K+ channels encoded by KCNQ genes are important determinants of neuronal excitability and influence the cardiac action potential. We now present data that implicate KCNQ channels, especially the neuronal specific KCNQ4 isoform, as crucial modulators of mouse aortic reactivity. Quantitative PCR with primers specific for KCNQ1-5 including the truncated form of KCNQ1 revealed that mouse aorta expressed KCNQ1, 4 and 5 with KCNQ4 the most abundant. PCR using RNA from 100 single myocytes confirmed that the smooth muscle cells expressed KCNQ4. Isometric tension studies with segments of thoracic and abdominal aorta showed that the specific KCNQ channel blockers XE991 and linopirdine (0.1--10 mM) produced robust contractions that were sensitive to nifedipine (n=9) and the KATP channel opener pinacidil (1 mM, n=7). Contractions evoked by these agents were not sensitive to the alpha-adrenoceptor blocker prazosin (1 mM, n=7). Interestingly, the anti-convulsant retigabine (20 mM) relaxed fully aortic segments pre-contracted with 1–2 mM 4-aminopyridine (n=6) and inhibited contractions produced by 10 mM phenylepherine by ~50% (n=4). These data suggest that KCNQ channels influence the resting membrane potential of mouse aortic myocytes.