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PMID:8524787

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Citation

Wang, X, Yue, TL, Barone, FC, White, RF, Clark, RK, Willette, RN, Sulpizio, AC, Aiyar, NV, Ruffolo, RR Jr and Feuerstein, GZ (1995) Discovery of adrenomedullin in rat ischemic cortex and evidence for its role in exacerbating focal brain ischemic damage. Proc. Natl. Acad. Sci. U.S.A. 92:11480-4

Abstract

Focal brain ischemia is the most common event leading to stroke in humans. To understand the molecular mechanisms associated with brain ischemia, we applied the technique of mRNA differential display and isolated a gene that encodes a recently discovered peptide, adrenomedullin (AM), which is a member of the calcitonin gene-related peptide (CGRP) family. Using the rat focal stroke model of middle cerebral artery occlusion (MCAO), we determined that AM mRNA expression was significantly increased in the ischemic cortex up to 17.4-fold at 3 h post-MCAO (P < 0.05) and 21.7-fold at 6 h post-MCAO (P < 0.05) and remained elevated for up to 15 days (9.6-fold increase; P < 0.05). Immunohistochemical studies localized AM to ischemic neuronal processes, and radioligand (125I-labeled CGRP) displacement revealed high-affinity (IC50 = 80.3 nmol) binding of AM to CGRP receptors in brain cortex. The cerebrovascular function of AM was studied using synthetic AM microinjected onto rat pial vessels using a cranial window or applied to canine basilar arteries in vitro. AM, applied abluminally, produced dose-dependent relaxation of preconstricted pial vessels (P < 0.05). Intracerebroventricular (but not systemic) AM administration at a high dose (8 nmol), prior to and after MCAO, increased the degree of focal ischemic injury (P < 0.05). The ischemia-induced expression of both AM mRNA and peptide in ischemic cortical neurons, the demonstration of the direct vasodilating effects of the peptide on cerebral vessels, and the ability of AM to exacerbate ischemic brain damage suggests that AM plays a significant role in focal ischemic brain injury.

Links

PubMed PMC40425

Keywords

Adrenomedullin; Amino Acid Sequence; Animals; Base Sequence; Brain Ischemia/physiopathology; Cerebral Arteries/pathology; Cerebral Cortex/blood supply; Cerebral Cortex/chemistry; Cerebral Cortex/pathology; DNA, Complementary/genetics; Dogs; Drug Administration Routes; Gene Library; Immunohistochemistry; Molecular Sequence Data; Peptides/administration & dosage; Peptides/genetics; Peptides/isolation & purification; RNA, Messenger/isolation & purification; Rats; Rats, Inbred SHR; Time Factors; Up-Regulation; Vasodilator Agents/administration & dosage; Vasodilator Agents/isolation & purification

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:ADML

enables

GO:0005102: signaling receptor binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:ADML

involved_in

GO:0006954: inflammatory response

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

RAT:ADML

GO:0007565: female pregnancy

ECO:0000314:

P

Figure 5 shows the cerebrovascular effects of AM which were assessed in rat pial arteries in situ (A andB) and canine basilar artery segments in vitro (C).

complete
CACAO 3494


See also

References

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