Background and PurposeRaised 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 ApproachThird‐order mesenteric or intra‐septal arteries from male Wistar rats were assessed in wire myographs for isometric tension, VSM membrane potential and VSM intracellular Ca2+ events.Key ResultsNPY 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 Y1 receptor antagonist BIBO 3304 and Y1 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 Ca2+ waves and whole‐field synchronised Ca2+ flashes in RMA and increased the frequency of Ca2+ 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 Ca2+ channels, as nifedipine abolished NPY‐mediated vasoconstriction.Conclusions and ImplicationsThese data suggest that the Gβγ subunit, which dissociates upon Y1 receptor activation, initiates VSM membrane depolarization and Ca2+ mobilisation to cause vasoconstriction. This model may help explain the development of microvascular vasospasm during raised sympathetic nerve activity.

Background Budesonide MMX is indicated for the induction of remission in mild to moderate Ulcerative Colitis (UC) patients when 5-ASA treatment is not sufficient. Unlike traditional first-generation glucocorticoid steroids such as prednisolone, budesonide MMX has demonstrated a robust safety profile, comparable to placebo in several randomised controlled trials1,2,3. There is however limited real-world evidence to substantiate this safety claim in clinical practice. The aim of this observational analysis is to evaluate the tolerability and ease of administration of budesonide MMX in the real-world setting using prednisolone as a benchmark. Methods Patients receiving treatment for mild to moderate UC were identified in 3 treatment centres between April and October 2019. After providing privacy and data consent, patients completed a detailed nurse-led questionnaire regarding their experiences with prednisolone treatment. Following 6 weeks of therapy with budesonide MMX, patients were sent a follow-up questionnaire. Data from both the initial and subsequent questionnaires were entered by the nurse into a database for assimilation and analysis. Results Twenty-eight patients completed initial and follow-up questionnaires. Of these, 78.6% (n = 22) had experienced ≥1 prednisolone-related side effects. In comparison, following treatment with budesonide MMX, 21.4% (n = 6) reported ≥1 side effects. Instances of these side effects are shown in Figure 1. 46.4% of patients (n = 13) reported the impact of prednisolone-related side effects on daily life as moderate or severe vs. 7.1% (n = 2) following treatment with budesonide MMX. By week 2 of treatment with budesonide MMX, rectal bleeding was resolved in 32.1% of patients (n = 9) and stool frequency in 35.7% (n = 10). 93.1% (n = 27) found the instructions to take budesonide MMX given by the health care professional very easy to understand and of those expressing a preference, 71.1% of patients (n = 19) would take budesonide MMX again if prescribed. Additional data will be presented. Conclusion Data from this ‘real-world’ observational study appear to support the safely profile of budesonide MMX reported in clinical trials. The incidence of patients who experienced > 1 side-effect was nearly 4 times lower for budesonide vs. prednisolone. In addition, budesonide MMX therapy was acceptable to the majority of patients and accompanying instructions easy to understand. Additional data will be presented. References