PubMed Health⌕ Search

Biomedical subjects

J F Morrison

Publications and source records attributed to J F Morrison.

At least 55 records · Page 3Linked to original sources

The influence of afferent inputs from skin and viscera on the activity of the bladder and the skeletal muscle surrounding the urethra in the rat.

(1) Somato-visceral and viscero-visceral reflex interactions have been studied in the bladder branches of the pelvic nerve and in the electromyographic (EMG) activity of the periurethral skeletal muscles of the anesthetized rat, and by observations of changes in bladder motility. (2) Slow distensions of the bladder caused some elevation of intravesical pressure, and culminated in a micturition contraction. Periurethral EMG activity increased gradually during the bladder distension, and showed an oscillatory marked increase during the bladder contraction. There was a small increase in pelvic nerve efferent activity during slow distension, and there was a substantial increase before, or at the start, of a micturition contraction. (3) Oscillatory bursting activity occurred in recordings of the EMG activity from periurethral skeletal muscle during the rising phase of micturition contraction; this was particularly so during the most rapid rise in intravesical pressure, and periods of electrical silence lasting 80-270 ms alternated with bursts of activity in the periurethral EMG. (4) In the present experiments, the switching mechanism activated by pelvic afferent signals related to intravesical pressure reversed the behavior of a number of reflex pathways. When the bladder pressure was low, nociceptive pinching of the perineal skin usually caused bladder contraction and a rise in pelvic nerve efferent activity and in periurethral EMG activity. When the bladder was full, micturition contractions were present and reduced in size and frequency by pinching of the perineal skin. The pelvic nerve efferent activity was correspondingly reduced, while the EMG activity increased during and following the nociceptive stimulus. Cooling the scrotal skin with ice also decreased the frequency of bladder contractions. (5) When the bladder pressure was low, distension of the anus and colon increased periurethral EMG activity, but did not affect bladder tone. However, when the bladder was full, these stimuli reduced the size and frequency of bladder contractions, associated with a reduction in the pelvic nerve efferent activity. There was usually a simultaneous reduction in the EMG activity in periurethral muscles. Similar results were obtained during distension of the seminal vesicles or vagina, or following injection of 20-60 microliters of saline into the lumen of the vas deferens. Reversal of the responses at extremes of intravesical pressure was observed in every case. (6) Following spinal transection at the upper cervical or thoracic level, micturition contractions were absent at high bladder volumes. However the effects described when the neuraxis was intact and the bladder pressure was low were still observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Afferent Pathways↗

The effects of pregnancy and parturition on the levels of substance P-like immunoreactivity in different areas of the hypothalamus.

1. The concentrations of substance P-like immunoreactivity (SPLI) have been measured in the rostral and caudal areas of the hypothalamus of male rats and of virgin, pregnant and puerperal female rats. 2. The rostral:caudal ratio of SPLI is similar in males and virgin females, but diminishes in pregnancy and decreases further during the puerperium. In the pre-optic area, the SPLI concentration fell significantly during parturition, from 241.8 to 177.2 pmols/g wet weight (P < 0.05), and in the medio-basal hypothalamus, the concentration rose during pregnancy and parturition, from 87.4 to 145.5 pmols/g wet weight (P < 0.001). 3. The results are discussed in relation to the endocrine and nociceptive aspects of pregnancy and parturition.

Animals↗

Effects of denervation on muscarinic receptors in the rat bladder.

OBJECTIVE: To demonstrate the specific distribution of muscarinic receptors in the rat urinary bladder and to investigate the effects of afferent and efferent denervation on the density and distribution of muscarinic receptors. MATERIALS AND METHODS: Urinary bladders were obtained from female rats which had been injected with vehicle (control), or neonatally with capsaicin (NC, afferent denervation) or which had their pelvic plexus removed (post-ganglionic denervation, PGD, efferent denervation). Tissue sections were used in radioligand-binding studies and for autoradiography with the muscarinic receptor ligand l-quinuclidinyl[phenyl-4-3H]benzilate (QNB). RESULTS: Binding of QNB was saturable and specific to a single population of binding sites, with a mean dissociation constant (Kd) of 1.05 +/- 0.14 nM in controls and 0.90 +/- 0.13 nM in rats with PGD. Post-ganglionic denervation caused a 37% increase in maximal binding (Bmax) of QNB from 437.1 +/- 39.1 fmol/mg protein (control group) to 599.1 +/- 4.5 fmol/mg protein (P < 0.02). Autoradiograms revealed muscarinic binding sites over the smooth muscle, but none over the epithelium. Smooth muscle binding sites were doubled after PGD but were unchanged after NC treatment. CONCLUSION: Muscarinic receptors were localized over the smooth muscle of the rat bladder and were increased after post-ganglionic denervation. This increase may be responsible for the increased sensitivity to muscarinic agonists reported to occur after bladder denervation.

Animals↗

The effects of pregnancy and parturition on the substance P content of the rat uterus: uterine growth is accompanied by hypertrophy of its afferent innervation.

The afferent innervation of the uterus might be expected to grow during pregnancy as the size of the uterus increases. Substance P-like immunoreactivity (SPLI) has been measured as a means of monitoring the changes in the afferent innervation of the urogenital tract of rats during pregnancy and following parturition. The great growth of uterine tissue during pregnancy causes an overall decrease in SPLI concentrations during pregnancy, but it has been found that the amount of SPLI present per uterine horn increases nearly 3-fold by the end of pregnancy. This increase is greater in uterine horns that contain more fetuses, suggesting that the SPLI innervation expands to a greater extent in uterine horns that undergo greater degrees of hypertrophy. There is a significant correlation between SPLI content and the number or total weight of fetuses throughout the latter two-thirds of pregnancy. There is a fall in SPLI content of uterine horns following parturition, but not to a statistically significant degree, and this may be related to the release of the peptide during parturition.

Afferent Pathways↗

Cytokine expression in normal, atopic, and asthmatic subjects using the combination of sputum induction and the polymerase chain reaction.

BACKGROUND: The importance of cytokines in the asthmatic inflammatory response is becoming apparent. The aim of this study was to determine whether the non-invasive method of induced sputum combined with the polymerase chain reaction would allow the detection of messenger RNA (mRNA) encoding a range of cytokines on a qualitative basis. METHODS: Four groups were studied comprising 10 normal subjects, six atopic, 10 mild and five moderately severe asthmatic subjects. Sputum was induced by the inhalation of nebulised 3.5% saline and total RNA extracted from the expectorated cells. Expression of cytokine message within induced sputum was examined by reverse transcription and the polymerase chain reaction (PCR) using primers specific for a range of cytokines (IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, RANTES, TNF alpha, IFN alpha, IFN gamma). Presence or absence of the signal was determined at 35 and 70 cycles of PCR by electrophoretic size fractionation on ethidium bromide stained agarose gels. RESULTS: Cytokine message was detectable in sputum by this method. All samples showed a positive result for actin control. Analysis of signal for the cytokines in all subjects showed that, at 70 cycles, IL-1, IL-5, IL-8, and TNF alpha were detected in more subjects than would be expected by chance. IL-5 mRNA was detected in more of the asthmatic patients (moderate 80%, mild 40%) than in the atopic subjects (33%), who in turn showed expression of this cytokine in more individuals than nonatopic subjects (10%). CONCLUSIONS: The combination of sputum induction and PCR appears to be a useful, non-invasive tool to explore the chronic inflammation of asthma and possibly other lung disorders. It should enable differences between normal and asthmatic subjects to be identified for future confirmation by quantitative techniques.

Adult↗

Multiple mechanisms of heterologous beta-adrenoceptor regulation in rat uterus.

The inhibitory effects of catecholamines on rat myometrium mediated by beta-adrenoceptors are modulated by ovarian steroids. Previously reported findings of radioligand binding studies on myometrial membranes have demonstrated changes in the numbers of beta-adrenergic binding sites following ovarian steroid treatment. However, these changes were not accompanied by parallel functional changes. In the present study, we have investigated possible mechanisms of heterologous beta-adrenoceptor regulation by ovarian steroids. Binding studies were performed on myometrial membrane and cytosolic preparations from rats which had been ovariectomized and subsequently received no hormonal treatment or had been treated with oestradiol, progesterone or combined oestradiol and progesterone. The beta-adrenergic antagonist [125I]iodocyanopindolol and the unlabelled competing agonist, isoprenaline, were used in the present studies. Hormonal treatment had no effect on the concentration of beta-adrenergic binding sites in the myometrium (i.e. the number of membrane-bound and cytosolic binding sites per mg protein). However, significant changes were found in the total number of binding sites; these were associated with the hormone-induced tissue hypertrophy. In myometrium from ovariectomized-alone rats, approximately 50% of beta-adrenergic binding sites were present in the cytosolic fraction. Oestradiol treatment, either on its own or in combination with progesterone, resulted in the translocation of binding sites to the cell membrane. However, in the absence of progesterone only 33% of the membrane-bound binding sites bound the beta-adrenergic agonist, isoprenaline, with a high affinity, suggesting that the majority of these membrane-bound binding sites represented non-functional beta-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗

The effects of aging on the rat bladder and its innervation.

1) Measurements of the cystometrogram, of the responsiveness of bladder muscle to pelvic nerve efferent stimulation and of the sensitivity of the pelvic nerve afferents to pressure and volume during distensions have been made in the bladders of young adult (2-3 months) and aged (26-29 months) rats, anesthetized with mixtures of urethane and chloralose. 2) The pressure-volume relationship differed in young adult and aged rats. The bladders of the aged rats held up to nearly six times the volume of the young animals, and these volumes were accommodated at lower pressures in the aged animals. The pressure at which micturition contractions appeared was similar in young adult and aged animals. 3) The passive pressure associated with each of a series of distending volumes was recorded when a pelvic nerve was cut unilaterally. The distal cut end of this cut pelvic nerve was stimulated for 10 s at 20 Hz, using square wave pulses of 10 V and 1.0 ms. The active pressure-volume relationship was constructed from this data. Both the active and the passive relationships were shifted to the right in the aged animals, and it was evident that aging was associated with a reduction in the maximal pressure generated during pelvic nerve stimulation. Also the change in intravesical pressure induced by bladder contraction was less in aged animals. 4) The most sensitive mechanoreceptor afferents appear to have pressure and volume thresholds that do not change significantly during aging. While the distension-sensitive afferents in the pelvic nerve appear to have a similar sensitivity to intravesical pressure in young adult and aged rats, they were less able to monitor volume in the aged animals. The stimulus response relationship for volume was often less steep in the aged animals. 5) In this study, aging was shown to be associated with a large increase in bladder volume and a reduced sensitivity of pelvic nerve afferents to volume, and a reduced ability to raise bladder pressure during contraction of bladder smooth muscle. The changes in bladder function associated with aging are discussed.

Aging↗

Effect of mechanical stimulation of the skin on the external urethral sphincter muscles in anesthetized cats.

Experiments were performed using anesthetized cats to examine the effects of cutaneous stimuli on the external urethral sphincter (EUS) activity and bladder motility, 1) when the bladder volume was changed from low to high, and in the latter case, in the presence or absence of micturition contractions, 2) in different neurological states, viz., in animals with an intact neuraxis and in acute or chronic spinal preparations. In animals with an intact neuraxis, when the volume of the bladder was low, the bladder was quiescent and noxious mechanical stimulation of the perineal skin produced abrupt and marked increases both in vesical pressure and EUS activity. Similar results were observed in acute spinal as well as chronic spinal animals. The effect of the stimulus was particularly potent in chronic spinal animals. In animals with an intact neuraxis, when the volume of the bladder was increased, rhythmic micturition contractions were produced and noxious stimulation of the perineal skin slowed the frequency of the large rhythmic micturition contractions of the bladder and increased the EUS activity. These effects in animals with an intact neuraxis were substantially similar to those in chronic spinal cats showing synergic states. The effects of these somatic stimuli on the integration and coordination of bladder motility (controlled mainly by the parasympathetic pelvic efferent nerves) and EUS activity (controlled by somatic pudendal efferent nerves) are discussed.

Animals↗

Bambuterol: effective in nocturnal asthma.

Bambuterol was compared with placebo in 28 patients with nocturnal asthma in a randomized, double-blind cross-over study. All patients were symptomatic despite taking inhaled beta 2-agonists, inhaled corticosteroids (in 26 patients the median daily dose was 1500 micrograms) and oral corticosteroids (in eight patients the median daily dose was 10 mg). Patients demonstrated > or = 20% overnight fall in peak expiratory flow (PEF) for at least half of the 14-day run-in period. They then entered two treatment periods lasting 14 days when bambuterol 20 mg nocte and placebo were given in random order. Compared to placebo, bambuterol produced a 16% improvement in mean PEF on waking (271 l min-1 vs. 239 l min-1 P = 0.0002) and a 10% improvement in evening PEF measured 24 h after drug intake (318 l min-1 vs. 296 l min-1 P = 0.01). Bambuterol significantly reduced frequency of nocturnal awakening from 1.1 to 0.7 per night (P = 0.01) and nocturnal beta 2-agonist use from 2.7 to 2.1 puffs (P = 0.0004). Other nocturnal symptoms: cough, wheeze and dyspnoea were also significantly reduced during bambuterol treatment and patients quality of sleep was improved. The results indicate bambuterol (20 mg nocte) provides effective nocturnal bronchodilation with sustained effect for 24 h and may have a useful therapeutic role in the control of symptomatic nocturnal asthma.

Adult↗

Effects of inhaled capsaicin in heart-lung transplant patients and asthmatic subjects.

We have studied the effects on FEV1 of inhaled capsaicin in concentrations of 3 x 10(-6) to 3 x 10(-1) mg/ml and methacholine (1 to 16 mg/ml) in 15 heart-lung transplant (HLT) patients who had undergone recent transbronchial lung biopsy to determine the relationships in chronically denervated lungs between these different forms of airway hyperreactivity and inflammation. A total of 10 normal subjects and 17 asthmatic subjects were included for comparison. Capsaicin caused bronchodilation in eight HLT patients (FEV1 rising by 6.4 to 26.8%) and bronchoconstriction in two (fall in FEV1 of 7.2 and 7.6%). By contrast, seven asthmatic subjects developed bronchoconstriction after capsaicin (fall in FEV1 5.6 to 40.4%); the remaining 10 asthmatic subjects showed no response. Bronchial hyperresponsiveness to methacholine was most evident in the asthmatic subjects, but six HLT patients demonstrated a > or = to 20% fall in FEV1 with < or = 8 mg/ml of methacholine. All normal subjects were nonresponsive to both agents, and all normal and asthmatic subjects, unlike HLT patients, coughed with capsaicin. No relationship existed between the methacholine and capsaicin responses. In the HLT patients neither form of airway responsiveness was related to the degree of inflammation seen on transbronchial lung biopsy. The results suggest that in normal subjects, although it provokes cough, inhaled capsaicin causes little airway narrowing.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

Human dihydrofolate reductase: reduction of alternative substrates, pH effects, and inhibition by deazafolates.

The kinetics of the NADPH-dependent reduction of 7,8-dihydrofolate, folate, and 7,8-dihydrobiopterin by human dihydrofolate reductase have been examined over the pH range from 4.0 to 9.5. The V and V/K profiles obtained with the three substrates indicate that a single ionizing residue at the active site of the enzyme must be protonated for catalysis. Both the maximum velocity of the reactions and the rate of interaction of the substrates with the enzyme-NADPH complex decrease in the order dihydrofolate greater than dihydrobiopterin much greater than folate. From the pK values of the V/K profiles, it can be concluded that, while dihydrofolate behaves as a sticky substrate and dihydrobiopterin exhibits slight stickiness, folate is not a sticky substrate. Further support for this conclusion comes from the results of deuterium isotope effects. The pK values obtained from both the V and V/Kfolate profiles are similar to the intrinsic pK value of 5.6 for both the free enzyme and the enzyme-NADPH complex. The folate analogue, 5-deazafolate, is not a substrate, but it undergoes strong interaction with the enzyme. This interaction, which is enhanced by the presence of NADPH, is due to protonation of the bound ligand that does not involve the single ionizing group at the active center of the enzyme. Difference spectra yield evidence for the protonation of bound 5-deazafolate and show that, on binding to the enzyme-NADPH complex, the pK of the N-8 atom is raised to about 10 from a value of about 4 in solution. The results are in accord with those of a recent paper on the three-dimensional structure of the enzyme-5-deazafolate complex [Davies, J.F., Delcamp, T.J., Prendergast, N.J., Ashfors, V.A., Freisheim, J.H., & Kraut, J. (1990) Biochemistry 29, 9467-9479] which indicate that there is hydrogen bond formation between N-8 of the ligand and the carbonyl group of Ile-7. However, the present findings do not support the idea that bound 5-deazafolate resembles the transition-state complex for folate reduction. Quinazolines also interact strongly with the enzyme but in a pH-independent manner. The dissociation constants for the binary complexes are an order of magnitude lower than that for the binding to the enzyme of unprotonated 5-deazafolate. This difference reflects the hydrophobic nature of the amino acid residues at the active site that are near the N-5 and N-8 nitrogens of bound pterins.

Folic Acid↗

Response to nebulized ipratropium bromide and terbutaline in acute severe asthma.

Outpatient studies on asthmatics have shown that inhaled anti-cholinergic agents decrease in efficacy as FEV1 falls. To determine whether there are changes in response to inhaled anti-cholinergics during acute bronchoconstriction we have examined the effects of nebulized ipratropium and terbutaline in nine hospitalized patients recovering from acute severe asthma. At 6 a.m. each day throughout the admission, baseline PEFR was recorded. Ipratropium bromide, 1 mg, was nebulized and PEFR measured again 1 h later. Following this, terbutaline, 5 mg, was nebulized with further measurement of PEFR 15 min after nebulization. Results were analysed by paired t-tests. Mean baseline PEFR rose from 157 l m-1 on patients worst day to 300 l m-1 on their best day (P less than 0.01). Ipratropium improved mean PEFR by 55 l m-1 and 42 l m-1 on patients worst and best days respectively (P less than 0.01). Subsequent terbutaline improved mean PEFR on patients worst day by 23 l m-1 (P less than 0.01) but only by a non-significant 4 l m-1 on their best day (P = 0.09). Hence, ipratropium produced 96% of total bronchodilatation when baseline was highest, but achieved only 71% of total response when baseline was lowest, a highly significant change in response (P less than 0.01). We conclude that in acute severe asthma as baseline PEFR rises response to inhaled ipratropium improves, compared with total response to combined ipratropium followed by terbutaline.

Acute Disease↗

Oesophageal motility, luminal pH, and electrocardiographic-ST segment analysis during spontaneous episodes of angina like chest pain.

The relation between oesophageal motility, luminal pH, and spontaneous pain events in 47 patients with recurrent angina like pain and normal coronary arteries was investigated. Preliminary investigation by conventional station pull through manometry (SPTM), was followed by a 24 hour period of ambulatory oesophageal motility and luminal pH monitoring. Computerised analysis of motility and pH data recorded during chest pain was then compared with pre-elected control samples taken before and after symptoms. Concurrent real time electrocardiographic (ECG)-ST segment analysis was performed to catalogue any ECG-STT wave changes indicative of myocardial ischaemia. SPTM showed a high group percentage incidence of simultaneous contractions (mean (SD) 11.1 (2.3)%) and a raised lower oesophageal sphincter tone (57.4 (15.2) mm Hg). During ambulatory monitoring, 35 patients experienced one or more episode of angina, providing a total of 59 pain events, although no significant change in group motility and reflux parameters peculiar to episodes of chest pain were found. Ischaemic ECG changes were detected in 10 (21%) patients, but were accompanied by pain in only two. Independent analysis of the ECG traces corresponding to these purported ischaemic ECG events determined them unequivocal in three patients and probable in a further two. No apparent correlation was noted, however, between these ECG events and corresponding patterns of motility or reflux.

Adult↗

Diurnal variation in FEV1 after heart-lung transplantation.

We have examined the diurnal variation in forced expiratory volume in one second (FEV1) in 25 heart-lung transplantation patients over a four week period in order to study the pathophysiological mechanisms underlying the increased mortality and morbidity which occurs at night in asthma. These patients do not have pulmonary autonomic nervous reflexes, but often have muscarinic receptor hypersensitivity. They also develop mixed cell infiltration of the lung tissue in the course of infection or rejection. Thus, they show many features in common with asthma. Seventeen patients (68%) showed a significant diurnal variation in airway calibre (mean amplitude of FEV1 was 4.6% (SD 3.7%)), which is similar to that reported in normal adults. One patient had a diurnal variation of 34.5% during an episode of rejection. This variation fell to 6.9% after steroid therapy, a change often seen in asthma. There was a correlation between increased amplitude of the variation and the presence in transbronchial biopsies of airway submucosal eosinophils and lymphocytes, associated with a histological diagnosis of acute rejection and with epithelial damage. No association was seen with muscarinic receptor sensitivity. The variation in FEV1 showed no alteration from the normal day/night synchronization, and the peak values were around 1300 h. We conclude that the diurnal variation in FEV1 after heart-lung transplantation is not dependent on autonomic nerve reflexes or muscarinic receptor sensitivity, but is related to the consequences of inflammation described above.

Adult↗

Assessing physiological benefit from domiciliary nebulized bronchodilators in severe airflow limitation.

In steroid resistant chronic obstructive pulmonary disease (COPD) we assessed the effect of q.i.d. domiciliary nebulized fenoterol (F) 1.25 mg and ipratropium (I) 0.5 mg for three weeks in a placebo-controlled, randomized, double-blind, crossover study. The twenty patients studied (mean forced expiratory volume in one second (FEV1) 0.8 l) all showed less than 20% increase in FEV1 to 200 micrograms inhaled salbutamol (S) and less than 20% increase in peak expiratory flow rate (PEFR) after 2 weeks prednisolone therapy. Respiratory function tests, 5 min walking distance (5 MWD), visual analogue scales (VAS) for breathlessness, oxygen cost diagrams and reversibilities were performed weekly for three weeks with patients on their usual therapy, after three weeks domiciliary F+I, after three weeks saline and, finally, after a further three weeks on usual therapy again. Primary end-points, selected prior to unblinding, were mean home twice daily PEFR, trapped gas volume, FEV1 and 5 MWD. Home PEFR rose from 164 l.min-1 on saline to 196 l.min-1 on F+I (p = 0.0001). Secondary end-point analysis revealed a fall in home inhaler usage and a rise in VAS. Using the criterion of +15% and greater than 20 l.min-1 increase in home PEFR, 11 out of 20 patients had a "positive" trial. We suggest that such patients, but not others, benefit from long-term, nebulized beta 2-agonist and ipratropium. Trials using home PEFR recordings should be used to identify them.

Aged↗

Effects of visceral distension on the activities of neurones receiving cutaneous inputs in the rat lumbar dorsal horn; comparison with effects of remote noxious somatic stimuli.

(1) Unitary extracellular recordings were made from 92 lumbar dorsal horn neurones in urethane-anaesthetised rats. These neurones were classed as 'noxious-only' (4), 'non-noxious-only' (33) or 'convergent' (55) by their responses to stimulation of their cutaneous receptive fields on the ipsilateral hindpaw. (2) Distension of abdominal viscera (colon, urinary bladder) depressed the activities of the vast majority (93%) of the convergent neurones but of only one other cell (a non-noxious-only neurone). Similarly, noxious stimulation of widespread somatic structures depressed activity in all but one of the convergent neurones but in only 3 other cells (one non-noxious- and two noxious-only neurones). One or other of these procedures also excited 3 cells--one convergent neurone responding to distension of the colon, another to stimulation of widespread somatic structures and one non-noxious-only neurone being excited by stimulation on the contralateral hindpaw. (3) The inhibitory effects of the noxious somatic stimuli were very like those described previously and termed 'diffuse noxious inhibitory controls' (DNIC) and it seems likely that the effects of the visceral stimuli were also manifestations of DNIC, particularly in view of their similar, nearly total, specificity to convergent neurones. There were however, some small differences in the extent and temporal evolution of the inhibitory effects of the visceral and of the somatic stimuli--the visceral stimuli generally producing weaker inhibitions with slower rates of onset and recovery. It is proposed that these differences may have reflected different amounts and patterns of activity in the relevant primary afferent fibres rather than being due to different central neural mechanisms. (4) These results and the likely explanation that the effects of the visceral stimuli were mediated by a diffuse mechanism should be taken into account when interpreting the results of other studies in which inhibitory effects are produced by visceral stimulation.

Afferent Pathways↗