Introduction:

Endothelin-1 (ET-1) causes long-lasting contractile effects. In rat mesenteric resistance arteries (MRA), most vasodilators and ET_A-antagonists transiently reduce contractile ET-1 effects, but calcitonin gene-related peptide (CGRP) terminates these effects by dissociation of ET-1/ET_A-receptor complexes (Hypertension, 2009; 54: 1186). The intracellular mechanism of this selective effect is unknown. We show that CGRP- induced effects in rat MRA are mediated by G-protein subunits (G) and that these effects are independent of i) adenylate cyclase (AC), ii) G- protein receptor kinase 2 (GRK2) and iii) phosphoinositide 3-kinase (PI3K).

Methods:

Intact 2^nd order rat MRA were investigated using wire-myography.

Results:

Isoproterenol (ISO; 0.01 – 10 M) and sodium nitroprusside (SNP; 0.01 – 10 M) caused relaxations during K⁺-induced contractions which were unaffected by inhibition of i) GRK2 (GRK2- inhibitor; 100 M), ii) G (gallein; 1–100 M) or iii) PI3K (wortmannin (WT); 0.1 M). During K⁺- or ET-1-induced contractions, neither GRK2- inhibition nor WT inhibited CGRP-induced dilatations (0.1–100 nM). But, independent of the contractile stimulus, gallein concentration-dependently inhibited relaxing responses to CGRP. Furthermore, gallein prevented the inhibitory effect of CGRP on persistent ET-1-induced contractions. IBMX (20 M) increased the sensitivity to SNP- and ISO-induced relaxation but did not modify the sensitivity to CGRP during contractions induced by K⁺ (40 mM) or ET-1 (32 nM).

Conclusion:

In contrast to previously reported vasodilator mechanisms induced by CGRP in other vascular beds, CGRP-induced relaxing and anti-ET-1 effects are AC independent in our setting. CGRP-induced effects are mediated by G but do not involve activation of PI3K or GKR2, two of the downstream targets of G.