Gβγ subunit signalling underlies neuropeptide Y-stimulated vasoconstriction in rat mesenteric and coronary arteries.

Background and Purpose: Raised serum concentrations of the sympathetic co-transmitter neuropeptide Y (NPY) are linked to cardiovascular diseases. However, the signalling mechanism for vascular smooth muscle (VSM) constriction to NPY is poorly understood. Therefore, the present study investigated the mechanisms of NPY-induced vasoconstriction in rat small mesenteric (RMA) and coronary (RCA) arteries.
Experimental Approach: Third-order mesenteric or intra-septal arteries from male Wistar rats were assessed in wire myographs for isometric tension, VSM membrane potential and VSM intracellular Ca ²⁺ events.
Key Results: NPY stimulated concentration-dependent vasoconstriction in both RMA and RCA, which was augmented by blocking NO synthase or endothelial denudation in RMA. NPY-mediated vasoconstriction was blocked by the selective Y ₁ receptor antagonist BIBO 3304 and Y ₁ receptor protein expression was detected in both the VSM and endothelial cells in RMA and RCA. The selective Gβγ subunit inhibitor gallein and the PLC inhibitor U-73122 attenuated NPY-induced vasoconstriction. Signalling via the Gβγ-PLC pathway stimulated VSM Ca ²⁺ waves and whole-field synchronised Ca ²⁺ flashes in RMA and increased the frequency of Ca ²⁺ flashes in myogenically active RCA. Furthermore, in RMA, the Gβγ pathway linked NPY to VSM depolarization and generation of action potential-like spikes associated with intense vasoconstriction. This depolarization activated L-type voltage-gated Ca ²⁺ channels, as nifedipine abolished NPY-mediated vasoconstriction.
Conclusions and Implications: These data suggest that the Gβγ subunit, which dissociates upon Y ₁ receptor activation, initiates VSM membrane depolarization and Ca ²⁺ mobilisation to cause vasoconstriction. This model may help explain the development of microvascular vasospasm during raised sympathetic nerve activity.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)