Abstract
BackgroundCalcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. The present study elucidates the differential interaction of CGRP, its receptor and the effect of the CGRP-receptor antagonist telcagepant on intracellular Ca2+ -levels and tension in rat middle cerebral arteries (MCA) by pressurized arteriography, FURA-2/wire myography and immunohistochemistry.MethodsA pressurized arteriograph system was used to evaluate changes in MCA tension when subjected to CGRP and/or telcagepant. Intracellular calcium levels were evaluated using a FURA-2/wire myograph system. Localization of the CGRP-receptor components was verified using immunohistochemistry.ResultsAbluminal but not luminal αCGRP (10-12-10-6 M) caused concentration-dependent vasorelaxation in rat MCA. Luminal telcagepant (10-6 M) failed to inhibit this relaxation, while abluminal telcagepant inhibited the relaxation (10-6 M). Using the FURA-2 method in combination with wire myography we observed that αCGRP reduced intracellular calcium levels and in parallel the vascular tone. Telcagepant (10-6 M) inhibited both vasorelaxation and drop in intracellular calcium levels. Both functional components of the CGRP receptor, CLR (calcitonin receptor-like receptor) and RAMP1 (receptor activity modifying peptide 1) were found in the smooth muscle cells but not in the endothelial cells of the cerebral vasculature.ConclusionsThis study thus demonstrates the relaxant effect of αCGRP on rat MCA. The vasorelaxation is associated with a simultaneous decrease in intracellular calcium levels. Telcagepant reduced relaxation and thwarted the reduction in intracellular calcium levels localized in the vascular smooth muscle cells. In addition, telcagepant may act as a non-competitive antagonist at concentrations greater than 10-8 M.
Highlights
Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date
We have evaluated in more detail the functional effects of high concentrations of the CGRP-receptor antagonist telcagepant (MK-0974) on α-calcitonin gene-related peptide (αCGRP)-induced vasodilatation in isolated middle cerebral arteries (MCA) of rat, using (i) pressurized myography and (ii) FURA-2-AM for measurement of intracellular calcium performed simultaneously with recordings of isometric tension development
The addition of 10-6 M telcagepant significantly offset both the dilatory response and the reduction in intracellular calcium mediated by CGRP
Summary
Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators identified to date. Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide belonging to the calcitonin family of peptides, which includes calcitonin, amylin and adrenomedullin. The peptide, which was first identified in 1982 [1], exists in two forms, αCGRP and βCGRP of which αCGRP is more abundant in the circulation and in the nervous system [2]. CGRP is widely distributed throughout the central, peripheral and enteric nervous systems [3,4,5] and has strong vasodilatory properties, especially in the microvasculature and in cerebral arteries [6,7,8]. Cerebral αCGRP is stored in perivascular sensory C-fibers that originates in the trigeminal ganglion. The vasomotor actions of αCGRP are implied in a variety of both physiological and pathological processes, including migraine and other primary headaches as well as subarachnoidal hemorrhage (SAH) [10, 11]
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