Antagonistic Effect of Human α-Calcitonin Gene–Related Peptide (8–37) on Regional Hemodynamic Actions of Rat Islet Amyloid Polypeptide in Conscious Long-Evans Rats

Gardiner, Sheila M.; Compton, A.M.; Kemp, P.A.; Bennett, T.; Bose, C.; Foulkes, Ronald; Hughes, Bernadette

doi:10.2337/diab.40.8.948

Cited by 38 publications

(19 citation statements)

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“…Gardiner et al (1991) showed that CGRP(8-37) antagonized the hemodynamic effects of amylin infusion in rats. In this study, we have also demonstrated that amylin shares some biological activities with CT in osteoclasts and with CGRP in osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of action of amylin in bone

Tamura

Miyaura

Owan

et al. 1992

Journal Cellular Physiology

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Amylin is a 37 amino acid peptide produced mainly by beta-cells of the endocrine pancreas. Human amylin has 43% homology with human calcitonin gene-related peptide (CGRP) and 13% homology with human calcitonin (CT). Amylin and CGRP have been reported to have CT-like hypocalcemic activity in vivo. To investigate the role of amylin in bone, we examined the mechanisms of action of human amylin, CGRP, and CT in osteoclasts and osteoblasts. Both human amylin and CGRP inhibited 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3]- induced bone resorption in an organ culture system, and the potencies of the two peptides were similarly approximately 60-fold lower than that of human CT. Using a recently developed procedure for preparing large numbers of osteoclast-like multinucleated cells (MNCs) formed in co-cultures of mouse osteoblasts and bone marrow cells in the presence of 1 alpha,25(OH)2D3, we found that both human amylin and CGRP stimulated cAMP production in osteoclast-like MNCs, but only at 60-fold higher concentrations than human CT. Specific binding of [125I]-human CT to osteoclast-like MNCs was detected (dissociation constant, 3 x 10(-8) M; binding sites, 3 x 10(7) per cell). To displace the bound [125I]-human CT from osteoclast-like MNCs, about 170-fold higher concentrations of human amylin and CGRP were required. No specific bindings of [125I]-amylin and [125I]-CGRP to osteoclast-like MNCs could be detected. Human CGRP stimulated cAMP production both in established mouse osteoblast-like cells (KS-4) and in mouse primary osteoblast-like cells. Amylin was a weak agonist for cAMP production in KS-4 cells. The increment in cAMP production induced by CGRP and amylin was abolished by the addition of human CGRP(8-37), a selective antagonist for CGRP receptors. CT did not stimulate cAMP production in KS-4 cells. Amylin, but not CT, displaced the bound [125I]-human CGRP from rat brain membranes. These results indicate that amylin binds not only to CT receptors in osteoclast-like MNCs but also to CGRP receptors in osteoblasts. The relative potencies of these compounds to induce cAMP production was CT greater than amylin not equal to CGRP in osteoclast-like MNCs and CGRP greater amylin much greater than CT in osteoblast-like cells.

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Section: Discussionmentioning

confidence: 99%

Mechanism of action of amylin in bone

Tamura

Miyaura

Owan

et al. 1992

Journal Cellular Physiology

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“…14C) (493). Intracoronary infusion of CGRP in dosages exceeding 10 pmol/min induces a marked increase in coronary blood flow (213, 240-243).…”

Section: Vol 17 Nomentioning

confidence: 99%

Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials

Wimalawansa¹

1996

Endocrine Reviews

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“…For instance, since the IAPP nullmutation is present from conception, genetic redundancy or some other form of adaptation with respect to vasoregulation cannot be ruled out. However, the vascular effects observed following nanomolar doses of IAPP (19,21,33), may also represent pharmacological effects; normally, the levels of endogenous IAPP in the circulation in rodents are in the lower picomolar range (34). It should be noted that the calcitonin peptide family consisting of IAPP, calcitonin, the calcitonin-gene related peptides (CGRPs) and adrenomedullin, with different potencies, seem to activate a group of heterodimeric receptors that include the calcitonin receptor (CTR), or a calcitonin receptor-like receptor (CRLR), combined with different receptor-activity-modifying proteins (RAMPs) (35 -37).…”

Section: Discussionmentioning

confidence: 99%

“…Along this route, at least some of the vascular islet effects observed at high concentrations of IAPP may represent activation of receptors that preferentially bind CGRP or adrenomedullin, both of which are potent vasodilators (cf. 19,33). IAPP has been reported to have mitogenic actions, for example on tubular epithelial cells in the kidney (38).…”

Section: Discussionmentioning

confidence: 99%

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Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice

Carlsson

Karlsson²,

Mulder

et al. 2002

European Journal of Endocrinology

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Objective: Several biological activities have been ascribed to islet amyloid polypeptide (IAPP). However, their physiological relevance remains unclear. Previous studies in rats with exogenous administration of IAPP suggest that the peptide may increase splanchnic vascular resistance and redistribute the blood flow within the pancreas to the islets. In this study, the use of IAPP-deficient mice allowed us to evaluate possible effects of the lack of IAPP on splanchnic blood perfusion and we could thereby circumvent the potentially pharmacological actions of exogenously administered IAPP. Design: Regional splanchnic blood flow was measured after exogenous administration of IAPP and in IAPP-deficient mice. Methods: Blood flow values were determined using a non-radioactive microsphere technique in anesthetized animals. Results: No differences in whole pancreatic blood flow or islet blood flow could be detected in IAPPdeficient mice when compared with control mice; neither did IAPP deficiency affect the glucoseinduced increase in islet blood flow. Duodenal, ileal and colonic blood flows were similar in IAPPdeficient and control mice. Exogenous administration of IAPP selectively increased islet blood flow in wild-type control mice. Conclusions: The present findings in the IAPP-deficient mice suggest that the vascular effects seen in the islets after exogenous administration of IAPP to normal mice reflect pharmacological, rather than physiological effects of the peptide. We conclude that the lack of endogenous IAPP within the splanchnic vascular system does not alter the blood perfusion of pancreatic islets or other splanchnic organs.

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Antagonistic Effect of Human α-Calcitonin Gene–Related Peptide (8–37) on Regional Hemodynamic Actions of Rat Islet Amyloid Polypeptide in Conscious Long-Evans Rats

Cited by 38 publications

References 0 publications

Mechanism of action of amylin in bone

Mechanism of action of amylin in bone

Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials

Unaltered pancreatic islet blood perfusion in islet amyloid polypeptide-deficient mice

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