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I MacIntyre

Publications and source records attributed to I MacIntyre.

At least 73 records · Page 4Linked to original sources
PubMed1987

Biology of peptides from the calcitonin genes.

Despite being products from the same gene, there is clearly a marked divergence in the distribution and physiological role of calcitonin and CGRP. Whereas calcitonin is predominantly distributed in the thyroid, CGRP is abundant in the nervous system throughout the body. Though the peptides have only weak structural homologies, a generally similar conformation enables them to interact at each other's receptors. Hence the pharmacological effects of the peptides faintly resemble one another. Calcitonin receptors are mainly found on osteoclasts and at certain sites in the nervous system. CGRP binding sites are abundant in the cerebellum and blood vessels. Calcitonin is a circulating hormone controlling osteoclastic activity. CGRP acts as a neurotransmitter or neuromodulator centrally, and released from perivascular nerve terminals, it modulates arteriolar tone. Released from motoneurones, CGRP may also play a trophic role regulating the muscle acetylcholine receptor state. The next decade should establish the physiological role of CGRP and the regulation of the expression of the calcitonin/CGRP gene complex.

Animals↗
PubMed1987

Regional distribution of calcitonin gene-related peptide and its specific binding sites in rats with particular reference to the nervous system.

The concentration of calcitonin gene-related peptide (CGRP) in rat tissue extracts was determined by a specific and sensitive radio-immunoassay, and the distribution of its specific binding sites was assessed by radioligand binding studies. A high concentration of immunoreactive CGRP was found at all levels of the spinal cord, in the trigeminal nucleus, in trigeminal and dorsal root ganglia, in the thyroid gland, in blood vessels and in nerves. The highest density of specific binding sites was detected in the cerebellum, where the CGRP content was minimal. The dorsal portion of the spinal cord contained a high concentration of CGRP and its specific binding sites. Specific binding of 125I-CGRP was also demonstrated in a number of other areas of the brain and in certain peripheral tissues. Among the other tissues examined, the spleen, adrenal gland, penis, lungs, bladder, heart and blood vessels all contained a large number of CGRP binding sites, whereas only a negligible number of sites were found in ganglia, nerves, muscle, kidney and liver. The distribution of CGRP and its specific binding sites demonstrated here suggests that CGRP is a neuropeptide with multiple physiological roles.

Animals↗
PubMed1987

Regional and total skeletal measurements in the early postmenopause.

In a cross-sectional study of 70 early postmenopausal women, regional bone measurements were compared with total body calcium (TBCa). Spinal and forearm trabecular bone were mainly related to age and time since menopause. In contrast, TBCa and forearm integral (cortical and trabecular) and cortical bone were unrelated to age, although the time since menopause also had some influence. Forearm integral and cortical bone measurements were quite well correlated with TBCa (r = 0.84 and 0.73, respectively, P less than 0.001). The correlation between spinal bone measurements and any of the forearm measurements, even purely trabecular bone, was weak (r less than 0.52, P less than 0.001). Our results show quite clearly that forearm bone measurements cannot be used to predict bone density in the vertebrae. Loss of ovarian function affects bone in general, and trabecular bone in particular. Bone measurements at specific anatomical sites are clearly necessary for studies of metabolic bone diseases and their response to treatment.

Adult↗
PubMed1987

A direct action of human calcitonin gene-related peptide on isolated osteoclasts.

The calcitonin gene encodes a small family of peptides: calcitonin, calcitonin gene-related peptide (CGRP) and katacalcin. Whereas calcitonin is concerned with skeletal maintenance, the function, if any, of katacalcin is still unknown. In the present study we have assessed resorption of human cortical bone substrate by isolated rat osteoclasts and have shown that CGRP acts directly on the osteoclast to inhibit bone resorption. The three CGRP peptides (rat, human(alpha) and human(beta) caused an almost equivalent decrease in osteoclastic bone resorption and were approximately 1000-fold less potent than human calcitonin in this respect. The responses of human calcitonin and human CGRP(alpha) were additive. Furthermore, prior treatment with trypsin to destroy receptors abolished the responsiveness of osteoclasts to CGRP and calcitonin. The carboxyl- and amino-terminal fragments of CGRP were found not to inhibit bone resorption, suggesting that the whole molecule of CGRP is necessary for biological activity. We have therefore suggested that the calcitonin-like effects of CGRP, seen both in vivo in the rat bioassay and in vitro in organ cultures, are due to the direct action of CGRP on the osteoclast, probably mediated through the calcitonin receptor. Though it is unlikely that CGRP is involved in the regulation of plasma calcium, the peptide may be an important local regulator of bone cell function.

Animals↗
PubMed1987

Calcitonin and the peptides from the calcitonin gene.

The alpha-calcitonin gene encodes a small family of peptides: calcitonin, katacalcin, and calcitonin gene-related peptide (CGRP). Calcitonin and katacalcin are produced from one precursor and CGRP from another. Calcitonin and katacalcin come mainly from the thyroid, while CGRP is present in both the thyroid and the central nervous system. Calcitonin is concerned with skeletal integrity, while the function of katacalcin, if any, is unknown. The secretion of calcitonin is, in part, estrogen dependent, and it appears likely that a postmenopausal decline in calcitonin secretion is a factor in the development of postmenopausal osteoporosis. It is possible that calcitonin may prove useful in the prevention and perhaps the treatment of this condition. CGRP, conversely, is one of the most potent vasodilators known and probably plays an important physiologic role in the control of vessel tone and blood flow. CGRP may also have a role as neurotransmitter or neuromodulator.

Amino Acid Sequence↗
PubMed1986

Distribution and origins of substance P (SP)-, calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-containing nerve fibers in the pineal gland of gerbils.

In the pineal gland of gerbils, substance P (SP)-, calcitonin gene-related peptide (CGRP)-, vasoactive intestinal polypeptide (VIP)- and neuropeptide Y (NPY)-containing nerve fibers were demonstrated immunohistochemically. After intrapineal injection of biotin-wheat germ agglutinin, origins of fibers were examined by the combined technique of tracing method and immunohistochemistry. It was confirmed that SP- and CGRP-fibers originated from the trigeminal ganglion, VIP-fibers from the pterygopalatine ganglion and NPY-fibers from the superior cervical ganglion.

Animals↗
PubMed1986

The calcitonin-like sequence of the beta CGRP gene.

We have identified a region within the beta CGRP gene which has the potential to encode a novel calcitonin-like peptide. The gene is located on the short arm of chromosome 11 (11p 12-14.2) and we suggest that it resulted from a local duplication of the alpha gene. We have been unable to detect the corresponding mRNA in a variety of tissues which express alpha-calcitonin. It is not clear whether this sequence can be expressed in man.

Base Sequence↗
PubMed1986

Ultrastructural observation of nerve fibers containing both substance P and calcitonin gene-related peptide in the nucleus tractus solitarii of the rat: a combination of immunofluorescence and PAP methods.

Nerve fibers and their axon terminals with substance P (SP)-like and calcitonin gene-related peptide (CGRP)-like immunoreactivity in the nucleus tractus solitarii were ultrastructurally characterized by a combination of immunofluorescent double staining and the PAP method. The axon terminals formed asymmetrical synaptic contacts with other non-reactive neuronal elements (perikarya, dendritic shafts and dendritic spines). Some terminals received synaptic inputs from non-reactive axon terminals. This suggests that some, if not all, afferents containing SP and CGRP are affected presynaptically by other afferents.

Animals↗
PubMed1986

Autoradiographic localization of calcitonin gene-related peptide binding sites in human and rat brains.

125I-calcitonin gene-related peptide (CGRP) binding sites were mapped in the human brain and rat brains by in vitro macroautoradiography, and compared to each other. Binding experiments were made to characterize 125I-CGRP binding on the human and rat brains. Scatchard analysis of saturation experiments from slide-mounted sections of the human and rat cerebellum displayed 125I-CGRP binding sites with a dissociation constant (Kd) of 0.17 nM and 0.11 nM, respectively, and a maximal number of binding sites (Bmax) of 96.8 fmol/mg and 23.0 fmol/mg protein. 125I-CGRP binding was time-dependent, reversible and saturable with high affinity in the brains. Autoradiograms showed a discrete distribution of 125I-CGRP binding sites throughout the brains of human and rat with patterns similar to each other. In the human brain, the highest binding was seen in the cerebellum, inferior olivary nuclear complex, certain parts of the central gray matter, arcuate nuclei of the medulla oblongata and dorsal motor nucleus of the vagus, and densities of CGRP-binding sites were high in the nucleus accumbens, amygdala, tail of the nucleus caudatus, substantia nigra, ventral tegmental area, medial portion of the inferior colliculus, medial pontine nuclei, locus coeruleus, inferior vestibular nucleus, substantia gelatinosa of the spinal trigeminal nucleus, nucleus of the solitary tract and nucleus cuneatus lateralis. In the rat, high densities were found in the hippocampus pars anterior, nucleus accumbens, ventral and caudal portions of the nucleus caudatus-putamen, central and basolateral nuclei of the amygdala, caudal portion of the insular cortex, medial geniculate body, superior and inferior colliculi, certain portions of the central gray matter, locus coeruleus, inferior olivary nuclei, vagal complex, nucleus cuneatus lateralis and cerebellum. In contrast, in both species, most of the cortical areas including the hippocampus, most of the thalamus, and hypothalamus exhibited few binding sites. In addition, high quantities of the binding sites were seen on the pia mater and on walls of blood vessels in the brain and subarachnoidea. These results revealed essentially homologous locations of CGRP binding sites in the human and rat central nervous systems and well corresponding distributions of binding sites and endogenous CGRP-like immunoreactivity.

Aged↗
PubMed1986

A second form of human calcitonin gene-related peptide which is a potent vasodilator.

A recently predicted form of human calcitonin gene-related peptide, (beta CGRP) exhibits potent vasodilator activity in rabbit skin with a similar potency to the form of human CGRP originally described (alpha CGRP). Both peptides, because of their vasodilator activity, cause a potentiation of inflammatory oedema induced by mediators of increased vascular permeability. The results demonstrate that changes can be made at certain positions in the amino acid sequence of human CGRP without loss of vasodilator activity.

Amino Acid Sequence↗
PubMed1986

Two distinct calcitonin gene-related peptide-containing peripheral nervous systems: distribution and quantitative differences between the iris and cerebral artery with special reference to substance P.

The present study first shows that calcitonin gene-related peptide(CGRP)-like immunoreactive (CGRPI) nerve fibers in the cerebral arteries contained substance P (SP) and originated from small- to medium-sized CGRPI cells exhibiting SP immunoreactivity (SPI) in the trigeminal ganglion. The iris contained CGRPI/SPI-costorage nerve fibers and many CGRPI fibers lacking SPI. These fibers originated from large CGRPI cells lacking SPI in the trigeminal ganglion. The heterogenous subpopulations of CGRPI fibers in the iris suggest that CGRP is involved in a variety of functions in this structure.

Animals↗
PubMed1986

Origins and distribution of calcitonin gene-related peptide-containing nerves in the wall of the cerebral arteries of the guinea pig with special reference to the coexistence with substance P.

The origins and overall distribution of calcitonin gene-related peptide-like immunoreactivity (CGRPI) in the wall of the cerebral arteries were investigated in the guinea pig by using whole-mounts. Two types of CGRPI fibers were seen; one forming dense fiber bands, located among the periadventitial nerves, and the other forming a meshwork. CGRPI fibers in the periadventitial nerves often leave these nerves to form a meshwork, of a density that varies according to the diameter or location of the blood vessel. The present study showed that CGRPI fibers in the walls of the carotid arterial system originated from the trigeminal ganglion, and those in the vertebrobasilar arterial system from other origins besides the trigeminal ganglion. We also examined the coexistence of this peptide with substance P-like immunoreactive (SPI) structures in a single neuron system. Double staining immunocytochemistry showed that the patterns of the running of CGRPI and SPI fibers in the wall of the cerebral arteries were similar, and this method also demonstrated the presence of neurons containing both CGRPI and SPI structures in single cells of the trigeminal ganglion, which is the major origin of these fibers in the cerebral arteries.

Animals↗
PubMed1986

Investigation of the structure/activity relationship of human calcitonin gene-related peptide (CGRP).

The biological activities of calcitonin gene-related peptide (CGRP) enzymic digest fragments, chemically modified products and beta-CGRP have been compared to that of intact alpha-CGRP on rat isolated paired atria. Tryptic and chymotryptic digests both produced inactive fragments. Acetylation of the N-terminal amino acid (Alanine) or either of Lys 24 or Lys 35, resulted in reduced, but measurable, biological activity. Destruction of the disulphide bridge between Cys 2 and Cys 7 abolished biological activity. Substitution of several amino acids, Asp 3, Val 22 and Asn 25, with Asn, Met and Ser respectively (beta-CGRP), produced a peptide with similar biological activity to alpha-CGRP.

Amino Acids↗
PubMed1986

Distribution of calcitonin gene-related peptide-containing fibers in the urinary bladder of the rat and their origin.

By use of indirect immunofluorescence, this study demonstrated the presence of calcitonin gene-related peptide-like immunoreactive (CGRPI) fibers in the bladder of the rat. These fibers were abundant in the muscle layer, in which they ran parallel to the muscles, submucosa, and epithelium. No immunoreactive cells were detected. We also examined the origins of these fibers, using a method that combined biotinized retrograde tracer (biotin-wheat germ agglutinin) (B-WGA) and immunocytochemistry. Injection of the tracer into the bladder resulted in the demonstration of small to medium-sized labeled cells that contain CGRPI structures in single dorsal root ganglion cells mostly at the level of L6 and S1, but also a few at L2. Double-staining for CGRPI and immunoreactive P-like substance (SPI) indicated that there are cells in the dorsal root ganglia at the level of L6 and S1 that react to both, but that there are many CGRPI-positive cells that contain no demonstrable SPI; most of the latter are large.

Animals↗
PubMed1986

The presence of a calcitonin gene-related peptide in the olivocochlear bundle in rat.

The origins of calcitonin gene-related peptide immunoreactive (CGRPI) fibers in the cochlea were examined in rats. Parasagittal transection of the brain just medial to the principal sensory trigeminal nucleus resulted in the ipsilateral disappearance of CGRPI fibers in the cochlea, indicating that the origins of these fibers lie in the central nervous system. Next, we used a highly sensitive method combining retrograde tracing and immunohistochemistry to identify the origins of the CGRPI fibers in the cochlea. After injection of biotin-wheat germ agglutinin (b-WGA) into the cochlea, CGRPI neurons in the ipsilateral lateral superior olivary nucleus also contained b-WGA granules. These findings indicated that CGRPI efferent fibers are major components of the olivocochlear bundle.

Animals↗
PubMed1986

Ontogeny of calcitonin gene-related peptide and calcitonin in the rat thyroid.

In this immunohistochemical study, the ontogenic development of calcitonin-gene-related peptide (CGRP) in the rat thyroid was investigated and compared with that of calcitonin using the indirect-immunofluorescence method. Parafollicular cells with immunoreactivity to both CGRP and calcitonin first appeared at an early stage of gestation (days 17 and 18) in the central portion of the thyroid. Cells immunoreactive to CGRP and calcitonin had became numerous by gestational day 22. After postnatal day 7, CGRP- and calcitonin-immunoreactive (C-IR) cells increased rapidly both in number and in the intensity of their fluorescence. In 14- to 90-day old rats, many intensely immunoreactive cells were distributed in the central portion of the thyroid. The cells immunoreactive to CGRP and to calcitonin had an almost identical ontogenic appearance. In 14-day-old and adult rats, C-IR cells also exhibited CGRP immunostaining, suggesting that these cells simultaneously produce and store CGRP during ontogeny.

Aging↗
PubMed1986

Human calcitonin gene related peptide: a potent endogenous vasodilator in man.

In addition to calcitonin and katacalcin, it is now known that the human calcitonin gene encodes a novel peptide called calcitonin gene related peptide (CGRP). In experimental animals, CGRP produces vasodilatation and complex changes in plasma calcium. We have now assessed its biological activity in man by infusing human CGRP (hCGRP) into six normal volunteers. hCGRP (545 pmol/min) caused the diastolic pressure to fall from 64 +/- 5 to 55 +/- 7 mmHg (P less than 0.05), the heart rate to increase from 61 +/- 7 to 87 +/- 5 beats/min (P less than 0.05) and the skin temperature to increase from 33.7 +/- 0.9 to 34.9 +/- 0.5 degrees C. Plasma noradrenaline increased from 481 +/- 126 to 835 +/- 65 pg/ml (P less than 0.05) and plasma adrenaline from 57 +/- 17 to 82 +/- 12 pg/ml (P less than 0.05). There were no significant changes in the albumin-corrected plasma calcium. hCGRP is thus a potent endogenous vasodilator in man and is in fact more potent than any other known vasodilator. Together with the observations that CGRP circulates in normal subjects at relatively high concentration (approximately 25 pmol/l) and that CGRP is present in perivascular nerves, this study suggests a possible role for CGRP in controlling peripheral vascular tone in man.

Adult↗