Biomedical subjects
Publications and source records attributed to R Ekman.
Rats were fed a liquid diet with the aim of decreasing nervous reflex activity in the parotid glands. In rats killed after 21 days on this diet the glands were atrophied and the total amounts of the neuropeptides, substance P, vasoactive intestinal peptide and calcitonin gene-related peptide, were lower than in control glands.
Calcitonin gene-related peptide (CGRP) is one of the peptides encoded for by the calcitonin gene. It has been demonstrated in man to be located in the thyroid and in perivascular nerves and to possess potent vasodilatory properties. In the present study we found plasma levels of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) to be significantly higher in females than in males and that women on contraceptive pills had significantly higher CGRP-LI levels than women not taking contraceptives. These data are in accordance with one earlier report on an increased CGRP level during pregnancy and suggest a positive influence of the female sex hormones on the plasma CGRP level in man, which should be considered in the establishment of a reference range for this analysis.
Calcitonin gene-related peptide (CGRP) is a neurotransmitter candidate together with the tachykinins in sensory fibres in the cerebral vasculature, with possible vasodilating properties. The origin of most of the CGRP-immunoreactive cerebrovascular nerve fibres seems to be the trigeminal ganglion. Experimentally produced vasoconstriction in cats after lesions of the trigeminal ganglion have shown marked prolonged constriction compared to controls. The possible involvement of the trigemino-cerebrovascular system as a defence system, with CGRP probably being the more potent vasodilatator, was investigated in 12 patients with subarachnoid haemorrhage (SAH). After operation with clipping of the aneurysm and treatment according to department policy, blood samples were taken from the external jugular vein on postoperative days 1, 2, 3, 5, 7, 9, frozen and analysed (radioimmunoassay) for CGRP-LI (-like immunoreactivity) levels. The patients were monitored with Doppler recordings from the middle cerebral arteries (MCA) and internal carotid arteries (ICA) following blood sampling. The relationship Vmean MCA/V mean ICA was used as an index of vasospasm. The highest CGRP-LI levels were found in the patient with highest velocities/index values. In patients with MCA aneurysms (n = 7), a correlation of r = 0.61 was found between the index and CGRP-LI levels. However, significant changes in the group as a whole was not found. The possible involvement of the trigemino-cerebrovascular system in SAH is discussed.
Plasma levels of the neuropeptides, vasoactive intestinal polypeptide (VIP, neuropeptide Y (NPY), calcitonin gene-related peptide (CGRP), substance P, and galanin were determined in 15 hyperthyroid patients before and at 3 occassions during 38 weeks of treatment. Treatment was performed with either 131I alone or with carbimazole, with combination of carbimazole and thyroxine, or with subtotal thyroidectomy. Before and after 11 (+/- 4), 24 (+/- 6) and 38 (+/- 5) weeks of treatment, plasma neuropeptide levels were analysed. A group of 9 premenopausal women served as controls. During hyperthyroidism, mean plasma level of CGRP was higher than in controls (P less than 0.001). In contrast, the mean plasma levels of the other measured neuropeptides did not differ from those in the controls. Mean serum level of tree T4 was lowered from 81.9 +/- 30.1 to 23.9 +/- 8.6 pmol/l and mean serum level of free T3 was lowered from 27.3 +/- 7.9 to 6.7 +/- 2.3 pmol/l during the course of the treatment. After 11 weeks of treatment, mean plasma NPY level was significantly increased (P = 0.004) compared to pretreatment levels. However, after 38 weeks of treatment, mean plasma NPY level had returned to control values. The mean plasma CGRP level was significantly reduced at 11 and 38 weeks of treatment compared to pre-treatment value (P = 0.002 and P = 0.004, respectively). Mean plasma level of neurotensin slowly declined during the treatment (P = 0.003). In contrast, mean plasma level of VIP, of substance P, and of galanin did not differ from control value before or after treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
By immunocytochemistry, delta sleep-inducing peptide (DSIP) was demonstrated to coexist with serotonin (5-HT) in a majority of midgut carcinoid tumour cells studied in biopsies and long-term cell cultures. Tumour cell colonies were characterized ultrastructurally and by confocal laser microscopy. The cultures produced several DSIP-like peptides chromatographically separated from culture media. DSIP has not yet proved to be a useful tumour marker clinically. Provocation with pentagastrin in patients with midgut carcinoid syndrome resulted in increased peripheral levels of 5HT, but not of DSIP.
The concentration of delta sleep-inducing peptide-like immunoreactivity (DSIP-LI) in rat brain regions was determined by radioimmunoassay following treatment with various psychoactive drugs or adrenalectomy. The antidepressant drugs imipramine and zimeldine, given orally twice daily for three weeks, reduced the concentrations of DSIP-LI in the hypothalamus, frontal cortex and cerebellum. The effects of zimeldine were similar but somewhat less pronounced than those of imipramine. The neuroleptic drug haloperidol, given i.p. once daily for two weeks, increased the concentration of DSIP-LI in the hypothalamus, but not in the frontal cortex. A single dose of haloperidol did not affect the concentration of DSIP-LI in either region. Like haloperidol, pentobarbital elevated the concentration of DSIP-LI in the hypothalamus; however, this effect of the barbiturate was seen after single but not after repeated administration. Cortical concentrations of DSIP-LI were unaffected following both single and repeated pentobarbital administration. Finally, adrenalectomy increased the concentration of DSIP-LI in the hypothalamus, but not in the other brain regions. In conclusion, the DSIP concentration in rat brain regions may be altered by a variety of interventions. The most profound and general alterations were observed following administration of antidepressant drugs.
To evaluate the previously reported depletion of pancreatic somatostatin by cysteamine (beta-mercaptoethylamine), mice were injected subcutaneously with the drug at 300 mg/kg. Immunocytochemical analysis performed on sections from tissue taken at 4 h after the injection revealed an elimination of somatostatin-14-like immunoreactivity without alterations in the somatostatin-28(1-12)-like immunoreactivity. In sections from tissues taken at 24 h after injection, no differences between cysteamine-injected animals and controls were observed. Immunochemical analysis of somatostatin-14-like immunoreactivity in pancreatic extracts showed a significant reduction of the concentration (P less than 0.001). In contrast, no change in the insulin concentration was observed. Functionally, cysteamine lowered the plasma glucose levels at 1 h after injection; this effect persisted for 6 h. Plasma insulin levels were likewise reduced transiently by cysteamine. Concomitant administration of somatostatin did not influence these effects of cysteamine. The plasma glucose-lowering effect of cysteamine was seen also in alloxan-diabetic mice. We conclude that cysteamine alters the immunoreactive characteristics of pancreatic somatostatin without affecting the immunoreactivity of insulin, and that cysteamine transiently reduces plasma glucose and insulin levels.
Cysteamine (1.95 or 3.90 mM/kg) administered subcutaneously (sc) markedly decreased the open-field activity of the rats, while the structurally related amino acid cysteine had only minor influence. Cysteamine (1.95 or 3.90 mM/kg) reduced the noradrenaline and increased the dopamine and dihydroxyphenyl acetic acid (DOPAC) levels in the hypothalamus. In striatum the drug decreased both the noradrenaline (1.95 or 3.90 mM/kg) and dopamine (3.90 mM/kg) levels without influencing the DOPAC content. Neither the hypothalamic nor the striatal catecholamines are influenced by administration of equimolar doses of cysteine. Cysteamine (1.95 or 3.90 mM/kg) decreased the somatostatin levels both in the hypothalamus and in the striatum without influencing neuropeptide Y (NPY) and corticotropin releasing hormone (CRH) concentrations. Cysteine administered in equimolar doses did not influence the peptide levels in these brain structures. These data suggest that the cysteamine-induced behavioural changes are related to the decrease of brain noradrenaline and somatostatin concentrations. The structurally related amino acid cysteine does not influence the behaviour or the central monoaminergic and peptidergic concentrations in the hypothalamus and striatum of rats.
At present our knowledge of enteric peptide-containing neurons in man is limited. In this study we have used human appendices removed at surgery to examine the peptidergic innervation by immunocytochemistry, immunochemistry, and pharmacological in vitro experiments. Immunocytochemistry revealed a variety of peptide-containing nerve fiber populations in the human appendix. VIP/PHI-, VIP/PHI/NPY-, SP/NKA-, galanin-, and enkephalin-containing nerve fibers were numerous; CGRP- and GRP-containing nerve fibers were moderate in number, while only scattered NPY-, enkephalin/BAM-, and somatostatin-containing nerve fibers could be found. No CCK-, dynorphin A-, or dynorphin B-immunoreactive nerve fibers could be detected. The coexistence of VIP/PHI, SP/NKA, and enkaphalin/BAM can be anticipated from the known sequence of their respective precursors. However, the coexistence of VIP/PHI and NPY was unexpected but corroborates previous observations in other species. Interestingly, SP and CGRP did not seem to coexist in nerve fibers of the human appendix. Immunochemistry (RIA and HPLC) confirmed the presence of VIP, NPY, SP, galanin, CGRP, GRP, enkephalin, and somatostatin. Motor activity studies suggest that acetylcholine plays a major role in the electrically evoked contractions, since atropine suppressed these contractions. Galanin (10(-8)-10(-6) M) and GRP (10(-9)-10(-7) M) caused concentration-dependent contractions that were unaffected by tetrodotoxin and thus probably reflect a direct action on smooth muscle receptors. GRP (10(-9) M) enhanced the electrically induced cholinergic contraction (to 193 +/- 24%), while met-enkephalin (10(-6) M) reduced it (to 54 +/- 6%). Both peptides failed to affect the contractile response to exogenous acetylcholine and probably act to modulate the release of acetylcholine. NPY, VIP, CGRP, SP, and somatostatin failed to induce contraction or to affect the electrically evoked contractions.
Neuroendocrine responses to the hypothalamic pituitary-adrenal axis following electroconvulsive treatment (ECT) were evaluated in twelve depressed (6 males/6 females) patients. Plasma concentrations of arginine vasopressin (AVP), corticotropin releasing factor (CRF), corticotropin (ACTH), and cortisol were measured using radioimmunological methods at four different ECT occasions. At each occasion plasma samples were taken immediately before ECT, at the recovery of spontaneous breathing and at 10 and 30 minutes after the ECT. No changes were observed in the plasma CRF concentrations. A large and rapid increase in plasma AVP concentrations was seen after the ECTs. This was followed by increased plasma ACTH and plasma cortisol levels. It is generally believed that AVP exerts a modulatory potentiating action on the CRF-induced ACTH release. The present results demonstrate that AVP per se can cause a release of ACTH from the anterior pituitary.
Twenty subjects (10 patients with a major depressive episode and 10 individually matched healthy controls) received 100 micrograms synthetic human corticotropin-releasing hormone (hCRH) as an i.v. bolus dose. Healthy subjects and depressed patients exhibited a significant increase of plasma somatostatin (SRIH) concentrations with no difference between both comparison groups. Compared to controls, depressed patients showed a significant attenuation of corticotropin (ACTH) responses, while cortisol secretion in response to hCRH was normal. No correlations were found among basal plasma concentrations of SRIH, ACTH or cortisol and SRIH, ACTH or cortisol responses following hCRH. These findings are compatible with the hypothesis that hypothalamic-pituitary-adrenal (HPA) hyperactivity in the depressive state may primarily be due to central hypersecretion of CRH and support the view of a hCRH-induced SRIH secretion which is not related to HPA dysfunction associated with major depression.
In patients undergoing aorto-coronary by-pass surgery, we found a 26% arterial-venous difference of immunoreactive gamma 2-melanocytostimulating hormone (MSH), a proopiomelanocortin (POMC) derived peptide known to possess profound hemodynamic effects. These results prompted an investigation of the presence of gamma 2-MSH in the human heart. Using a two-step extraction procedure, regions of human hearts were examined by sensitive and specific radioimmunoassays to determine their gamma 2-MSH content. Mean (+/- SEM) concentrations of 0.14 +/- 0.023 pmol/g and 0.12 +/- 0.017 were found in right atrium and right ventricle, respectively. High performance liquid chromatography indicated that 80-90% of the total immunoreactivity eluted in a single sharp peak in a position identical to that of synthetic gamma 2-MSH.
We investigated the possible release of galanin-, calcitonin gene-related peptide (CGRP)-, and neuropeptide Y (NPY)-like immunoreactivity from the pancreatic nerves in thiopental-anaesthetized pigs. Ten minutes stimulation of the mixed autonomic pancreatic nerves during infusion of atropine (8 or 40 Hz, 5 ms, 10 mA, n = 5) inhibited insulin secretion, during both normoglycemia (9.1 +/- 0.2 mmol/l) and hyperglycemia (28.1 +/- 0.4 mmol/l). Concomitantly, pancreatic venous concentrations of NPY-like immunoreactivity increased. For example during normoglycemia, a nerve stimulation by 8 Hz increased the pancreatic venous levels of NPY-like immunoreactivity from 294 +/- 26 pmol/l to 391 +/- 23 pmol/l (P less than 0.001). In contrast, the pancreatic venous concentrations of galanin- or CGRP-like immunoreactivity did not change during the nerve stimulation. We conclude that electrical pancreatic nerve stimulation in the pig releases NPY-like immunoreactivity without affecting the pancreatic venous concentrations of galanin- or CGRP-like immunoreactivity.
The localization, molecular nature and secretion of Peptide YY (PYY), a putative gut hormone belonging to the Pancreatic Polypeptide family of peptides, was studied in pigs. Immunoreactive PYY was identified in a population of endocrine cells in the mucosal epithelium of the pig ileum. Release of PYY was observed in isolated perfused pig ileum in response to luminal stimulation with glucose and vascular administration of the neuropeptide gastrin-releasing peptide (GRP). Electrical stimulation of the vagus nerve supply to the distal small intestine in intact anaesthetized pigs resulted in release of PYY into the circulation. Stimulation of the splanchnic nerves did not affect the basal release of PYY. PYY-immunoreactivity extracted from ileal tissue or released to plasma or perfusate from the ileum was indistinguishable from synthetic porcine PYY by gel filtration and reverse phase HPLC. It is concluded that the secretion of PYY in the pig ileum may be regulated not only by nutritional luminal factors, but also by postsynaptic parasympathetic nerves.
The perivascular neuropeptide Y (NPY) innervation and its relation to adrenergic nerves of uterine arteries from non-pregnant and pregnant guinea pigs was analyzed immunocytochemically. The NPY content of the uterine artery was, in addition, measured radioimmunologically (RIA). Vasomotor effects of NPY per se and in combination with other vasoconstrictors were examined using a sensitive in vitro method. Pregnancy did not visibly affect density and distribution of NPY-immunoreactive fibres. The NPY fibres contained in addition immunoreactivity to dopamine-beta-hydroxylase (marker for noradrenergic neurons). RIA revealed a slight decrease of NPY content during pregnancy, probably due to the increased smooth muscle volume of uterine arteries. The contractile effect of NPY on uterine arteries was weak, while vasoconstriction induced by various agonists was potentiated by NPY, particularly during pregnancy. It is concluded that perivascular NPY-containing nerve fibres may be involved in the dramatic blood flow alterations that occur in the uterine circulation in connection with pregnancy and partus.
1. NPY is a 36 amino acid tyrosine-rich peptide. It is one of the most abundant and widely distributed neuropeptides known today within the central nervous system with particularly high concentrations in the hypothalamus and in several limbic regions. 2. NPY seems to coexist with other on neurotransmitters like somatostatin, galanin, GABA and the catecholamines noradrenaline and adrenaline in discrete brain regions. 3. NPY binding sites are widely distributed in the brain. However they do not always overlap with the distribution of NPY-like immunoreactivity. 4. NPY is suggested to be involved in a large number of neuroendocrine functions, stress responses, circadian rhythms, central autonomic functions, eating and drinking behaviour, and sexual and motor behaviour. 5. Psychotropic drugs and neurotoxins can alter the NPY concentrations in discrete brain regions. 6. It is possible that NPY is related to various neurological and psychiatric illnesses, like Huntington's chorea, Alzheimer's disease, Parkinson's disease, eating disorders, and major depressive illness.
Eleven healthy male volunteers, ages 25-39 years, received a single dose of synthetic delta sleep-inducing peptide (DSIP) (25 nmol/kg BW) or saline intravenously in a randomized cross-over, double-blind study. The concentrations of neuropeptides related to the hypothalamic pituitary-adrenal (HPA) axis and cortisol were examined in serial plasma samples. In addition, cortisol and monoamine metabolites were determined in urine. A significant reduction of ACTH-like immunoreactivity (ACTH-LI) in plasma was detected for at least 3 hr after the DSIP injection, compared to the control subjects, in whom a slightly elevated concentration of ACTH-LI occurred. Plasma cortisol levels were unaffected and followed the normal diurnal decline. No differences in urinary cortisol or monoamine metabolite concentrations occurred between the two groups. The results indicate an inhibitory action of DSIP on ACTH secretion in man, as previously suggested by animal experiments.
Cerebrospinal fluid (CSF) concentrations of beta-endorphin-like immunoreactivity (END-IR) were determined in 11 female and 6 male patients fulfilling the diagnostic criteria of panic disorder (PD) and in matched controls. Eleven of the PD patients had been taking moderate doses of benzodiazepines (BZD) irregularly without satisfactory effect against the panic attacks while six were totally drug-free. No medication was allowed for at least 24 hours before the lumbar puncture. In six patients a second lumbar puncture was performed after 2 to 3 months of treatment with imipramine or clomipramine. In PD patients, CSF levels of END-IR were significantly higher than in controls. Patients that had been taking BZD had somewhat higher concentrations of END-IR than those taking no medication; however, totally drug-free patients also displayed END-IR levels that were significantly higher than in controls. Although they effected a dramatic reduction of the panic attacks, antidepressants did not influence CSF END-IR concentrations.