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Beta-adrenoceptor antagonists and human sperm motility.

Several beta-adrenoceptor blocking agents have been evaluated for spermicidal activity using a transmembrane migration method. The rank order of potency of the active compounds was: penbutolol greater than (+)-propranolol greater than bufuralol greater than (-)-alprenolol greater than oxprenolol greater than metoprolol. Atenolol, pindolol, practolol, tolamolol were without activity. The observed potencies of spermicidal activity are believed to be unrelated to beta-blocking activities, and we have shown that whilst they are not predictable from lipid solubility or nonspecific membrane properties of the compound alone, both these aspects appear to play a role in this pharmacological activity.

Adrenergic beta-Antagonists↗

Sympathetically evoked secretory potentials in the parotid gland of the cat.

1. In cats under chloralose anaesthesia micro-electrodes were inserted into parotid gland cells. 2. The average resting potential was found to be -35 . 6 +/- 4 . 7 (S.D.) mV. 3. Stimulation of the auriculo-temporal nerve caused hyperpolarizing, or occasionally depolarizing, secretory potentials of 5--10 mV, which were abolishable with atropine. 4. Stimulation of the cervical sympathetic trunk regularly caused, after long latency (several seconds), slow depolarizations of 15--20 mV, accompanied by a decrease in input resistance. They were antagonized by practolol and therefore assumed to be mediated by beta 1-adrenoceptors. Occasionally hyperpolarization, ascribed to an effect on alpha-adrenoceptors, was observed. 5. In many units the slow depolarization on sympathetic stimulation was preceded by short-lasting hyperpolarizing (sometimes depolarizing) transients. They resembled the evoked cholinergic responses but could be abolished not only by atropine but also by guanethidine.

Adrenergic alpha-Antagonists↗

The action of beta-adrenoceptor agonists on acid secretion by the rat isolated stomach.

1. The action of beta-adrenoceptor agonists on acid secretion by an immature rat isolated stomach preparation has been studied. 2. Isoprenaline, salbutamol, salmefamol, adrenaline and noradrenaline all stimulated acid output over a concentration range of 2 X 10(-7) M--10(-5) M. 3. These responses were antagonized by propranolol (2 X 10(-5) M), pindolol and timolol (10(-6) M). 4. The antagonism of isoprenaline and salmefamol by propranolol was consistent with competitive inhibition. 5. Selective beta-adrenoceptor antagonists (practolol, atenolol, butoxamine and ICI 118 551) caused significant inhibition of noradrenaline-stimulated secretion but not of that due to the other agonists. 6. An adult rat isolated mucosa preparation responded to adrenaline in a similar manner to the immature stomach preparation. 7. Acid secretion stimulated by beta-adrenoceptor agonists was not antagonized by atropine (10(-5) M), metiamide (10(-4) M) or prostaglandin E2 (10(-5) M). The concentrations of these three antagonists caused marked inhibition of the responses to submaximal concentrations of bethanechol, histamine and pentagastrin respectively. 8. The results are discussed in relation to the possible mechanisms of action of beta-adrenoceptor stimulation of acid secretion: it is concluded that the response is probably mediated by beta-receptors on the parietal cell.

Adrenergic Agonists↗

Quantitative tear lysozyme assay in units of activity per microlitre.

An accurate method of assaying the tear lysozyme concentration in units of activity/mul has been developed. Normal physiological levels which vary with age have been determined. It has been demonstrated that measurement of the volume of tear fluid collected and assay with a calibrated standard are essential for the accurate determination of the precise concentration of lysozyme in the tear fluid. Tear lyozyme concentration can be used as an index of lacrimal gland function, and in the diagnosis of the sicca syndrome and associated conditions. We believe that this method of tear lyozyme assay has important applications in drug toxicity states in humans (for example, practolol toxicity) and also in animal drug toxicity studies.

Adult↗

Comparison of adrenergic beta-receptor antagonists in angina pectoris.

The symptomatic, electrocardiographic, and circulatory effects of intravenous and oral preparations of propranolol, oxprenolol, and practolol were compared in 16 patients with uncomplicated angina pectoris precipitated by exertion. The method of study included treadmill exercise, double-blind assessment, single-blind analysis, with placebo control and randomized serial comparison of each drug in each patient. The doses used were selected to give the same near-maximum suppression of the heart rate response to exercise. The symptomatic, electrocardiographic, and circulatory response of each patient to both preparations of each of the three drugs was similar. Exercise tolerance was increased in two-thirds, unchanged in one-sixth, and significantly worsened in one-sixth of the studies. Electrocardiographic evidence of myocardial ischaemia was conspicuously reduced by all three drugs in most studies irrespective of their symptomatic effects. Though the exclusive choice of patients, the single dose design of the trial, and the treadmill method of assessment limit the general application of these results, they do clearly indicate that in doses that induce equal suppression of the exercise heart rate these three drugs have similar distinct anti-anginal activity. Their ancillary pharmacological properties are probably of little importance in this respect. Equally, the similarity in the symptomatic, circulatory, and electrocardiographic response to the intravenous and oral preparations suggests that metabolic breakdown products are probably of therapeutic importance only in so far as they antagonize beta-receptor activity.

Acetanilides↗

The case for recording events in clinical trials.

The value of clinical trials in detecting unwanted effects of new medicines would be enhanced if doctors recorded all adverse events experienced by patients and not just those regarded as adverse reactions to drugs. All events should be reported to the centre co-ordinating the trial and analysed in treated patients and controls. This method might have revealed the ocular toxicity of practolol before the drug was marketed in 1970.

Attitude of Health Personnel↗

One year's treatment with propranolol after myocardial infarction: preliminary report of Norwegian multicentre trial.

A prospective, randomised, double-blind study was performed to compare the effects of propranolol and placebo on sudden cardiac death in a high-risk group of patients who survived acute myocardial infarction. Altogether 4929 patients with definite acute myocardial infarction were screened for inclusion: 574 (11.6%) died before randomisation, and 3795 (77%) were excluded. Five hundred and sixty patients aged 35 to 70 years were stratified into two risk groups and randomly assigned treatment with propranolol 40 mg four times a day or placebo. Treatment started four to six days after the infarction. By one year there had been 11 sudden deaths in the propranolol group and 23 in the placebo group (p less than 0.038, two-tailed test analysed according to the "intention-to-treat" principle). Altogether there were 25 deaths in the propranolol group and 37 in the placebo group (P less than 0.12), with 16 and 21 non-fatal reinfarctions respectively. A quarter of the patients were withdrawn from each group. Withdrawal because of heart failure during the first two weeks of treatment was significantly more common among propranolol-treated patients than among the controls, but thereafter the withdrawal rate was the same. The significant reduction in sudden death was comparable with that after alprenolol, practolol, and timolol, which suggests that the mechanism of prevention is beta-blockade rather than any other pharmacological property of the individual drugs.

Adult↗

Assessment of proximal tubular sodium reabsorption during water diuresis in patients with heart disease.

In order to examine the relation between cardiac state and the capacity to excrete a water load, 10 normal subjects and 61 patients with heart disease were studied during water diuresis. Under these conditions, urine flow approximates to the rate of delivery of filtrate, and therefore of sodium, from the proximal tubule of the kidney to the loop of Henle, while free water clearance is a function of distal sodium reabsorption. In 12 patients with complete heart block, ventricular pacing was associated with increased urine flow and free water clearance. Oral propranolol in 3 normal subjects and in 9 patients with intact atrial septa caused a reduction, and oral practolol in 4 normal subjects and 8 patients caused no change. In 6 patients with atrial septal defect, propranolol was without effect. Maximum urine flow correlated with left ventricular end-diastolic pressure but not mean left atrial pressure in 16 patients with chronic rheumatic heart disease. In 7 patients with ischaemic heart disease, maximum urine flow was higher than in those with chronic rheumatic heart disease and similar increase in left ventricular end-diastolic pressure. These results reflect a close relation between proximal tubular sodium reabsorption and cardiac state, and suggest that inappropriate sodium reabsorption at this site may contribute to fluid retention in heart disease.

Acetanilides↗

Haemodynamic effects of atenolol in patients with coronary artery disease.

The haemodynamic effects of atenolol, a new cardioselective beta-blocking agent, have been studied at rest in 8 patients with coronary artery disease. The drug was administered intravenously in cumulative doses of 0.03, 0.06, and 0.12 mg/kg body weight. A significant decrease in heart rate was associated with a fall in cardiac output. However, this cardiac output fall was not entiely rate dependent, since stroke volume fell significantly both during spontaneous sinus rhythm and when heart rate was maintained constant by atrial pacing. A dose related and significant reduction occurred in left ventricular dP/dt max without significant change in left ventricular filling pressure or mean aortic pressure. Total peripheral resistance at rest rose after atenolol. The haemodynamic findings more closely resemble those which follow intravenous propranolol than those after intravenous practolol in a similar group of patients. These actions of atenolol suggest that it may be a useful agent in the treatment of patients with angina pectoris.

Adult↗

In vitro studies on cetamolol, a new potent cardioselective beta-adrenoceptor blocking agent with intrinsic sympathomimetic activity.

In vitro studies on the new beta-adrenoceptor antagonist, cetamolol (Betacor), have demonstrated that the compound is a potent antagonist of the chronotropic effects of isoproterenol on guinea pig atria. The pA2 value (8.05) of cetamolol was slightly lower than that of propranolol (8.44). The compound was shown to possess a moderate degree of cardioselectivity as indicated by a lower pA2 value for the antagonism of isoproterenol-induced relaxation of the isolated guinea pig trachea (pA2 = 7.67) compared with that derived from atrial experiments (pA2 = 8.05). Up to concentrations of 10(-4) M, cetamolol displayed negligible negative inotropic activity relative to propranolol in the electrically stimulated guinea pig left atrial preparation. When applied to isolated right atria from reserpinized rats, cetamolol had a positive chronotropic effect (approximately 75% of that displayed by practolol) which was antagonized by pretreatment with propranolol, thus indicating intrinsic sympathomimetic activity. Specificity experiments in a number of isolated tissues indicated that cetamolol had very little antihistaminic, anticholinergic, alpha 1-adrenergic blocking, or calcium antagonistic properties. Biochemical receptor binding studies are in general agreement with the observations from the isolated tissue experiments.

Acetamides↗

Cetamolol: a new cardioselective beta-adrenoceptor blocking agent without membrane-stabilizing activity.

Cetamolol, a new beta-adrenoceptor blocker with partial agonist activity and cardioselectivity, was studied in vivo to determine its membrane-stabilizing effects. Comparisons were carried out with atenolol, pindolol, practolol, propranolol, timolol, dexpropranolol, lidocaine, and procaine. The following results indicated that cetamolol lacked membrane-stabilizing activity: (i) failure to cause local anesthesia on the rabbit cornea and motor nerve of the rat tail; (ii) ineffectiveness in reversing ventricular arrhythmias induced by coronary artery litigation in dogs; (iii) failure to reduce cardiac automaticity in catecholamine-depleted dogs as determined by the rate of a subatrial rhythm during ventricular (vagal) escape; and (iv) lack of a significant increase in atrioventricular conduction time in vagotomized or atropinized dogs in contrast to the effect in normal dogs indicating a reflex effect of cetamolol. Other results include a restoration of sinus rhythm in dogs with ventricular tachycardia induced by ouabain, and a dose-related decline in the force of cardiac contraction in anesthetized dogs at doses from 3 to 15 mg/kg, which occurred after an initial increase in force owing to intrinsic sympathomimetic activity. Although the mechanisms for the latter two effects are not clear at this time, explanations other than membrane-stabilizing activity have been considered in view of the other findings. It is concluded that cetamolol lacks membrane-stabilizing activity even at inordinately high doses.

Acetamides↗

Relationships between cardiac hyperactivity, oxygen tension, and release of vasodilator material in coronary autoregulation of guinea-pig hearts.

Increases in cardiac activity induce autoregulatory coronary vasodilation. The intermediate steps which trigger this process are thought to be myocardial hypoxia which induces the release of vasodilator mediator(s). The present study examines the relationships between mechanical activity, oxygen tension, and release of vasodilator material in isolated perfused hearts. Guinea-pig isolated hearts were perfused in series, the effluent from donor hearts being regassed prior to entry to recipient hearts. Histamine (1 microgram) and isoproterenol (10 ng) increased the rate and tension of donor hearts and produced predominant coronary vasodilator responses which were followed by the appearance of vasodilator material in the recipient (falls in perfusion pressure, 9.8 +/- 1.1 and 9.1 +/- 2.5 mmHg) (1 mmHg = 133.322 Pa). Exposure of donor hearts to hypoxia also caused vasodilatation and release of vasodilator material (fall in pressure, 11.4 +/- 1.6 mmHg). Pacing-induced tachycardia (6 Hz) of donor hearts promoted the release of vasodilator material, the fall in recipient heart pressure being 11.5 +/- 1.8 mmHg. This was abolished by beta-adrenoceptor blockade and when donor hearts were from reserpine-pretreated guinea pigs. In was concluded that pacing released endogenous catecholamines which in turn released the vasodilator material. Pacing per se did not cause vasodilatation or release of the vasodilator. The Po2 of perfusates from donor hearts was reduced by pacing at 5 Hz (25.7 +/- 5.2 mmHg) and by isoproterenol (10 ng, 32.0 +/- 3.7 mmHg), indicative of an elevated oxygen extraction. The isoproterenol-induced falls in Po2 were abolished by beta-adrenoceptor blockade. However, the pacing-induced falls in Po2 persisted, the values occurring before (25.7 +/- 5.2 mmHg) and after propranolol (45.7 +/- 4.5 mmHg) and before (32.1 +/- 1.1 mmHg) and after practolol (27.3 +/- 4.1 mmHg) not differing significantly (p greater than 0.05). These falls in perfusate Po2 were not accompanied by coronary vasodilatation or release of vasoactive material. Perfusate Po2 changes could therefore be dissociated from the coronary vasodilatation and vasoactive material release, suggesting that hypoxia may not be a prerequisite for the metabolic autoregulatory vasodilatation in response to myocardial hyperactivity induced by cardiac stimulants.

Adenosine↗

Responses of the isolated rectum of the rainbow lizard (Agama agama) to sympathomimetics.

The relaxant effects of isoprenaline, noradrenaline, and adrenaline on the isolated rectum of the rainbow lizard (Agama agama) were studied. Responses were measured as a reduction of carbachol-induced contractions for each sympathomimetic agent. Isoprenaline, adrenaline, noradrenaline produced a dose-dependent relaxation of this preparation and the order of potency was as given. The pD2 value of 8.15 +/- 1.88 obtained for isoprenaline was significantly different (p less than 0.05) from those for adrenaline (5.80 +/- 0.90) and noradrenaline (5.25 +/- 1.18). H35/25, propranolol, and practolol competitively antagonized the relaxant effects of isoprenaline on the isolated lizard rectum. The pA2 values for these beta-adrenoceptor antagonists did not differ significantly (at p less than 0.05). alpha-Adrenoceptor antagonists, phentolamine and phenoxybenzamine, failed to alter the relaxant responses of these sympathometics to any appreciable extent. These results are interpreted to suggest that the relaxant effect produced by these sympathomimetics are mediated predominantly by beta-adrenoceptors that are not significantly differentiated into subtypes. alpha-Adrenoceptors in this preparation contribute minimally to the observed inhibitory response following sympathomimetic stimulation.

Adrenergic alpha-Antagonists↗

Beta-adrenergic and prostanoid inhibition of canine fundic mucosal mast cells.

We examined regulation of histamine release from canine hepatic and fundic mucosal mast cells in short-term culture. We found that beta- but not alpha-adrenergic agonists markedly inhibited concanavalin A (ConA)-stimulated histamine release. Inhibition by epinephrine was reversed by the beta-antagonist propranolol, but not by the alpha-adrenergic antagonists phentolamine or yohimbine. The beta 2-selective antagonist ICI 115881 reversed the effects of epinephrine, whereas the beta 1-antagonists practolol and betaxolol had little effect. Prostaglandin E2 (PGE2), but not its analogue enprostil, inhibited ConA-stimulated histamine release. This difference may relate to the ability of PGE2, but not enprostil, to stimulate adenosine 3',5'-cyclic monophosphate (cAMP) production. Forskolin, cAMP analogues, and the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine also effectively inhibited ConA-stimulated histamine release. Neither adrenergic agonists nor PGE2 inhibited histamine release stimulated by the combination of phorbol 12-myristate-13-acetate plus the calcium ionophore A23187. These data suggest that inhibition was mediated via cAMP-dependent mechanisms and was exerted on primary cell activation, rather than on postreceptor activating events.

1-Methyl-3-isobutylxanthine↗

Adrenal contribution to cardiac responses elicited by acute hypoxia in piglets.

The adrenal contribution to cardiac responses elicited by acute hypoxia was assessed in 16 piglets, 1-12 wks old, anesthetized with pentobarbital (30 mg/kg). External cardiac work was held constant and parasympathetic blockade was produced in each animal with atropine (1 mg). Hypoxia was produced by addition of N2 to the respirator. In a sham-adrenalectomy group (n = 6) left ventricular (LV) dP/dtmax increased significantly during hypoxia (PaO2 approximately 30 mmHg) to 3,680 +/- 414 mmHg/s from control values of 2,686 +/- 317 mmHg/s (P < 0.01). Heart rate rose from 171 +/- 6 to 186 +/- 7 beats/min (P < 0.02). These responses were not significantly altered by ganglionic blockade with trimethaphan camsylate (0.5 mg x kg-1 x min-1). Equally large increases of LV dP/dtmax appeared when heart rate was held constant by pacing. beta-Adrenoreceptor blockade with practolol (4 mg/kg) sharply reduced but did not eliminate the response. In contrast, no changes in LV dP/dtmax or heart rate were observed during hypoxia in adrenalectomized piglets (n = 6). These findings indicate that the increased cardiac contractility during acute hypoxia in piglets is dependent on the integrity of the adrenal glands and that there is minimal contribution from cardiac sympathetic nerves.

Acute Disease↗

Adrenoceptor desensitization after immobilization stress or repeated injection of isoproterenol.

Immobilization stress (2.5 h daily) or repeated injection of isoproterenol (1 mg/kg, 3 times daily) for 1 wk caused a subsensitivity to the chronotropic and pressor effect of epinephrine in pithed rats. Propranolol (1 mg/kg) inhibited, to a greater extent in control than in immobilized rats, the chronotropic effect of epinephrine. The residual heart rates did not differ significantly among control, immobilized, and isoproterenol-treated rats. Practolol (1 mg/kg) but not butoxamine (5 mg/kg) mimicked the effect of propranolol. The subsensitivity in the blood pressure responses was not abolished by injection of either of the beta-adrenoceptor blockers. Butoxamine or propranolol shifted the epinephrine dose-blood pressure response curves to the left. The degree of shift was similar in control and immobilized or isoproterenol-treated rats. Daily injection of quinacrine (16 mg/kg), an antimalarial agent that inhibits phospholipase A2, blocked the subsensitivity to the chronotropic effect of epinephrine, but not that to the pressor effect of epinephrine. These observations suggest that immobilization stress causes desensitization of alpha- and beta 1-receptors but not beta 2-receptors. The mechanism of desensitization of beta 1-receptors by immobilization appears to be similar to that after isoproterenol treatment, possibly due to increased turnover of phospholipids.

Adrenergic beta-Antagonists↗

Myocardial responses to alpha-adrenoceptor stimulation with methoxamine hydrochloride in lambs.

This study was undertaken to evaluate the effects of methoxamine on left ventricular performance, coronary blood flow (CBF), and myocardial oxygen consumption (MVO2) in lambs. Measurement of maximum rate of rise of left ventricular pressure (LV dP/dtmax), left ventricular end-diastolic pressure (LVEDP), CBF, and MVO2 were made in nine lambs using a hemodynamically controlled preparation. The lambs were given atropine sulfate (1 mg), tetraethylammonium chloride (100 mg), and practolol (4 mg/kg) to provide parasympathetic, ganglionic, and beta-adrenergic blockades. Aortic pressure and blood flow and heart rate were held constant in each lamb. Dose-related increases in LV dP/dtmax and decreases in LVEDP were observed after progressively larger doses of methoxamine ranging from 0.4 to 6.0 mg/kg were given. These positive inotropic responses were eliminated by giving phentolamine (2 mg/kg). CBF, myocardial O2 extraction, and MVO2 did not change significantly. A positive inotropic action of methoxamine was also demonstrated in five additional animals by obtaining ventricular function curves. Initially the mean stroke volume at LVEDP 10 cmH2O (SV10) was 4.11 +/- 0.16 (SE) ml. This value increased to 5.09 +/- 0.28 ml after methoxamine (P less than 0.01). After phentolamine, SV 10 fell to 4.37 +/- 0.08 ml (P less than 0.05). These observations support the hypothesis that alpha-adrenergic receptors are present and mediate a substantial positive inotropic action on neonatal lamb myocardium.

Animals↗

Enhanced sensitivity of diabetic hearts to alpha-adrenoceptor stimulation.

Inotropic responses to alpha-adrenergic stimulation with methoxamine were compared in 12 normal (N) and 12 diabetic (Db) lambs. Diabetes was produced by giving alloxan monohydrate (150 mg/kg iv). Measurements of maximal rate of rise of left ventricular pressure (dP/dtmax), left ventricular end-diastolic pressure (LVEDP), coronary flow, and myocardial O2 consumption were made simultaneously in hemodynamically controlled preparations. All animals were subjected to ganglionic blockade (tetraethylammonium chloride, 100 mg) and beta1-adrenergic blockade (practolol, 4 mg/kg). Methoxamine was given in incremental doses ranging from 0.4 to 6.0 mg/kg. dP/dtmax increased progressively to 126 +/- 4% of initial values in N. However, the increase was twice as large (150 +/- 4%) in the diabetics (P less than 0.005). LVEDP fell in both groups. These changes were abolished by phentolamine (2 mg/kg). Inotropic responses to methoxamine in lambs 2 and 3 wk after induction of diabetes did not differ from those with acute (2 days) diabetes. Dose-response curves obtained by infusing Ca2+ (2-8 mg X min-1 X kg-1) were identical in N and Db. It is concluded that lamb myocardium possesses an alpha-adrenergic receptor system that is stimulated by methoxamine in a dose-dependent manner and blocked by phentolamine. Db hearts are supersensitive to alpha-receptor activation. The mechanistic basis for this latter finding has not been examined but may relate to altered receptor density or nucleotide regulation.

Animals↗