Chronic Intermittent Hypoxia-Induced Vascular Dysfunction in Rats is Reverted by N-Acetylcysteine Supplementation and Arginase Inhibition

Abstract

Chronic intermittent hypoxia (CIH), the main attribute of obstructive sleep apnea (OSA), produces oxidative stress, endothelial dysfunction, and hypertension. Nitric oxide (NO) plays a critical role in controlling the vasomotor tone. The NO level depends on the L-arginine level, which can be reduced by arginase enzymatic activity, and its reaction with the superoxide radical to produce peroxynitrite. Accordingly, we hypothesized whether a combination of an arginase inhibitor and an antioxidant may restore the endothelial function and reduced arterial blood pressure (BP) in CIH-induced hypertensive rats. Male Sprague-Dawley rats 200 g were exposed either to CIH (5% O2, 12 times/h 8 h/day) or sham condition for 35 days. BP was continuously measured by radio-telemetry in conscious animals. After 14 days, rats were treated with 2(S)-amino-6-boronohexanoic acid (ABH 400 μg/kg day, osmotic pump), N-acetylcysteine (NAC 100 mg/kg day, drinking water), or the combination of both drugs until day 35. At the end of the experiments, external carotid and femoral arteries were isolated to determine vasoactive contractile responses induced by KCL and acetylcholine (ACh) with wire-myography. CIH-induced hypertension (~8 mmHg) was reverted by ABH, NAC, and ABH/NAC administration. Carotid arteries from CIH-treated rats showed higher contraction induced by KCl (3.4 ± 0.4 vs. 2.4 ± 0.2 N/m2) and diminished vasorelaxation elicits by ACh compared to sham rats (12.8 ± 1.5 vs. 30.5 ± 4.6%). ABH reverted the increased contraction (2.5 ± 0.2 N/m2) and the reduced vasorelaxation induced by ACh in carotid arteries from CIH-rats (38.1 ± 4.9%). However, NAC failed to revert the enhanced vasocontraction (3.9 ± 0.6 N/m2) induced by KCl and the diminished ACh-induced vasorelaxation in carotid arteries (10.7 ± 0.8%). Femoral arteries from CIH rats showed an increased contractile response, an effect partially reverted by ABH, but completely reverted by NAC and ABH/NAC. The impaired endothelial-dependent relaxation in femoral arteries from CIH rats was reverted by ABH and ABH/NAC. In addition, ABH/NAC at high doses had no effect on liver and kidney gross morphology and biochemical parameters. Thus, although ABH, and NAC alone and the combination of ABH/NAC were able to normalize the elevated BP, only the combined treatment of ABH/NAC normalized the vascular reactivity and the systemic oxidative stress in CIH-treated rats.

N-acetyl Cysteine Can Blunt Metabolic and Cardiovascular Effects via Down-regulation of Cardiotrophin-1 in Rat Model of Fructose-induced Metabolic Syndrome

“…Furthermore, NAC has been proven to restrain renin expression in the renal tissue [45]. Finally, according to Krause et al [46], NAC by its antioxidant activity and glutathione supply could improve hypertension in cases of increased OS associated with elevated blood pressure.…”

Stim‐activated TRPC‐ORAI channels in pulmonary hypertension induced by chronic intermittent hypoxia

“… 12 – 14 We have previously demonstrated that the CIH pattern used in this study produces systemic oxidative stress 31 and endothelial dysfunction. 32 , 33 High levels of ROS raise [Ca 2+ i], in PASMC, which is the key factor in differentiation and proliferation of vascular smooth muscle. 42 , 43 In PASMC, [Ca2+i] may increase by the activation of two mechanisms: (1) release of Ca2+ from the sarcoplasmic reticulum, mediated by intracellular channels sensitive to inositol trisphosphate (IP3) or by ryanodine receptors (RyR), or (2) by the entry of Ca2+ from the extracellular space mediated by the Na+/Ca2 exchanger, Ca2+ type L channels, and stretch-activated Ca2+ channels.…”

“…Unrestrained, freely moving rats were housed in individual chambers and exposed to hypoxic cycles of 5% inspired O 2 for 20 s, followed by 280 s of room air, 12 times per hour for 8 h a day for 14, 21, and 28 days. 31 – 33 Rats were exposed to CIH from 8:00 a.m. to 4:00 p.m. The O 2 level inside the chambers was continuously monitored with an oxygen analyzer (Ohmeda 5120, BOC Healthcare, Manchester, UK).…”

“…Small arteries (2nd generation 300–400 µm) were dissected from the right lobules and mounted on a wire myograph (model 610 A; Danish Myo Technology A/S, Denmark). 32 , 33 The arteries were maintained at 37°C and equilibrated with 95% O 2 –5% CO 2 in Krebs buffer at pH 7.4. The internal diameter of vessels was defined by determining the stretch condition at which the maximal contractile response to KCl was obtained.…”

Mitochondrial separation protein inhibitor inhibits cell apoptosis in rat lungs during�intermittent hypoxia

“…A computerized system controlled the valve inlets and the alternating cycles of the extractors. The CO 2 in the chamber was maintained at a low level by continuous air extraction (14). Rats in the control group were maintained under normoxic conditions during the experiment.…”