Diminished arteriolar responses in nitrate tolerance involve ROS and angiotensin II

Our purpose was to evaluate hyporesponsivity to nitric oxide (NO)-induced dilation in small arterioles during nitrate tolerance. An Alza osmotic pump was implanted in the left flank of adult rats (n = 56) for continuous administration of nitroglycerin (140 μg/h) or vehicle (propylene glycol). On postoperative day 3, arcade (∼50-μm diameter) and terminal (∼20 μm) arterioles were observed in the cremaster preparation with in vivo video microscopy. Local vascular responses were obtained with micropipette-applied NO donors, with and without superoxide dismutase (SOD), Mn(III) tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP), or losartan. On day 3, NO-mediated dilation was significantly attenuated in nitroglycerin-treated rats. Attenuation was greater in the terminal arterioles compared with the arcades. Control responses were restored by SOD, MnTBAP, or losartan, suggesting a role for elevated angiotensin II and reactive oxygen species (ROS) as mediators of the attenuated NO dilation (nitrate tolerance). Addition of losartan to the drinking water likewise prevented nitrate tolerance. In summary, terminal arterioles are affected by nitrates to a greater extent than the arcade arterioles that feed them, in a process dependent on angiotensin II and ROS.