Enkephalin-like immunoreactivity in gland cells and nerve terminals of the adrenal medulla.
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Biomedical subjects
Publications and source records attributed to M Goldstein.
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The indirect immunofluorescence technique of Coons and collaborators was used to study the distribution of substance P-like and luliberin (luteinizing hormone-releasing hormone)-like immunoreactivity in the eminentia mediana (eminentia medialis or infundibulum) of rats, monkeys, and human beings. In rats, abundant luliberin-positive fibers were present in the external layer (mainly lateral parts) whereas almost no substance P-immunoreactive nerves were observed in this region. In contrast, in the external layer of the primate eminentia medialis a dense plexus of substance P-positive nerve terminals was observed close to the blood vessels supplying the anterior pituitary gland. Luliberin-immunoreactive fibers were also present, but with a more even distribution all over the eminentia medialis and in lower numbers. The present findings indicate that substance P may play a role in the control of hormone secretion from the anterior pituitary, either by being released into the portal vessels, i.e., acting as a releasing or inhibitory hormone, or by an action as local regulator (modulator or transmitter) at the level of the eminentia medialis. Thus, in agreement with many earlier studies, substances other than the "classical" releasing and inhibitory hormones may be important for the regulation of the pituitary gland. Furthermore, there may exist marked species differences with regard to the type of substances involved in the central control of the pituitary.
The ontogenetic pattern of noradrenergic differentiation in rat embryonic autonomic neuroblasts was defined in vivo. Noradrenergic specialization was examined by documenting the immunohistochemical appearance of tyrosine hydroxylase [Tyr-OH; tyrosine 3-monooxygenase; L-tyrosine,-tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2] and the development of histofluorescence due to catecholamine (CA). Tyr-OH and CA were undetectable in the dorsal neural crest or the ventrally migrating crest cells and first appeared at 12.5 days of gestation (36--37 somite stage) in sympathoblasts that had formed sympathetic ganglion primordia. Fluorescence intensity and the number of fluorescent cells increased progressively thereafter. In addition, Tyr-OH and CA transiently appeared in scattered presumptive neuroblasts in the gut. The enzyme and transmitter were first detectable at 11.5 days of gestation and thereafter decreased progressively so that, by 14.5 days, only rare cells were encountered. There was remarkable synchrony in the appearance and disappearance of Tyr-OH and CA. These observations suggest that a number of noradrenergic transmitter mechanisms develop simultaneously in the differentiating neuroblast. The relevance of these results to the elucidation of developmental regulatory mechanisms is discussed.
Using the indirect immunofluorescence technique of Coons and collaborators, neurons containing substance P-, enkephalin-, vasoactive intestinal polypeptide (VIP)--and somatostatin-like immuno-reactivity have been identified in the peripheral nervous system. They have a widespread distribution, particularly in the gastrointestinal and urinary tracts. Whereas part of these peptide containing fibres may belong to sensory neurons, the majority seem to have their origin in peripheral autonomic ganglia, indicating a complex built up of the autonomic nervous system. There is evidence that some noradrenergic neurons contain somatostatin, which may suggest that one neuron can synthesize and store two transmitters. The significance of such neurons, as well as of peripheral peptide neurons in general, remains to be elucidated.
The antiparkinsonian activity of bromocriptine and of lergotrile was investigated in monkeys with surgically induced tremor and in parkinsonian patients. Both drugs effectively relieve tremor in experimental monkeys and induce less pronounced abnormal involuntary movements than L-dopa or piribedil. Both drugs were shown to be of therapeutic value in a group of patients with advanced Parkinson's disease who were no longer responsive to levodopa combined with carbidopa. Adverse effects were similar to those observed with levodopa and carbidopa, except that in individual patients abnormal involuntary movements and diurnal oscillations in performance ("on-off" effect) were decreased, while mental changes were increased. The interactions of bromocriptine and of lergotrile with dopamine and alpha-adrenergic receptors were investigated. Both drugs have mixed agonist-antagonist activities with respect to the dopamine receptors; lergotrile has a higher affinity for the agonist site while bromocriptine has a higher affinity for the antagonist site of the receptors. Both drugs effectively displace the binding of the alpha-adrenergic antagonist WB-4101 to cerebral cortex membranes. The mechanisms underlying the antiparkinsonian efficacies of these two drugs were discussed.
The interactions of ergot alkaloids and of other drugs with dopamine (DA) and alpha-adrenergic receptors were investigated. The tested ergot alkaloids inhibit synaptosomal tyrosine hydroxylase activity and reverse the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity. Thus, ergot alkaloids interact as both agonists and antagonists with the presynaptic DA receptors. Ergot alkaloids also compete effectively for the binding of 3H-DA and 3H-haloperidol to bovine striatal membranes. These results show that these drugs are mixed agonist-antagonists with respect to the postsynaptic DA receptors. To determine the effects of ergot alkaloids and of neuroleptics on the alpha-adrenergic receptors in the CNS, we have measured their effects on the binding of 3H-dihydroergocryptine and 3H-WB-4101 to cerebral cortical membranes. The displacing potencies of the tested ergot alkaloids and of the neuroleptics indicated that they have a high affinity for the alpha-adrenoreceptors in the CNS. The mechanisms underlying the therapeutic efficacy of mixed agonist-antigonists of DA and alpha-adrenergic receptors in Parkinson's disease and in geriatric disorders were considered.
In four patients with Parkinson disease, we compared carbidopa combined with levodopa (Sinemet) and benserazide combined with levodopa (Madopar). All of these patients had responded to treatment, first with levodopa and then with Sinemet; after 6 years two continued to show a good response, while two developed marked "on-off" phenomena. Clinically, Sinemet and Madopar were similar; however, DOPA levels were higher, but with a shorter half-life, on Madopar. The higher DOPA levels may have been offset by the shorter half-life, resulting in no clinical change. DOPA levels were lower and half-life was shorter in patients with on-off phenomena. These differences may be responsible in part for the on-off phenomena.
A 21-year old woman with poorly controlled diabetes mellitus was examined for persistent hyperchloremic metabolic acidosis. There was no evidence of ingestion of hydrochloric acid or its equivalent. Gastrointestinal loss of bicarbonate was absent. Proximal tubular bicarbonate reabsorption and distal nephron hydrogen-ion secretion were normal. Ammonia and net acid excretions were high, and thus there was no obvious cause for this acidosis. Further study revealed a very large loss of beta-hydroxybutyrate in the urine that closely approximated net acid excretion. This loss of potential bicarbonate was the principal cause for the hyperchloremic metabolic acidosis. Phosphate, urate, and beta-hydroxybutyrate fractional excretions were all abnormally high. Generalized aminoaciduria was also present, but the renal handling of glucose and bicarbonate was normal. With improved control of her diabetes, the generalized aminoaciduria disappeared, the urine beta-hydroxybutyrate loss ceased, the fractional excretions of phosphate and urate approached normal, and the acidosis was rapidly corrected.
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Gaucher's disease has been associated with plasma cell dyscrasias. A patient had Gaucher's disease, nephrotic syndrome, and systemic amyloidosis. Plasmacytosis in the bone marrow, the presence of light chains in the urine and renal glomeruli, and the finding of low circulating immunoglobulin levels suggest that the amyloid in this patient is related to a plasma cell dyscrasia.
Lergotrile mesylate, an ergot alkaloid derivative and putative dopamine agonist, was effective in the majority of patients with Parkinson's disease who were showing signs of disease progression despite treatment with levodopa combined with a peripheral decarboxylase inhibitor (carbidopa). Among 20 patients completing a six-month trial, there was a significant (P less than .01) reduction in rigidity, tremor, bradykinesia, gait disturbance, and total score when lergotrile was added to levodopa plus carbidopa. Mean daily dose of lergotrile mesylate was 52 mg, and the mean daily dose of levodopa was reduced by 15%. Abnormal involuntary movements were decreased on addition of lergotrile and reduction in levodopa while mental changes and orthostatic hypotension were increased. Elevations in serum transaminase levels were noted in three patients. The ergot alkaloids promise to be an important new class of antiparkinsonian drugs.
Eleven instances of a mixed acid-base disorder consisting of chronic respiratory acidosis and metabolic alkalosis were recognized in eight patients with chronic obstructive lung disease and carbon dioxide retention. Correction of the metabolic alkalosis led to substantial improvement in blood gas values and clinical symptoms. Patients with mixed chronic respiratory acidosis and metabolic alkalosis constitute a common subgroup of patients with chronic obstructive lung disease and carbon dioxide retention; these patients benefit from correction of the metabolic alkalosis.
Several sympathetic ganglia of the guinea pig, cat and rat were studied with indirect immunofluorescence technique using antibodies to substance P (SP) and dopamine-beta-hydroxylase (DBH), the latter of which represents a marker for noradrenaline containing neurons. In all ganglia studied SP-like immunoreactivity could be observed in certain nerve fibers (SP-positive fibers). Their number, localization fluorescence intensity and 'fluorescence morphology' varied considerably between the different ganglia as well as between species. In the inferior mesenteric ganglion and the coeliac-superior mesenteric ganglion complex of all species, and in particular of the guinea pig, a dense plexus of varicose SP-positive fibers was observed around the mostly DBH-positive, principal ganglion cells. In contrast no such fibers were seen in relation to the DBH-positive SIF cells of the ganglia. No SP-positive ganglion cells were observed in any of the ganglia studied. Previous biochemical and immunohistochemical studies have indicated that peripheral SP-positive fibers may represent the branches of primary sensory neurons. The rich supply of varicose, SP-positive nerve terminals, often surrounding the noradrenergic ganglion cells in a basket-like manner, may indicate that these fibers may play a functional role within the ganglia. Instead of merely passing through the ganglion they may be involved in special types of reflex arches.
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The rat olfactory bulb was studied at the light and electron microscopic level with the indirect immunofluorescence technique and the unlabelled antibody enzyme method (PAP-technique), respectively. Antibodies to all 4 enzymes in the catecholamine synthesis were used. In the principal bulb the first two enzymes, tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC), but not dopamine-beta-hydroxylase (DBH), were present in a proportion of periglomerular cell bodies and dendrites indicating that these neurons synthesize dopamine (DA). This amine may therefore be released as a transmitter substance at some of the intraglomerular dendrodendritic synapses which periglomerular cells form with the mitral cells. There is evidence to suggest that some periglomerular cells use GABA as their transmitter. Thus, a morphologically and physiologically homogenous population of neurons can be subdivided on the basis of transmitter histochemical criteria. There was an impression of more DDC-positive than TH-positive fibers in the glomeruli. Such presumably DDC-positive, but TH-negative processes may represent 5-hydroxytryptamine (5-HT) nerve terminals. DBH-positive fibers were seen in the granular, external plexiform, and very rarely, in the glomerular layers, probably representing noradrenaline (NA) nerve terminals ascending from the lower brain stem. Weakly fluorescent DDC-positive fibers may represent nerve terminals of ascending 5-HT neurons. No phenylethanolamine-N-methyltransferase (PNMT)-positive neurons were observed.