production in human neutrophils that were stimulated by phorbol 12-myristate 13-acetate (PMA) in a buffered saline lacking calcium. Concentrations of these drugs giving 50% control activity (IC50) were 0.3, 0.45 and 0.01 mM respectively. This inhibition was also observed in the presence of ethylene glycol bis (beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) and was not reversed by the addition of calcium. This suggests that calcium channel antagonists inhibited superoxide production independently of extracellular calcium. These calcium channel antagonists inhibited the mobilization of membrane-associated calcium, and protein phosphorylation probably catalyzed by C-kinase, both of which are thought to be involved in the signal transmission for the induction of superoxide production. Calcium channel antagonists also inhibited NADPH oxidase, responsible for superoxide production, with IC50 = 0.5, 3 and more than 0.08 mM, respectively, for verapamil, diltiazem and nisoldipine. The results indicate that calcium channel antagonists inhibit superoxide production by affecting not only the catalytic activity by also the activation of NADPH oxidase. Inhibition of superoxide production by calcium channel antagonists suggests that these antagonists do not affect cell functions merely by affecting calcium influx.     

Oxdralazine, a new peripheral vasodilator, combined with propranolol and hydrochlorothiazide: a rational approach to antihypertensive treatment

Forty-three patients suffering from hypertension of different origin (chronic renal failure, gout, or idiopathic) were treated with propranolol (121 +/- 12 mg q.d.) plus hydrochlorothiazide (50 mg q.d.) for 75 +/- 9 days. Blood pressure did not return to normal limits in 15 patients, who were continued on the same protocol plus 10 to 50 mg oxdralazine q.d. After an average of 68 +/- 35 days blood pressure fell from 180/110 mm Hg to 145/90 mm Hg without orthostatism, significant side effects, or changes in GFR. This combination seems particularly successful since propranolol will prevent the undesired rise in cardiac output due to oxdralazine as well as the activation of the renin-angiotensin axis due to diuretics. Thus, the antihypertensive properties of each agent will be enhanced by a reduction in side effects by the associated drug, resulting in optimal blood pressure control.     

The protein kinase C inhibitor, K252a, inhibits superoxide production in human neutrophils activated by both PIP2-dependent and -independent mechanisms.

We report that the putative protein kinase C inhibitor, K252a, at concentrations of 0.2 and 1 microM, inhibited the respiratory burst induced by fluoride and formyl-methionyl-leucyl-phenyl-alanine respectively, both in human neutrophils primed with a subthreshold dose of phorbol myristate acetate and in non-primed neutrophils. In addition, K252a effectively inhibited ConA-zymosan-mediated superoxide generation in Ca2(+)-depleted neutrophils, with virtually maximal inhibition seen at 1 microM. These results suggest that protein kinase C is involved in the putative phosphatidylinositol bisphosphate-independent signal transduction mechanism of the respiratory burst as well as the pathway dependent on phosphatidylinositol bisphosphate hydrolysis.     

SD-3211, a novel benzothiazine calcium antagonist, alone and in combination with a beta-adrenoceptor antagonist, produces antihypertensive effects without affecting heart rate and atrioventricular conduction in conscious renal hypertensive dogs.

We compared the effects of SD-3211, a novel calcium antagonist, on blood pressure, heart rate, and atrioventricular conduction with those of diltiazem using conscious renal hypertensive dogs (one-kidney, one-clip type). We also examined the combined effects of these calcium antagonists with a beta-adrenoceptor antagonist, propranolol, on these variables. Oral administration of SD-3211 (1.25, 2.5, and 5 mg/kg) resulted in a dose-dependent decrease in blood pressure without affecting heart rate. SD-3211 at all three doses significantly decreased systolic blood pressure. At 2.5 and 5 mg/kg the compound elicited significant decreases in mean blood pressure and diastolic blood pressure. Hypotension obtained with the highest dose of SD-3211 lasted for at least 9 h. No significant alteration in PR interval was observed in electrocardiograms after administration of SD-3211. Diltiazem, given orally at doses of 2.5 and 5 mg/kg but not 1.25 mg/kg, produced significant hypotension with little change in heart rate. The duration of hypotension induced by the highest dose of diltiazem was only 3 h. Diltiazem prolonged PR interval in a dose-dependent manner, causing second-degree atrioventricular block in some dogs. Combined administration of SD-3211 or diltiazem (2.5 mg/kg) with propranolol (30 mg/kg) resulted in enhanced hypotension with no alteration in heart rate. SD-3211 plus propranolol had little effect on the PR interval, whereas diltiazem plus propranolol caused a markedly enhanced prolongation. These results indicate that SD-3211 is an antihypertensive agent with long-lasting action and little effect on heart rate and atrioventricular conduction and, when administered alone or in combination with propranolol, may be useful in the treatment of hypertension.     

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.