Some effects of noradrenaline on electrical activity of guinea-pig ureteric smooth muscle.
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Biomedical subjects
Publications and source records attributed to J M Allen.
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Spontaneous isometric contractions of isolated lymphatic vessels were studied in the single sucrose gap apparatus. Contractions were also elicited by applying single electrical pulses either within the Krebs solution (field stimulation) or across the sucrose gap (gap stimulation), or by means of high-K+ Krebs. Reductions in the calcium concentration increased the frequency but decreased the force of spontaneous contractions and ultimately abolished them. The loss of mechanical activity in calcium free solution was associated with failure of action potential firing. Increasing external [Ca2+] had no apparent effect on the force of spontaneous contractions but these became less frequent and finally stopped. The calcium antagonist D600 decreased the force of spontaneous contractions without increasing their frequency. The contractions elicited by electrical stimulation and by high-K+ Krebs were less readily abolished by calcium removal. This was particularly true of field stimulation where contractions could still be elicited up to 40 min after exposure to a calcium-free solution. It is concluded that calcium ions are important for the control of pacemaking, for the propagation of the impulse, and for the contractile response itself in these bovine lymph vessels.
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Isolated rabbit hearts, perfused under constant pressure (Langendorff technique) were used to study the effect of neuropeptide Y (NPY) on heart rate, force of heart contraction and rate of myocardial perfusion. No significant net change in heart rate was noted. A dose-dependent negative inotropic effect was consistently demonstrated which was characterised by slow onset and was often preceded by a transient positive inotropic response. Addition of small doses of NPY resulted in a prompt reduction in flow of the perfusate through the coronary vasculature. Since NPY is present locally in cardiac nerves, these effects may have physiological importance.
1. Plasma cortisol concentration was measured in three subjects with homozygous familial hypercholesterolaemia immediately before, and 30 and 60 min after, an intramuscular injection of adrenocorticotrophic hormone. The baseline values and the values at 30 and 60 min were within the normal range. 2. We conclude that in the presence of a genetic deficiency of low-density lipoprotein receptors, the human adrenal cortex can respond to a single injection of adrenocorticotrophic hormone with a normal increase in corticosteroid production.
Fifteen patients with advanced carcinoma of the prostate were treated with a luteinising hormone releasing hormone agonist ICI 118 630. Three of 5 patients who had failed conventional hormone therapy have had a marked alleviation of bone pain, though no objective evidence of disease regression. Nine of 10 patients previously untreated have shown objective evidence of disease response. This drug appears to have advantages over conventional hormone therapy.
Norepinephrine increases the spontaneous contraction frequency of isolated bovine lymphatic vessels but, paradoxically, reduces contraction force. In this investigation contractions were elicited by electrical stimulation, applied as field stimulation or across a sucrose gap. Evoked contractions were not reduced in force by concentrations of norepinephrine that have previously been shown to dramatically reduce contractility in spontaneously active vessels. However, at higher concentrations a beta-inhibitory component of the norepinephrine effect was often observed. Simultaneous recordings of electrical and mechanical activity from spontaneously active vessels showed that each spontaneous contraction was initiated by a single action potential. Norepinephrine significantly disrupted electrical activity causing increased action potential frequency, reduction in action potential amplitude, and frequent failure of full action potential development. We conclude that norepinephrine depresses the force of spontaneous contractions by disruption of spontaneous pacemaking rather than by any direct effect on vessel contractility.
The integrated response of the regulatory peptides of the gastrointestinal tract to a test meal was studied in six hypercholesterolaemic patients who had undergone partial ileal bypass (PIB) and compared with responses in ten age- and sex-matched controls. Plasma motilin was found to rise significantly whereas plasma pancreatic polypeptide release was impaired after PIB. Plasma cholecystokinin rose promptly in both controls and the partial ileal bypass patients, and the latter group showed marked further rises, at 60 and 120 minutes after the meal, which were significantly higher than controls. Basal and postprandial plasma gastrin, gastric inhibitory peptide, neurotensin, enteroglucagon, insulin and pancreatic glucagon were similar in the two groups.
Responses of 11 gastrointestinal regulatory peptides to a standard test meal were assessed in 10 adult patients with cystic fibrosis. The basal plasma neurotensin was significantly elevated in patients with cystic fibrosis, being 31.5 +/- 6.1 pmol/L compared with a control value of 10.3 +/- 1.5 pmol/L (p less than 0.005). Plasma neurotensin remained elevated throughout the test period. Basal plasma enteroglucagon was similarly elevated, the patients with fibrocystic disease having levels of 51.3 +/- 4.6 pmol/L compared to controls with levels of 33.2 +/- 6.7 pmol/L (p less than 0.02). There was, however, no significant difference in postprandial levels of plasma enteroglucagon. Postprandial motilin was significantly elevated in the patients with cystic fibrosis; this elevation is in contrast with previous findings in children. Release of gastric inhibitory polypeptide was impaired, while release of cholecystokinin showed no significant difference in control values, although there was a tendency for delay. There was no significant postprandial rise of pancreatic polypeptide in the patients, whose levels were grossly lower than controls. Insulin showed a delayed response. No significant differences were observed between patients and controls in levels of gastrin, pancreatic glucagon, somatostatin, or vasoactive intestinal peptide. The elevation of plasma neurotensin and enteroglucagon in the basal state may reflect an adaptive response and may be part of the improved digestive function in adults compared with children with fibrocystic disease.
The process of reepithelialization after laser vaporization of normal cervical squamous epithelium was examined using light and electron microscopy. Tissue specimens were obtained from seven patients at time intervals ranging from seven to 16 days after laser vaporization. Immature squamous epithelium appeared at the edge of the laser crater between seven and 14 days, and by 14 to 16 days, the immature epithelium covered the entire crater area. The observations made in this study concur with those of other studies of the healing process of squamous epithelium, whereby immature cells from the surrounding undamaged epithelium migrate into the damaged area, eventually differentiating into a full thickness of epithelium.
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Plasma pancreatic polypeptide concentrations rise by 320 +/- 81 per cent following administration of electroconvulsive therapy. This rise is observed in the first ten minutes despite premedication of patients with 0.6 mg atropine. Pancreatic polypeptide release is dependent on cholinergic tone and is very sensitive to atropine. The dramatic rise in pancreative polypeptide observed following electroconvulsive therapy probably results from vagal stimulation and reflects insufficient atropine premedication.
Constipation is a frequent effect of treatment with antidepressant and neuroleptic drugs as a result of interference with neuronal control of colonic muscular activity. Motilin, a circulating peptide, is involved in induction of myoelectric complexes in the colon. Significantly elevated circulating basal motilin levels were found in patients receiving tricyclic antidepressant drugs, mean 128 +/- 33 pmol/l (control 48 +/- 6 pmol/l) or neuroleptic therapy, mean 213 +/- 29 pmol/l (control 87 +/- 8 pmol/l).
The phospholipid mediator of anaphylaxis, platelet-activating factor (PAF) is chemotactic for polymorphonuclear leukocytes (PMN). We have examined this agent's effects on several other PMN functions. Human PMN were prepared from heparinized venous blood by Ficoll gradient. Metabolic burst was examined by measurement of O2 use and O2.- production in the presence or absence of PAF (10(-6)--10(-9) M). Unless cells were treated with cytochalasin-B (5 micrograms/ml), no significant respiratory burst was demonstrated. However, pretreatment with PAF (10(-7) M) enhanced approximately threefold the O2 utilization found when cells were subsequently stimulated with 10(-7) M FMLP. PAF also stimulated arachidonic acid metabolism in 14C-arachidonic acid-labeled PMN. Thin-layer chromatography analysis of chloroform-methanol extracts showed substances that comigrated with authentic 5-hydroxyeicosatetraenoic acid had a marked increase in radioactivity following PAF stimulation at 10(-7) M. PAF failed to stimulate release of granule enzymes, B-glucuronidase, lysozyme, or myeloperoxidase unless cytochalasin-B were added. PAF from 10(-6) M to 10(-10) M affected PMN surface responses. PMN labeled with the fluorescent dye, chlorotetracycline, showed decreased fluorescence upon addition of PAF, suggesting translocation of membrane-bound cations. Further, the rate of migration of PMN in an electric field was decreased following PAF exposure, a change consistent with reduced cell surface charge. PMN self-aggregation and adherence to endothelial cells were both influenced by PAF (10(-6) M--10(-9) M). Aggregation was markedly stimulated by the compound, and the percent PMN adhering to endothelial cell monolayers increased almost twofold in the presence of 10(-8) M PAF. Thus, PAF promotes a variety of PMN responses: enhances respiratory burst, stimulates arachidonic acid turnover, alters cell membrane cation content and surface charge, and promotes PMN self-aggregation as well as adherence to endothelial cells.
Rabbit granulocyte lactoferrin, when infused into hamsters or rabbits, induces transient neutropenia, and in hamsters the lactoferrin promotes adherence of the granulocytes to the endothelial cell wall as monitored visually. In contrast, neither rabbit granule lysozyme nor human transferrin induces neutropenia in the rabbit nor does transferrin or bovine serum albumin affect the adherent properties in vivo of the phagocytic cells of the hamster. Thus lactoferrin enhances granulocyte adherence both in vivo and in vitro. It would appear that the promotion of margination of leukocytes by lactoferrin in vivo may contribute to the phenomenon of neutropenia during activation of granulocytes by chemotactic factors.
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The surface ultrastructure of normal and abnormal endometrial cells from patients receiving oestrogen therapy for the climacteric syndrome was studied by scanning electron microscopy. Patients with endometrial pathology were treated with oral progestogens. Excessive oestrogen stimulation caused proliferation of cilia and microvilli. Cystic hyperplasia was characterised by a proliferation of cilia until they covered more than one-third of the surface area of the endometrium; further proliferation occurred in cases of adenomatous hyperplasia when the surface was almost completely covered with cilia. Cell morphology remained apparently normal until atypical hyperplasia, when occasional cells appeared large and irregular, or adenocarcinoma occurred, when the surface cells appeared large, pleomorphic and sometimes wrinkled, being mostly devoid of cilia. Although cystic hyperplasia was converted to a normal histological picture of atrophic or pseudo-decidual endometrium by courses of progestogen, the deciliated endometrial cells showed persisting abnormal ultrastructural characteristics.