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 microg/h) or vehicle (propylene glycol). On postoperative day 3, arcade (approximately 50-microm diameter) and terminal (approximately 20 microm) 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.
Frame
Mary D
MD
Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA. molly_frame@urmc.rochester.edu
Fox
Randall J
RJ
Kim
Dongsoo
D
Mohan
Amy
A
Berk
Bradford C
BC
Yan
Chen
C
D000804:Angiotensin II / Q000502:physiology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001160:Arterioles / Q000187:drug effects* / Q000502:physiology; D004361:Drug Tolerance; D016166:Free Radical Scavengers / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009566:Nitrates / Q000494:pharmacology*; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000494:pharmacology; D005996:Nitroglycerin / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D016166:Free Radical Scavengers; D008665:Metalloporphyrins; D009566:Nitrates; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D000804:Angiotensin II; D009569:Nitric Oxide; D013482:Superoxide Dismutase; D005996:Nitroglycerin; D019808:Losartan