| Summary: | 碩士 === 國防醫學院 === 藥理學研究所 === 106 === Patients who suffer from infections combined with multiple organ dysfunction will be diagnosed as sepsis. During sepsis, endothelial cells overproduce vasodilators such as nitric oxide (NO), carbon monoxide (CO), hydrogen peroxide (H2O2), prostaglandins (PGs), and hydrogen sulfide (H2S). They cause excessive vasodilation through the overactivation of soluble guanylyl cyclase (sGC), adenylyl cyclase (AC) and potassium channels in the smooth muscle cells, leading to hypotension and vascular hyporesponsiveness to vasopressors in septic shock. In recent years, perivascular adipose tissue (PVAT) has been demonstrated to be a source of releasing various biologically vasodilating substances (e.g. NO, CO, H2O2, PGs and H2S) to exert its anti-contractile effect. In addition, the anti-contractile effects of PVAT are significantly suppressed in patients with obesity or hypertension. However, the influences of PVAT on sepsis-induced vascular dysfunction remain unclear. Therefore, I try to clarify the mechanisms of vascular hyporeactivity caused by PVAT in septic rats. Male Wistar rats were divided into sham-operated (SOP) and cecal ligation and puncture (CLP) groups. The changes of blood pressure, heart rate, pressor responses to norepinephrine (NE), blood glucose and biochemical variables were examined during the experimental period. Rats were euthanatized at the end of experiment, and second branch of mesenteric arteries were mounted in the wire myograph. The concentration-response curve to phenylephrine (PE) in the absence or presence of 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a sGC inhibitor) or Nω-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) were evaluated. In addition, PVAT were collected to analyze the protein expressions of inducible NO synthase (iNOS), endothelial NO synthase (eNOS), heme oxygenase-1 (HO-1), superoxide dismutase 2 (SOD2), cyclooxygenase-2 (COX-2), prostaglandin I2 synthase (PTGIS), prostaglandin D2 synthase (PTGDS), cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). CLP-induced septic rats showed significant decreases in blood pressure, blood glucose and pressor responses to NE, and a significant increase in heart rate. The plasma levels of LDH, CPK, ALT, and BUN were increased, whereas platelet count was decreased in CLP group. The ex vivo results showed the EC50 value of PE was significantly increased in both PVAT-free and PVAT-containing mesenteric arteries isolated from CLP-induced septic rats. Strikingly, the maximal contraction response of PE was significantly attenuated only in PVAT-containing mesenteric arteries isolated from septic rats. In addition, The EC50 value of PE was significantly increased in PVAT-free and PVAT-containing endothelium-denuded mesenteric arteries isolated from septic rats. The increase of EC50 in PVAT-containing mesenteric arteries was higher than that in PVAT-free mesenteric arteries. Moreover, the maximal contraction response and EC50 value of PE were not affected by ODQ in the PVAT-containing mesenteric arteries from SOP group. However, treatment of PVAT-containing mesenteric arteries with ODQ not only decreased the EC50 value but also augmented the maximal contraction response of PE in the CLP animals. Furthermore, the protein levels of iNOS, eNOS, HO-1, SOD2, and COX-2 in PVAT were significantly increased in the CLP group. These data imply that PVAT plays an important role in the attenuation of vasoconstriction in the mesenteric arteries of CLP-induced septic rats. PVAT could activate the sGC/cGMP pathway to diminish PE-induced vasoconstriction in the mesenteric arteries of septic rats through the overexpression of iNOS, eNOS, HO-1, SOD2, and COX-2. However, the detailed mechanisms need to be further explored.
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