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Biomedical subjects

J A Fischer

Publications and source records attributed to J A Fischer.

At least 127 records · Page 7Linked to original sources
PubMed1986

Specific receptor and cardiovascular effects of calcitonin gene-related peptide.

Specific binding sites for calcitonin gene-related peptide (CGRP) were demonstrated in the rat heart and spleen. Autoradiography revealed rat [125I]iodo CGRP binding associated with the intima and media of the aorta, the coronary arteries and the heart valves, and the red pulp of the spleen. Half-maximal inhibition of rat [125I]iodo-CGRP binding to membranes of the rat atria and the spleen was obtained with, respectively, 5 and 0.35 nM unlabeled rat CGRP; these values correspond to EC50 values of 3 and 0.14 nM for activation of adenylate cyclase by CGRP. In the isolated, spontaneously beating right atrium, the EC50 values of stimulation of the force and rate of contraction by rat CGRP were 120 and 70 nM, respectively. Rat CGRP caused relaxation of splenic strips, precontracted with noradrenaline; the EC50 was 50 nM. The beta-adrenergic blocking agent metoprolol, while obliterating the increase in the force and rate of contraction evoked by noradrenaline in the right atrium, did not significantly change the action of CGRP. Similarly, preserved action of CGRP in the presence of indomethacin as well as mepyramine and cimetidine argues against a role of prostaglandins or histamine in the functional responses of CGRP. Much like CGRP, capsaicin, which releases mediators from sensory neurons, caused stimulation of the force and rate of contraction of the isolated right rat atrium. After tachyphylaxis to CGRP, the response to noradrenaline was intact, while the positive chronotropic and inotropic effects of capsaicin were suppressed. The results indicate that the cardiac effects of capsaicin may be due to the release of endogenous CGRP through a local mode of action.

Animals↗
PubMed1986

Reduced parathyroid hormone response to peroral phosphate in osteoporotic patients.

To determine whether PTH secretion can be stimulated in osteoporosis by peroral phosphate (1.5 g phosphorus), we have compared serum PTH and urinary cyclic AMP responses in 8 osteoporotic patients with vertebral compression fractures to those of 7 age-matched control subjects. While there was no statistically significant difference in the rise of serum phosphate and urinary phosphate excretion and in the fall of serumionized calcium concentrations, serum PTH and urinary cyclic AMP were increased in control subjects, but not in osteoporotic patients (osteoporotics vs. control group: PTH, p less than 0.01; cyclic AMP/glomerular filtrate, p less than 0.05). Moreover, plasma levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were the same in the 2 groups of subjects. Serum levels of the carboxyl-terminal flanking peptide (PDN-21) encoded by the calcitonin gene and cosecreted with calcitonin were similar in normal and osteoporotic subjects before and 3 min after 1-min intravenous calcium infusions (2 mg/kg body weight), and of calcitonin after the calcium infusions. We conclude that calcitonin and PDN-21 responses to intravenous calcium are the same in normal and osteoporotic subjects, whereas stimulation of PTH secretion by peroral phosphate is impaired in some osteoporotic patients.

Administration, Oral↗
PubMed1985

Distinct binding sites for calcitonin gene-related peptide and salmon calcitonin in rat central nervous system.

Calcitonin gene-related peptide (CGRP) binding sites have been identified in homogenates from the rat brain and spinal cord. Autoradiography with [125I]rat CGRP (rCGRP) revealed high grain density over the lateral hypothalamus, vestibular nuclei, colliculi, medial geniculate body, corpus mamillare and the molecular layer of the cerebellum which lacked binding sites for [125]salmon calcitonin (sCT). In contrast, no rCGRP labeling was seen over the anterior and dorsomedial hypothalamus which showed high sCT binding. The different regional distribution of rCGRP and sCT binding sites indicates that the structurally related peptides interact with separate receptors. The overlap between the localization of CGRP binding sites and endogenous CGRP in many regions of the central nervous system suggests that CGRP exerts unique physiological functions in the central nervous system.

Animals↗
PubMed1985

Structure and transcription of the Drosophila mulleri alcohol dehydrogenase genes.

The D. melanogaster Adh gene is transcribed from two different promoters; a proximal (larval) promoter is active during late embryonic and larval stages, and a distal (adult) promoter is active primarily in third instar larvae and in adult flies (1). Genetic analyses suggest that several species of the mulleri subgroup (distant relatives of D. melanogaster) have two closely-linked Adh genes, Adh-1 and Adh-2, each of which expresses a different ADH protein (2). The temporal pattern of expression of Adh-1 and Adh-2 is similar to the expression of D. melanogaster Adh from the proximal and distal promoters (2,3,4). We are interested in the molecular basis for the pattern of Adh expression in the mulleri subgroup species and in the mechanism of the switch in Adh promoter utilization. For these reasons, we have studied the structure and transcription of the Adh locus of D. mulleri, a species of the mulleri subgroup. We show that the ADH-1 and ADH-2 proteins are expressed from two distinct genes separated by 2 kilobase pairs, and that Adh-1 and Adh-2 are transcribed in the expected temporal pattern. In addition, we find a pseudogene 1.2 kb upstream from Adh-2, which is transcribed in a temporal pattern similar to Adh-2.

Age Factors↗
PubMed1985

Calcitonin and calcitonin gene-related peptide interact with the same receptor in cultured LLC-PK1 kidney cells.

Calcitonin and calcitonin gene-related peptide stimulate adenylate cyclase activity and plasminogen activator production in cultured renal tubular LLC-PK1 cells. Salmon [125I]calcitonin and human [125I]calcitonin gene-related peptide bound specifically to the cells. Salmon [125I]calcitonin binding was reduced at lower concentrations of non-radioactive salmon calcitonin than of human calcitonin gene-related peptide. For the stimulation of adenylate cyclase activity and plasminogen activator production, the potency of salmon calcitonin was higher than that of human calcitonin and calcitonin gene-related peptide. In a subclone of LLC-PK cells lacking salmon calcitonin binding sites, no specific binding of [125I]CGRP occurred, and adenylate cyclase activity and plasminogen activator production was not increased by the peptides. Thus, in LLC-PK1 cells the stimulation of adenylate cyclase activity and plasminogen activator production by calcitonin gene-related peptide is probably mediated by the calcitonin receptor.

Adenylyl Cyclases↗
PubMed1985

Co-existence of substance P and calcitonin gene-related peptide-like immunoreactivities in sensory nerves in relation to cardiovascular and bronchoconstrictor effects of capsaicin.

Immunohistochemical studies showed that substance P (SP) and calcitonin gene-related peptide (CGRP) immunoreactivity co-exist in capsaicin-sensitive primary sensory neurons. Varicose SP- and CGRP-immunoreactive nerve fibres with a similar distribution pattern were seen in the lower airways and heart. The functional analysis revealed that CGRP caused cardiac stimulation and had, together with SP and neurokinin A, potent hypotensive effects. Vascular permeability was increased by SP and neurokinin A, and the bronchial smooth muscle was particularly sensitive to neurokinin A. Thus, multiple peptides stored in an possible released from the same nerve endings by capsaicin may exert differential effects in various target tissues.

Animals↗
PubMed1985

Cardiovascular action of calcitonin gene-related peptide in humans.

Calcitonin gene-related peptide (CGRP) has been localized in cardiac nerve fibers and blood vessels from which it may be released as neurotransmitter or neuromodulator. Acute cardiovascular effects of i.v. administered CGRP have been studied in human subjects. CGRP (25.3 nmol) caused a mean maximal increase of the heart rate of 41 beats per min (P less than 0.01) and lowered arterial systolic and diastolic pressures by 26 mm Hg and 20 mm Hg, respectively (P less than 0.01) (n = 6 subjects). These effects were associated with facial flushing, and a rise of plasma levels of norepinephrine and epinephrine of 257 pg/ml and 9 pg/ml, respectively (P less than 0.01). Administration of equimolar amounts of human calcitonin caused no cardiovascular effects except for minor facial flushing. Serum calcium was marginally lowered with both CGRP (0.2 mg/100 ml) and calcitonin (0.4 mg/100 ml) (P less than 0.05). Furthermore, CGRP (12.7 nmol) reduced the preejection period and duration of the electromechanical systole by 26 msec and 66 msec, respectively (P less than 0.001 and P less than 0.01), presumably acting as positive inotropic agent. Labetalol, blocking adrenergic receptors, obliterated these inotropic effects, whereas the positive chronotropic and hypotensive actions of CGRP remained unchanged.

Adult↗
PubMed1985

Novel peptides from the calcitonin gene: expression, receptors and biological function.

Calcitonin gene products include calcitonin and its carboxyl-terminal flanking peptide (in man PDN-21), and calcitonin gene-related peptide (CGRP). Alternative splicing of the initial gene transcripts results in the production of two distinct messenger RNA encoding precursors of CGRP and of calcitonin. CGRP messenger RNA is the predominant transcription product of the calcitonin gene in neural tissues, but it is also present in the pituitary and the C-cells of normal thyroid glands and in medullary thyroid carcinoma. Immunoreactive CGRP has, moreover, been recognized around blood vessels of the heart. Calcitonin and PDN-21 are cosecreted from thyroid C-cells, but they are also found in the brain and pituitary. CGRP receptors are present in the brain and the heart, and calcitonin receptors in bone and kidney cells and in the hypothalamus. Calcitonin administered peripherally and in vitro inhibits bone resorption and stimulates renal 1.25-dihydroxycholecalciferol production. CGRP used in the same manner has potent cardiovascular effects (vasodilation, hypotension, positive chronotropic and inotropic action in the heart). Intracerebroventricular administration of CGRP raises the blood pressure, and both CGRP and calcitonin inhibit gastric acid secretion and food intake. The distinct but overlapping effects of calcitonin and CGRP raise important regulatory and functional issues.

Amino Acid Sequence↗
PubMed1985

Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary.

Binding sites for synthetic human 125I-labeled calcitonin gene-related peptide (125I-CGRP) have been demonstrated in membranes of the human nervous system. Binding was high in the cerebellar cortex (1.35 +/- 0.27 fmol/mg of tissue; mean +/- SEM), spinal cord (1.06 +/- 0.27 to 1.27 +/- 0.23 fmol/mg), and nucleus dentatus (1.02 +/- 0.15 fmol/mg), intermediate in the inferior colliculus (0.80 +/- 0.14 fmol/mg) and substantia nigra (0.75 +/- 0.14 fmol/mg), low in the neocortex, globus pallidus, nucleus caudatus, hippocampus, amygdala, superior colliculus, thalamus, and hypothalamus (0.15-0.32 fmol/mg), and negligible in spinal and sympathetic ganglia and pituitary (less than 0.04 fmol/mg). Autoradiography showed distinct 125I-CGRP binding over the molecular and Purkinje cell layers of the cerebellar cortex and over the substantia gelatinosa posterior of the spinal cord. The highest levels of CGRP-like components were recognized in the dorsal part of the spinal cord and the pituitary gland. In the ventral part of the spinal cord as well as in the pituitary and thyroid glands, CGRP values were higher when measured by radioreceptorassay as compared to RIA, indicating that at least two CGRP-like components are present. The predominant CGRP-like peak on HPLC had the retention time of synthetic human CGRP. Immunohistochemistry revealed the presence of a dense plexus of CGRP immunoreactive nerve fibers in the dorsal horn of the spinal cord.

Autoradiography↗
PubMed1985

Suppression of parathyroid secretion after administration of WR-2721 in a patient with parathyroid carcinoma.

WR-2721 is an organic thiophosphate, known as a radioprotective agent, which also inhibits parathyroid hormone (PTH) secretion and reduces the plasma calcium level in euparathyroid animals and human subjects. In this study we present evidence that WR-2721 is also able to reduce an abnormal PTH secretion in a case of parathyroid carcinoma. The intravenous infusion of a single dose (750 mg/m2) of WR-2721 was followed within 3 h by a reduction in the plasma concentration of PTH by 60%, and of Ca by about 0.45 mmol/l. These changes were associated with a diminution in urinary cAMP excretion. Based on this observation it appears that WR-2721 merits further investigation as a possible agent for the medical treatment of hyperparathyroidism.

Amifostine↗
PubMed1985

Distribution of intraventricular salmon calcitonin and suppression of gastric secretion.

Intracerebroventricularly (ICV) administered [125I] salmon calcitonin (sCT) was rapidly transported to the blood, but the permeability of the blood-brain barrier to sCT was low. ICV injected intact [125I]sCT was predominantly deposited in the periventricular mesencephalon and in the kidneys, and intravenously (IV) injected [125I]sCT in the kidneys, respectively. After both ICV and IV administration [125I]sCT was not retained by the stomach in large amounts. ICV and subcutaneously (SC) injected sCT caused suppression of gastric secretion volume, and of acid and pepsin outputs; the potency ratios between half maximal inhibitory amounts of sCT administered SC and ICV were 161, 252 and 13, respectively. On the other hand, perfusion of isolated whole mouse stomachs with sCT did not affect basal or stimulated acid and pepsin secretion. These findings indicate that sCT inhibits gastric acid secretion via receptors localized in the hypothalamus and in adjacent areas of the brain.

Animals↗
PubMed1985

Diagnostic evaluation of measurements of carboxyl-terminal flanking peptide (PDN-21) of the human calcitonin gene in human serum.

Calcitonin and its carboxyl-terminal flanking peptide (PDN-21), also encoded by the calcitonin gene, were measured by RIA in unextracted serum of normal subjects and patients with primary hyperparathyroidism and surgically verified and suspected medullary thyroid carcinoma. Serum PDN-21 was detectable (greater than 0.005 ngeq/ml) in the large majority of normal subjects (92%), and the values increased significantly more in men than women (4.8- and 2.0-fold, respectively; P less than 0.01) in response to 1-min iv calcium injections. Calcitonin was detectable (greater than 0.025 ngeq/ml) in only 25% of normal subjects before iv calcium and became measurable after iv calcium in 88% of men and 41% of women. In patients with chronic hypercalcemia due to primary hyperparathyroidism, PDN-21 and calcitonin were within normal limits. In normal subjects, iv pentagastrin (0.5 microgram/kg BW) did not increase PDN-21, and calcitonin remained undetectable. In 41 medullary thyroid carcinoma patients, basal PDN-21 and calcitonin levels were increased similarly, and they were stimulated in response to iv calcium or iv pentagastrin. In 5 siblings of medullary thyroid carcinoma patients, PDN-21 and calcitonin were increased in response to iv pentagastrin, and we suspect C-cell hyperplasia or medullary thyroid carcinoma. In conclusion, a diagnostically useful RIA for the measurement of PDN-21 in unextracted serum which complements calcitonin measurements has been developed.

Adolescent↗
PubMed1984

Immunoreactive calcitonin gene-related peptide and substance P coexist in sensory neurons to the spinal cord and interact in spinal behavioral responses of the rat.

Using immunohistochemistry evidence was obtained for the coexistence of calcitonin gene-related peptide (CGRP)- and substance P (SP)-like immunoreactivity in spinal sensory neurons. Analysis of caudally directed biting and scratching (CBS) behavior was carried out after intrathecal administration of CGRP and SP alone or in combination. Thus, SP (up to 20 micrograms) alone caused CBS only for a few minutes after injection, whereas SP (10 micrograms) plus CGRP (20 micrograms) caused a response with a duration up to 40 min. CGRP (20 micrograms) alone had no effects in this model. These findings provide support for a possible interaction of the two peptides at synapses in the dorsal horn of the spinal cord.

Animals↗
PubMed1984

Parathyroid hormone responses to the dopaminergic agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene.

Plasma parathyroid hormone (PTH) responses to the dopaminergic agonist 2-amino-6,7-(OH)2-1,2,3,4-tetrahydronaphthalene (ADTN) have been studied in cattle. During ADTN infusions PTH increased within min in a dose-dependent manner, while calcium remained unchanged. Prolonged administration of ADTN caused transient PTH responses and crosstachyphylaxis to the subsequent administration of the beta-adrenergic agonist isoproterenol, but not to hypocalcemia, caused by infusions of ethylene-glycol-bis (beta-aminoethylether)-N,N'-tetraacetate. PTH responses were not modified by the beta-adrenergic blocking agent propranolol, infused in amounts earlier shown to suppress PTH responses to isoproterenol and epinephrine. In conclusion, the dopaminergic agonist ADTN caused a direct and transient stimulation of PTH secretion, not mediated by hypocalcemia or by beta-adrenergic receptors on parathyroid cells. However, crosstachyphylaxis to isoproterenol, but not to hypocalcemia, was observed.

Animals↗
PubMed1984

Lack of effects of 1,25- and 24,25-dihydroxy vitamin D on parathyroid hormone response to hypocalcemia in cattle.

Effects of 1,25(OH)2D3 or 24,25(OH)2D3 on plasma PTH were examined following induced hypocalcemia with EGTA. EGTA infusions caused an elevation of plasma PTH within 10 min. Sixty min after the start of EGTA infusions, 1,25(OH)2D3 or 24,25(OH)2D3 were IV administered. Transient (within 5 min) elevations in plasma PTH were observed in two of five animals following the administration of 1,25(OH)2D3 or of 24,25(OH)2D3. Neither secosterol had an effect on the induced elevations in plasma PTH during the remaining 60 min of the EGTA infusions. Twenty-two hr following 24,25(OH)2D3 administration, plasma PTH, ionized and total calcium, inorganic phosphate, and magnesium were normal, while plasma 24,25(OH)2D was elevated. The plasma PTH response to EGTA-induced hypocalcemia was not significantly altered from that observed prior to the administration of 24,25(OH)2D3. Animals, which were IV injected with 1,25(OH)2D3 received the same amount IM 60 min later. Twenty-two h following IM 1,25(OH)2D3, plasma 1,25(OH)2D, ionized and total calcium, and plasma inorganic phosphate were elevated. Plasma PTH and magnesium were lowered. The PTH response to EGTA-induced hypocalcemia was significantly reduced in these animals. A similar reduction in the PTH response to induced hypocalcemia was observed in animals receiving 7 hr IV infusions of calcium chloride. The findings suggest that the blunted response was, in part, the consequence of the preceding hypercalcemia. These results indicate that 1,25(OH)2D3 does not directly regulate plasma PTH secretion and that 24,25(OH)2D3 has no effect on plasma PTH during induced hypocalcemia in the bovine species.

24,25-Dihydroxyvitamin D 3↗
PubMed1984

Calcitonin gene-related peptide in the human thyroid, pituitary and brain.

Alternative splicing of rat calcitonin (CT) gene transcripts resulting in the production of calcitonin gene-related peptide (CGRP) in neural tissue and of CT in the thyroid has been proposed by Rosenfeld et al. (1983b). We have recognized CGRP- and CT-like peptides in extracts of the human brain, pituitary and thyroid using a combination of gel filtration analysis and HPLC, and specific RIAs. Immunoreactive CGRP was estimated in a heterologous RIA using 125I-labelled rat CGRP as ligand and antibodies raised to the rat hormone, and human CT in a homologous RIA. The levels of CGRP and CT are measured against synthetic rat CGRP and monomeric human CT, respectively, and expressed in ng and micrograms equivalents (eq). The content of immunoreactive CGRP of the neocortex (n = 3), the cerebellar cortex (n = 6), the periventricular mesencephalic region (n = 3) and the thyroid (n = 5) was similar (mean +/- SE, 0.79 +/- 0.16 ng eq/g wet tissue, 1.51 +/- 0.14 ng eq/g, 1.84 +/- 0.12 ng eq/g and 5.0 +/- 0.9 ng eq/g, respectively), whereas pituitary glands (n = 21) and medullary thyroid carcinomas (n = 6) contained higher levels (31.3 +/- 5.1 ng eq/g and 7.66 +/- 5.42 micrograms eq/g, respectively). Immunoreactive CT was lowest in the neocortex, cerebellar cortex and the periventricular mesencephalon (0.31 +/- 0.07 ng eq/g, 0.30 +/- 0.09 ng eq/g and 0.26 +/- 0.09 ng eq/g, respectively), followed by the pituitary and thyroid (2.77 +/- 0.62 ng eq/g and 146 +/- 26 ng eq/g, respectively), and was highest in medullary thyroid carcinoma tissue (680 +/- 372 micrograms eq/g).(ABSTRACT TRUNCATED AT 250 WORDS)

Brain Chemistry↗