Role of Na+-K+ ATPase in Vascular Hyporeactivity Induced by Septic Shock

• Main Authors: Chen, Kuo-Hsiang, 陳國祥
• Other Authors: Wu, Chin-Chen
• Format: Others
• Language: zh-TW
• Published: 2001
• Online Access: http://ndltd.ncl.edu.tw/handle/59575481722693002882

碩士 === 國防醫學院 === 藥理學研究所 === 89 === Na+-K+ ATPase is widely distributed in the body. Its fundamental function is to maintain the concentration of ions moving between cell membrane and the gredient of membrane potential. This results in a higher concentration of K+ and a lower concentration of Na+ in the cytosol. Thus, the permeability of cell membrane to these two ions will affect the cell membrane potential. Activation of Na+-K+ ATPase will hyperpolarize cell membrane and then leads to vascular relaxation. Previous studies have demonstrated that protein kinase A (PKA), protein kinase C (PKC), and protein kinase G (PKG) are the most important mediators to regulate the activity of Na+-K+ ATPase. In addition, lipopolysaccharide (LPS) can regulate the activities of these kinases. Also, it is recongnized that septic shock causes hypotension and vascular hyporeactivity to vasocontrictor agents and that treatment of animals with endotoxin (LPS) is able to mimic the symptoms of septic shock. Thus, in this study, Wistar rats were treated with LPS (10 mg/kg, i.p.) for 6 h to induce septic shock. We aimed to (1) examine the role of Na+-K+ ATPase in the vascular hyporeactivity induced by LPS, (2) investigate whether PKA, PKC, and PKG were involved in the regulation of Na+-K+ ATPase activity in septic shock, and (3) compare the activity of Na+-K+ ATPase between aortas and mesenteric arteries. Results demonstrated that (1) removal of the endothelium reduced the relaxation in both preparations, (2) K+ induced a greater relaxation in the mesenteric arterial rings than in the aortic rings, (3) an augmentation of K+-induced relaxation was seen in vessels from LPS-treated rats, (4) treatment of aortas, but not of mesenteric arteries, with 8-Br-cAMP (0.1 mM) in vitro attenuated the relaxation induced by K+, whereas an inhibitor of adenylate cyclase MDL-12330A (10 mM) had no significant effects on the K+-induced relaxation, (5) treatment of aortas, but not mesenteric arteries, with a PKC activator phorbol-12-myristate-13-acetate (PMA, 1 mM) in vitro attenuated the relaxation induced by K+, whereas an inhibitor of PKC Ro-31-8220 (3 mM) had no significant effects on the K+-induced relaxation, (6) however, treatment of aortas from controls, but not from LPS-rats, with both MDL-12330A and Ro-31-8220 further enhanced the relaxation induced by K+, and (7) treatment of both vessels with sodium nitroprusside (10 nM) or 8-Br-cGMP (0.1 mM) increased the relaxation induced by K+, whereas this enhancement was inhibited by an inhibitor of NO-cGMP pathway ODQ (3 mM). This inhibition was significantly greater in vessels from LPS-treated rats than those from normal controls. In conclusion, our results suggest that (1) Na+-K+ ATPase exists not only in the vascular smooth muscle but also in the vascular endothelium, and it is more in the mesenteric arteries than in the aortas, (2) PKA and PKC inhibit the activity of Na+-K+ ATPase in vessels from LPS-treated rats, and (3) the NO/cGMP/PKG pathway plays a more important role than PKA and PKC do in the activation of Na+-K+ ATPase in vascular hyporeactivity seen in septic shock.