Background: Voltage-gated potassium (K+) channels encoded by KCNQ genes (Kv7 channels) are present functionally in vascular and non-vascular smooth muscle cells (Yeung et al., 2007; Greenwood and Ohya, 2009). However, nothing is known about the functional impact of these channels in vascular disease. The aim of the present study was to compare the effect of structurally different activators of Kv7.2-7.5 channels: S-1, retigabine and BMS-204352, on blood vessels from normotensive and hypertensive animals. Methods and Results: Isometric tension recordings were performed on segments of mesenteric artery and thoracic aorta and the coronary blood flow was studied using the Langendorff heart preparation, in which rats were anaesthetised with i.p. injection of 50 mg/kg sodium pentobarbitone according to the Danish guidelines for animal experiments. Blood vessel segments from normotensive rats were relaxed by all three Kv7 activators with potencies of BMS-204352= S-1 >retigabine. In the Landendorff isolated-heart BMS-204352 and S-1 dose-dependently increased coronary perfusion at concentrations between 0.1-10 µM whereas retigabine was effective at 1-10 µM. The ability of these agents to relax precontracted vessels and increase coronary flow was considerably impaired in tissues isolated from spontaneously hypertensive rats (SHRs). For example, segments of mesenteric artery from normotensive rats were relaxed by S-1 with an EC50 of 2.5 µM but in segments from SHRs S-1 had an EC50 of 47.2 µM. Of the 5 KCNQ gene isoforms the expression of KCNQ4 was reduced (~3.7 fold) in the SHR aorta. Kv7.4 protein levels were ~50 % lower in aortae and mesenteric arteries from SHRs compared to the normotensive vessels. A similar attenuated response to S-1 and decreased Kv7.4 abundance was observed in mesenteric arteries from mice made hypertensive by angiotensin II infusion compared to normotensive controls. Conclusions: In two different models of hypertension the functional impact of Kv7 channels is dramatically down-regulated.