Introduction: Calcitonin gene-related peptide (CGRP)–receptors can relax vascular smooth muscle cells (VSMC) via G-protein as subunits (Gas) and by promoting dissociation of endothelin-1 (ET-1) from ETA-receptors (Meens et al. 2010). The latter "terminator effect" is not mimicked by stimuli of Gas. Thus, we evaluated involvement of G-protein bg subunits (Gbg) using i) myograph studies with isolated rat arteries, ii) radioligand-binding on membranes from CHO cells expressing human CGRP-receptors and iii) cAMP production assays on cultured rat VSMC. In several types of arteries, isoproterenol (ISO), forskolin and CGRP caused relaxation during K+-induced contractions. Relaxing effects of CGRP did not correlate with those of ISO or forskolin. In mesenteric arteries, contracted with K+ or ET-1, IBMX (PDE-inhibitor) increased sodium nitroprusside (SNP)- and ISO- but not CGRP-induced relaxations. While fluorescein (negative control) was without effect, gallein (Gbg-inhibitor) increased receptor binding of [125I]-CGRP in the absence and presence of GTPgS. Gallein also significantly increased CGRP-induced cAMP production by VSMC but did not modify the sensitivity for CGRP. In isolated arteries, gallein and M119 (related Gbg-inhibitor) selectively inhibited the relaxing and anti-endothelinergic effect of CGRP while not altering contractile reponses to K+ or ET-1 or relaxing reponses to ISO or SNP. Activated CGRP-receptors cause cyclic nucleotide-independent relaxation of VSMC and terminate arterial effects of ET-1 via Gbg. Also, Gbg may restrict agonist-binding to CGRP-receptors independently from Ga.