Therapeutic Research

2009年11月14 −18日，米国オーランドにて第82回米国心臓協会学術集会（AHA2009）が行われた。臨床医の関心が集まる最大規模のセッションLate-Breaking Clinical Trialsは抗血小板療法をテーマに始まったが，偶然にも本テーマのすべてが抗血小板薬P2Y12 拮抗薬とその薬効評価法に関する話題で占められた。今後選択肢が増えていくと予想される抗血小板療法において，臨床家が押さえておくべき薬剤の特性とは何なのか。また，血小板機能の活性度合いから薬効を評価し予後を予測するというストラテジーは，はたして妥当なのか。ここでは第31回欧州心臓病学会（ESC2009）に引き続き東海大学の後藤信哉氏に，「血小板機能検査の何たるか」，「大規模臨床試験だけでは読みとることのできない各種P2Y12拮抗薬の特性」についてわかりやすく解説してもらった。

Nicorandil, an adenosine triphosphate−sensitive potassium channel opener, induces vasodilation, blood pressure decrease and cardioprotection. However, the intracellular mechanism of nicorandil remains to be delineated. The aims of this study were to test the hypothesis that nicorandil may alter strain−induced endothelin−1（ET−1）secretion and nitric oxide（NO）production, and to identify the putative underlying signaling pathways in human umbilical vein endothelial cells（HUVECs）. Cultured HUVECs were exposed to cyclic strain in the presence of nicorandil, ET−1 expression was examined by reverse transcriptase− polymerase chain reaction and ELISA. Activation of extracellular signal−regulated protein kinase（ERK）and endothelial nitric oxide synthase（eNOS）were assessed by Western blot analysis. We show that nicorandil inhibits strain−induced ET−1 expression. Nicorandil also inhibits strain−increased reactive oxygen species（ROS）formation and ERK phosphorylation. On the contrary, NO production and eNOS phosphorylation were enhanced by nicorandil treatment in HUVECs. Furthermore, L−NAME, an inhibitor of NO synthase, and the siRNA transfection for eNOS partially attenuated the inhibitory effect of nicorandil on strain−induced ET−1 expression. We demonstrate for the first time that nicorandil inhibits strain−induced ET−1 secretion via the suppression of ROS production and the enhancement of strain−increased NO production in HUVECs. This study delivers important new insight in the molecular pathways that may contribute to thebeneficial effects of nicorandil in the cardiovascular system.

We have compared the effect of two antihypertensive drugs, imidapril and telmisartan, on hyperinsulinemia and steroid hormone levels in essential hypertensive patients with insulin resistance. Imidapril is the only angiotensin converting enzyme（ACE）inhibitor that is permitted to be used in treating type 1 diabetic nephropathy in Japan. Telmisartan is an angiotensin I I receptor blocker（ARB）that acts as a PPAR−γ agonist and improves insulin resistance. Twenty essential hypertensive patients with insulin resistance were randomly segregated into imidapril and telmisartan treatment groups. Blood pressure（BP）, fasting plasma glucose, HbA1c, fasting serum immunoreactive insulin（F−IRI）, insulin resistance index as assessed by homeostasis model assessment（HOMA−R）, serum dehydroepiandrosterone（DHEA）, serum DHEA−sulfate（DHEA−S）, plasma ACTH, serum cortisol, plasma renin activity and serum aldosterone were measured before and after three to six months of treatment. Both treatments lowered BP, F−IRI and HOMA−R, significantly. Serum levels of DHEA and DHEA−S increased significantly in both groups. Imidapril had the same effect on lowering BP, improving insulin resistance and increasing adrenal androgens（DHEA and DHEA−S）as telmisartan.

CT で脳出血を否定した脳卒中の症例にアルガトロバン高用量投与を行い，軽症例や発症早期来院例では神経学的症候の消失例が多くみられた。今回重症例にアルガトロバン高用量投与を続けると有効例が多いこと，また責任血管が開通するなどの著効例も存在したことを 5 症例を中心に報告する。