Inhibitory effect of BIBN4096BS, CGRP(8-37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery.

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Abstract

Background and purpose: A new concept for the inhibition of CGRP signalling has been developed by interaction with the CGRP molecule per se by using a CGRP antibody or a CGRP binding RNA-Spiegelmer (NOX-C89). We have compared these CGRP scavengers with two known receptor antagonists (CGRP8-37 and BIBN4096BS) on CGRP-induced relaxations in the rat middle cerebral artery (MCA). Furthermore, the role of the endothelial barrier has been studied. Experimental approach: We used the luminally perfused MCA in an arteriograph, pressurized to 85mm Hg and myograph studies of isolated ring segments of the MCA. Key results: In myograph studies and in the perfusion system during abluminal application, alpha CGRP and beta CGRP induced concentration-dependent dilatation of the MCA. Given luminally neither peptide was significantly vasodilator. Adrenomedullin and amylin induced weak dilatations. In myograph experiments, relaxation induced by a alpha CGRP was prevented by the four CGRP blockers (CGRP8-37, BIBN4096BS, the CGRP antibody and NOX-C89.). In abluminal perfusion experiments, the relaxant response to alpha CGRP was prevented by these agents to a varying degree. Dilatation induced by abluminal application of alpha CGRP was inhibited by luminal CGRP8-37 but not by luminal BIBN4096BS, CGRP antibody or NOX-C89. Conclusions and Implications: alpha or beta CGRP acted on smooth muscle cell CGRP receptors in rat MCA and were effectively prevented from reaching these receptors by the endothelial barrier. The CGRP blockers significantly inhibited alpha CGRP induced relaxation but were also prevented from reaching the CGRP receptors by the arterial endothelium.

Detaljer

Författare
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Farmakologi och toxikologi

Nyckelord

Originalspråkengelska
Sidor (från-till)633-640
TidskriftBritish Journal of Pharmacology
Volym150
Utgivningsnummer5
StatusPublished - 2007
PublikationskategoriForskning
Peer review utfördJa