Functional Antagonism between Endogenous Neuropeptide Y and Calcitonin Gene-Related Peptide in Mesenteric Resistance Arteries

Abstract

To test the hypothesis that endogenous neuropeptide Y (NPY) counteracts the vasodilator effects of calcitonin gene-related peptide (CGRP), we used isolated mesenteric resistance arteries of rats and mice. With immunohistochemistry, we observed CGRP-containing fibers along and in the vicinity of a subset of NPY-or tyrosine hydroxylase-immunoreactive fibers. The CGRP1 receptor component calcitonin-related-like receptor was expressed by periarterial nerves and smooth muscle cells, whereas receptor activity-modifying protein 1 was observed primarily on the smooth muscle. In organ chambers, exogenous CGRP caused relaxations that were reversed by exogenous NPY. The effects were inhibited by 1-piperidinecarboxamide, N-[2-[[5-amino-1-[[4-(4-pyridinyl) NPY increased contractile responses to K ϩ and BIBP3226 (400 nM) reduced contractile responses to EFS. These effects were inhibited by capsaicin and BIBN4096BS, respectively. Furthermore, the relaxing effect of exogenous CGRP (10 nM) during phenylephrine-induced contraction (30 M) was reversed by EFS, and this effect was reduced in the presence of BIBP3226. We confirmed that bioactive concentrations of endogenous CGRP and NPY can be released from periarterial sensory-motor and sympathetic nerves, respectively, and we demonstrate for the first time functional antagonism between endogenous NPY and CGRP at the level of the smooth muscle.The potent 37-amino acid vasodilator calcitonin-gene related peptide (CGRP) can be released by perivascular sensory-motor nerves (for review, see Brain and Grant, 2004). CGRP contributes to cardiovascular homeostasis in the fetus (Thakor and Giussani, 2005) and to the cardiovascular adaptations to pregnancy (Yallampalli et al., 2002). It lowers blood pressure and reduces end-organ damage in several experimental models (Deng and Li, 2005;Supowit et al., 2005; Márquez-Rodas et al., 2006). In experimental hypertension, changes in the expression and effects of CGRP either contribute to the increase in blood pressure or they play a compensatory role (Wang and Wang, 2004;Deng and Li, 2005;Supowit et al., 2005; Márquez-Rodas et al., 2006). Interventions that increase the efficacy of the vasodilator effects of endogenous CGRP could thus be a welcome addition to antihypertensive therapy. Enzymatic breakdown of CGRP (Fernandez-Patron et al., 2000), the density of CGRP-containing nerve fibers (Kawasaki et al., 1999), and the expression of CGRP receptor components (Zhang et al., 2006) are subjects of ongoing research. We hypothesize that effects of CGRP are modulated by other neuropeptides.During development, afferent sensory-motor nerves and efferent postganglionic sympathetic nerves align with outgrowing arteries (for review, see Carmeliet and TessierLavigne, 2005). This suggests that depending on their sensiThis study was supported by grants from the Transnational University of Limburg and contract T2-108 from TIPharma (Leiden, The Netherlands), an initiative financed by the Dutch government that encourages collaborative pharmacological rese...

Calcitonin Gene-Related Peptide Terminates Long-Lasting Vasopressor Responses to Endothelin 1 In Vivo

“…We previously attributed this to stimulation and subsequent desensitization of peri-arterial SMN-releasing CGRP. 27,28 This response to CAPS differed markedly between different types of artery ( Figure 1B). The response was most marked in mesenteric arteries and intermediate in, for instance, coronary septal and renal arteries, and was not observed in spermatic and basilar arteries.…”

Calcitonin Gene-Related Peptide in Serum After Spontaneous Subarachnoid Hemorrhage

“…One of the most important functional antagonists of NPY is CGRP. Described the functional antagonism of NPY and the vasodilator Calcitonin Gene-Related Peptide (CGRP) in mesenteric resistance arteries (De Mey et al, 2008). This antagonism had also been proposed to be present in the central nervous system and some research groups have evaluated the possible role of CGRP in SAH (Kokkoris et al, 2012;Juul et al, 1990;1995;Schebesch et al, 2013b).…”

Impaired Autonomic Regulation of Resistance Arteries in Mice With Low Vascular Endothelial Growth Factor or Upon Vascular Endothelial Growth Factor Trap Delivery

“…18 To study whether VEGF modulates vasoregulatory responses of SMCs, we induced vasoconstriction by exposing arteries to stimuli that have direct effects on SMCs through distinct signal transduction pathways, ie, high potassium (K ϩ ), angiotensin II, noradrenaline, or the thromboxane A 2 analog U46619. Because the contractile response of an artery depends on the intrinsic SMC properties but also on the thickness of the SMC layer (and because VEGF Ѩ/Ѩ arteries were generally smaller; Table I of the online-only Data Supplement), we not only measured active wall tension (N/m), defined as the force generated by the artery divided by the arterial segment length, but also calculated active wall stress (N/m 2 ), a parameter of intrinsic SMC function, by correcting active wall tension for media thickness.…”