Fifth W.D.M. Paton Memorial Lecture. Waterton and Wouralia.
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Animals↗
Biomedical subjects
A T Birmingham
Publications and source records attributed to A T Birmingham.
Expression of muscarinic M3-receptors coupled to inositol phospholipid hydrolysis in human detrusor cultured smooth muscle cells.
PURPOSE: To investigate the effect of muscarinic receptor agonists and antagonists on the accumulation of inositol phosphates in cultures of human detrusor smooth muscle cells. MATERIALS AND METHODS: Primary explant culture was used to derive smooth muscle cell lines from small bladder biopsies. The cells were loaded with [3H]-myoinositol, stimulated with muscarinic agonists, and the accumulation of [3H]-inositol phosphates was measured by liquid scintillation counting. RESULTS: Carbachol (EC50 8.3 microM.), methacholine (EC50 7.5 microM.), oxotremorine (EC50 2.5 microM.) and pilocarpine (EC50 8.3 microM.) produced concentration-dependent rises in the accumulation of total [3H]-inositol phosphates. M1 (pirenzepine), M2 (methoctramine) and M3 (4-DAMP and pf-HHSiD) muscarinic receptor antagonists significantly antagonized the response induced by a submaximal concentration of carbachol (100 microM.). The apparent pA2 values were atropine (9.4), 4-DAMP (9.2), pfHHSid (7.4), pirenzepine (6.9) and methoctramine (6.3). CONCLUSIONS: These results indicate that human detrusor smooth muscle cells in culture express M3 muscarinic receptors which are linked to phosphoinositide hydrolysis.
Carbachol↗
Partial mediation by nitric oxide of the relaxation of human isolated detrusor strips in response to electrical field stimulation.
1. A method for reproducing relaxation of human isolated detrusor smooth muscle in vitro in response to electrical field stimulation is described. 2. The parameters of stimulation associated with relaxation were those which would be expected to give a largely nerve-mediated response: the relaxations were not reduced by tetrodotoxin (3 x 10(-7) M) and were therefore not dependent on voltage sensitive sodium channels. 3. The relaxations were decreased (mean 74.1%) by nitro L-arginine (NOARG, 10(-5) M). 4. Methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase, abolished the relaxations. 5. These results indicate that there may be a relaxation mechanism in the human bladder which is at least partly mediated via the production of nitric oxide.
Arginine↗
Assessment of the precorneal residence of an ophthalmic ointment in healthy subjects.
1. The precorneal residence of an ophthalmic ointment radiolabelled by inclusion of technetium-99m tin colloid was assessed in seven volunteer subjects using the technique of gamma scintigraphy and compared with a solution of 0.3% w/v hydroxypropylmethylcellulose, (HPMC) radiolabelled by inclusion of technetium-99m diethylenetriaminepentaacetic acid in the same subjects. 2. The mean half-times (+/- s.d.) of corneal residence were 6490 +/- 5404 s (108 min) for the ointment and 13 +/- 24 s for the 0.3% w/v HPMC solution (P < 0.01). 3. The area-under-curve value (AUC(0,540 s)), which reflects the total residence time of the preparation on the ocular surface, was calculated for each vehicle in each subject. The mean (+/- s.d.) AUC(0,540 s) value for the ointment was 42170 (+/- 5032)% s and for the 0.3% w/v HPMC solution it was 8394 (+/- 4641)% s (P < 0.01).
Adult↗
Scintigraphic studies on the corneal residence of a New Ophthalmic Delivery System (NODS): rate of clearance of a soluble marker in relation to duration of pharmacological action of pilocarpine.
1. A gamma scintigraphic study has been carried out on the precorneal residence and pharmacodynamic action of a radiolabelled New Ophthalmic Delivery System (NODS) containing pilocarpine nitrate in 12 healthy volunteers. 2. The NODS was radiolabelled with the soluble marker technetium-99m labelled diethylenetriaminepentaacetic acid, to mark the release characteristics of soluble drugs contained within the matrix. 3. The relationship between the precorneal residence time of the marker and the duration of drug effect on intraocular pressure and pupil diameter was monitored. Results obtained following administration of the NODS were compared with those obtained after administration of a 25 microliters drop of a 2% w/v pilocarpine nitrate solution. Each formulation was administered to one eye only, the other eye acting as a control. 4. Dissolution of the radiolabel from the NODS in vivo showed considerable intersubject variation with half-times of dissolution ranging from 46 s to 833 s (mean +/- s.d. -280 +/- 217 s), the mean (+/- s.d.) half-time of clearance of the radiolabel from the NODS and corneal region of interest was 406 +/- 214 s whereas the radiolabelled solution had a mean (+/- s.d.) ocular surface residence time of 2.9 +/- 1.5 s. 5. Pupil diameter and intraocular pressure were measured for 5 h post-administration of the NODS and the solution. After both treatments pupil diameter was significantly constricted in the test eye when compared with the control eye (P less than 0.001; Student's paired t-test). Pupil diameter was constricted by 52% after administration of the NODS and by 35% after administration of the solution.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
A comparison of the precorneal residence of an artificial tear preparation in patients with keratoconjunctivitis sicca and normal volunteer subjects using gamma scintigraphy.
The precorneal residence of an artificial tear preparation has been compared in twelve patients with keratoconjunctivitis sicca (KCS) and twelve normal healthy volunteers. The artificial tear solution was radiolabelled by the inclusion of 1 MBq technetium-99m diethylenetriaminepentaacetic acid (99Tcm-DTPA), and 25 microliters was instilled into one eye only. Deposition of the preparation was followed by gamma scintigraphy. Precorneal clearance of the solution was found to follow bi-exponential kinetics in all subjects with no significant differences in clearance rates between the two study populations. There was also no significant difference in the area under the time-activity profile for the two study groups. This suggests that the reduced reflex tearing and basal lacrimation in KCS patients, indicated by the Schirmer's test, are not important in the clearance of isotonic solutions from the eye surface.
Adult↗
Agonist-induced contraction and accumulation of inositol phosphates in the guinea-pig detrusor: evidence that muscarinic and purinergic receptors raise intracellular calcium by different mechanisms.
In vitro contractile responses to electrical stimulation, ATP, histamine, and carbachol were measured in strips of guinea pig detrusor. The contractile responses were redetermined at intervals after replacement of the Krebs bicarbonate buffer with a nominally calcium-free medium. Agonist induced accumulation of [3H]-inositol phosphates was measured in a suspension of detrusor slices. Electrical stimulation (five second train; frequency 20 Hz; pulse width 100 microseconds) produced a contraction that was abolished by tetrodotoxin (10(-6) M) and reduced by approximately 50% in the presence of atropine (10(-8) M). This atropine resistant component was abolished by desensitization of the purine receptors with alpha, beta-methylene ATP, confirming that the response was mediated by nerves that released ATP and acetylcholine. Carbachol, ATP, and histamine produced concentration dependent contractions in guinea-pig detrusor strips. The response to ATP was much more dependent on extracellular calcium than the response to carbachol. Muscarinic, but not purine-receptor stimulation induced the accumulation of [3H]-inositol phosphates. These data suggest that ATP stimulates a purine receptor which opens a membrane ion channel and allows an influx of calcium while muscarinic receptor stimulation can mobilize intracellular calcium via hydrolysis of inositol phospholipid and production of the second messenger inositol triphosphate.
Adenosine Triphosphate↗
Effects of a sedative and of a non-sedative H1-antihistamine on the event-related potential (ERP) in normal volunteers.
Measurements of the amplitude and latency of the P3b component of the event-related potential (ERP), simple reaction time (SRT) and four psychomotor tests (VAS, DSST, DSp and CFF) were made on 12 male subjects (aged 19-24 years) 1.0-1.5 and 4.0-4.5 h after single oral doses of triprolidine (7.5 mg), terfenadine (60 mg) and placebo. Neither triprolidine nor terfenadine changed P3b amplitude or latency although VAS, CFF and DSST scores were significantly altered by triprolidine at 1.0-1.5 h after dosage. These results suggest that the P3b is too robust to reflect the mild sedative properties of an H1-receptor antihistamine, or that H1-receptors are not involved in P3b generation.
Adult↗
Metabolic and cardiovascular effects of infusions of low doses of isoprenaline in man.
1. The cardiovascular and metabolic responses to low doses of isoprenaline (15 and 5 ng min-1 kg-1 body weight infused over 30 min) were determined in six healthy males. The study was performed to investigate whether there were sustained effects after the termination of the isoprenaline infusion, as has been observed previously after the infusion of adrenaline. 2. The isoprenaline infusions produced dose-dependent increases in heart rate, systolic blood pressure and metabolic rate, but similar increases in calf blood flow and decreases in diastolic blood pressure for the two infusion rates. Finger tremor was increased in amplitude by the 15 ng min-1 kg-1 infusion only. The changes in each of these physiological variables largely resolved within a few minutes of discontinuing the isoprenaline infusions. 3. There were no changes in arterialized venous plasma adrenaline or noradrenaline levels during the isoprenaline infusions. Mean peak plasma isoprenaline levels were 0.16 +/- 0.02 nmol/l during the 5 ng min-1 kg-1 infusion and 0.71 +/- 0.05 nmol/l during the 15 ng min-1 kg-1 infusion. 4. Plasma insulin levels increased with isoprenaline but blood glucose concentrations were unchanged, consistent with a direct effect of isoprenaline on beta 2-adrenoceptors mediating insulin release from pancreatic beta-cells. Blood glycerol concentration also increased with isoprenaline but blood lactate concentration was unaltered. 5. The present study demonstrates pronounced cardiovascular and metabolic effects of low dose isoprenaline infusions. Differences in the rate of resolution of the changes induced by isoprenaline and by adrenaline seen in previous studies may result from a significant difference in their metabolism.
Adult↗
Interaction of adrenaline with neostigmine and tubocurarine at the skeletal neuromuscular junction.
The effects of neostigmine, and of neostigmine with adrenaline, on the response of the rat isolated hemidiaphragm to stimulation of the phrenic nerve are reported. Neostigmine augmented the response: a maximum augmentation occurred at a concentration of 6.4 X 10(-7) mol litre-1. At greater concentrations of neostigmine the response was reduced. Adrenaline in the absence of neostigmine produced no significant change in the contraction response. However, in the presence of neostigmine further augmentation occurred and achieved a maximum in the presence of adrenaline 3.2 X 10(-7)-1.3 X 10(-6) mol litre-1. Adrenaline 4.0 X 10(-8)-1.3 X 10(-6) mol litre-1 combined with neostigmine 4.0 X 10(-8)-6.4 X 10(-7) mol litre-1 reversed tubocurarine-induced neuromuscular blockade more effectively than neostigmine alone (P less than 0.001). Adrenaline appeared to enhance the antagonistic effect of neostigmine by increasing acetylcholine release and by enhancing the response at the post-junctional acetylcholine receptor.
Animals↗
The comparative effects of ICI 118551 and propranolol on essential tremor.
1. The effects of the selective beta 2-adrenoceptor antagonist ICI 118551 on essential tremor, heart rate and blood pressure were compared with those of propranolol. 2. ICI 118551 (150 mg daily for 7 days) and propranolol (120 mg daily for 7 days) were about equally effective in reducing essential tremor (by about 40%) and were more effective than placebo. 3. When compared with the effect of placebo, propranolol reduced blood pressure and exercise heart rate whereas ICI 118551 had no significant effect on blood pressure and produced a small but significant reduction in exercise-induced tachycardia. 4. ICI 118551 may be useful in the management of essential tremor while having fewer cardiovascular side-effects than non-selective beta-adrenoceptor antagonists.
Adrenergic beta-Antagonists↗
Low plasma concentrations of adrenaline and physiological tremor in man.
Finger tremor was measured in six normal subjects during intravenous infusions of adrenaline (10 ngkg-1min-1 and 50 ngkg-1min-1) resulting in venous plasma adrenaline concentrations within the physiological range (0.77 +/- 0.08 and 2.28 +/- 0.18 nmoll-1). Tremor amplitude significantly increased after 15 and 25 minutes infusion at the higher dose of adrenaline. The lower dose of adrenaline increased tremor in three of the six subjects.
Adult↗
The influence of fasting and of caffeine intake on finger tremor.
The effect of finger tremor of the administration of 150 mg of caffeine three times daily for two days was measured using an accelerometer in 7 healthy subjects taking their normal diet (excluding caffeine-containing beverages). The effect on finger tremor of a short period of fasting with and without the 450 mg daily dose of caffeine was also studied in the same 7 subjects. Fasting increased finger tremor significantly when caffeine was administered. In doses comparable to the likely adult daily intake in this country, caffeine did not increase finger tremor whilst subjects were taking their normal diet.
Adult↗
The effect of a week's beta-adrenoceptor antagonism on daytime heart-rates, subjective responses to exercise, and physical activity in normal subjects.
The effects on heart rate (HR) and physical activity of 1 week's treatment with three different beta-adrenoceptor antagonists (20 mg betaxolol (Lorex); 160 mg propranolol LA; or 100 mg atenolol daily) have been compared with placebo in a double-blind study of 12 normal men. On the fifth day of each treatment a body-borne tape-recorder was worn during waking hours for recording of ECG and footfall signals. Each record was calibrated in terms of the subject's response to laboratory ergometer exercise, and a computer analysis provided objective indices of physical activity. While on beta-adrenoceptor antagonists the subjects perceived standard exercise as significantly harder than on placebo and reported more side-effects (albeit mild and transient). Ambulatory monitoring of HR showed that subjects spent 13% of their waking day at heart rates below 50 beats min-1 while on propranolol, compared with 1% on placebo and 20% on atenolol and betaxolol. On these latter drugs, the group spent as much as 10% of their waking time with HR below 45 beats min-1. The lowest individual heart-rates recorded were below 35 beats min-1. Objective indices of physical activity, such as the duration of periods spent with heart rates above the HR found at 100 W in the ergometer test, showed no differences between the treatments. This negative finding was confirmed by pedometer step counts over the whole week.
Adrenergic beta-Antagonists↗
The variation of finger tremor with age in man.
The variation of the amplitude and frequency of finger tremor was studied in 190 subjects ranging in age from 7 to 77 years. Tremor was measured in various postures with an accelerometer and a transduced signal was analysed by Fourier analysis. The variation of tremor frequency and amplitude with age depended upon the posture adopted for measurement and in certain postures some of the variation was related to changes in stature with age.
Adolescent↗
Effect on finger tremor of withdrawal of long-term treatment with propranolol or atenolol.
The effect of the withdrawal of long-term beta-adrenoceptor blockade on pulse rate and finger tremor was studied in 27 patients who had been treated for 2 years following an uncomplicated myocardial infarction with either atenolol, propranolol or placebo. During treatment, pulse rate was significantly lower in patients treated with propranolol or atenolol compared with placebo. Compared with the response in the placebo group the mean increase in tremor on withdrawal of propranolol was statistically significant for postural and for work tremor in both hands. A significant increase in tremor on withdrawal of atenolol occurred only in the postural position and in a narrow frequency band (left hand, 7-11 Hz; right hand, 7-9 Hz). The differences in the effect on tremor of withdrawal of treatment with propranolol or atenolol in doses which produced similar reductions in heart rate, emphasise the beta 2 classification of peripheral receptors associated with normal muscle tremor but do not exclude the involvement of beta 1-adrenoceptors.
Atenolol↗
A comparison of some psychological and physiological effects exerted by zetidoline (DL308) and by oxazepam.
In a double-blind, balanced crossover study, eight healthy male volunteers ingested either DL-308 (10 mg), DL-308 (20 mg), oxazepam (30 mg) or placebo. Subjective estimates of coordination and anxiety, objective performance measurements and cardiovascular measurements were taken at 1, 3, 5 and 8 h after ingestion. DL-308 (20 mg) exerted a strong sedative effect as judged by self-reported coordination scores and performance on logical reasoning and reaction time tests. The effect was evident almost immediately and, on the coordination and reasoning tests, lasted up to 8 h following ingestion. Attention is drawn to the need to extend performance testing in order to maximise test sensitivity. No drug had any consistent or strong influence on cardiovascular measures.
Adult↗
The effect of ascorbic acid on the interaction of adrenaline and neostigmine on neuromuscular transmission.
Ascorbic acid is used in the laboratory as a stabilizing agent to delay the oxidation of adrenaline solutions. The rat isolated phrenic nerve-diaphragm preparation was used to study the interaction of ascorbic acid, adrenaline and neostigmine on neuromuscular transmission. While ascorbic acid itself did not affect the response of the preparation to phrenic nerve stimulation, it significantly reduced the response of the preparation to neostigmine and the augmentation of this response by adrenaline. The results emphasize the need to consider the consequences of including preservatives or stabilizing agents in drug solutions when quantitative comparisons are made.
Animals↗