Urinary Excretion Of Thromboxane B2 Research Articles

Enhanced urinary excretion of thromboxane B2 in non-alcoholic fatty liver disease. Implication for antiplatelet treatment

Aim: Non-alcoholic fatty liver disease (NAFLD) represents the most common liver disease worldwide. Patients with NAFLD are at high risk for cardiovascular diseases that represents the major cause of morbidity and mortality in this setting. Platelets play a key role in precipitating atherosclerotic complications as indicated by interventional studies with aspirin, which significantly reduces cardiovascular events by impairing platelet Thromboxane B2 (TxB2) biosynthesis. We investigated the behaviour of platelet activation in patients with NAFLD.

Effect of rapid desensitization on platelet inhibition and basophil activation in patients with aspirin hypersensitivity and coronary disease

To determine antiplatelet efficacy after desensitization in patients with a history of aspirin hypersensitivity. We conducted a case-control study to evaluate the efficacy of aspirin 1 day (D1) and 6-8 weeks (W6-8) after desensitization. We also assessed ex vivo basophil reactivity to aspirin after desensitization. Cases were patients with coronary artery disease (CAD) and documented history of aspirin hypersensitivity who underwent rapid successful oral desensitization to aspirin. Controls were patients with stable CAD without hypersensitivity and receiving aspirin. Among 56 cases, 27 received aspirin for acute coronary syndromes and 29 were treated for stable CAD. Aspirin was effective (defined as light transmission aggregometry induced by arachidonic acid ≤20%) at D1 in 86% of cases (P = 0.045 vs. controls) and in 95% at W6-8, vs. 100% of controls (P = 0.39). Urinary excretion of thromboxane B2 diminished substantially in cases (P < 0.0001, D0 vs. W6-8) but remained higher than in controls (P = 0.03). Platelet reactivity (defined by platelet P-selectin expression, activated glycoprotein IIb/IIIa inhibitors, and platelet-monocyte aggregates) was similar in cases between D0 and D1 but decreased at W6-8. Basophil activation (quantified by upregulation of CD203c in response to aspirin) was higher in cases at W6-8 than in controls (P = 0.0002). Thus, following rapid desensitization, aspirin achieves rapid biological efficacy, which is slightly lower at D1, but becomes indistinguishable from chronically treated patients at W6-8. Persistent basophil activation several weeks after desensitization suggests infraclinical hypersensitivity and the need to continue aspirin to maintain desensitization.

The Paradox of Platelet Activation and Impaired Function: Platelet-von Willebrand Factor Interactions, and the Etiology of Thrombotic and Hemorrhagic Manifestations in Essential Thrombocythemia and Polycythemia Vera

Patients with essential thrombocythemia (ET) and polycythemia vera (PV), complicated by microvascular ischemic or thrombotic events, have shortened platelet survival, increased beta-thromboglobulin, platelet factor 4, and thrombomodulin levels, and increased urinary thromboxane B2 excretion. These are all reversible by inhibition of platelet cyclooxygenase 1 with aspirin, and are therefore indicative of platelet activation and platelet-mediated thrombotic processes. The thrombotic tendency persists as long as platelet counts are above the upper limit of normal (400 x 10 (9)/L). Despite strong evidence of in vivo platelet activation, the ex vivo platelet function tests are impaired. Platelet dysfunction in ET and PV typically is characterized by a missing second-wave adrenaline aggregation, an increased adenosine diphosphate aggregation threshold, and reduced secretion products, but a normal arachidonic acid or collagen-induced aggregation. The proposed concept is that platelets in thrombocythemia (ET and PV) are hypersensitive. Due to the existing high shear stress in the microvasculature (end-arterial circulation), platelets spontaneously activate, secrete their products, form aggregates mediated by von Willebrand factor (vWF) that transiently plug the microcirculation, deaggregate, and then recirculate as exhausted defective platelets with secondary storage pool disease on ex vivo analysis. At increasing platelet counts from below to above 1000 x 10 (9)/L, the thrombotic condition changes into an overt spontaneous bleeding tendency as a result of a functional vWF deficiency that is caused by proteolysis of large vWF multimers. This is consistent with acquired type 2 von Willebrand syndrome (AvWS). AvWS is reversible by reduction of the platelet count to normal. The acquired JAK2 V617F gain of function mutation is the cause of trilinear myeloproliferative disease with the sequential occurrence of ET and PV. Heterozygous JAK2 V617F mutation with slightly increased kinase activity is enough for the induction of spontaneous megakaryopoiesis and erythropoiesis, and an increase of hypersensitive platelets is the cause of aspirin-sensitive, platelet-mediated microvascular ischemic and thrombotic complications in ET and early PV mimicking ET. Homozygous JAK2 mutation with pronounced increase of kinase activity is associated with pronounced trilinear megakaryocyte, erythroid, and granulocytic myeloproliferation, with the most frequent clinical picture of classical PV complicated by major thrombosis, in addition to the platelet-mediated microvascular thrombotic syndrome of thrombocythemia.

Cyclooxygenase‐2 inhibition ameliorates early renal injury in Han:SPRD‐ cy rats with inherited kidney disease

Selective cyclooxygenase-2 (COX-2) inhibition appears to be renoprotective in some models of kidney disease, but not in others. The objective of our study was to examine the effects of COX-2 inhibition in a rat model of chronic kidney disease. Four week old Han:SPRD-cy rats were given either a standard rodent diet containing 3mg/kg body weight NS-398 (a selective COX-2 inhibitor) or a control diet with no drug for 7 weeks. Morphometric and immunohistochemical analyses revealed that NS-398 fed animals had reduced renal fibrosis, macrophage infiltration, epithelial cell proliferation and oxidant injury, compared to control fed animals. COX-2 inhibition did not alter the degree of cystic change or creatinine clearance. Kidney disease was associated with higher renal COX-1 and -2 enzyme activities. Treatment with NS398 blunted this increase in enzyme activity only for COX-2 (as indicated by 26% lowerrenal prostaglandin E2 (PGE2), 29% lower 6-keto-prostaglandin F1α (6-keto-PGF1α) and 28% lower total prostanoid production). NS398 decreased urinary excretion of thromboxane B2, PGE2 and 6-keto-PGF1α. In conclusion, COX-2 inhibition reduces the elevated renal COX-2 activity, prostanoid production and attenuates renal injury in this rat model of chronic renal disease. (Supported by funding from the Natural Sciences and Engineering Research Council of Canada)

Issue Highlights

HomeCirculationVol. 112, No. 7Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published16 Aug 2005https://doi.org/10.1161/circ.112.7.935Circulation. 2005;112:935REAL-TIME THREE-DIMENSIONAL ECHOCARDIOGRAPHY: A NOVEL TECHNIQUE TO QUANTIFY GLOBAL LEFT VENTRICULAR MECHANICAL DYSSYNCHRONY, by Kapetanakis et al.Left ventricular (LV) dyssynchrony is recognized as being an important contributor to LV dysfunction in patients with wide QRS complexes. Optimal evaluation of patients with dyssynchrony is uncertain, and various techniques have been described to identify appropriate candidates for cardiac resynchronization therapy (CRT) and to optimize settings after implantation. Kapetanakis et al describe a real-time 3-dimensional echocardiography technique in which global and regional volume and function are assessed in 89 healthy volunteers and 174 patients with and without LV dysfunction. A dyssynchrony index of the entire LV is derived that increases with worsening LV function irrespective of QRS duration. In 26 patients treated with CRT, the dyssynchrony index improves, and this correlates with reverse remodeling. This real-time, 3-dimensional, echo technique may help to quantify objectively the degree of dyssynchrony, direct CRT settings, and identify a larger group of patients with dyssynchrony in the absence of increased QRS duration. See p 992.CONTRIBUTION OF CYCLOOXYGENASE-2 TO ELEVATED BIOSYNTHESIS OF THROMBOXANE A2 AND PROSTACYCLIN IN CIGARETTE SMOKERS, by McAdam et al.In recent months, we have experienced an intense and fierce debate about the cardiovascular safety of COX-2 inhibitors. One of the issues in this context is their effects on the biosynthesis of prostaglandins. In this issue of Circulation, McAdam et al report on the effects of rofecoxib at a high dose on the biosynthesis of thromboxane A2 and prostacyclin in smokers and nonsmokers. Prostacyclin metabolites were increased in smokers and were reduced by rofecoxib; this also occurred to some degree in nonsmokers. Furthermore, the metabolites of thromboxane were increased in smokers and reduced by rofecoxib in smokers but not in nonsmokers. In contrast to the urinary excretion of thromboxane B2, plasma levels of thromboxane did not differ in smokers and nonsmokers and were unaffected by rofecoxib. This study demonstrates that, particularly in smokers, the increase in the biosynthesis of prostacyclin is largely derived from cyclooxygenase-2. Inhibition of this most likely compensatory mechanism in this group of patients at high risk for cardiovascular effects by COX-2 inhibitors may be disadvantageous in this context and potentially may facilitate thrombus formation in smokers. See p 1024.BILIRUBIN: A NATURAL INHIBITOR OF VASCULAR SMOOTH MUSCLE CELL PROLIFERATION, by Öllinger et al.Atherosclerosis is a disorder associated with vascular stress response, and heme oxygenase induction is one component of vascular stress. Considerable data demonstrate that induction of heme oxygenase ameliorates many features of vascular disease. The mechanism(s) responsible for such observations, however, have been unclear. In this issue, Öllinger and colleagues have examined the biological activity of a heme oxygenase product, bilirubin, with regard to vascular injury and smooth muscle cell proliferation. This study increases our understanding of how heme oxygenase induction may limit the vascular injury response. See p 1030.Visit http://www.circ.ahajournals.org:Clinician UpdateShould Aspirin Be Discontinued Before Coronary Artery Bypass Surgery? See p e85.Images in Cardiovascular MedicinePrinzmetal Angina in an Adolescent: Adjunctive Role of Tissue Synchronization Imaging. See p e91.Visualization of Regional Left Ventricular Mechanical Delay by Tissue Synchronization Imaging in Heart Failure Patients With Wide and Narrow QRS Complexes Undergoing Cardiac Resynchronization Therapy. See p e93.Adult Patient With Isolated Noncompaction of Ventricular Myocardium. See p e96. Download figureDownload PowerPointBook ReviewInside the FDA: The Business and Politics Behind the Drugs We Take and the Food We Eat. See p e98.CorrespondenceSee p e99. Previous Back to top Next FiguresReferencesRelatedDetails August 16, 2005Vol 112, Issue 7 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.112.7.935 Originally publishedAugust 16, 2005 PDF download Advertisement

Platelet-mediated microvascular inflammation and thrombosis in thrombocythemia vera: a distinct aspirin-responsive arterial thrombophilia, which transforms into a bleeding diathesis at increasing platelet counts

Erythromelalgia is the main, pathognomonic and presenting symptom in patients with essential thrombocythemia and thrombocythemia associated with polycythemia vera. Complete relief from erythromelalgic and acrocyanotic pain is obtained with the cyclooxygenase inhibitors aspirin and indomethacin, but not with sodiumsalicylate, dipyridamol, sulfinpyrozone and ticlopedine. Thus, cyclooxygenase metabolites are necessary for erythromelalgia to develop. Local platelet consumption in erythromelalgic areas became evident by the demonstration of arteriolar fibromuscular intimal proliferation and occlusions by platelet-rich thrombi in skin biopsies, by the findings of shortened platelet survival times, significant higher levels of platelet activation markers β-thromboglobulin, thrombomoduline and increased urinary thromboxane B2 excretion in thrombocythemia patients suffering from erythromelalgia. Aspirin treatment of erythromelalgia in thrombocythemia patients resulted in the disappearance of the erythromelalgic, thrombotic signs and symptoms, correction of the shortened platelet survival times, and a significant reduction of the increased levels of β-TG, PF4, TM and urinary TxB2 excretion to normal. Erythromelalgia is frequently preceded or followed by atypical transient neurologic, ocular or coronary ischemic symptoms, which specifically respond to low-dose aspirin or reduction of platelet counts to normal. The broad spectrum of acropareshesias, erythromelalgia and acrocyanotic ischemia together with the episodic and transient atypical TIAs and ocular or coronary ischemic symptoms are caused by spontaneous activation and aggregation of hypersensitive platelets in the end-arterial microvasculature involving the peripheral, cerebral and coronary circulation of thrombocythemia patients. These microvacular circulation ischemic disturbances in thrombocythemia vera already occur at platelet counts in excess of 400 × 10 9 l –1. Low-dose aspirin is highly effective and safe in the cure and prevention of thrombotic and ischemic events and does not elicit bleedings at platelet counts below 1000 × 10 9 l –1. Spontaneous hemorrhages usually occur at very high platelet counts far in excess of 1000 × 10 9 l –1 (HT) due to an acquired von Willebrand factor deficiency at increasing platelet counts. At platelet counts between 1000 and 2000 × 10 9 l –1, thrombosis and bleeding (ETT and HT) frequently occur in sequence or paradoxically and low-dose aspirin does prevent thrombotic complications but aggravates or may elicit bleeding symptoms. Reduction of the platelet count to below 1000 × 10 9 l –1 by platelet lowering agents usually results in the disappearance of the bleeding tendency and improvement of the von Willebrand syndrome, but the thrombotic tendency persists as long as platelet counts are above the upper limit of normal.

Dietary chloride does not correlate with urinary thromboxane in deoxycorticosterone acetate–treated rats

Renal vascular resistance in deoxycorticosterone acetate (DOCA) salt–treated uninephrectomized rats is increased by high dietary chloride. Because DOCA salt–hypertensive rats exhibit an increased urinary excretion of thromboxane B2 (TXB2), a metabolite of thromboxane A2 (TXA2), the increased TXB2 excretion by DOCA salt–treated rats could relate to elevated dietary chloride, increased blood pressure, and/or the presence of intact renal tubules. We hypothesized that high NaCl intake, resulting in an elevated tubular chloride excretion, stimulates TXA2 production. A result of that production could be renal vasoconstriction. Baseline blood pressures were measured for 10 days, and then the rats were treated with DOCA (30 mg/kg) and fed (1) normal NaCl, (2) normal sodium with high chloride, or (3) high sodium chloride (NaCl) for 4.5 weeks. Next, the rats were uninephrectomized (1K) or unihydronephrectomized (1KHK) to yield one kidney without an intact tubular system and therefore no macula densa. Two and a half weeks later, urinary excretion of TXB2 was determined. DOCA-high NaCl-fed 1KHK or 1K rats had significant increases in systemic blood pressure to 172 ± 12 and 190 ± 5 mm Hg, respectively, compared with no significant increase in blood pressure among the other groups. Urinary TXB2 excretion was increased to 29 ± 4 pg per 24 hours per gram of body weight in all DOCA-treated 1KHK and 1K animals regardless of diet compared with DOCA-treated animals with two intact kidneys (13 ± 2 pg per 24 hours per gram of body weight). DOCA treatment in rats with one functional kidney results in the excretion of high levels of urinary TXB2 unrelated to dietary chloride load, blood pressure, or intact renal tubules. (J Lab Clin Med 2000;135:493-7)

Low density lipoprotein apheresis therapy for steroid-resistant nephrotic syndrome

The pathogenic role of hyperlipidemia in long-standing nephrotic syndrome (NS) is known to be responsible for both the progression of glomerulosclerosis and tubulointerstitial injury, especially in focal segmental glomerulosclerosis (FGS). Aggressive lipid lowering treatment by low density lipoprotein (LDL) apheresis (LDL-A) using a dextran sulfate cellulose column to treat patients with steroid-resistant or frequently recurrent severe NS was performed first without fixing the protocol in eight patients with FGS and one with minimal change nephrotic syndrome (MCNS). The period of NS before LDL-A, number and average intervals of LDL-A until the end of the therapy, and the prognosis were investigated. Next, a multicenter study with a fixed protocol of LDL-A treatment was designed in combination with steroid therapy for treatment twice a week for three weeks and weekly for six weeks, and was performed in 17 patients with FGS. The effects on the state of NS in addition to the change of urinary eicosanoid metabolites and remission rates were evaluated. In the preliminary study, along with a rapid improvement of hyperlipidemia, a high incidence of remission was achieved by LDL-A performed at relatively short intervals. In the multicenter study with a fixed protocol, there was a significant decrease of urinary protein (P < 0.001) and increase of serum albumin (P < 0.02) as well as a decrease of thromboxane B2 (TXB2) excretion (P < 0.05) after the treatment. Urinary excretion of TXB2 was significantly reduced after LDL-A (P < 0.05). The rate of entering into complete or incomplete remission was 71% with a relatively short duration of nephrotic-range proteinuria using the LDL-A therapy in comparison with steroid therapy alone. The rapid improvement of hypercholesterolemia with LDL-A treatment may provide a new approach for a high rate of improvement in the degree of NS in steroid-resistant NS of FGS and MCNS.

Effects of Ridogrel, a Thromboxane Synthase Inhibitor and Receptor Antagonist, on Blood Pressure in the Spontaneously Hypertensive Rat

Ridogrel is a dual acting thromboxane synthase inhibit or/TP receptor antagonist. We examined the effects of single and multiple doses on systolic blood pressure in stroke-prone spontaneously hypertensive rats. Single doses of ridogrel (5 to 125 mg/kg) did not affect systolic blood pressure or furosemide-stimulated excretion rates of thromboxane B2 or 6-keto-prostaglandin F1α, although ex vivo serum thromboxane B2 was dose-dependently reduced up to 95%. In contrast, repeated dosing (7 days) with ridogrel (3 to 25 mg/kg/day), had an antihypertensive effect in 12-week-old stroke-prone spontaneously hypertensive rats. At 25 mg/kg/day, ridogrel reduced systolic blood pressure from 200±6.1 to 173±6.7 mmHg (n=12, P<0.01). Ridogrel dose-dependently reduced serum thromboxane B2 and increased plasma renin activity. Unlike single doses, repeated dosing reduced urinary thromboxane B2 excretion (from 103 ±7 ng/day to 49±10ng/day, P<0.01) while preserving 6-keto-prostaglandin F1α excretion. Ketoprofen, a cyclo-oxygenase inhibitor, (10 mg/kg/day for 7 days), depressed urine 6-keto-prostaglandin F1α in addition to attenuating serum and urine thromboxane B2. Ketoprofen prevented the antihypertensive effects of ridogrel. Ridogrel did not lower systolic blood pressure in Sprague-Dawley rats. We conclude that the antihypertensive effect of ridogrel involves preserving renal prostaglandin synthesis during thromboxane attenuation.

Reduction of chronic ciclosporin nephrotoxicity by thromboxane synthase inhibition with OKY-046.

Ciclosporin A (CsA) is a potent immunosuppressive agent which is extremely effective in controlling allograft rejection and in the treatment of autoimmune disease and nephrotic syndrome. Unfortunately, its use is limited by chronic, irreversible nephrotoxicity. Administration of CsA induces renal vasoconstriction, causing a reduction in renal blood flow. An alteration of the prostaglandin-thromboxane cascade may be involved in the vasoconstriction. We studied the role of thromboxane A2 in CsA nephrotoxicity and the ability of a thromboxane synthase inhibitor, OKY-046, to reduce the CsA nephrotoxicity. Daily administration of CsA 25 mg/kg for 28 days to Sprague-Dawley rats resulted in increased excretion of urinary thomboxane B2 (47.9+/-11.5 vs. 27.2+/-9.7 ng/24 h; p<0.05) and decreased creatinine clearance (0.25+/-0.07 vs. 0.43+/-0.17ml/min/100 g; p<0.01) as compared with administration of vehicle only. Histologically, large numbers of lysosomes in the tubular epithelium were characteristic. Coadministration of OKY-046 prevented both the rise in urinary thromboxane B2 excretion (40.0+/-11.8 ng/24 h) and the reduction in the creatinine clearance (0.44+/-0.11 ml/min/100 g). The severity of the histological changes was significantly diminished. Selective inhibition of thromboxane production with OKY-046 may be valuable in the attenuation of CsA nephrotoxicity.

Effects of dietary n-3 fatty acid supplementation versus thromboxane synthetase inhibition on gentamicin-induced nephrotoxicosis in healthy male dogs

Abstract Objective To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin. Design Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration. Animals Eighteen 6-month-old male Beagles, 6 in each group. Results After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs, TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1α (PGF1α) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF1α-to-TXB2 ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs. Conclusion Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis. Clinical Relevance Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis. (Am J Vet Res 1996;57:948–956)

Adriamycin-Related Hypertension in Pregnant Rats: Response to a Thromboxane Receptor Antagonist

1. In previous works we have described the development of hypertension and aggravation of proteinuria in rats who became pregnant after the administration of Adriamycin. This was associated with an increase in the glomerular thromboxane B2-prostaglandin E2 ratio. 2. To assess the pathogenetic role of thromboxane in this model, female Wistar rats were mated 2 weeks after receiving Adriamycin (3.5 mg/kg intravenously). Rats were then treated with the thromboxane-receptor antagonist daltroban, 60 mg day-1 kg-1 orally, beginning on day 11 of pregnancy. Systolic blood pressure, proteinuria and the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 were measured serially before mating, and on days 14 and 21 of pregnancy. The results were compared with those in Adriamycin-(treated) pregnant rats not treated with daltroban, Adriamycin-treated virgin rats and normal virgin or pregnant rats either treated or untreated with daltroban. 3. In daltroban-treated pregnant and virgin rats treated with Adriamycin, systolic blood pressure remained normal, whereas it increased significantly (P < 0.05) in untreated animals. On day 14, blood pressure was higher in non-daltroban-treated Adriamycin-treated pregnant rats than in non-daltroban-treated Adriamycin-treated virgin rats. Treatment had no effect on blood pressure in normal virgin or pregnant rats. Proteinuria was higher in pregnant rats treated with Adriamycin than in Adriamycin-treated virgin rats, but it was not reduced by daltroban.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of swim training on blood pressure, catecholamines and prostaglandins in spontaneously hypertensive rats.

A 6-month program of exercise with a daily swimming time of 30 minutes 3 times a week was carried out in female spontaneously hypertensive rats (SHR) to assess the roles of catecholamine and prostaglandin metabolism in the antihypertensive effect of chronic exercise conditioning. Swim training resulted in a significant reduction of mean blood pressure in SHR by 13.3 mmHg as compared with sedentary controls (158.8 +/- 5.0 versus 172.1 +/- 3.3 mmHg, p < 0.05). The increase in plasma levels of norepinephrine and epinephrine after acute blood loss of 2% of body weight were smaller in trained than control SHR. The daily urinary excretion of thromboxane B2, a stable metabolite of thromboxane A2, was significantly decreased by 33% in swim trained SHR as compared with control SHR (p < 0.01), while there was no difference in urinary excretion of prostaglandin E2 or 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin. These findings indicate that both the suppression of the sympathoadrenal system and decrease in vasoconstrictory prostaglandins in the kidney may have shared in the antihypertensive effect of exercise training in SHR.

Incomplete Inhibition of Platelet Secretion by Low-dose Aspirin

This study determines the effects of low-dose oral acetylsalicylic acid (Aspirin) on platelet aggregation and dense granule secretion in relation to inhibition of thromboxane formation. In addition, possible modifications of inhibition of platelet function by iloprost and linsidomine (SIN-1) were also studied. Aspirin (40 mg/day) was administered to 15 healthy male non-smoking volunteers for 8 consecutive days. Platelet function was measured ex vivo before and 12 h after the last drug intake. At the same times urinary excretion of thromboxane B(2) (TXB(2)) and 6-oxo-PGF(1α) were determined. Asirin treatment resulted in a significant (P < 0.01), by 65%, reduction of urinary TX B(2) excretion, whereas urinary excretion of 6-oxo-PGF(1α) remained unchanged, demonstrating the expected selectivity of low-dose aspirin for the platelet cyclooxygenase. There was also a nearly complete (93-95%) inhibition of collagen (0.3-5 μg/ml)-induced thromboxane formation in platelets. However, collagen-induced ATP-and 5-HT secretion was much less inhibited by aspirin and was reduced by only 20% at 5 μg/ml collagen. Similar results were obtained with ADP while thrombin (> 1.2 IU/ml)-induced 5-HT secretion was not antagonized at all. Also aspirin did not affect the inhibition of platelet function by iloprost and linsidomine (SIN-1). It is concluded that stimulation of platelet secretion by stronger stimuli, such as collagen or thrombin, is largely cyclooxygenase-independent and may not be detected by measuring serum thromboxane levels. This may be relevant for clinical situations with shear-stress-induced platelet activation, for example at carotis stenoses or other types of atherosclerotic plaques.

Endothelial vasoactive mediators in preeclampsia

In recent years an increasing amount of evidence supports the concept that preeclampsia is an endothelial disease. The purpose of our study was to evaluate the extent to which endothelial cell dysfunction is involved in pathophysiology of preeclampsia. We studied the urinary excretion of thromboxane B2 and 6-keto-prostaglandin F1 alpha and the venous plasma endothelin levels in 23 preeclamptic patients and in control subjects. In six of these patients and in six controls arterial plasma endothelin levels were also measured. In addition, plasma levels of calcitonin gene-related peptide and plasma fibronectin levels were measured. Results were analyzed by Wilcoxon's rank-sum test or signed-rank test. In preeclampsia the urinary thromboxane B2/6-keto-prostaglandin F1 alpha ratio (p < 0.001), venous plasma endothelin levels (p < 0.001), and plasma fibronectin levels (p < 0.001) were significantly elevated compared with normotensive pregnancy. Arterial plasma endothelin levels were significantly higher than venous plasma endothelin levels in normotensive and hypertensive patients (p < 0.05). Calcitonin gene-related peptide levels showed a wide range in normotensive pregnancy and in preeclampsia, but the difference was not significant. These results confirm the extensive involvement of the endothelium in the pathophysiology of preeclampsia. Preeclamptic vasoconstriction seems to be mediated by an increase in the vasoconstrictor autocoids thromboxane A2 and endothelin. Production of prostacyclin by the vessel wall and endovascular trophoblast might be just a pivotal escape mechanism of the uteroplacental circulation. Calcitonin gene-related peptide appears not to be involved in the pathophysiology of preeclampsia.

Pharmacokinetics and biochemical efficacy of pirmagrel, a thromboxane synthase inhibitor, in renal allograft recipients.

The effects of a 48-hour 0.5 mg/kg/hr infusion of the thromboxane synthase inhibitor pirmagrel were studied in 10 renal allograft recipients with cyclosporine nephrotoxicity. Plasma concentrations reached a mean steady-state plasma level of 1798 +/- 481 ng/ml. Biphasic, rapid elimination of pirmagrel was observed with a distribution half-life of 6.7 minutes and a terminal half-life of 73 minutes. Plasma clearance and the volume of distribution of the drug were 300 +/- 87 ml/hr/kg and 497 +/- 232 ml/kg, respectively. The pharmacodynamic effects of pirmagrel were marked by a mean 96% suppression of serum thromboxane B2 (TXB2), which coincided with a suppression of urinary excretion of TXB2, 2,3-dinor-TXB2, and 11-dehydro-TXB2 of 85% +/- 8%, 91% +/- 5%, and 89% +/- 9%, respectively. Urinary excretion of all thromboxane metabolites measured at the end of 1 week after termination of infusion was returned to the baseline. In conclusion, pirmagrel caused effective and sustained suppression of all thromboxane derived metabolites in plasma and urine during continuous infusion in kidney transplant patients receiving cyclosporine.

Altered prostaglandin synthesis and impaired sodium conservation in the kidneys of old rats.

1. The aim of this investigation was to study the role of prostaglandins in the impaired Na+ conservation of the ageing kidney. 2. We measured the urinary excretion of thromboxane B2, 6-keto-prostaglandin F1 alpha and prostaglandin E2 in young (3-4 months) and old (20-21 months) rats after 12, 24 and 36 h of Na+ deprivation. In a separate protocol, we measured prostanoid synthesis by isolated glomeruli, cortical homogenates, medullary slices and papillary slices from young and old rats in basal conditions and after 15 days of dietary Na+ deprivation. 3. In the acute study, urinary excretion of 6-keto-prostaglandin F1 alpha and prostaglandin E2 decreased in young but not in old rats. Urinary excretion of prostaglandin E2 was lower in old rats, but did not vary significantly with Na+ deprivation. 4. In old rats, thromboxane B2 synthesis was increased in all the portions of the kidney except the medulla. Production of 6-keto-prostaglandin F1 alpha was elevated in glomeruli and tended to increase in the cortex. Prostaglandin E2 synthesis was also elevated in the cortex. Thromboxane B2 synthesis tended to increase in the medulla and was enhanced in the papilla. After Na+ deprivation, only glomerular prostaglandin E2 synthesis increased in young rats. In old rats, cortical and papillary synthesis of 6-keto-prostaglandin F1 alpha increased, whereas prostaglandin E2 synthesis did not change. 5. The results suggest increased thromboxane synthesis in the ageing kidney. Increased prostacyclin and prostaglandin E2 synthesis may be an attempt to counteract enhanced thromboxane production.(ABSTRACT TRUNCATED AT 250 WORDS)

The renotropic effect of ovine luteinizing hormone on subtotally nephrectomized rats.

Some of luteinizing hormone (LH) isoforms can stimulate renal growth. The objective of this study is to determine whether the administration of LH modifies subtotal nephrectomy-induced chronic renal failure. Castrated 3/4-nephrectomized male rats were divided into four groups of seven each and fed a low-protein (6%) diet. Ovine LH with renotropic activity (40 micrograms/day) or vehicle only (control) was given for three weeks or six weeks. Compared with controls, remnant kidney weights (% body weight) in LH-treated rats had increased significantly at three weeks (0.385 +/- 0.019 vs 0.443 +/- 0.052, P less than 0.02), but not at six weeks (0.281 +/- 0.004 vs 0.272 +/- 0.013). 24 h creatinine clearance (ml/day/100 g body weight) increased significantly both by three weeks (242 +/- 58 vs 301 +/- 36, P less than 0.05), and six weeks (323 +/- 55 vs 395 +/- 10, P less than 0.01). Urinary thromboxane B2 excretion increased in LH-treated rats, suggesting that hemodynamic changes may play a role in increasing creatinine clearance. Our results suggest that renotropically active oLH stimulated the glomerular function in castrated rats with reduced renal mass. Further study may clarify its clinical usefulness.

Adrenergic stimulation of renal prostanoids in the Lyon hypertensive rat.

Young, genetically hypertensive Lyon (LH) rats exhibited an increased renal in vivo turnover of norepinephrine and an elevated urinary excretion of thromboxane B2 when compared with normotensive (LN) and low blood pressure (LL) controls. Therefore, the effects of norepinephrine (1.2 x 10(-8) to 9.6 x 10(-7) M) and of phenylephrine (5 x 10(-8) to 1.9 x 10(-6) M) on renal function and the urinary excretion of prostanoids were assessed in isolated perfused kidneys of 8-week-old LH, LN, and LL rats. In addition, the effects of norepinephrine were assessed before and during thromboxane A2/prostaglandin H2 receptor blockade by AH23848 (4 x 10(-6) M). Before drug infusion, LH kidneys differed from those of LN and LL controls by having an elevated renal vascular resistance and a decreased natriuresis and glomerular filtration rate; the urinary output of prostaglandin E2 and F2 alpha, of 6-ketoprostaglandin F1 alpha, and of thromboxane B2 was similar in the three strains. The constrictor effects of norepinephrine and phenylephrine were significantly increased in LH rat kidneys compared with LL but not with LN controls, and their pressure-natriuresis was markedly reduced. Norepinephrine and phenylephrine induced a 10- to 20-fold dose-dependent increase in the synthesis of the four prostanoids, which was more pronounced in LH than in LN and LL rats for thromboxane B2 only. AH23848 infusion significantly reduced the vascular effects of norepinephrine and increased the natriuretic response of LH but not of LN and LL rat kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)

THE RELATIONSHIP OF URINARY THROMBOXANE EXCRETION TO CYCLOSPORINE NEPHROTOXICITY

Alterations in renal prostaglandin production have recently been postulated to modulate the decrease in renal blood flow associated with cyclosporine nephrotoxicity. In particular, increases in renal production of the potent vasoconstrictor thromboxane A2 have been implicated in the pathogenesis of this disorder. The present study was undertaken to explore the relationship between alterations in urinary thromboxane B2 excretion (UTxB2V) and CsA nephrotoxicity in two rat models. Male Sprague-Dawley (SD) rats were treated for 14 days with CsA 50 mg/kg/day (n = 8) or olive oil (C) (n = 9) by gavage. Creatinine clearance (Ccr), urine flow (V), and urinary excretion rates of sodium, N-acetyl-beta-D-glucosaminidase (NAG), glucose, and TxB2 were determined before and after treatment. A similar study was conducted using Fischer rats (CsA: n = 10, C: n = 13). In Fischer rats, CsA caused a 35% decrease in Ccr (P = 0.01), a 33% decrease in sodium excretion (P = 0.02), and a greater than 2-fold increase in NAG excretion (P = 0.03), while V, glucose excretion, and UTxB2V did not change. Although similar changes in sodium and NAG excretion were seen after CsA administration in SD rats, Ccr was not affected. Additional findings in SD rats included a 3-fold increase in V (P less than 0.01), a 24-fold increase in glucose excretion (P = 0.03), and a 5-fold increase in UTxB2V (P = 0.04). Thus, Fischer rats developed CsA nephrotoxicity in the absence of increased UTxB2V. In contrast, SD rats failed to develop nephrotoxicity despite a marked increase in UTxB2V. We conclude that changes in renal TxA2 production are unrelated to the development of CsA nephrotoxicity.