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Doxycycline ameliorates 2K-1C hypertension-induced vascular dysfunction in rats by attenuating oxidative stress and improving nitric oxide bioavailability.

Abstract
Vascular dysfunction associated with two-kidney, one-clip (2K-1C) hypertension may result from both altered matrix metalloproteinase (MMP) activity and higher concentrations of reactive oxygen species (ROS). Doxycycline is considering the most potent MMP inhibitor of tetracyclines and attenuates 2K-1C hypertension-induced high blood pressure and chronic vascular remodeling. Doxycycline might also act as a ROS scavenger and this may contribute to the amelioration of some cardiovascular diseases associated with increased concentrations of ROS. We hypothesized that in addition to its MMP inhibitory effect, doxycycline attenuates oxidative stress and improves nitric oxide (NO) bioavailability in 2K-1C hypertension, thus improving hypertension-induced arterial endothelial dysfunction. Sham operated or 2K-1C hypertensive rats were treated with doxycycline 30 mg/kg/day (or vehicle). After 8 weeks of treatment, aortic rings were isolated to assess endothelium dependent vasorelaxation to A23187. Arterial and systemic levels of ROS were respectively measured using dihydroethidine (DHE) and thiobarbituric acid reactive substances (TBARS). Neutrophils-derived ROS were tested in vitro using the fluoroprobe Carboxy-H(2)DCFDA and human neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA). NO levels were assessed in rat aortic endothelial cells by confocal microscopy. Aortic MMP activity was determined by in situ zymography. Doxycycline attenuated 2K-1C hypertension (169 ± 17.3 versus 209 ± 10.9mm Hg in hypertensive controls, p<0.05) and protected against hypertension-induced reduction in endothelium-dependent vasorelaxation to A23187 (p<0.05). Doxycycline also decreased hypertension-induced oxidative stress (p<0.05), higher MMP activity (p<0.01) and improved NO levels in aortic endothelial cells (p<0.01). Therefore, doxycycline ameliorates 2K-1C hypertension-induced endothelial dysfunction in aortas by inhibiting oxidative stress generation and improving NO bioavailability, in addition to its inhibitory effects on MMP activity.
AuthorsMichele M Castro, Elen Rizzi, Carla S Ceron, Danielle A Guimaraes, Gerson J Rodrigues, Lusiane M Bendhack, Raquel F Gerlach, Jose Eduardo Tanus-Santos
JournalNitric oxide : biology and chemistry / official journal of the Nitric Oxide Society (Nitric Oxide) Vol. 26 Issue 3 Pg. 162-8 (Mar 31 2012) ISSN: 1089-8611 [Electronic] United States
PMID22327038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • Calcium Ionophores
  • Reactive Oxygen Species
  • Nitric Oxide
  • Calcimycin
  • Matrix Metalloproteinase 9
  • Doxycycline
Topics
  • Animals
  • Aorta (drug effects, metabolism)
  • Blood Pressure (drug effects)
  • Calcimycin (pharmacology)
  • Calcium Ionophores (pharmacology)
  • Disease Models, Animal
  • Doxycycline (pharmacology)
  • Hypertension, Renal (drug therapy, metabolism, pathology)
  • Kidney (blood supply)
  • Linear Models
  • Male
  • Matrix Metalloproteinase 9 (metabolism)
  • Neutrophils (metabolism)
  • Nitric Oxide (metabolism)
  • Oxidative Stress (drug effects)
  • Rats
  • Rats, Wistar
  • Reactive Oxygen Species (metabolism)

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