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Abstract
Context: Dihydromyricetin (DMY) has oxidation resistance, anti-inflammatory and free radical scavenging capabilities. The preventive effects of DMY for vascular hyporeactivity remain unclear.Objective: This study investigates the preventive effects of DMY in vascular hyporeactivity.Materials and methods: The experimental sepsis was induced by transvenous administration of lipopolysaccharide (LPS) to Sprague–Dawley (SD) rats. DMY-treated rats received daily administration of DMY, 5 μg/kg dissolved in DMSO through the tail vein for 7 days. The invasive mean arterial pressure (MAP) of the caudal ventral artery was measured. Dose-response curves for norepinephrine (NE, doses from 10−9 to 10−6 M) were obtained in isolated thoracic aorta in a cumulative manner. The function of MaxiK and KATP channels were investigated using whole-cell patch clamp recording. The Elisa was adopted to measure the serum concentration of NO, MDA, 3-NT, IL-1β and TNF-α.Results: The increased MAP in septic rats induced by vasopressor agents was smaller than that in control rats. However, the % of increased MAP induced by vasopressor agents was raised by DMY injection (NE: 20.4 ± 8.495 vs. 15.16 ± 5.195%; AVP: 14.05 ± 2.459 vs. 9.583 ± 2.982%, p < 0.05). The vascular hyporesponsiveness to NE (10−6 M) in vitro. was increased by 51% in LPS + DMY group compared with that in LPS + Con group (2.74 ± 0.81 vs. 1.82 ± 0.92 g, p < 0.05). Charybdotoxin (a potent MaxiK channel blocker) and glibenclamide (a KATP channel blocker) pretreatment, instead of 4-aminopyridine (4-AP) and BaCl2, could diminish the DMY-induced improvement of vasoconstrictor hyporeactivity (ChTX: 73.2 ± 11.8 vs. 71.8 ± 13.5%; Glib: 63.1 ± 12.5 vs. 58.1 ± 13.7%, p > 0.05). DMY blunted the highly sensitized MaxiK and KATP channels of arterial smooth muscle cells isolated from the thoracic aorta of LPS rats. DMY decreased the serum level of NO, MDA, IL-1β and TNF-α, which had increased in LPS rats.Discussion and conclusions: Our results indicate that DMY administration ameliorated the impaired contractility of the rat aorta in experimental sepsis. Such an effect is mediated by normalization of the over-excited MaxiK and KATP, channels possibly via oxidative stress inhibition.
Highlights
Sepsis, often presenting with multiple organ dysfunction syndrome and organ failure, is a major problem that causes the most challenging efforts in intensive care today (Johnson and Mayers 2001)
The principal findings of this work were that DMY administration improved vascular hyporesponsiveness in LPS induced sepsis, via attenuating the over-excited MaxiK and KATP channels and free radical scavenging, this is supported by the following observations: (1) DMY administration ameliorated LPS-induced vascular hyporesponsiveness, represented by increased mean arterial pressure (MAP); (2) MaxiK and KATP channels mediated the DMY produced improvement of vasoconstrictor hyporeactivity in experimental sepsis; (3) DMY blunted the highly sensitized MaxiK and KATP
Channels of Aortic smooth muscle cells (ASMCs) isolated from the thoracic aorta of LPS rats; (4) DMY decreased the degree of oxidative stress induced by LPS injection
Summary
Often presenting with multiple organ dysfunction syndrome and organ failure, is a major problem that causes the most challenging efforts in intensive care today (Johnson and Mayers 2001). One of the most important clinical characteristics of sepsis and septic shock is the vascular hyporesponsivity to vasopressor agents (Donaldson and Myers 1996; Strunk et al 2001). It represents an important condition for patient survival. According to Wu et al (2004), antioxidant treatment, before cecal ligation and puncture (CLP) surgery to induce sepsis, increases mice survival and decreases hypotension, plasma NO metabolites, oxidative stress, NOS2 mRNA and angiotensin II (AngII) hyporesponsivity. Ample evidence from experimental animal models and the identification of KATP channel mutations in patients indicate that KATP channel plays a critical role in vascular tone regulation (Shi et al 2012)
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