Prevention and reversal of motor and sensory peripheral nerve conduction abnormalities in streptozotocin-diabetic rats by the prostacyclin analogue iloprost

Summary The effects of the prostacyclin analogue iloprost on nerve function were examined in streptozotocin-diabetic rats. Rats were treated either with iloprost from induction of diabetes over 2 months in a preventive experiment, or for 1 month following a 1 month untreated period of diabetes in a reversal experiment. One and 2 months untreated diabetic control, non-diabetic control, and iloprost-treated non-diabetic groups were also used.Diabetes of 1 month duration caused a 21% (P < 0.001) reduction in sciatic motor conduction velocity and a 14% (P (0.001) deficit in saphenous sensory conduction. This was not significantly changed over a subsequent month without treatment. Diabetic rats given iloprost treatment in both preventive and reversal studies had motor and sensory conduction velocities not significantly different from those of non-diabetic controls, but greater than for untreated diabetes (P < 0.01). Iloprost treatment did not have a significant effect on nerve conduction in non-diabetic rats. The time taken for sciatic nerve compound action potential amplitude to be reduced by 80% under hypoxic conditions in vitro was progressively elevated by 19% and 57% after 1 and 2 months diabetes respectively. Iloprost treatment significantly attenuated this for both preventive (47%, P < 0.001) and reversal (50%, P < 0.001) studies. There was no effect on hypoxic resistance for non-diabetic rats. In the preventive group there was a 28010 increase in sciatic nerve endoneurial capillary density (P < 0.001), a lesser effect (16%, P < 0.05) in the reversal group, and no effect in non-diabetic rats. Sciatic nerve sorbitol, fructose and myo-inositol levels were measured in 2 month diabetic control and reversal iloprost-treated groups. Treatment had no significant effect on the elevation of polyol pathway metabolites or myo-inositol concentration.We conclude that iloprost treatment may compensate for reduced prostacyclin production by vasa nervorum. Although short durations of experimental diabetes do not result in the severe degenerative changes found in clinical neuropathy, it is nevertheless possible that iloprost may have therapeutic potential for vascular-related diabetic complications. Correspondence to N. E. Cameron at the above address     

Exogenous prostacyclin,but not prostaglandin E2, produces similar responses in both G6PD activity and RNA production as mechanical loading,and increases IGF-II release,in adult cancellous bone in culture

Summary Cyclic mechanical loadingin vivo that leads to new bone formation is also associated in osteocytes and surface bone cells with almost immediate increases in G6PD activity, and later increases in RNA production. Both these early, loading-related, responses can be reproduced in organ culture of adult cancellous bone, and both are abolished by the presence of indomethacin in the culture medium at the time of loading. The implication that prostaglandins (PGs) are involved in the control of loading-related osteogenesis is supported by increases in prostacyclin (PGIZ) and PGE₂ release from cores of cancellous bone during loading. In the experiments reported here, PGE₂ and PGI₂ were added exogenously (10^–6 M) to perfusable cores of adult canine cancellous bone to determine whether they would simulate the loading-related responses in G6PD activity and RNA synthesis. PGE₂ increased GOD activity in surface cells and osteocytes within 8 minutes but had no effect on [³H]-uridine incorporation at 6 hours. PGI₂ stimulated both G6PD activity and [³H]-uridine incorporation equally in osteocytes and surface cells. Neither PG produced any significant change in medium concentrations of IGF-I, and PGE₂ had no effect on IGF-II. In contrast, PGI₂ elevated the medium concentration of IGF-II threefold. IGF-I and IGF-II were localized immunocytochemically to osteocytes and surface cells in both treated and untreated cores. Prostacyclin, but not PGE₂, appears to imitate the early loading-related increases in G6PD activity and RNA synthesis in bone cellsin situ. Prostacyclin, but not PGE₂, also stimulates the early release of IGF-II.     

二次脑创伤后大鼠皮层脑血流及前列腺素变化及血红蛋白液的作用

目的：探讨二次脑创伤后大鼠皮层脑血流（ＣｏＣＢＦ）与前列腺素变化及双阿斯匹林联偶血红蛋白液（ＤＣＬＨｂ）的作用。方法：在一种新的大鼠加速性弥漫性脑损伤模型基础上，采用抽血及颈动脉结扎造成低血压及脑缺血、缺氧，观察大鼠ＣｏＣＢＦ与血栓素Ａ２（ＴＸＡ２）、前列环素（ＰＧＩ２）含量变化以及ＤＣＬＨｂ治疗作用。３２只ＳＤ大鼠随机分为假手术对照、单纯脑损伤、脑损伤并二次脑创伤及治疗四组。所有动物均气管内插管并实施同步生理监护。结果：伤后４小时，与假手术组对比，合并二次脑创伤组ＣｏＣＢＦ显著降低，ＴＸＡ２含量增高（Ｐ＜０．０５）；ＤＣＬＨｂ治疗组无ＣｏＣＢＦ降低，但ＴＸＡ２及ＰＧＩ２含量均有增高。结论：合并二次脑创伤组有ＣｏＣＢＦ降低及ＴＸＡ２含量增高，提示在其病理过程中存在脑血管痉挛及微血栓形成，导致脑缺血、缺氧。ＤＣＬＨｂ则可能通过增加ＰＧＩ２合成发挥脑保护作用。     

急性胆管炎胆汁前列环素、血栓素的变化及茵陈胆道汤对其影响的研究

本文采用放射免疫法对２组兔和１ｌ例胆管结石术后病人服菌陈胆道汤之前、中、后的胆汁测定ＰＧＩ２与ＴＸＡ２和稳定代谢产物６—ｋｅｔｏ—ｐＧＦｌａ与ＴＸＢ２及两者之比值，观察三值的变化，探讨茵陈胆道汤对其影响，为胆管结石和胆管炎症的防治提供实验依据。结果显示：急性胆管炎组兔胆汁６—ｋｅｔｏ—ＰＧＦｌａ与ＴＸＢ２较实验对照组明显增高，６—ｋｅｔｏ—ＰＯＦｌａ／ＴＸＢ２明显降低。胆管结石术后病人服茵陈胆道汤至停药７天，胆汁中６—ｋｅｔｏ—ＰＧＦｌａ与ＴＸＢ２较服药前明显降低，停药２天６—ｋｅｔｏ—ＰＧＦｌａ／ＴＸＢ２较服药前增高。结果认为：①胆汁ＰＧＩ２的增高对急性胆管炎的发生和胆管结石的形成有着密切的关系；②ＰＧＩ２／ＴＸＡ２失衡，ＴＸＡ２）增加在急性胆管炎中的毒性作用十分重要；③茵陈胆道汤有降低ＰＧＩ２和ＴＸＡ２的作用，是防治胆管结石的胆管炎症的有效中药方剂。     

Cisternal and lumbar CSF concentration of arachidonate metabolites in vasospasm following subarachnoid hemorrhage from ruptured aneurysm: biochemical and clinical considerations

Two representative cases of subarachnoid hemorrhage in which prostaglandin D2 (PGD2) and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), stable metabolite of prostacyclin (PGI2), were monitored with serial lumbar punctures and detected in cisternal CSF during operations for aneurysm, are reported. In the case with demonstrated arterial vasospasm, prostaglandin D2 has a concentration trend with characteristic peak related to vasospasm; the synthesis of prostacyclin appears inhibited after the hemorrhage. In the patient without radiologic evidence of vasospasm, arachidonate metabolite concentration trend appears in a steady-state. Cisternal prostaglandin D2 concentration in the patient with demonstrated vasospasm is two times the highest lumbar CSF concentration, while 6-keto-prostaglandin F1 alpha concentration is very low. This suggests the role of the clotting phenomenon and likely confirms the importance of arachidonate metabolites in the genesis of cerebral arterial spasm following subarachnoid hemorrhage.     

EFFECT OF ERYTHROCYTES AND PROSTACYCLIN PRODUCTION IN THE EFFECT OF FRUCTOSE AND SORBITOL ON PLATELET ACTIVATION IN HUMAN WHOLE BLOOD IN VITRO

We analyzed the in vitro effects of sorbitol and fructose on platelet function. Sorbitol and fructose increased platelet aggregation induced with adenosine diphosphate (ADP) or collagen in whole blood, but had no effect in platelet-rich plasma. The concentration that increased basal aggregation by 50% with ADP as the inducer was 12.89 ± 1.55 mmol/L for fructose, and 18.99 ± 2.01 mmol/L for sorbitol. When collagen was the inducer, these concentrations were 15.02 ± 0.98 mmol/L for fructose, and 12.94 ± 1.57 mmol/L for sorbitol. Both sugars increased, in a concentration-dependent way, the proaggregatory effect of erythrocytes, and erythrocyte uptake of adenosine. Time to uptake of 50% adenosine was 2.1 ± 0.3 min in control samples, 0.14 ± 0.01 min in the presence of fructose, and 0.23 ± 0.03 min with sorbitol. Both sugars reduced vascular prostacyclin synthesis, with 50% inhibitory concentrations of 26.48 ± 1.97 mmol/L for fructose, and 39.53 ± 2.81 mmol/L for sorbitol. Both sugars also increased arterial lipid peroxidation by 30% (sorbitol) and 23% (fructose). We conclude that these two sugars enhance platelet function and disrupt the thromboxane/prostacyclin ratio. © 1997 Elsevier Science Ltd     

The effect of the stable prostacyclin analogue ZK 36374 on experimental coronary thrombosis in the pig

The hemodynamic and antithrombotic action of ZK 36374, a stable carbacyclin derivative of prostacyclin, was studied during electrically-induced coronary artery thrombosis in the open chest anesthetized pig. Infusion of ZK 36374 (100 ng/kg/min, n = 6) had no effect on heart rate and cardiac output, but caused a 20% reduction in mean arterial blood pressure by peripheral vasodilation. In animals receiving solvent or no drug prior to thrombosis induction, the time to occlusive coronary artery thrombosis (TOT) was 30 +/- 2 minutes (mean +/- SEM, n = 17). Pretreatment with an i.v. infusion of ZK 36374 (100 ng/kg/min) prolonged TOT by 50% to 47 +/- 7 minutes (p less than 0.005, n = 6). This prolongation of TOT was not due to the lower blood pressure in the ZK 36374 group, as dihydralazine in a dose that lowered arterial blood pressure to the same extent had no effect on TOT (32 +/- 4 minutes, n = 4). The results indicate that ZK 36374 may be useful in delaying (or preventing) occlusive coronary artery thrombi.     

Formation and elimination of prostacyclin metabolites in the cat in vivo as determined by radioimmunoassay of unextracted plasma

Using newly developed radioimmunoassays for 6-keto-prostaglandin F_1α and 6,15-diketo-13,14-dihydro-prostaglandin F_1α, the plasma concentrations of these two prostacyclin derivatives were measured in anaesthetized cats. After the administration of angiotensin II, which releases prostacyclin into the circulation, concentrations of both derivatives rose simultaneously, the major immunoreactivity being 6,15-diketo-13,14-dihydro-prostaglandin F_1α. Angiotensin II-induced prostacyclin release was not caused by vasoconstriction alone, since comparable vasopressor responses to noradrenaline and vasopressin were not accompanied by increases in prostacyclin plasma levels. Injection of exogenous prostacyclin resulted in a shortlasting peak of 6-keto-prostaglandin F_1α, which rapidly declined ($\text{t}\text{1}\text{2}\text{: 1.29–1.52}\text{min}$). 6,15-diketo-13,14-dihydro-prostaglandin F_1α appeared with a $\text{t}\text{1}\text{2}\text{of}\text{0.48–1.38}\text{min}$ and was eliminated with a $\text{t}\text{1}\text{2}\text{of}\text{8.0–9.0}\text{min}$. Due to its longer half-life in the circulation 6,15-diketo-13,14-dihydro-prostaglandin F_1α again was the predominant derivative after 3 min. These data suggest that in vivo prostacyclin is mainly inactivated by the 15-hydroxy-PG-dehydrogenase-, Δ¹³-reductase-pathway, rather than by hydrolysis. Therefore, 6,15-diketo-13,14-dihydro-prostaglandin F_1α seems to be a better indicator or prostacyclin plasma levels than 6-keto-prostaglandin F_1α, although under certain conditions the additional determination of this product of hydrolysis can be valuable.     

Zur Bedeutung der Prostaglandine für die in vitro Adhäsivität und die in vivo Margination der neutrophilen Granulozyten

Summary The (patho-)physiological role of prostaglandins and thromboxanes on granulocyte function remains controversial. In a combined in vitro and in vivo study, we analyzed the influence of these arachidonic acid metabolites on granulocyte adhesion and margination. A dichotomous dose-dependent effect on epinephrine-induced granulocyte demargination parallels the paradoxical effect of low (0.5 g)- and high (4 g)-dose aspirin on bleeding time. These observations suggest that prostacyclin acts as a modulator for low-affinity adhesion and margination of granulocytes. With respect to the induction of high-affinity adhesion, which is reflected in a state of hypermargination in vivo and accompanied by potentially cytotoxic cell activation, prostaglandins in general and prostacyclin in particular are without effect when such activation is induced, either by endotoxin, by formylated chemotactic peptide, or by activated complement.

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Abkürzungen ADP Adenosindiphosphat - n-formyl-Met-Leu-Phe n-formyl-Methionin-Leucin-Phenylalanin - PG 12 Prostazyklin