INCREASED CONVERSION OF ARACHIDONIC ACID TO VASODILATOR PROSTANOIDS IN SPONTANEOUSLY HYPERTENSIVE RATS

1. Vasodepressor responses to intravenous injection of prostacyclin, arachidonic acid, and nitroprusside were examined in anaesthetized, spontaneously hypertensive rats (SHR) of the Okamoto strain, and in their normotensive Wistar– Kyoto (WKY) controls. 2. Depressor responses to prostacyclin and nitroprusside did not differ significantly between the two strains. 3. The vasodepressor effects of arachidonic acid were greater and much more prolonged in SHR than in WKY. In rats treated with indomethacin (2 mg/kg) arachidonic acid induced only transient depressor responses which did not differ significantly between these strains. 4. It is concluded that SHR do not differ from WKY in their sensitivity to prostacyclin but they have enhanced ability to transform exogenous arachidonic acid into vasodilator prostanoids.     

乙酰丹酚酸A对血小板花生四烯酸代谢的影响

乙酰丹酚酸Ａ对血小板花生四烯酸代谢的影响吁文贵徐理纳（中国医学科学院、中国协和医科大学药物研究所，北京１０００５０）乙酰丹酚酸Ａ（ａｃｅｔｙｌｓａｌｖｉａｎｏｌｉｃａｃｉｄＡ，ＡＳＡＡ）在体内外能明显抑制花生四烯酸（ａｒａｃｈｉｄｏｎｉｃａｃｉｄ，Ａ...     

METABOLISM OF ARACHIDONIC ACID IN THE AORTA OF SPONTANEOUSLY HYPERTENSIVE RATS

The metabolism of [¹⁴C]-arachidonic acid has been studied in isolated aortae from age-matched spontaneously hypertensive (SH) rats and their normotensive Wistar Kyoto (WK) controls. High pressure liquid chromatography of extracts of the incubation mixture from both SH and WK rats revealed the presence of 6-oxo-prostaglandin F_1α, the hydration product of prostacyclin, and a single, broad peak of unknown metabolites. No thromboxane B₂, or prostaglandins E₂ or F_2α could be detected in aortic incubations. The SH rats produced significantly more 6-oxo-prostaglandin F_1α than the WK rats, xbut there was no difference between the strains in the proportion of label appearing in the unknown peak of the chromatograms. These data confirm that vascular tissue of SH rats has enhanced ability to transform arachidonic acid into prostacyclin. Induction of these enzymes may be an adaptive response to elevated blood pressure, but the mechanism of this effect has yet to be elucidated.     

MECHANISMS OF CAPTOPRIL-INDUCED POTENTIATION OF THE DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN RATS

The mechanisms underlying potentiation by captopril of the depressor responses to arachidonic acid were studied in chloralose-anaesthetized rats. Captopril, in a dose (0.5 mg/kg, i.v.) which inhibited the pressor responses to angiotensin I (0.03-1 microgram/kg, i.v.), enhanced the depressor responses to bradykinin (3-300 micrograms/kg, i.v.) and potentiated the hypotensive action of arachidonic acid (3 mg/kg, intravenously). This phenomenon was observed not only when captopril and arachidonic acid were administered intravenously, but also when these compounds were injected directly into the aortic arch. The enhancement of arachidonic acid-induced hypotension by captopril was not significantly affected by pretreatment with a low dose of aprotinin (3 mg/kg, i.v.), but was abolished by bilateral nephrectomy or by pretreatment with a higher dose of aprotinin (6 mg/kg, i.v.). It is suggested that captopril augments the depressor responses to arachidonic acid by inhibiting angiotensin converting enzyme. This results in accumulation of bradykinin which in turn increases release of vasodilator prostaglandins, originating most probably, from the kidneys. The possibility that blockade of angiotensin II formation by captopril may leave the vasodilator action of prostaglandin unopposed cannot be excluded.     

阿魏酸钠对花生四烯酸代谢的影响

利用放射薄层方法测定兔血小板花生四烯酸代谢产物TXB₂,PGE₂和PGF_2α。用放射免疫法测定兔血小板TXB₂及主动脉6-keto-PGF_1α。阿魏酸钠(SF,0.1～3.2 mmol/L),抑制¹⁴C-花生四烯酸转化为TXB₂,呈剂量效应关系,IC₅₀为0.762 mmol/L。SF在较高浓度(0.8～3.2mmol/L)时亦抑制PGE₂,PGF_2α的生成。用放免法观察到,SF对血小板TXB₂和动脉壁6-keto-PGF_1α的生成均有抑制作用,对TXB₂的作用较强。结果提示,SF可抑制兔血小板和动脉壁环氧酶活性。     

花生四烯酸、二十碳五烯酸及二十二碳六烯酸对兔主动脉条张力的影响

外源性AA引起兔动脉条收缩,呈剂量依赖性;EPA抑制AA收缩血管亦呈浓度依赖性;DHA对AA收缩血管作用无明显影响。破坏血管内皮后AA收缩血管作用大为减弱,EPA抑制AA收缩血管作用也几乎消失。吲哚美辛能阻断AA收缩兔主动脉条的作用。兔主动脉6-keto-PGF_1α、TXB₂及其比值随AA浓度升高而增加,低剂量EPA对前列腺素类代谢无明显影响,较大剂量时则降低上述指标。     

EFFECTS OF ORPANOXIN ON ARACHIDONIC ACID METABOLISM OF HUMAN POLYMORPHONUCLEAR LEUCOCYTES AND PLATELETS IN VITRO

1. The effect of orpanoxin, a nonsteroidal anti-inflammatory drug, on cyclooxygenase and lipoxygenase activity in human polymorphonuclear leucocytes (PMNL) and platelets was studied ex vivo to see if lipoxygenase inhibition contributed to orpanoxin's mechanism of action. 2. In PMNL, orpanoxin (50, 100, and 200 μmol/l), like indomethacin (100 μmol/l), had little effect on synthesis of leukotriene B₄ or 5S-hydroxy-6-trans,8,11,14-cis-eicosatetraenoic acid. BW755c at 100 μmol/l inhibited synthesis of both. 3. In PLT, orpanoxin (100 μmol/l) inhibited formation of cyclooxygenase products (thromboxanes, prostaglandins, and 12-l -hydroxy-5,8,10-heptadecatrienoic acid) and increased synthesis of the lipoxygenase product, 12S-hydroxy-5,8-cis, 10-trans,14-cis-eicosatetraenoic acid. Effects of indomethacin (100 μmol/l) and benoxaprofen (100 μmol/l) in platelets were qualitatively similar to those of orpanoxin. 4. These results indicate that the discrepancy between the low potency of orpanoxin in inhibiting bovine seminal vesicle cyclooxygenase in vitro and its high potency as an anti-inflammatory agent in vivo is not explained by its having an additional lipoxygenase inhibitory mechanism.     

INHIBITION OF ARACHIDONIC ACID ESTERIFICATION IN HUMAN AIRWAY EPITHELIAL CELLS EXPOSED TO OZONE IN VITRO

There is evidence that some lung responses to ozone (O3) exposure are mediated through the altered metabolism of arachidonic acid (AA). Increased concentrations of some AA metabolites such as prostaglandin E2 (PGE2) and prostaglandin F2 (PGF2) are observed in the bronchoalveolar lavage fluid recovered from human subjects exposed to O3. Airway epithelial cells may contribute to this increase in eicosanoid formation. Previous reports have shown increased PGE2 and PGF2 production by O3-exposed air way epithelial cells, believed to be mediated at least in part by increased phospholipase activity. We examined other potential biochemical mechanisms for the increased formation of these two prostaglandins by O3-exposed epithelial cells. Cultured normal human bronchial epithelial (NHBE) cells, prelabeled with 3H-AA, were exposed to air or to 0.1 ppm or1.0 ppm O3 for 60 min in a Transwell cell culture system. NHBE cells produced increased amounts of 3H-PGE2 and 3H-PGF2 in response to 0.1 ppm O3 exposure but not with 1.0 ppm exposure as measured in the conditioned media by high-performance liquidchromatography. Other 3H-AA products, including [3H]-15-hydroxyeicosatetraenoic acid, [3H]-12-heptadecatrienoic, and [3H]aldehydic substances derived from the ozonation of 3H-AA, also were observed in increased amounts. Pulsing of cells with 15 n 3H-AA after 0.1 ppm and 1.0 ppm O3 exposure revealed a decrease in 3H-AA esterification into cellular phospholipids, resulting in an increase in free 3H-AA available for metabolism to prostaglandins. No O3-induced alteration in NHBE cell cyclooxyge nase activity was observed with the 0.1 ppm exposures. Impaired esterification of free AA into cellular phospholipids appears to be a very sensitive target for O3-induced effects on AA metabolism, and may play a role in the increased prostaglandin production observed upon O3 inhalation in vivo.     

花生四烯酸、二十碳五烯酸及二十二碳六烯酸对兔主动脉条张力的影响

外源性AA引起兔动脉条收缩,呈剂量依赖性;EPA抑制AA收缩血管亦呈浓度依赖性;DHA对AA收缩血管作用无明显影响。破坏血管内皮后AA收缩血管作用大为减弱,EPA抑制AA收缩血管作用也几乎消失。吲哚美辛能阻断AA收缩兔主动脉条的作用。兔主动脉6-keto-PGF_(1α)、TXB_2及其比值随AA浓度升高而增加,低剂量EPA对前列腺素类代谢无明显影响,较大剂量时则降低上述指标。     

CAPTOPRIL POTENTIATES DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN THE RAT

1. In chloralose anaesthetized rats intravenous administration of captopril (0.5 mg/kg) was followed by an approximately 100-fold decrease in sensitivity to the pressor actions of angiotensin I. Concomitantly there was a 100-fold increase in sensitivity to the depressor effects of bradykinin. 2. Depressor responses to intravenous prostacyclin (PGI₂), prostaglandin E₂ (PGE₂) or a low dose of arachidonic acid (1 mg/kg) were not changed by captopril administration, but responses to a high dose of arachidonic acid (3 mg/kg), given either intravenously or into the aortic arch, were enhanced for up to two hours afterwards. 3. Depressor responses to arachidonic acid, both before and after captopril, were inhibited after intravenous indomethacin (1 mg/kg). 4. These results support the hypothesis that increased synthesis of prostaglandins in the circulation contributes to the hypotensive action of captopril.     

POTENTIATION OF DEPRESSOR RESPONSES TO ARACHIDONIC ACID BY ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN THE RAT

In chloralose anaesthetized rats, intravenous administration of captopril, SQ 20881, SA 446 or MK 421 (0.5 mg/kg) potentiated the depressor responses to arachidonic acid 3 mg/kg given intravenously. Same doses of the above angiotensin converting enzyme inhibitors caused an approximately 100-fold decrease in sensitivity to the pressor effects of angiotensin I, with a concomitant similar increase in sensitivity to the depressor effects of bradykinin. Depressor responses to arachidonic acid, both before and after administering the converting enzyme inhibitors, were abolished by intravenous indomethacin (5 mg/kg). These results suggest that increased synthesis of prostaglandins in the circulation may contribute to the hypotensive effect of the angiotensin converting enzyme inhibitors, a group of newly developed antihypertensive agents.     

CARDIOVASCULAR EFFECTS OF CENTRALLY ADMINISTERED ARACHIDONIC ACID IN HAEMORRHAGE-INDUCED HYPOTENSIVE RATS: INVESTIGATION OF A PERIPHERAL MECHANISM

• 1 The aims of the present study were to determine the cardiovascular effects of arachidonic acid (AA) and to investigate the peripheral mechanisms mediating these effects in haemorrhage‐induced hypotensive rats.
• 2 Acute haemorrhage was induced by withdrawing a total volume of 2.2 mL blood/100 g bodyweight over a period of 10 min. Rats were then injected with 75–300 µg, i.c.v., AA and cardiovascular changes were monitored over the next 60 min. Plasma catecholamine and vasopressin levels, as well as plasma renin activity (PRA), were measured 10 min after injection of 150 µg AA in haemorrhage‐induced hypotensive awake rats. In addition, rats were pretreated with saline (1 mL/kg, i.v.), the vasopressin V₁ receptor antagonist [β‐mercapto‐β,β‐cyclopentamethylenepropionyl¹,O‐Me‐Tyr²,Arg⁸]‐vasopressin (10 µg/kg, i.v.), the α₁‐adrenoceptor antagonist prazosin (500 µg/kg, i.v.), the non‐specific angiotensin II receptor antagonist saralasin (250 µg/kg, i.v.) or a combination of these three antagonists 5 min before injection of AA (150 µg, i.c.v.). The effects of these antagonists on responses to AA were determined.
• 3 Arachidonic acid caused dose‐ and time‐dependent increases in mean arterial pressure and heart rate and reversed hypotension in haemorrhaged rats. Haemorrhage itself produced an increase in plasma catecholamine and vasopressin levels, as well as PRA; injection of AA produced further increases in these parameters, ranging from 39–123%, under hypotensive conditions. Under hypotensive conditions, pretreatment of rats with all three receptor antagonists produced similar partial blockade of the pressor response to AA, but not the increase in heart rate. Moreover, combined administration of all three receptor antagonists prior to the i.c.v. injection of 150 µg AA completely abolished the pressor response to AA in haemorrhage‐induced hypotensive rats.
• 4 These results indicate that centrally administered AA reverses hypotension by increasing blood pressure and heart rate in the hypotensive setting. The observed increases in plasma catecholamine and vasopressin levels, as well as PRA, mediate the pressor response to AA in haemorrhage‐induced hypotensive rats.

     

GC/MS内标法测定蛋黄磷脂中花生四烯酸和二十二碳六烯酸含量

ＧＣ／ＭＳ内标法测定蛋黄磷脂中花生四烯酸和二十二碳六烯酸含量沈晓京，赖炳森，汪聪慧，董风霞（解放军北京医学高等专科学校生化教研室，北京１０００７１；北京公安部第二研究所仪器分析室，１０００３８）磷脂中不饱和脂肪酸是体内多烯酯酸的重要来源，尤其是机体正...     

DIFFERENCES IN ARACHIDONIC ACID METABOLISM AND EFFECTS OF ASPIRIN BETWEEN ONE- AND TWO-KIDNEY GOLDBLATT HYPERTENSIVE RATS

Vasodepressor responses to prostacyclin, nitroprusside and arachidonic acid were compared in two groups of anaesthetized, two-kidney, one-clip Goldblatt rats. The groups were composed of rats which had high blood pressure (greater than 150 mmHg systolic) or normal blood pressure (less than 140 mmHg systolic). The vasodepressor effects of prostacyclin and nitroprusside and arachidonic acid did not differ significantly between hypertensive and normotensive groups when measured as percentages of resting blood pressure. Thus, in contrast to one-kidney Goldblatt hypertensive rats, there is no evidence for increased vascular conversion of arachidonic acid to prostacyclin in the two-kidney hypertensive model. The effect of cyclo-oxygenase inhibition on development of hypertension in one- and two-kidney Goldblatt rats was also studied by treating them daily with aspirin (200 mg/kg orally) from 3 days before until 3 weeks after clipping the renal artery. Aspirin-treated two-kidney rats developed significantly higher blood pressures than vehicle-treated controls, but the blood pressures of aspirin-treated one-kidney rats increased less after clipping than those of vehicle-treated controls. It appears paradoxical that transformation of arachidonic acid to prostacyclin is increased, while aspirin has a blood pressure lowering effect in one-kidney Goldblatt rats. It is suggested that there might be a more fundamental disturbance in arachidonate metabolism in hypertension which might contribute to increased vascular reactivity.     

蒲黄及其提取物对花生四烯酸诱导血小板聚集功能的影响

蒲黄及提取物总黄酮、有机酸、多糖对花生四烯酸诱导兔体内外血小板聚集功能具有明显的抑制作用,抑制最大聚集%的作用强度依次为:总黄酮>多糖>煎液>有机酸;抑制聚集坡度的作用强度为:总黄酮>煎液>多糖>有机酸;说明黄酮类物质可能是蒲黄抗血小板聚集的主要有效成分,同时表明这些药物对血小板最大聚集%和坡度的作用是有差别的。     

蝙蝠葛碱对血小板聚集及花生四烯酸代谢的影响

蝙蝠葛碱(Dau) 抑制AA及ADP诱导的大鼠血小板聚集,也能抑制AA,ADP及Adr诱导的人血小板聚集。这种抑制作用与Dau剂量呈依赖关系。Dau抑制大鼠洗涤血小板对[1-¹⁴C]AA经环氧酶途径的代谢,TXB₂与HHT的形成均呈剂量依赖性减少。当Dau浓度达到0.1 mmol/L时亦能抑制12-HETE的形成。Dau对AA代谢的上述影响可能是其抑制血小板聚集的机理之一。     

银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶和细胞内钙水平的影响

目的　观察银杏内酯B对大鼠中性白细胞花生四烯酸代谢酶及细胞内钙水平的影响。方法　反相高效液相色谱及Fura-2/AM荧光指示剂法。结果　银杏内酯B在0.1-10μmol·L^-1范围内,使花生四烯酸释放量降低10.9%-22.2%;0.1-50μmol·L^-1时,LTB₄和5-HETE生成量分别降低29.4%-88.6%和26.2%-89.3%;在0.1-100μmol·L^-1使PAF和fMLP刺激引起的细胞内游离钙浓度分别降低13.9%-51.4%和2.2%-36.6%。结论　银杏内酯B能抑制体外大鼠中性白细胞花生四烯酸代谢酶的活性及细胞内游离钙浓度的升高。     

山莨菪碱对大鼠胸水中性白细胞花生四烯酸代谢的影响

本文研究了654-2对大鼠胸水中性白细胞代谢[1-¹⁴C]AA及内源性AA的影响。大鼠白细胞AA经5-LPO代谢途径形成的主要产物为LTB₄及5-HETE,经CO途径的主要产物为HHT及TXB₂。654-2对白细胞代谢[1-¹⁴C]AA无抑制作用,但显著减少白细胞从内源性AA形成的LTB₄,5-HETE,HHT及TXB₂。这种抑制作用与654-2呈剂量依赖关系。本实验结果表明,654-2抑制PG及LT的形成可能是影响了AA从胞膜的释放,而并非直接抑制CO及5-LPO。     

EFFECT OF INDOMETHACIN ON RESPONSES OF SHEEP ISOLATED CORONARY ARTERY TO ARACHIDONIC ACID

Indomethacin (2.8 μmol/1) did not consistently affect basal tone of sheep coronary artery strips, while a ten-fold higher concentration increased tension in 50% of the preparations tested. When acetylcholine was used as a spasmogen, oscillations in induced tone and relaxations produced by arachidonic acid (6.6 μmol/1) were abolished by indomethacin, 2.8 μmol/1 and 7 μmol/1, respectively. Prostacyclin (PGI₂) and prostaglandin E₁ decreased and PGE₂ increased arterial tension while PGF_2α was inactive. Responses to PGI₂ were reduced by indomethacin (28 μmol/1) but not by indomethacin (2.8 μmol/1). It is suggested that sheep isolated coronary arteries synthesize and release prostacyclin in the presence of acetylcholine and arachidonic acid and that such synthesis can be inhibited by indomethacin.