The role of intracellular calcium in A-23187 stimulated and beta-adrenoceptor blocking drug treated blood platelets.

A significant concentration-dependent difference was found between beta-adrenoceptor blocking drugs in their ability to inhibit A23187-induced isolated platelet aggregation. In the absence of extracellular calcium ions the following rank order of potency to inhibit calcium ionophore stimulated platelet aggregation was shown: propranolol > bevantolol > alprenolol > metipranolol > oxprenolol > atenolol > pindolol > metoprolol approximately sotalol approximately practolol. The interruption of induced aggregation, as well as inhibition of aggregation, in the absence of extracellular calcium ions indicated interference of inhibitory beta-adrenoceptor blocking drugs with intramembrane or intraplatelet calcium pools activated with A23187. This suggestion was supported by the reversal of the inhibitory effect of beta-adrenoceptor blocking drugs in the presence of extracellular calcium ions. The effect was dose dependent and occurred within 30 sec after calcium administration. The results indicated that inhibitory beta-adrenoceptor blocking drugs, possessing a cationic amphiphilic structure, suppressed calcium mobilization in A23187-stimulated platelets, most probably after entering platelets. This explains why lipophilic drugs are more effective than hydrophilic ones in calcium ionophore A23187-stimulated platelets.

The analysis of plasma kinetics and beta-receptor binding and -blocking activity of timolol following its small intravenous dose.

Plasma kinetics and beta-receptor blocking and -binding activity of timolol was studied in six healthy volunteers following its intravenous 0.25 mg dose. Timolol concentrations were measured using radioreceptor assay (RRA), blocking activity by comparing the dose ratios (DRs) of the infusion rates of isoprenaline required to increase heart rate by 25 bpm (I25) and binding activity by determining the extent to which timolol occupied beta 1-receptors of rabbit lung and beta 2-receptors of rat reticulocytes in undiluted plasma samples. Timolol was eliminated from plasma with a mean half-life for the elimination phase of 2.6 hours. The dose antagonized potently isoprenaline-induced tachycardia at least for four hours. The effect was excellently correlated with the estimated beta 2-receptor binding activity of timolol in the circulating plasma. In conclusion, the small intravenous timolol dose was eliminated from plasma by a fashion, which was very similar to its eighty-fold higher oral doses reported earlier in the literature. The 0.25 mg dose was of considerable systemic beta-receptor blocking and -binding activity, that may help to explain its reported side-effects following ocular drug administration. The extent to which beta-blocking agents occupy rabbit lung beta 1- and rat reticulocyte beta 2-receptors in the circulation appears to predict the intensity and selectivity of their beta-blocking effects in healthy volunteers.

Effects of amosulalol, a combined alpha 1- and beta-adrenoceptor-blocking agent, on ischemic myocardial energy metabolism in dogs.

The effect of amosulalol, a combined alpha 1- and beta-adrenoceptor-blocking agent, on changes in myocardial energy and carbohydrate metabolism during ischemia was studied. Ischemia was induced by ligating the left anterior descending coronary artery for 3 or 30 min during open-chest surgery in anesthetized dogs. The myocardial energy stores were depleted, and the levels of glycolytic intermediates were altered by 3 and 30 min of ischemia, indicating that anaerobic myocardial metabolism had occurred. Amosulalol (0.3 or 1 mg.kg-1) was injected intravenously 5 min before ischemia. Pretreatment with amosulalol, particularly at a dose of 0.3 mg.kg-1, reduced the myocardial energy depletion and the alteration of carbohydrate metabolism induced by ischemia. This result indicates that amosulalol can reduce ischemic influences on the myocardium.

Myocardial anti-ischemic characteristics of a novel class of beta-adrenoceptor blockers.

The effect of different beta-adrenoceptor blockers on free radical-mediated cardiac membrane lipid peroxidation (CMLP) was compared to their beta-blocking potency (pA2). CMLP was determined by the measurement of malondialdehyde (MDA) formation in rat cardiac membrane homogenates exposed to a free radical generating system (FeCL3/ADP/DHF) in the presence or absence of the beta-adrenoceptor blockers (1-1,000 microM). beta-adrenoceptor blocking potency (pA2) was determined using guinea pig right atria stimulated with isoproterenol. The catechol containing beta-blocker (DCC-10255) was shown to be a potent inhibitor of CMLP via an iron-dependent mechanism. On the other hand, the non-catechol beta-adrenoceptor blocker, timolol, was shown to be a weak inhibitor of CMLP. Furthermore, dl- and d-propranolol were active and equipotent though less potent than DCC-10255 in inhibiting CMLP. The myocardial cytoprotective efficacy for catechol and non-catechol beta-adrenoceptor blockers was evaluated in an isolated rat myocyte model. It was demonstrated that catechol-containing agents with either strong or weak beta-adrenoceptor blockade possess a relatively potent in vitro antioxidant and myocardial cytoprotective efficacy against free radical mediated CMLP and myocyte injury, respectively. It is concluded that the inhibition of CMLP by beta-adrenoceptor blockers is independent of their beta-adrenoceptor blockade.

Effects of chromium supplementation on serum high-density lipoprotein cholesterol levels in men taking beta-blockers. A randomized, controlled trial.

OBJECTIVE: To determine the efficacy of glucose tolerance factor (GTF)-chromium for increasing serum levels of high-density lipoprotein (HDL) cholesterol in patients taking beta-blockers. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Mixed primary and referral-based outpatient clinic at a university-affiliated VA Medical Center. PATIENTS: Referred sample of 72 men receiving beta-blockers, mainly for hypertension. Sixty-three patients (88%) completed the study. INTERVENTIONS: Current medications, including beta-blockers, were continued. During the 8-week treatment phase, patients in the chromium group received a total daily dose of 600 micrograms of biologically active chromium divided into three equal doses; control patients received a placebo of identical appearance and taste. MEASUREMENTS: Serum levels of total cholesterol and HDL cholesterol were measured. MAIN RESULTS: Mean baseline levels of HDL and total cholesterol (+/- SD) were 0.93 +/- 0.28 mmol/L and 6.0 +/- 1.0 mmol/L (36 +/- 11.1 mg/dL and 232 +/- 38.5 mg/dL), respectively. The difference between groups in adjusted mean change in HDL cholesterol levels, accounting for baseline HDL cholesterol levels, age, weight change, and baseline total cholesterol levels, was 0.15 mmol/L (5.8 mg/dL) (P = 0.01) with a 95% Cl showing that the treatment effect was greater than +0.04 mmol/L (+1.4 mg/dL). Mean total cholesterol, triglycerides and body weight did not change significantly during treatment for either group. Compliance as measured by pill count was 85%, and few side effects were reported. Two months after the end of treatment, the between-group difference in adjusted mean change from baseline to end of post-treatment follow-up was -0.003 mmol/L (-0.1 mg/dL). CONCLUSION: Two months of chromium supplementation resulted in a clinically useful increase in HDL cholesterol levels in men taking beta-blockers.

Effect of tertatolol and of its metabolites and structural analogues in isolated perfused rat kidney vasculature.

The renal vascular effect of tertatolol and analogues was investigated in isolated rat kidney perfused at constant flow in an open circuit with Krebs-Henseleit solution after vascular tone had been reestablished by bolus injections of serotonin or other vasoconstrictor drugs. Against serotonin-induced vasoconstriction, (+/-)tertatolol (3 X 10(-7)-3 X 10(-5) M) evoked concentration-dependent relaxation (IC 50 = 4.6 +/- 0.4 X 10(-6) M), (-)tertatolol was more active than the racemic and (+)tertatolol was less active. (+/-)Tertatolol competitively antagonized serotonin-induced renal constriction (pA2 = 5.6 +/- 0.2). Tertatolol metabolites (4-OH tertatolol, 4,5-di-OH tertatolol, and sulfoxy tertatolol) were inactive. (+/-)Sotalol and (+/-)nadolol, were also inactive in this model and (-)bunolol induced renal vasodilatation only at concentrations 40 times higher than (-)tertatolol. The renal response to tertatolol was not linked to release of prostaglandins or dopamine or to interaction with the dopamine receptor, since neither indomethacin nor SCH 23390 affected tertatolol-induced renal vasodilatation. Tertatolol also elicited relaxation of N6-cyclohexyladenosine-induced renal vasoconstriction (34 +/- 7% relaxation at 3 X 10(-5) M) but was inactive when renal vascular tone was raised by prostaglandin F2 alpha, angiotensin II, or neuropeptide Y in the presence of norepinephrine.

[Pharmacological studies of celiprolol: II. Alpha 2-Adrenoceptor blocking effects of a cardioselective beta-blocker, celiprolol].

alpha-Adrenoceptor blocking effects of the cardioselective beta-blocker celiprolol were tested. 1. Celiprolol antagonized the contractions induced by UK-14304, but not those by phenylephrine, in isolated rat tail arteries with a pA2 value of 4.95. 2. In the isolated rat vas deferens, twitch contractions elicited by the transmural electrical stimulation (TS) were almost blocked by TTX (10(-7) M). Clonidine inhibited the TTX-sensitive contraction in a concentration-dependent manner. Celiprolol produced little effect on the inhibitory effects of clonidine. The concentration-inhibition curve of clonidine was shifted to the right by yohimbine (10(-8) M), but not by prazosin (10(-8) M). 3. Although celiprolol slightly increased the 3H-efflux to TS from the [3H]-norepinephrine-loaded rat vas deferens, the increment was not significant. Yohimbine (10(-7) M) significantly increased the 3H-efflux. TTX (10(-7) M) and bretylium (3 x 10(-5) M) blocked the 3H-efflux. 4. In the spinal rat treated with propranolol (3 mg/kg, i.v.) and prazosin (0.1 mg/kg, i.v.), celiprolol (30 and 100 mg/kg, i.v.) and yohimbine (0.1-1 mg/kg, i.v.) inhibited the pressor response to clonidine. 5. These results indicate that celiprolol may have a weak alpha 2-blocking effect which was more effective on postsynaptic alpha 2-receptors than presynaptic ones.

Beta-adrenergic receptors on human lymphocytes: comparison of down-regulation in vivo and in vitro.

beta-Adrenergic receptors on isolated human lymphocytes were enumerated using 125I-cyanopindolol (125I-CYP), after a 90-min exposure to 50 mumols/l l-isoproterenol in vitro. No change in receptor density could be shown in assays performed at 37 degrees C, although a 40% reduction was apparent in binding studies carried out at 4 degrees C. In contrast, beta-adrenergic receptors on lymphocytes from mild asthmatics after a 3-week course of oral terbutaline showed a 40% reduction in receptor density regardless of the assay temperature, in addition to a 2.5-fold reduction in the receptor affinity for isoproterenol. The data are consistent with reports that a fraction of receptors are sequestered during short-term exposure to agonists. Sequestered receptors may or may not be detected by radioligand binding assays depending on the ligand of choice, temperature of the binding assay and duration of prior exposure to the agonist. After extended exposure to an agonist in vivo, the number of surface receptors was reduced, and sequestered receptors were not present, presumably as a result of degradation.

Inhibitory action of carvedilol, a novel alpha, beta-adrenoceptor antagonist, on catecholamine secretion and calcium influx in cultured bovine adrenal chromaffin cells.

The effect of carvediolol on the secretory function was studied using cultured bovine adrenal chromaffin cells. Carvedilol caused the concentration-dependent inhibition of catecholamine secretion evoked by carbamylcholine, high K+ or veratridine. The drug also caused the inhibition of radioactive calcium uptake stimulated by these secretagogues into the cells, and the inhibition of calcium uptake was observed in parallel with that of catecholamine secretion. The inhibitory action of carvedilol on catecholamine secretion was shown to be similar to that caused by a classical beta-adrenoceptor antagonist, propranolol. Furthermore, although the level of carbamylcholine-stimulated catecholamine secretion inhibited by diltiazem, a potent calcium channel antagonist, was significantly raised by elevating the calcium concentration in the reaction mixture, increasing the concentration of calcium ions in the mixture failed to induce any substantial influence on the secretion inhibited by carvedilol, as well as propranolol, under the same experimental conditions. These results seem to indicate that carvedilol may cause the inhibition of catecholamine secretion through its blocking action on calcium influx into the cells, and suggest the possibility that the inhibitory action of carvedilol on calcium influx is presumably based on its stabilizing action on the plasma membranes rather than its blocking action on the calcium channels in the chromaffin cell.

Effects of arotinolol, an alpha- and beta-adrenoceptor antagonist, on renin release from rat kidney cortical slices.

The effects of arotinolol on changes in renin release in rat kidney cortical slices in response to isoproterenol (IP) or norepinephrine (NE), were studied in comparison with those of AC-623, a main metabolite of arotinolol, and other typical adrenoceptor antagonists. Arotinolol, at concentrations of 10(-8) to 10(-4) mol/l, inhibited the increasing effect of 10(-6) mol/l IP on renin release, in a concentration-dependent manner. Similar results were observed with AC-623, propranolol or labetalol, although the inhibitory potencies of these agents were considerably lower than that of arotinolol. The blocking effect of arotinolol on the 10(-5) mol/l NE-induced decrease in renin release was much less potent than seen with other alpha-adrenoceptor blocking agents such as prazosin, phenoxybenzamine and labetalol. These data suggest that the potent blocking effects of arotinolol and its metabolite on the increased renin release in response to beta-adrenoceptor stimulation may contribute to the antihypertensive effect of this agent.

Autonomic regulation involved in the ocular hypotensive action of beta-adrenergic blocking agents.

The effects of racemic propranolol and some related drugs on the intraocular pressure (IOP) were studied after topical application in rabbits. These drugs produced a significant reduction in IOP with the following order of potency: (-)-propranolol greater than timolol greater than (+/-)-propranolol greater than sotalol greater than (+)-propranolol greater than pranolium. Pretreatment of rabbit eyes with atropine significantly antagonized the ocular hypotensive action of (+/-)-propranolol, timolol and pranolium. Both (+/-)-propranolol and timolol produced a significant increase in pupil diameter in the presence of a submydriatic dose of atropine. The activities of monoamine oxidase and carbonic anhydrase were unaffected by (+/-)-propranolol, timolol and pranolium in-vitro. It is concluded from the results that both cholinergic and adrenergic mechanisms may be involved in the ocular hypotensive effects of the drugs.

Pharmacological characteristics of beta blockers and their role in clinical practice.

Since beta-adrenoceptor blocking drugs were originally discovered and shown to be important therapeutic agents in the management of both angina pectoris and hypertension, many other similar drugs have become available. These share the common property of beta-adrenoceptor antagonism, though they may vary in terms of potency. However, they differ from one another in terms of their additional pharmacological properties--cardioselectivity, partial agonist activity, and membrane stabilizing activity. Cardioselectivity refers to the ability of some drugs, notably atenolol and metoprolol, to block beta 1 receptors without blocking beta 2 receptors. This has been considered to be of potential importance in patients with obstructive airways disease, patients with peripheral vascular disease, and patients with insulin-dependent diabetes during hypoglycemic crisis. Partial agonist activity is the intrinsic activity that some drugs have to stimulate the beta adrenoceptor while they are competitively antagonizing catecholamines. In consequence, they may have less effect on resting heart rate, cardiac output, peripheral vascular blood flow, and resting respiratory function. However, there is no good evidence that major adverse effects of beta-adrenoceptor blocking drugs such as congestive heart failure, bronchospasm, or symptoms of peripheral vascular disease are prevented by drugs with partial agonist activity: bradycardia may be improved, but its importance has probably been overemphasized. Membrane-stabilizing activity appears to be unimportant. As far as pharmacokinetic differences between drugs are concerned, lipid solubility is seen to be of increasing importance. The more water-soluble drugs have longer elimination half-lives, produce less interindividual variation in steady-state plasma concentrations, and penetrate the central nervous system less readily.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium interferes with the cardiodepressive effects of beta-blocker overdose in isolated rat hearts.

Propranolol, timolol and sotalol were compared with respect to their cardiotoxic properties in isolated, spontaneously beating rat hearts. Propranolol and timolol induced a dose-dependent decrease in myocardial contractility. A high dose of sotalol had only modest negative inotropic effects. Similar reductions in myocardial contractility were observed in isolated, ventricle-stimulated rat hearts. These observations were similar to those in a previous study in which spontaneously beating and ventricle-stimulated reserpinized rat hearts were investigated. Spontaneously beating rat hearts were perfused with a high-, a normal- and a low-Ca++ medium, each with and without propranolol, timolol and sotalol. Addition of each beta-blocker to a normal-Ca++ medium induced a decrease of myocardial contractility and of heart rate and an increase of AV-conduction time when compared with the drug-free medium. In a high-Ca++ medium containing the same concentration of each beta-blocker, a less pronounced decrease of myocardial contractility was observed. Heart rate decreased and AV-conduction time increased to the same extent as after perfusion with the drug containing normal-Ca++ medium. With respect to the corresponding drug-free medium perfusion with a low-Ca++ medium with each beta-blocker enhanced the decline in myocardial contractility, most pronounced in propranolol and timolol containing media. For propranolol and sotalol the decrease in heart rate and increase in AV-conduction time were similar to the results after administration of the same beta-blocker in a high- and a normal-Ca++ perfusion media. Timolol caused an electromechanical dissociation. It was concluded that in beta-blocker intoxication the negative-inotropic phenomena cannot be explained by an action of the drugs on the beta-receptor since the results in reserpinized and non-reserpinized rat hearts were similar. Other effects have to be responsible for the observed cardiotoxic phenomena. The present results indicate that these phenomena can be influenced by Ca++ and or can be attributed to differences in lipophilicity.

Interactions of NSAIDs with diuretics and beta-blockers mechanisms and clinical implications.

Indomethacin attenuates the antihypertensive effect of both thiazide diuretics and beta-adrenoceptor blocking drugs. The mechanisms of these interactions are poorly understood but sodium and water retention, suppression of plasma renin activity, alterations in adrenoceptor sensitivity and impaired synthesis of vasodilator prostaglandins may all contribute to this effect. Other non-steroidal anti-inflammatory drugs (NSAIDs) may share this property of indomethacin but sulindac, which is a selective inhibitor of extrarenal prostaglandin synthesis, appears not to. This may have important clinical and theoretical implications. Clinicians must beware of this potential interaction in any patient receiving treatment for hypertension. NSAIDs may also inhibit the natriuretic response to diuretics with resultant adverse effects in patients with heart failure and other forms of oedema. NSAIDs may also have adverse nephrotoxic effects which may be exacerbated by diuretic therapy.

Effect of desipramine on propranolol-induced diminution of noradrenaline release by nerve stimulation.

In atria from rats killed 1 h after either chronic parenteral (daily subcutaneous injections of 5 mg/kg/day for 15 days) or prolonged oral administration of (-)-propranolol (1 mg/ml ad libitum during 15 days) there was a 50% decrease in the overflow of [3H]noradrenaline ([3H]NA) elicited by cardioaccelerans nerve stimulation at 2 Hz, as previously reported for the in vitro exposure of guinea pig atria to propranolol. The chronotropic responses to nerve stimulation and to isoprenaline were also significantly reduced. On the other hand, 40 h after the last injection of propranolol, the overflow of [3H]NA induced by stimulation was still reduced to 50% of the control values, whereas no blockage to nerve stimulation or to isoprenaline was observed. Neither the basal output of [3H]NA nor the tissue levels of the endogenous transmitter were modified by any of the treatment schedules applied. In a separate set of experiments performed in isolated guinea pig atria stimulated at 4 Hz during 1 min, the in vitro exposure to 0.5 microM desipramine prevented the 30% decrease in the overflow of [3H]NA caused by 0.1 microM (-)-propranolol. Desipramine, by itself, did not modify the overflow of the transmitter. It is concluded that propranolol, both in vitro and after chronic in vivo treatments, reduces the overflow of [3H]NA in response to nerve stimulation. The fact that the in vitro effect of the beta-blocker is antagonized by desipramine suggests that propranolol may have to be taken up by the nerve terminals in order to exert its presynaptic inhibition on the release of noradrenaline.

Pharmacodynamic effects of prenalterol in healthy subjects.

1. Prenalterol induces a dose-dependent effect on different variables reflecting myocardial contractility and heart rate. A clearcut effect can be demonstrated after an oral dose of 2.5 mg. The duration of the effect increases considerably when prenalterol is administered as a controlled release preparation partly due to an increased bioavailability. 2. Prenalterol induces a lipolytic effect manifested as a rise in free fatty acids and glycerol. Also a slight increase of plasma insulin is recorded while plasma potassium decreases somewhat. 3. When prenalterol is administered together with therapeutic doses of a selective or non-selective beta-adrenoceptor blocker it induces the same haemodynamic effects as before the beta-blocker but the dose has to be increased ten-fold. These results suggest that prenalterol might be a useful drug to counteract unwanted haemodynamic effects of a beta-blocker. 4. In animal studies it has been shown that prenalterol has affinity for both beta 1- and beta 2-adrenoceptors. However, it has a stimulating effect mainly on beta 1-adrenoceptors. Therefore, theoretically it might act as a beta 2-adrenoceptor antagonist. Preliminary results from studies in patients with chronic asthma indicate that prenalterol only has an insignificant beta 2-blocking effect when the drug is administered in doses which induce a significant beta 1-adrenoceptor stimulating effect.

Clinical experiences with prenalterol as an antidote to Beta-adrenoceptor blockade.

The cases presented in this paper suggest that prenalterol is useful in the treatment of myocardial depression due to beta-blockade. According to its pharmacological properties, prenalterol might even be the drug of choice in these situations. It is wellknown that massive beta-blocker overdosage may be difficult to manage and as the therapeutic guidelines in these cases have not yet been definitely stated, it is obvious that prenalterol in this context will be of utmost importance. What remains to be solved is the dosage level. So far, experience has shown that high doses, widely exceeding the recommended initial dose of 50-100 micrograms/kg, are necessary to restore normal circulation in massive beta-blocker overdosage.