1. Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2006 年９月７日 8:20-8:50 B 棟８階 カンファレンス室

3. Background A meta-analysis of 90,000 patients included in these previous statin trials showed that the reduction in the risk of stroke was primarily related to the extent to which low-density lipoprotein (LDL) cholesterol levels were lowered. No data exist to show that statin treatment decreases the risk of stroke among patients with a history of stroke or TIA

4. Stroke 2004;35;2902-2909

5. AIM To determine whether a daily dose of 80 mg of atorvastatin would reduce the risk of stroke in patients with no known coronary heart disease who had had a stroke or TIA within the previous six months.

6. Study Subjects LDL cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter) and no more than 190 mg per deciliter (4.9 mmol per liter). men and women over 18 years of age who had had an ischemic or hemorrhagic stroke or a TIA (diagnosed by a neurologist within 30 days after the event) 1 to 6 months before randomization Stroke was defined by focal clinical signs of central nervous system dysfunction of vascular origin that lasted for at least 24 hours; TIA was defined by the loss of cerebral or ocular function for less than 24

9. The primary outcome: the time from randomization to a first nonfatal or fatal stroke. There were seven prespecified secondary composite outcomes: Storke or TIA major coronary event (death from cardiac causes, nonfatal myocardial infarction, resuscitation after cardiac arrest), major cardiovascular event (stroke plus any major coronary event), acute coronary event (major coronary event or unstable angina), any coronary event (acute coronary event plus a coronary revascularization procedure, unstable angina, or angina or ischemia requiring emergency hospitalization), revascularization procedure (coronary, carotid, or peripheral), any cardiovascular event (any of the former plus clinically significant peripheral vascular disease).

14. The cause-specific adjusted hazard ratios in the atorvastatin group, as compared with the placebo group, were 0.78 (95 percent confidence interval, 0.66 to 0.94) for ischemic stroke, 1.66 (95 percent confidence interval, 1.08 to 2.55) for hemorrhagic stroke, and 0.55 (95 percent confidence interval, 0.21 to 1.40) for unclassified stroke.

15. SUMMARY In patients with a recent stroke or TIA, treatment with 80 mg of atorvastatin per day decreased the risk of stroke, major coronary events, and revascularization procedures. CONCLUSION These results support the initiation of atorvastatin treatment soon after a stroke or TIA.

18. Ichikawa K. et al. : Arzneim. -Forsch. / Drug Res. : 52, 605, 2002 × ③ depolarization Ca 2+ K+K+ increased ④ ⑤ ⑤ （ GLUT2 ） glucose Insulin Secretion Voltage dependent Ca channel SUR1 ② ① Glucose Metabolism ［ ATP ］ ［ ADP ］ Increased Intra cellular Ca 2+ K ATP channel Insulin Secretion

19. Binding Sites of SUR1

20. Background How glucose metabolism regulates KATP channel activity remains controversial. Channel activity is readily observed in cell-attached patches on intact -cells, where intracellular concentration of ATP ([ATP]i) is at least 1 mmol/l, when in excised inside-out membrane patches, the channel is almost completely blocked by 1 mmol/l MgATP. 1) a lower ATP concentration in the vicinity of the channel because of the activity of local ATPases 2) the presence of membrane lipids like hosphatidylinositol 4,5-bisphosphate (PIP2) and longchain acyl-CoAs (LC-CoAs) 3) the presence of MgADP We used S. aureus -toxin to permeabilize single -cells in a controlled manner. The pores produced by -toxin are 1.5 nm in diameter and exclude substances with a molecular mass of 3 kDa, enabling permeation of ATP (500 Da) but not proteins.

21. AIM To investigate how metabolism regulates K ATP channel activity, and the channel sensitivity to inhibition by ATP in its native environment

22. FIG. 1. Schematic of cell-attached (A, top panel) and open-cell (B, top panel) patch-clamp configurations. The same single beta-cell before (A, middle panel) and after (B, middle panel) permeabilization with alpha- toxin. The external solution contained the membrane-permeant dye fluorescein diacetate (green fluorescence) and the membrane- impermeant nuclear stain propidium iodide (red fluorescence). Intact cells accumulate fluorescein diacetate but exclude propidium iodide (A). After permeabilization, fluorescein diacetate diffuses out, and propidium iodide enters the cell (B). Photomicrographs (A and B, bottom panels) show the gross structure of the cell remains unchanged after permeabilization.

23. K ATP channel activity (NPo) is expressed as a fraction of that in nucleotide-free solution (NPoc) Lipid kinase inhibitor LY294002 a poorly hydrolyzable ATP analog Single-channel currents recorded at 60 mV 1mM Beta-Cells were isolated from NMRI mice pancreata.

24. Kir6.2/SUR1 channels expressed in HEK cells K ATP conductance (G) is expressed as a fraction of that in nucleotide- free solution (Gc). 3-s voltage ramps from -110 to +100 mV at a holding potential of 0 mV. The lysine residues in the Walker A motifs of NBD1 (K719) and NBD2 (K1384) of SUR1 were mutated to alanine and methionine, respectively: SUR1-KAKM

27. 1 mmol/l phosphocreatine (PCr) 100  mol/l ATP 100  mol/l ATP plus 1 mmol/l phosphocreatine 100  mol/l ATP alone, 100  mol/l ATP plus 15 mmol/l Na, 100  mol/l ATP plus 0.5 mol/l thapsigargin (TGG). a specific inhibitor of the endoplasmic reticulum Ca2+ ATPases Phosphocreatine should enhance ATP inhibition of K ATP channels in mouse - cells by enabling endogenous creatine kinases to minimize MgADP levels by rapid regeneration of MgATP

28. Increase of the ATP sensitivity of the K ATP channel is caused by increased Mg- nucleotide stimulation at the NBDs of SUR1. This shifts the ATP concentration-inhibition curve into a range of intracellular ATP levels over which glucose induced changes in ATP occur. Thus, changes in K ATP channel activity in response to glucose might be mediated by the increase in MgATP, the associated fall in MgADP, or both. CONCLUSION