6. The increase of NOS activity in vessels from B1−/− and B2−/− probably is attributed to increase in activity of eNOS or nNOS, since experiments performed in absence of Ca2+ to determine iNOS activity (Ca2+-independent) showed similar results among strains. The advent of potent and selective B1 and B2 receptor antagonists has permitted to assess the role of kinins in several biological Selleckchem PD-166866 systems; however,

receptor antagonists are not devoid of unspecificity. The recent development of genetically engineered mice lacking the kinin B1 and B2 receptor has allowed the opportunity to investigate the physiological role of the kallikrein–kinin system in absence of pharmacological interventions. By analyzing the effect of vasoactive agents in mesenteric arterioles and RG7422 measuring circulating and tissue NO production, we find several evidences that targeted deletion of kinin B1 or B2 receptor impairs endothelium-mediated vasodilation by reducing NO

bioavailability. Firstly, we observed that B2−/− arterioles exhibit increase in basal perfusion pressure in comparison to WT and B1−/−. Although most of the studies have reported that B2−/− are normotensive [1], [2], [3], [11], [12], [26], [35], [37] and [39], these mice appear to exhibit exaggerated responses to hypertensive stimuli [3], [11], [12], [15], [20] and [21]. Thus, even without an essential role in blood pressure regulation, B2 receptor is clearly related to modulation of vascular tonus and control of regional blood flow to the organs. Considering that vasodilation induced by ACh is directly dependent on endothelial NO release [17] and that relaxating effect of SNP is attributed to direct NO delivery on the smooth muscle [8], our results demonstrate a severe impairment in the endothelial NO – dependent vasodilation in mesenteric

arterioles from both B1−/− and B2−/−. This finding is in agreement with previous data showing that the vasodepressor response to injection of ACh was shifted to the right in B2−/−[2]. In the present study, we demonstrated for the first time that impaired vascular response TCL to ACh is also present in the B1−/− mice. Contrasting in part with our results, a preserved response to ACh in B2−/− mesenteric vessels has been previously related by Berthiaume et al. [6]. This discrepant result can be explained by marked differences in the methodology employed for vascular reactive experiments. Indeed, studies in mice mesenteric vessels have been performed under a wide range of flow velocities, pre-contracting agents, Krebs composition and enzymatic blockers or other inhibitors added to the perfusion. In the present study, flow velocity was chosen on the basis of its ability to induce a sustained and sub-maximal vasoconstriction to NE (10 μmol/L), in the absence of other drugs.