E. C. Meyer

Possible mechanisms of anti-cholinergic drug-induced bradycardia

SummaryAtropine-induced bradycardia is traditionally ascribed to central vagal stimulation, although bradycardia has also been observed after administration of quarternary amines. Pirezepine, a selective M1-antagonist, causes bradycardia in therapeutic doses for which a peripheral mechanism is postulated. This hypothesis has been investigated in healthy volunteers.Atropine 0.5 mg caused significant bradycardia from 210 min and pirenzepine 10 mg after 60 min. After prior beta-blockade, the bradycardic action of the anti-cholinergic drugs was more marked. Pirenzepine-induced bradycardia was reversed by higher doses of atropine.It is suggested that atropine- and pirenzepine-induced bradycardia results from M1-blockade of sympathetic ganglia. In addition, low concentrations of atropine and therapeutic doses of pirenzepine may cause an increase in acetylcholine, perhaps due to a presynaptic effect on nerve endings.

Fraction of theophylline in sustained-release formulation which is absorbed from the large bowel

SummaryIn a cross-over study of six healthy male volunteers, 500 mg theophylline was administered either as plain tablets or in a sustained release preparation. On each occasion 2 g of non-enteric coated sulphasalazine was administered simultaneously as the time of appearance of sulphapyridine, the product of hydrolysis, in the blood provides an approximation of the oral — caecal transit time. The mean fraction absorbed — time profile was calculated from serial serum concentration measurements of theophylline by a modification of the Wagner-Nelson equation. The mean cumulative fraction of the dose absorbed following administration of the plain tablets was maximal at 3 h i.e. approximately 3 h ahead of the mean oral-caecal transit time, which was 5.9 h. Thus complete absorption occurred in the small intestine.With the sustained — release formulation, approximately only half of the dose was absorbed at the time the medication reached the large bowel i.e. at about 5.4 h. Absorption continued and at least 38% of the administered dose was additionally absorbed over the next 25 h.A reliable lengthened dosage interval is therefore possible with this particular sustained — release formulation.

Aldosterone response to metoclopramide is mediated through the autonomic nervous system in man

SummaryThis study primarily examines the role of the autonomic nervous system in the aldosterone response to metoclopramide since there is conflicting evidence as to the involvement of a dopaminergic mechanism in this response.Six normal male volunteers in metabolic balance at 100 mmol sodium/day and 60 mmol potassium/day constant intake received metoclopramide, 10 mg i.v., on five different occasions. The dosing was either metoclopramide alone or combined with ganglionic, muscarinic, β-adrenergic or calcium-channel blockade.Metoclopramide increased serum aldosterone significantly to 163.3% of basal level at 10 min. Atropine blunted this response and the 10 min level was significantly reduced to 116.03% of the basal value. The highest aldosterone levels were attained when metoclopramide was administered during a trimethaphan infusion and a peak of 292.8% of basal level occurred at 90 min. In the presence of atenolol, with or without nifedipine, the metoclopramide-induced aldosterone response was significantly greater at 15 min than with metoclopramide alone.The results of this investigation suggest that the aldosterone response to metoclopramide is mediated by acetylcholine released from post-ganglionic cholinergic nerve terminals, and that an adrenergic mechanism exerts a tonic inhibitory influence on aldosterone secretion in man.

Circulating met-enkephalin in trained athletes during rest, exhaustive treadmill exercise and marathon running

SummaryTwelve trained male athletes were subjected to a progressive intensity treadmill exercise test to total exhaustion and at a later date took part in the Comrades Marathon. Blood was taken in order to determine whether plasma met-enkephalin levels increase in an exercise-intensity dependent manner.The mean concentrations in f mol/ml were as follows: post-exercise levels (266) were significantly higher than basal levels (172), and the post-marathon levels (378) rose significantly above the post-exercise levels.The magnitude of the responses is thus correlated with the amount of work performed and would suggest that this opioid peptide is involved in physiological actions that perhaps extend beyond the pharmacological actions of opiate drugs.

Inotropic effects of ranitidine.

SummaryThe purpose of this controlled study was to study the effect of cimetidine and ranitidine on the myocardium of 8 healthy male volunteers using systolic time intervals.Ranitidine caused a significant decrease in the QS2I, as from 40 min indicating a positive inotropic effect. There were no significant changes in heart-rate or blood-pressure.It is postulated that ranitidine, differing structually from cimetidine, may have a higher affinity for H2-presynaptic receptors at the sympathetic myocardial junction resulting in an increase in noradrenaline and an increasd inotropic effect.

Effects of diclofenac on isradipine pharmacokinetics and platelet aggregation in volunteers.

SummaryIn this open, two-period crossover study in 18 healthy male volunteers, a single oral dose of 50 mg diclofenac was administered alone and on day 7 of multiple oral dosing of 5 mg b.i.d. isradipine to assess a possible pharmacokinetic interaction. The effect of these drugs on ex vivo platelet function was also determined.Serial blood samples were obtained over 12-hour periods on three occasions: after the single diclofenac dose; after the morning dose of isradipine on day 6 and after co-administration of both drugs on day 7 of steady-state isradipine administration. Additional samples were taken at 2 h post dose for determination of ex vivo platelet aggregation. Isradipine plasma concentrations were determined by a gas chromatographic method and diclofenac plasma concentrations by an HPLC method.The pharmacokinetic characteristics of diclofenac were unaltered during co-administration. The maximum plasma concentration of isradipine was increased 19.6% during co-administration from 5.06 to 6.05 ng·ml−1. This is not expected to be of clinical importance. Isradipines apparent total body clearance and steady-state AUC remained unchanged. Ex vivo induced platelet aggregation was not affected by any of the treatments.

The effect of verapamil on cardiac sympathetic function

SummaryWe have used systolic time intervals (STI) to measure inotropy and chronotropy as indirect measures of the actions of noradrenaline, in order to ascertain whether the depletion of cardiac noradrenaline stores which has been shown to occur in laboratory rats after chronic verapamil treatment could be demonstrated in healthy volunteers.Placebo, verapamil, or atenolol were given by slow intravenous injection to 8 healthy volunteers and QS2I, LVETI, and PEP/LVET were measured.Verapamil pretreatment resulted in a positive inotropic state. Intravenous verapamil after oral pretreatment caused accentuated negative inotropic and chronotropic responses as compared with acute verapamil without pretreatment.We postulate that the observed initial inotropic effect may be in part due to an increase in the amount of noradrenaline available to the myocardium intrasynaptically, and that the accentuated negative response after intravenous or oral verapamil may result from a decrease in cardiac noradrenaline storage.

The effect of neostigmine on metoclopramide-induced aldosterone secretion after the administration of muscarinic antagonists in man

SummaryIn this study the effects of neostigmine on metoclopramide-induced aldosterone secretion were examined in the presence of a relatively selective M1-antagonist, pirenzepine and of a non-selective muscarinic antagonist, atropine.Six normal male volunteers received metoclopramide, 10 mg i.v. on three different occasions, each study day being preceded by a day in which the intake of sodium and potassium was limited. The dosing was either metoclopramide alone or combined with either neostigmine and pirenzepine or with neostigmine and atropine.Serum aldosterone increased significantly with all three regimens. The highest levels were attained with the metoclopramide/neostigmine/prienzepine regimen and those were significantly higher than those after metoclopramide alone and also, from 45 min onwards, from those after the metoclopramide/neostigmine/atropine regimen.The results of this investigation suggest that the metoclopramide-induced aldosterone secretion in humans is augmented by an accumulation of acetylcholine at the nerve-zona glomerulosa junctions and that the receptors mediating aldosterone secretion are of the M2-subclass of muscarinic receptors.

Effects of enhancement and antagonism of 5-hydroxytryptamine activity on metoclopramide-induced aldosterone secretion in man

SummaryThis study examines the contribution of the serotonergic system to metoclopramide-induced aldosterone secretion. Six normal male volunteers, at 13h, 9h, and 2h before the i.v. bolus of 10 mg metoclopramide, received the following pre-treatments in a single-blind cross-over randomized sequence: fluoxetine 20 mg, metergoline 6 mg, pizotifen 0.5 mg, or methysergide 2 mg. One regimen consisted of metoclopramide alone. Pizotifen and fluoxetine pre-treatment increased metoclopramide-induced aldosterone secretion significantly after 15 min, for the duration in the case of fluoxetine, and up to 90 min with pizotifen. The increase with metergoline was never significant, while methysergide had a negligible influence. Serotonin is postulated to play an intermediary role in acetylcholine-facilitated aldosterone release. The mechanism of fluoxetine-mediated serotonin increase is a re-uptake inhibition and that of pizotifen is suggested to be the elimination of an auto-inhibitory mechanism.

Effect of exercise on met-enkephalin in unfit and superfit individuals

SummaryTwenty-four unfit volunteers and twenty-three superfit athletes were subjected to a progressive intensity treadmill exercise to total exhaustion in order to study the plasma met-enkephalin response to exercise. Blood samples were collected before and 5 min post-exercise.The basal met-enkephalin levels were significantly higher in the superfit individuals (180 fmol·ml−1) than in the unfit individuals (126 fmol·ml−1). Post-exercise the increase from basal levels of plasma met-enkephalin was significantly higher in the superfit athletes (180–278 fmol·ml−1) than in the unfit individuals (126–157 fmol·ml−1).The magnitude of the met-enkephalin responses to exercise therefore appears to be dependent on the amount of work performed and the degree of previous physical training. Peripherally circulating opioid peptides may, therefore, possibly play a role in the bodys adaptation to exercise training.