Thromboxane A2 synthetase inhibitor （trapidil）の実験的脳虚血に及ぼす効果

PROTECTIVE EFFECT OF THROMBOXANE A2 SYNTHETASE INHIBITOR (TRAPIDIL) ON ACUTELY-INDUCED CEREBRAL ISCHEMIA

　抄録　脳虚血急性期におけるthromboxane A₂の役割を検討するため，SHRを用いて両側総頸動脈結紮法（BLCL）により脳虚血を作成し，thromboxane A₂ synthetase inhibitor （TXI）であるtrapidil （15mg／kg）をBLCL前2hr．とBLCL後15min．の2回投与を行い，脳代謝諸量（ATP, lactate, pyruvate），脳含水量および血漿thromboxane B₂（TXB₂），6Keto PGF_1αを測定した。また，走査電顕にて中大脳動脈および脳実質内動脈を観察した。脳代謝諸量では，TXI治療群にてATPは高値を，　lactateは低値を，またpyruvateは高値を示しlactate／pyruvate比を低下させた。脳含水量はTXI治療群にて有意の減少を示した。一方，TXI治療により血漿TXB₂は減少傾向を，6Keto PGF_1αは増加傾向を示し，TXB₂／6Keto PGF_1α比は有意の低下を示した。電顕観察ではTXI治療群では，非治療群で認められた血管収縮，fibrin netsおよびblood born cellsの血管内腔の内皮細胞への付着は認められなかった。以上の結果より，脳虚血急性期のthromboxane A₂（TXA₂）の増加およびTXA₂とPGI₂のバランスの崩解は虚血の増悪因子の一つとして重要な役割を果たしていると考えられた。

The experimental study presented was under-taken to evaluate the role of thromboxane A₂ contributing to aggravating cerebral ischemia, and to examine the effect of a thromboxane A₂ synthe-tase inhibitor, trapidil on cerebral ischemia. Cerebral ischemic model was induced in 16 week old spontaneously hypertensive rats (SHR) by bilateral common carotid artery ligation (BLCL). Two doses of trapidil 15 mg/kg was intraperito-neally administered one dose 2 hr before and one dose 15 min after BLCL in SHR. While control animals only underwent BLCL. Brain tissue meta-bolites such as ATP, lactate and pyruvate, brainwater content and plasma thromboxane B₂ and 6 Keto PGF_1α. were determined 3 hr after BLCL. Scanning electron microscopic observations were also recorded.

ATP concentrations were 1. 36±0.23 n moles/mg wet tissue in the trapidil treated group, 0. 61±0.26 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P<0. 001). Lactate concentrations were 4. 70±1. 20 n moles/mg wet tissue in the treated group, 12. 17±8. 53 n moles/mg wet tissue in the control group, the difference between the treated and the control being significant (P<0.02). Pyruvate concentrations were 0. 59±0.11 11 n moles/ mg wet tissue in the treated group, 0. 43±0. 16 n moles/mg wet tissue in the control, the difference was also significant (P<O. 05).

Average water content was 78. 87-±0. 59% in the treated group, 79.82±0. 33% in the control. There was a statistical difference between the two groups (P <0.01).

The treated group had a tendency of decrease of plasma thromboxane B₂ and a tendency of increase of plasma 6 Keto PGF_1α., and had a stati-stical difference of thromboxane B₂/ 6 Keto PGF_1α ratio from those of the control group (P <0. 05). In scanning electron microscopic observation, the treated rats had very few adhering fibrin nets and blood born cells in the surface of the endothelial cells in the intracerebral arterioles and the middle cerebral artery, whereas the control rats showed remarkable vasoconstriction and had many micro-villi, many adhering fibrin nets and blood born cells.

The present results show that a thromboxane A₂ synthetase inhibitor, trapidil ameliorates im-paired cerebral metabolism and brain edema in acutely-induced cerebral ischemia. It indicates that an increased thromboxane A₂ and thromboxane A₂ priority to PGI₂ in cerebral ischemia play an important role as an aggravating factor of ische-mia through the disturbance of microcirculation.