Effect of thromboxane synthase inhibition on eicosanoid levels and blood flow in ischemic rat brain.

Abstract

Reperfusion of ischemic brain is associated with production of thromboxane A 2 (TXAJ, a proaggregatory vasoconstrictor. We used an animal model of transient forebrain ischemia to study the effects of 1-benzylimidazole (1-BI), a selective inhibitor of thromboxane synthase, upon cerebral eicosanoid levels and cerebral blood flow. Male Wistar rats were subjected to 30 minutes of four-vessel occlusion. The mean±SEM brain level of TXB 2 , the stable metabolite of TXA 2 , determined after 60 minutes of reperfusion was 101 ±20 pg/mg brain protein in five ischemic control rats. Infusion of 10 figlg 1-BI reduced mean±SEM cerebral TXB 2 concentration to 11±3 pg/mg brain protein in five rats (p^0.002). Mean±SEM hemispheric cerebral blood flow measured in four ischemic control rats after 60 minutes of reperfusion was 42 ±9 ml/ 100 g brain/min compared with 104±13 ml/100 g brain/min in three 1-BI-treated rats (p:£0.001). Mean±SEM hippocampal blood flow in four ischemic control rats after 60 minutes of reperfusion was 51±14 ml/100 g brain/min compared with 125±25 ml/100 g brain/min in three 1-BI-treated rats (p^O.04). We conclude that selective inhibition of thromboxane synthase may alleviate ischemic brain damage by reducing cerebral TXA 2 concentrations and elevating cerebral blood flow. (Stroke 1989;20:627-632) T hromboxane A 2 (TXA2), an enzymic product of arachidonic acid (AA), has been implicated in causing platelet aggregation and vasoconstriction leading to the reduction of microcirculatory blood flow in various organ systems. The synthesis and release of TXA 2 from activated platelets may promote secondary aggregation by interacting with TXA 2 /prostaglandin H 2 (PGHJ receptors on platelet membranes. 12 The vasoconstrictive properties of TXA 2 have been demonstrated in bioassay experiments showing contraction of vascular smooth muscle and reduction of renal and coronary blood flow. 34Cerebral ischemia causes a massive release of AA, stearic acid, and other free fatty acids cleaved by phospholipases from phospholipid membranes in damaged cells.5 - 8 The release of AA is considered to be the rate-limiting step in eicosanoid metabolism within ischemic brain. The cyclooxygenase and peroxidase Received June 6, 1988; accepted November 23, 1988. activities of prostaglandin endoperoxide synthase convert AA to the proaggregatory endoperoxide PGH 2 . Thromboxane synthase (TX synthase) in activated platelets converts PGH 2 to TXA 2 , thereby promoting secondary platelet aggregation, arterial thrombosis, and vasoconstriction in brain subjected to ischemia or subarachnoid hemorrhage. 9 - 11Selective inhibition of TX synthase during early reperfusion of ischemic brain may augment recovery of microcirculatory blood flow. We tested this hypothesis by studying the effects of 1-benzylimidazole (1-BI), a selective inhibitor of TX synthase, 12 in an animal model of transient forebrain ischemia. Materials and MethodsWe divided 33 male Wistar rats into two groups for the determination of eicosanoid levels in brain (n=20, Group A) and m...

Chinese medicine Tongxinluo capsule alleviates cerebral microcirculatory disturbances in ischemic stroke by modulating vascular endothelial function and inhibiting leukocyte–endothelial cell interactions in mice: A two‐photon laser scanning microscopy study

“…TXA2 from activated platelets causes platelet aggregation and vasoconstriction resulting in the reduction of microcirculatory blood flow in multiple organ systems. Research showed that reducing cerebral TXA2 levels may elevate cerebral blood flow and alleviate ischemic brain damage . It has been reported that the balance between PGI2 and TXA2 is important for the cardiovascular system because PGI2 is a physiologic antagonist of TXA2.…”

Secreted Forms of β‐Amyloid Precursor Protein Protect Against Ischemic Brain Injury

“…Twenty-four hours later, animals were rendered ischemic, according to institutional guidelines, by a modification of the four-vessel occlusion technique (Pulsinelli and Brierly, 1979) that had been adapted to include modest hypotension (Globus et al ., 1988 ;Pettigrew et al ., 1989). Rats were anesthetized with a methoxyflurane (Metofane)-filled nose cone while the femoral artery was catheterized .…”

Key metabolite kinetics in human skeletal muscle during ischaemia and reperfusion: measurement by microdialysis

“…Immediately after energy failure due to ischaemia, liberation of arachidonic acid from damaged cell membranes and subsequent synthesis of TxA2 were observed in ischaemia-reperfusion models [3,11,12]. TxA2 has been implicated in causing reperfusion injury, and selective inhibition of thromboxane synthetase has been shown to alleviate postischaemic tissue damage by reducing the effects of TxA2 on blood flow [13]. TxA2, measured as thromboxane B2 (TxB,), the stable, inactive metabolite of TxA2 could therefore be a useful marker for quantifying reperfusion muscle injury.…”