Changes in prostacyclin, thromboxane A2 and F2-isoprostanes, and influence of eicosapentaenoic acid and antiplatelet agents in patients with hypertension and hyperlipidemia

Prostacyclin (PGI2), thromboxane A2 (TXA2) and F2-isoprostanes, prostaglandin F2-like compounds, have wide and contrasting spectrum of biological activities and may influence blood pressure and atherogenesis. To investigate the dynamics of PGI2, TXA2 and F2-isoprostanes in patients with hypertension and hyperlipidemia (HH group), we measured the major urinary metabolites of PGI2: 6-keto PGF1alpha (Keto) and 2,3-dinor-6-keto PGF1alpha, (Dinor), those of TXA2:TXB2 and 11-dehydro TXB2 (Dehydro), and urinary 8-isoprostane (Iso) in 34 patients. Urinary excretion of Dinor was significantly lower in patients than in controls and that of Dehydro was significantly higher in patients than in controls. Keto, TXB2 and Iso were not significantly different between them. Antiplatelet agents decreased not only TXA2 metabolites but also PGI2 metabolites. Urinary C-peptide immunoreactivity was correlated with Dinor and Dehydro. After administration of eicosapentaenoic acid (EPA), total cholesterol (T-cho) and triglycerides (TG) significantly decreased. Although prostanoids did not show significant change, changes in T-cho were correlated with changes in Dinor and changes in Iso. These results suggest that PGI2 and TXA2 of systemic origin might be related to the pathophysiology of hypertension and hyperlipidemia and that the dynamics of PGI2, TXA2 and F2-isoprostanes might be related to not only blood pressure regulation but also lipid and glucose metabolism.     

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

1. Effects of a single intravenous dose of aspirin (600 mg) on bradykinin-stimulated prostaglandin (PG) and on thromboxane (TX) biosynthesis were determined in nine healthy male volunteers. Plasma concentrations of 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha were measured in samples obtained during repeated 10 min intravenous infusions of bradykinin before and up to 6 h after the dose of aspirin. TXB2 was measured in serum from blood allowed to clot at 37 degrees C. 2. Aspirin inhibited bradykinin stimulated PG and platelet TX biosynthesis 0.5 h after the dose. Serum TXB2 remained low, whereas PG synthesis recovered within 6 h. 3. Effects of intravenous sodium salicylate (600 mg) were studied identically in eight subjects. Prostanoid biosynthesis was not inhibited. 4. Biosynthesis of prostacyclin and TXA2 under basal conditions was studied in eight subjects by measuring 2,3-dinor-6-oxo-PGF1 alpha and 2,3-dinor-TXB2 in hourly urine samples obtained during and after intravenous infusion of aspirin and, on a separate occasion, of vehicle. 5. Aspirin infusion reduced urinary excretion of both metabolites greater than 90%, but excretion of 2,3-dinor-6-oxo-PGF1 alpha recovered more rapidly than did that of 2,3-dinor-TXB2. 6. We conclude that cyclo-oxygenase is rapidly synthesised in bradykinin-responsive tissues in vivo and that this reflects similarly rapid enzyme biosynthesis in tissues that produce PGI2 under basal conditions.     

Prostaglandins and thromboxane in the delayed phase of shock induced by Serratia marcescens endotoxin.

The cardiovascular and metabolic effects of an endotoxin derived from Serratia marcescens were examined in anaesthetized, spontaneously-breathing cats. There was a marked initial elevation of right atrial pressure (the result of pulmonary vasoconstriction) and decreases in systemic arterial pressure and in arterial PO2. The 'delayed' effects of endotoxin shock in this species (1-8 h) consisted of a reduced cardiac output and decreased urinary excretion. Blood pressure and myocardial contractility (assessed from measurement of left ventricular (LV) dP/dt and LV end-diastolic pressure) were maintained throughout this phase. There was evidence of a metabolic (lactic) acidosis largely compensated by hyperventilation. Plasma levels (both arterial and mixed venous blood samples) of prostaglandin (PG)E2, PGF2 alpha, 6-keto PGF1 alpha and thromboxane (TX)B2 were measured by radioimmunoassay techniques. Endotoxin administration caused substantial increases in the plasma levels of all four derivatives of arachidonic acid, especially between 1 and 6 h. Separation of the endotoxin-treated cats into survivors and non-survivors showed that the non-survivors had significantly higher circulating levels of PGE2, TXB2 and PGF2 alpha. It is suggested that TXB2 and PGF2 alpha might contribute to some of the detrimental effects of endotoxin (e.g. pulmonary, mesenteric, renal vasoconstriction; platelet aggregation with resulting organ failure) and that prostacyclin may be beneficial in endotoxin shock in this species.     

Systemic synthesis of prostaglandin I2 following sustained infusion of angiotensin II in conscious dogs

Acute infusion of pharmacological doses of angiotensin II stimulates the release of prostaglandin I2 (PGI2), which may modulate the vasoconstrictor response. It is uncertain whether sustained small increases in the plasma concentration of angiotensin II has the same effect. To investigate this further, low doses of angiotensin II were infused into conscious sodium replete dogs for 3 h. PGI2 synthesis was assessed by measurement of a major metabolite of PGI2, 2,3-dinor-6-keto PGF1 alpha, in urine and plasma, using gas chromatography mass spectrometry. Angiotensin II infusion (15 ng/min per kg body weight) resulted in a 3-fold increase in plasma angiotensin II (50.8 +/- 5.4 to 149 +/- 11.2 pg/ml, P less than 0.01). Mean blood pressure increased (84.8 +/- 4.3 to 108 +/- 4.7 mm Hg, P less than 0.02) and renal blood flow decreased (201 +/- 46 to 127 +/- 13 ml/min, P less than 0.01) throughout the infusion. However there was no change in either the plasma concentration (11.3 +/- 2.5 to 9.1 +/- 1.0 pg/ml) or rate of urinary excretion of dinor-6-keto PGF1 alpha (1.75 +/- 0.28 to 1.85 +/- 0.41 ng/30 min) during the angiotensin II infusion. The results suggest that small sustained elevations of the plasma concentration of angiotensin II such as are likely to occur in conscious animals, do not persistently stimulate release of PGI2 in the systemic circulation.     

A study of the calcium carbimide-ethanol interaction in man

Summary In six male alcoholic volunteers, oral administration of calcium carbimide (0.7 mg/kg) before ingestion of ethanol (0.5 g/kg) produced an interaction consisting of increased blood acetaldehyde level, tachycardia and increased pulse pressure, which was due mainly to decreased diastolic blood pressure. For these experimental conditions, calcium carbimide had a duration of action of at least 24 h to produce an interaction with ethanol. The order of intensity of the interaction with regard to the calcium carbimide pretreatment time interval was 4>812>24 h. Using the criterion of heart rate above 100 as indicative of the calcium carbimide-ethanol interaction, the onset was 0.13, 0.25, 0.25 and 0.38 h for the 4-, 8-, 12- and 24-h pretreatment experiments and the duration of the interaction was 1.6, 1.0, 1.0 and 0.12 h, respectively. There were positive linear correlations between acetaldehyde level and heart rate and between acetaldehyde level and pulse pressure. There was appreciable interindividual variability in the heart rate and blood pressure responses. Increased blood acetaldehyde level seemed to be required for the physiological changes to occur. Calcium carbimide pretreatment at the 4-h interval produced increased blood ethanol level for the last hour of the interaction and reduced the rate of ethanol metabolism.     

Effects of salicylic and acetylsalicylic acid alone and in combination on platelet aggregation and prostanoid synthesis in man.

The present study was designed to investigate the effects of salicylate on the antiplatelet action of acetylsalicylic acid as well as on in vivo prostanoid formation and platelet function in healthy volunteers. In the first study six female volunteers received 350 mg acetylsalicylic acid intravenously, with and without previous oral administration of sodium salicylate (1200 mg daily for 3 days). Urinary prostanoid excretion as well as platelet aggregation and thromboxane formation were measured before and during salicylate and after acetylsalicylic acid. In the second study seven female volunteers received sodium salicylate (52.6 mg kg-1) or acetylsalicylic acid (60.7 mg kg-1) for 8 days in a randomized cross-over protocol. Urinary prostanoid excretion, platelet aggregation and thromboxane formation as well as salicylate plasma concentrations were determined before, during and after administration of each drug. Sodium salicylate did not impair the complete suppression of arachidonic acid-induced platelet thromboxane formation and aggregation obtained by the single intravenous dose of acetylsalicylic acid in the first study. Sodium salicylate in the second study did not affect urinary excretion of prostaglandin E2, its major urinary metabolite (7 alpha-hydroxy-5,11-diketo-tetranor-prostane-1,16-dioic acid), and 2,3-dinor-6-keto-prostaglandin F1 alpha, the main urinary metabolite of epoprostenol (prostacyclin, PGI2). In contrast, acetylsalicylic acid significantly decreased excretion rates of these prostanoids by 64, 59 and 61%, respectively. In both studies platelet aggregation and thromboxane formation induced by collagen, thrombin or arachidonic acid were not significantly affected by salicylate administration, whereas acetylsalicylic acid inhibited platelet aggregation induced by all three agents as well as thrombin- and arachidonic acid induced thromboxane formation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Breath and blood acetaldehyde concentrations and their correlation during normal and calcium carbimide-modified ethanol oxidation in man

With the use of new and improved analytical techniques, concentrations of acetaldehyde in antecubital venous blood and breath of human volunteers were measured after (a) pretreatment of subjects with ethanol and the aldehyde dehydrogenase inhibitor, calcium carbimide and (b) treatment with ethanol only. Breath acetaldehyde concentrations were converted to equivalent pulmonary blood concentrations using an experimentally determined blood: breath partition ratio for acetaldehyde of 190. Under all experimental conditions, blood acetaldehyde concentrations calculated from breath analysis were seen to closely reflect those measured by direct blood analysis. Treatment of subjects with calcium carbimide resulted in elevated blood and breath acetaldehyde concentrations which were rapidly lowered by the intravenous infusion of 4-methyl pyrazole. Peak blood acetaldehyde concentrations ranged from 25 to 188 μM after calcium carbimide and ethanol treatment, but were only 6–11 μM after ethanol treatment alone (1.2g/kg).     

Improvement of vascular function by chronic administration of a cyclo-oxygenase inhibitor in cholesterol-fed rabbits

1. Atherosclerotic cardio- and cerebrovascular disease is a leading cause of mortality in Western countries. Aspirin-like drugs are widely used to prevent and treat these occlusive cardio- and cerebrovascular diseases. The beneficial effects of these drugs have been largely attributed to inhibition of platelet cyclo-oxygenase activity and thromboxane (TX) A2 production. We investigated the effect of an aspirin-like drug, namely indomethacin, on endothelial function, plaque and platelet aggregation and the formation of vasoactive substances during the development of atherosclerosis in cholesterol-fed rabbits. 2. Rabbits were fed 1% cholesterol (n = 8), 1% cholesterol plus 25 mg/day indomethacin (n = 8) or normal rabbit chow (control group; n = 8) for 12 weeks. Urinary excretion rates of 2,3-dinor-TXB2, 6-keto-prostaglandin (PG) F1alpha, 8-iso-PGF2alpha and nitrate were analysed at the beginning of dietary intervention and at 4 weekly intervals thereafter. At the end of the study period, platelet aggregation, aortic plaque formation and endothelium-dependent and -independent vascular functions of isolated aortic rings ex vivo were assessed. 3. Compared with control, in the cholesterol-fed group, urinary 2,3-dinor-TXB2, 6-keto-PGF1alpha and 8-iso-PGF2alpha excretion and platelet aggregation were significantly increased (P < 0.05), but urinary excretion of nitrate was decreased (P < 0.05). Treatment with indomethacin significantly reduced platelet aggregation, urinary 2,3-dinor-TXB2, 6-keto-PGF1alpha and 8-iso-PGF2alpha excretion (P < 0.05 vs the cholesterol-fed group) and attenuated the reduction in urinary nitrate excretion. 4. Cholesterol feeding progressively increased aortic intimal thickening and impaired endothelium-dependent vasodilator function (P < 0.05 vs control), whereas indomethacin partially prevented aortic plaque formation and restored endothelium-dependent vasodilation (P < 0.05 vs the cholesterol-fed group). 5. The present study demonstrates that indomethacin reduces the progression of atherosclerotic lesions and improves endothelium-mediated vascular responses ex vivo in cholesterol-fed rabbits. The beneficial effects of indomethacin may be due to its ability to prevent the elevation of platelet aggregation, TXA2 (measured as urinary 2,3-dinor-TXB2 excretion) and 8-iso-PGF2alpha formation and to retard the decrease in endogenous nitric oxide synthesis (assessed as urinary excretion of nitrate). Despite indomethacin treatment leading to the suppression of prostacyclin biosynthesis (assessed as urinary 6-keto-PGF1alpha excretion), according to our data, indomethacin appears to preserve endothelial function.     

Effects of non-steroidal anti-inflammatory drugs on prostacyclin and thromboxane biosynthesis in patients with mild essential hypertension.

1. The effects of non-steroidal anti-inflammatory drugs (NSAID) on prostacyclin and thromboxane biosynthesis and on blood pressure were determined in 46 patients with mild essential hypertension. Patients who had abstained from antihypertensive therapy for 2 weeks before study were treated with either aspirin, ibuprofen, sulindac or placebo for 7 days. 2. Excretion rates of 2,3-dinor-6-oxo-prostaglandin (PG) F1 alpha, 6-oxo-PGF1 alpha, 2,3-dinorthromboxane (TX) B2 and TXB2 were measured as indices of prostacyclin and TXA2 biosynthesis. Samples were assayed using immunoaffinity chromatography and gas chromatography/electron capture chemical ionisation mass spectrometry. 3. Aspirin and ibuprofen reduced urinary excretion of all prostacyclin- and thromboxane-derived products. Sulindac inhibited excretion of 2,3-dinor-6-oxo-PGF1 alpha, 6-oxo-PGF1 alpha and 2,3-dinor-TXB2, but had no significant effect on TXB2. 4. Systolic blood pressure increased in the ibuprofen-treated group when compared with the placebo group. There were no other significant changes in systolic or diastolic pressure in any of the treatment groups. Among the patients as a whole, there was a significant negative correlation between change in blood pressure and change in excretion of the prostacyclin-derived but not of the thromboxane-derived products. 5. We conclude that, in patients with mild essential hypertension, neither sulindac nor aspirin (in the doses used) selectively spares prostacyclin biosynthesis by the kidney. The significant relationship between increase in blood pressure and reduction in prostacyclin biosynthesis favours the possibility that in individuals who become hypertensive, prostacyclin biosynthesis determines, in part, the severity of the hypertensive state.     

Experimental coronary artery thrombosis in the absence of thromboxane A2 synthesis: evidence for alternate pathways for coronary thrombosis

The actions of the thromboxane synthetase inhibitor, U-63557A, were evaluated in vivo in anesthetized open-chest dogs by inducing left circumflex coronary artery (LCCA) thrombosis with low amperage electrical stimulation (100 microA for 6 h) of the intimal surface of the vessel, and ex vivo by assessing platelet aggregation and TXB2 production. U-63557A, 10 mg/kg + 5 mg/kg/h i.v., reduced ex vivo platelet aggregation in response to arachidonic acid (0.65 mM) by 93 +/- 2% (p less than 0.05, means +/- SEM), whereas the concurrent formation of TXB2 was decreased by 78 +/- 8% (p less than 0.05). TXB2 concentration also was reduced significantly in vivo as measured from coronary sinus blood samples; however, 6-keto-PGF1 alpha concentration was unchanged from predrug values. Despite the significant inhibition of platelet aggregation and TXB2 production, thrombus mass was not reduced: control, 32.0 +/- 5.9 mg (n = 7); U-63557A, 30.8 +/- 12.0 mg (n = 5, p = NS). These results suggest that U-63557A effectively inhibits TXA2 synthetase, but lacks antithrombotic activity in our experimental model. Therefore, substances other than TXA2 may be capable of mediating occlusive coronary artery thrombosis.     

Urinary thromboxane, prostacyclin, cortisol, and 8-hydroxy-2'-deoxyguanosine in nonsmokers exposed and not exposed to environmental tobacco smoke.

This study tested the hypotheses that (1) increased platelet aggregation, as measured by 2,3-dinor-thromboxane B(2) (Tx-M) and 2,3-dinor-6-keto-prostaglandin F(1alpha) (PGI-M), and (2) increased oxidative stress, as measured by 8-Hydroxy-2'-deoxyguanosine (8-OHdG), would occur in ETS-exposed nonsmokers as compared with non-ETS-exposed nonsmokers. The concentrations of the stable urinary metabolites of thromboxane (Tx-M) and prostacyclin (PGI-M), cortisol and 8-OHdG were measured in a 24-h urine sample from 3 groups of subjects: 21 nonsmokers with minimal (15 min or less per day) ETS exposure (termed non-ETS-exposed), 22 nonsmokers with at least 5 h per day of ETS exposure (termed ETS-exposed), and 20 cigarette smokers who served as a positive control group. The self-reported levels of ETS exposure were verified by personal air monitors. As compared with either group of nonsmokers, cigarette smokers excreted significantly more urinary Tx-M. Non-ETS-exposed nonsmokers showed a statistically significantly higher level of urinary Tx-M over that seen in nonsmokers with considerably more ETS exposure. Urinary concentrations of PGI-M were marginally higher in the smokers and did not differ between the nonsmoker groups. Nonsmokers exposed to at least five h of ETS per day did not have significantly higher excretion of 8-OHdG than non-ETS-exposed nonsmokers. The results from this study suggest that platelet aggregation, as measured by the thromboxane metabolite Tx-M and prostacyclin metabolite PGI-M, is not associated with ETS exposure. Therefore, platelet aggregation is not a plausible or quantitatively consistent mechanism to explain the nonlinear dose-response hypothesis of cardiovascular disease and ETS exposure.     

Prostacyclin and thromboxanes in carrageenan-induced pleurisy in the rat

The cellular origin and kinetics of TXB2 and 6-keto PGF1 alpha in carrageenan-induced pleurisy has been studied. Maximum levels of these prostanoids occurred 1 hour after induction of pleurisy. Mononuclear cells initially present in the pleural cavity synthesized TXB2 and 6-keto PGF1 alpha from (14C) arachidonic acid. By contrast, PMN cells harvested 6 hours after the induction of inflammation did not produce 6-keto-PGF1 alpha. Selective inhibition of thromboxane synthetase with drugs in vitro and in vivo increased the formation of 6-keto-PGF1 alpha, the stable breakdown product of PGI2. This metabolic effect was parallel to an increase in the volume of exudate and in PMN migration. These results suggest that TXA2 seems to be implicated not only as a chemotactic agent but also as an antagonist of PGI2 vasodilator effects.     

A thromboxane A2 synthetase inhibitor retards hypertensive rat diabetic nephropathy.

Spontaneously hypertensive rats (SHR) were injected with streptozotocin (STZ-SHR) to induce diabetes. The effect of DP-1904, a thromboxane A2 synthetase inhibitor, on diabetic nephropathy was then studied by administering it for 5 months (1 or 10 mg/kg). DP-1904 did not affect renal 6-keto prostaglandin (PG)F1 alpha production in STZ-SHR, but markedly inhibited renal thromboxane (TX) B2 production, so that the 6-keto PGF1 alpha/TXB2 ratio was significantly increased (P less than 0.05). STZ-SHR showed significant uraemia and proteinuria, plus increases in urinary gamma-glutamyl-transpeptidase and urinary N-acetyl-beta-glucosaminidase. DP-1904 significantly decreased (P less than 0.01) the urinary changes. STZ-SHR also showed an increase in mesangial periodic acid-Schiff-positive substance and in relative renal weight, both of which were significantly inhibited by DP-1904 (P less than 0.05). Thus, DP-1904 inhibited both TXB2 production and the progression of renal damage in STZ-SHR.     

Effects on prostanoid formation and pharmacokinetics of dazmegrel (UK-38,485), a novel thromboxane synthase inhibitor, in man

The pharmacokinetics of dazmegrel (UK-38,485), a novel selective thromboxane synthase inhibitor, and its effects on in vivo prostanoid formation were studied in a 2 weeks, multiple dose, placebo controlled, double blind trial in man. The drug was well tolerated. After dazmegrel 50-200 mg p.o. peak plasma levels of 0.7-3 mu/ml were reached within 1 hr. Elimination was of first order with a half life of 0.88 +/- 0.17 hr. Platelet count and bleeding time were unchanged by all regimes of dazmegrel used (100 and 200 mg b.i.d.; 50, 100 and 200 mg t.i.d.). Serum thromboxane (TXB2) was more than 95% suppressed one hour after all doses studied, but 200 mg t.i.d. were needed suppress circadian serum TXB2 profiles more than 90% at all times. Urinary excretion of 2,3-dinor-TXB2 (TXA2-M) fell by over 90%. An increase in the excretion of 2,3-dinor-6-keto-PGF1 alpha (PGI2-M), the major metabolite of prostacyclin, was largely transient and fell short of significance at all times. The ratio of TXA2-M to PGI2-M was lowered from about 5.0 to 0.2 and sustained throughout treatment. Dazmegrel selectively blocks in vivo and ex vivo TXA2 formation. Redirection of endoperoxides from total body TXA2 formation into prostacyclin formation is only minor under basal conditions.     

Characterization of the effects of isoprostanes on platelet aggregation in human whole blood

We tested the effects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer. None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub-threshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE(1)>8-iso PGE(2)>8-iso PGF(2alpha)>8-iso PGF(3alpha)>8-iso-13,14-dihydro-15-keto PGF(2alpha)). Blood incubated with LPS to induce a gross inflammatory response exhibited a time dependent (2 - 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. Thus, in human whole blood the action of 8-iso PGE(1), 8-iso PGE(2), 8-iso PGF(2alpha), 8-iso PGF(3alpha), and 8-iso-13,14-dihydro-15-keto PGF(2alpha) is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation.     

Inhibition of leukotriene B4 formation in human neutrophils after oral nafazatrom (Bay g 6575)

Three grams of nafazatrom (Bay g 6575), given orally to healthy male volunteers in a single dose, significantly reduce the formation of leukotriene B4 in polymorphonuclear leukocytes. LTB4 synthesis fell from 57.1 +/- 17.0 ng/10(7) PMNL, mean +/- S.D., in control to 34.3 +/- 14.4 ng/10(7) PMNL 3 hr after nafazatrom (2 P less than 0.001). In vitro, nafazatrom inhibited LTB4 formation in human PMNL in a dose dependent manner. At 1 microM nafazatrom LTB4 formation was reduced to 65% of the control value. Nafazatrom had no effect on the excretion of 2,3-dinor-6-keto-PGF1 alpha and 2,3-dinor-TXB2, the major urinary metabolites of endogenously synthesized PGI2 and TXA2, respectively. Serum levels of TXB2 in clotted whole blood also remained unchanged. The inhibitory effect of nafazatrom on leukotriene biosynthesis in human PMNL suggests a therapeutic potential of this drug in processes like allergy and chronic inflammation, where leukotrienes play a pathogenetic role.     

Nitrendipine and the humoral control of sodium homeostasis.

1. Nine healthy volunteers received 10 mg nitrendipine or placebo orally in random order. 2. In the subsequent 5 h urinary sodium excretion was 20% higher after nitrendipine, without any significant difference between the volume of urine excreted after nitrendipine or placebo. Mean blood pressure fell by 5 mm Hg (P less than 0.001), and mean heart rate increased by 5 beats min-1 (P less than 0.01) after nitrendipine but did not change after placebo. 3. These changes were accompanied by a significant elevation in plasma renin activity (P less than 0.001). A fall in plasma aldosterone following placebo appeared to be attenuated by nitrendipine. Plasma noradrenaline increased to a peak 3 h after nitrendipine administration (P less than 0.05) but did not change following placebo. A fall in the excretion of 6-keto PGF1 alpha following placebo was attenuated by nitrendipine. The total excretion of 6-keto PGF1 alpha after nitrendipine was significantly greater (P less than 0.05) than after placebo but not difference in the total excretion of PGE2 was detected. Nitrendipine did not affect urinary kallikrein excretion. 4. The natriuretic action of nitrendipine is not mediated by the kallikrein-kinin system, but may be related to changes in renal prostaglandins.     

蝙蝠葛酚性碱对血栓形成和血小板聚集的影响蝙蝠葛酚性碱对血栓形成和血小板聚集的影响

目的观察蝙蝠葛酚性碱(PAMD)对血栓形成、血小板聚集的影响并研究其作用机制。方法用动静脉短路血栓形成模型观察血栓形成；比浊法测定血小板聚集度；电镜技术观察血小板超微结构变化；放射免疫法测定TXB₂和6-酮基-PGF1α的水平；硝酸还原酶法测定兔血浆NO浓度。结果PAMD体内给药可剂量依赖性地抑制血栓形成及由ADP，AA和THR诱导的大鼠和兔的血小板的聚集；可显著抑制血小板超微结构的变化；能明显升高兔血管壁6-酮基-PGF1α产生量，对血小板释放的TXB₂无明显影响；还可提高兔血浆NO的浓度。结论PAMD具抗血栓形成和抗血小板聚集的作用，其机制与增加血管壁PGI₂含量，提高兔血浆NO的浓度有关。     

Effects of very low dose and enteric-coated acetylsalicylic acid on prostacyclin and thromboxane formation and on bleeding time in healthy subjects

Objective: Low dose acetylsalicylic acid (ASA) is widely used as an anti-aggregatory agent in the primary and secondary prevention of cardiovascular diseases. In an effort to spare prostacyclin formation and to reduce gastrointestinal side-effects, both very low doses and enteric-coated formulations of ASA have been introduced. However, it still remains unclear whether these different formulations and dosages are equally effective with respect to inhibition of platelet aggregation and thromboxane A₂ (TXA₂) formation. Methods: In a randomized study, we therefore investigated the effects of 100?mg ASA plain (p), 100?mg ASA enteric-coated (ec) and 40?mg ASA (p) to 36 healthy male subjects given for 7 days on platelet aggregation and endogenous prostanoid formation rates. Platelet aggregation and platelet TXB₂ release in platelet rich plasma (PRP) and serum TXB₂ and 6-keto-PGF_1α levels were determined at baseline and after 7 days of each medication. The urinary metabolites of TXA₂ (2,3-dinor-TXB₂) and prostacyclin (2,3-dinor-6-keto-PGF_1α) were measured by gas chromatography/tandem mass spectrometry in 24-h-urines at baseline and on day 7 of each medication. Results: Collagen-induced platelet aggregation was 73.1?±?1.6% of maximal aggregation at baseline. It was inhibited by 68.9%, 58.6% and 24.0% by ASA 100?mg plain, 100?mg enteric-coated, and 40?mg plain on day 7, respectively. Platelet TXB₂ release was 11?592.0?± 367.5?pg?·?ml^?1 PRP. It was inhibited by 90.1%, 86.5%, and 55.2% by ASA 100?mg plain, 100?mg enteric-coated, and 40?mg plain, respectively. Serum TXB₂ was almost completely reduced on day?7 by 100?mg ASA, but not by 40?mg ASA; serum 6-keto-PGF_1α was slightly, but significantly reduced in all three groups. Urinary 2,3-dinor-TXB₂ excretion was 196.0?±?41.5?pg?·?mg^?1 creatinine at baseline. It was reduced by 80.3% and 79.1% by ASA 100?mg plain and enteric-coated, respectively (each P?<?0.05 versus baseline), but only by 55.4% by ASA 40?mg plain (P?<?0.05 versus both formulations of ASA 100?mg). Conclusions: Our present data show that the plain and enteric-coated formulations of 100?mg ASA are equally effective in inhibiting platelet aggregation, platelet thromboxane production, and urinary 2,3-dinor-TXB₂ excretion rates. In contrast, a very low dose of 40?mg ASA was significantly less effective in inhibiting these indices of platelet activation in healthy human subjects. ASA enteric-coated 100?mg may be a useful alternative to 100?mg ASA (p) in patients with gastrointestinal side-effects, whereas 40?mg ASA (p) may be too low to inhibit sufficiently platelet activity in patients with cardiovascular diseases in whom platelet activity is increased.     

Opposite effects of nicotinic acid and pyridoxine on systemic prostacyclin,thromboxane and leukotriene production in man

The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6-ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6-8). Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4 excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.