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.

Matrix Metalloproteinase 2 as a Potential Mediator of Vascular Smooth Muscle Cell Migration and Chronic Vascular Remodeling in Hypertension

“…b , c Photomicrographs of aortas stained for collagen and elastin with Sirius red and Orceine, respectively. The techniques are described in [107] and [15]. Doxy = Doxycycline. …”

The relationship between oxidative stress markers and visual evoked potentials in different hypertension models

“…These results suggest that elevated blood pressure may be related with the "lipid peroxidation mediated" electrophysiological changes in the brain. Thus, whereas previous studies demonstrated that hypertension is associated with well known functional and structural vascular alterations that may result from the interplay of several mechanisms (21), the current study is the first to report in different hypertension models that decreased PON1 activity might be a risk factor for reduced physiological activity of the brain, in particular, in patients with chronic hypertension.…”

“…Increased ROS concentrations play an important role in the vascular dysfunction found both in clinical and experimental hypertension. High levels of superoxide react with NO in the aortic endothelium, thus reducing its bioavailability and leading to endothelial dysfunction and impaired vascular relaxation (21). The mean latencies of all VEPs components in the L-NAME group were found to be longer than those in other hypertensive groups, indicating that NO may play an important role in visual system.…”

Resveratrol affects histone 3 lysine 27 methylation of vessels and blood biomarkers in DOCA salt-induced hypertension

“…Elevated reactive oxygen species-induced oxidative stress had been reported in human and different animal models of hypertension [23][24][25]. Oxidative stress causes the reduction of NO bioavailability due to removing NO by a super oxide radical and decreasing NO synthesis/release from endothelium.…”