Increase In Thromboxane A2 Research Articles

Kidney in the net of acute and long-haul coronavirus disease 2019: a potential role for lipid mediators in causing renal injury and fibrosis.

Severe COVID-19 disease is often complicated by acute kidney injury (AKI), which may transition to chronic kidney disease (CKD). Better understanding of underlying mechanisms is important in advancing therapeutic approaches. SARS-CoV-2-induced endothelial injury initiates platelet activation, platelet-neutrophil partnership and release of neutrophil extracellular traps. The resulting thromboinflammation causes ischemia-reperfusion (I/R) injury to end organs. Severe COVID-19 induces a lipid-mediator storm with massive increases in thromboxane A2 (TxA2) and PGD2, which promote thromboinflammation and apoptosis of renal tubular cells, respectively, and thereby enhance renal fibrosis. COVID-19-associated AKI improves rapidly in the majority. However, 15-30% have protracted renal injury, raising the specter of transition from AKI to CKD. In COVID-19, the lipid-mediator storm promotes thromboinflammation, ischemia-reperfusion injury and cytotoxicity. The thromboxane A2 and PGD2 signaling presents a therapeutic target with potential to mitigate AKI and transition to CKD. Ramatroban, the only dual antagonist of the thromboxane A2/TPr and PGD2/DPr2 signaling could potentially mitigate renal injury in acute and long-haul COVID. Urgent studies targeting the lipid-mediator storm are needed to potentially reduce the heavy burden of kidney disease emerging in the wake of the current pandemic.

To the Heart of the Matter

When cyclooxygenase (COX)-2–selective inhibitors (coxibs) first entered the market about 5 years ago, the major concern with regard to cardiovascular side effects related to their potential to increase blood pressure and cause salt and water retention, in a manner similar to conventional (nonselective) nonsteroidal antiinflammatory drugs (NSAIDs). In the short time since, wariness about these side effects has grown into widespread alarm about putative prothrombotic actions and generation of excess major cardiovascular events with these agents. See p 1024 In September 2004, safety findings of the Adenomatous Polyp Prevention on Vioxx (APPROVe) study indicated an increase in risk for myocardial infarction and stroke among subjects randomized to rofecoxib compared with those randomized to placebo. This study had been designed to examine recurrent colonic polyps rather than cardiovascular disease end points and therefore could only be considered hypothesis generating. Subsequent data from a number of observational studies further implicated the drug’s association with arterial thromboembolic disease. As with APPROVe, no single study generated sufficiently robust attestation by itself, but they provided concordant signals, and the accumulating evidence eventually reached a critical mass. As the data on rofecoxib emerged, concerns about other COX-2–selective agents on the market also grew. This was based on the assumption of a “class effect” for an increase in risk of cardiovascular disease related to preferential inhibition of prostacyclin over thromboxane and thus a tendency toward prothrombosis. The results presented by McAdam and colleagues in this issue of Circulation 1 challenge our view with regard to this prostanoid hypothesis and raise new questions about the mechanisms underlying the potential cardiovascular side effects of coxibs and traditional NSAIDs. The authors hypothesized that the enhanced systemic biosynthesis of prostacyclin in smokers was dependent on COX-2 activity. They also sought to determine the functional importance of COX2–derived prostacyclin (PGI2) in limiting platelet activation in smokers in vivo. Contrary to the conventional wisdom of an expected increase in the biosynthesis of TxA2 (related to increased platelet activation via COX-1), the authors demonstrated the opposite finding—ie, that COX-2 contributed to, and a COX-2 inhibitor reduced, TxA2 biosynthesis in smokers.

Vascular biology of thrombosis: platelet-vessel wall interactions and aspirin effects.

The antithrombotic effect of aspirin has long been recognized, and administration of low doses (80-160 mg/day) for the prevention of ischemic events in patients with coronary artery disease (CAD) is now generally considered to be routine practice. The action of aspirin derives mostly from the selective inhibition of cyclo-oxygenases (Cox). These enzymes (Cox-1 and Cox-2) catalyze the synthesis of eicosanoids, which play an important part in platelet-vessel wall interactions. Cox-1 catalyzes the synthesis of thromboxane A2 (Tx-A2), which causes platelet activation, vasoconstriction, and smooth muscle proliferation. Tx-A2 levels are elevated in conditions associated with platelet activation, including unstable angina and cerebral ischemia. Conversely, Cox-2 controls the synthesis of prostacyclin (PGI2), a local platelet regulator with an effect opposite to that of Tx-A2. PGI2 is produced as a compensatory response to increases in Tx-A2 during ischemic events. Aspirin is a more potent inhibitor of Cox-1 than of Cox-2, unlike other non-steroidal anti-inflammatory drugs (NSAIDs), which have limited selectivity. Aspirin at low doses selectively inhibits the formation of Tx-A2 without inhibiting the basal biosynthesis of cardioprotective PGI2. Furthermore, aspirin causes complete enzyme inhibition, without the recovery of enzyme activity at trough drug levels associated with conventional NSAIDs. The effect of aspirin in the prevention of ischemic events has been well documented in many recent clinical trials involving more than 50,000 patients with CAD. It is clear from these studies that aspirin, alone or in combination with other antithrombotics, significantly reduces the incidence of cardiovascular death, stroke, and myocardial infarction.

Altered coronary dilation in deoxycorticosterone acetate-salt hypertension.

To compare coronary dilation in uninephrectomized hypertensive deoxycorticosterone acetate (DOCA)-salt rats (HTRs), treated for 2 or 4 weeks, with age-matched uninephrectomized normotensive rats (NTRs). DESIGN AND METHODS Coronary perfusion pressure was recorded in isolated hearts perfused at a constant flow rate to evaluate coronary resistance. A decreased vasoconstriction due to NG-nitro-Larginine (NNLA, 30 pmol/I) in hearts from HTRs suggested a reduced basal nitric oxide (NO) release. In contrast, coronary vasodilation due to the NO donor, sodium nitroprusside (3 pmol/I), remained unaffected in 2-week HTRs, and was enhanced in 4-week HTRs. Cumulative dose-response curves to bradykinin induced an important vasodilation in NTRs, with a maximal response that remained unaffected in the presence of either NNLA (30 pmol/I), indomethacin (10 pmol/l) or the two combined. In contrast, hearts from HTRs showed a diminished maximal relaxation to bradykinin, suggesting an altered endothelium-dependent relaxation. The presence of NNLA or indomethacin had no effect on the weak relaxation observed in HTRs. However, NNLA and indomethacin combined unmasked an important relaxation due to bradykinin in HTRs. The addition of clotrimazole (1 pmol/I) to NNLA and indomethacin blunted the relaxation due to bradykinin in both NTRs and HTRs. Perfusion with superoxide dismutase (120 IU/ml) restored most of the coronary relaxation due to bradykinin in hearts from HTRs. Bradykinin-induced prostaglandin 12 (PGI2) and E2 (PGE2) production was unaffected by hypertension. No increase in thromboxane A2 (TXA2) due to bradykinin was detected. Finally, reduced reactivity to papaverine and forskolin was observed in hearts from HTRs. DOCA-salt hypertension is associated with alterations in coronary reactivity. Basal NO formation appears to be reduced in HTRs, but the intact relaxation to exogenous NO suggests a preserved guanylate cyclase pathway. In addition, alteration in adenylate cyclase activity, and not in prostaglandin production, may explain the blunted cAMP-mediated responses in HTRs. The combined nitric-oxide synthase (NOS) and cyclo-oxygenase (COX) inhibition unmasked an endothelium-derived hyperpolarizing factor (EDHF) involvement in the coronary dilation due to bradykinin in hearts from HTRs, suggesting that endothelial NO and PGI2, although unable to induce coronary smooth-muscle relaxation, can inhibit EDHF production in HTRs. Impairment in the adenylate cyclase pathway and the suppression of NO by free radicals may explain the blunted vasodilation in DOCA-salt hypertension.

Thromboxane A2 receptor mediation of calcium and calcium transients in rat cardiomyocytes.

We have examined the effect of the selective thromboxane A2 (TxA2) receptor agonist U46,619 on intracellular ionized Ca ([Ca2+]i) and the calcium transient rate (CATR) in cultured neonatal rat cardiomyocytes using the Ca-sensitive probe fura 2 and ratiometric microfluoroscopy. U46,619, 10(-6)-10(-8)M, increased basal diastolic Ca fluorescence and 10(-6) and 10(-7) M increased CATR. These effects were completely blocked by the highly selective TxA2 receptor antagonist SQ-29,548 (p > 0.5, n = 4 compared to baseline), confirming this response is a specific receptor-mediated event in the cardiomyocytes. TxA2 blockade did not diminish the Angiotensin (Ang II)-mediated [Ca2+]i and calcium transient rate response from that observed in non-blocked cells (p = 0.18 and 0.21 respectively, n = 4). The TxA2-mediated changes in Ca2+ fluorescence did not exhibit homologous desensitization as does Ang II, they did not exhibit heterologous desensitization, and maximally stimulating concentrations were additive in their effect on peak [Ca2+]i. These data support the hypothesis that TxA2 secretion or release following ischemia or other pathophysiologic events could alter cardiac calcium homeostasis. Although Ang II is reported to stimulate the release of TxA2 in a variety of tissues, including the heart, the Ca2+ and CATR response to Ang II are not diminished when TxA2 receptors are blocked. This study cannot rule out the possibility that Ang II-mediated increases in TxA2 may have an additive effect on Ca homeostasis.

Induction by endothelin‐1 of epithelium‐dependent relaxation of guinea‐pig trachea in vitro: role for nitric oxide

1. The purpose of the present experiments was to study the underlying mechanisms responsible for the relaxant action of endothelin-1 (ET-1) in the guinea-pig trachea in vitro. 2. In tracheal strips precontracted (60-70% of the maximum) with carbachol, ET-1 (1-100 nM) evoked slowly developing concentration-dependent relaxations. Preincubation of the tissues with the thromboxane A2/prostaglandin H2 receptor antagonist, BM 13505 (5 microM) significantly potentiated the relaxant response to ET-1. 3. Removal of the epithelium changed the response of precontracted tracheal preparations to ET-1 from a relaxation to a sustained contraction. 4. ET-1-induced relaxations were abolished by methylene blue (10 microM) and were almost completely attenuated by oxyhaemoglobin (5 microM) and NG-monomethyl-L-arginine (L-NMMA, 100 microM), an inhibitor of nitric oxide synthesis, but were not altered by indomethacin (10 microM). 5. In tracheal strips under passive tension, ET-1 (1-100 nM) elicited dose-dependent contractions. The sensitivity of tissues to ET-1 was significantly enhanced by removal of the epithelium (apparent EC50 values were 28.1 +/- 4.1 and 12.5 +/- 0.8 nM in intact and rubbed trachea, respectively, n = 7, P < 0.01). 6. Preincubation of intact tracheal strips with methylene blue, oxyhaemoglobin or L-NMMA did not mimic the effect of epithelium removal on ET-1-induced contractions. 7. There was a concentration-dependent increase in thromboxane A2 but not in PGE2 and prostacyclin release from intact tracheal strips following stimulation with ET-1 (5-100 nM). 8. These results show that ET-1 exerts a dual action on guinea-pig isolated trachea: it evokes contractions at low resting tone, whereas it induces relaxations at higher resting tone. The relaxant action of ET-1 may be mediated by nitric oxide released from epithelial cells and resultant activation of smooth muscle guanylate cyclase.

Low-dose aspirin in the prevention of preeclampsia and fetal growth retardation: Rationale, mechanisms, and clinical trials

Preeclampsia is characterized by a functional imbalance between vascular prostacyclin and thromboxane A2 production. On the basis of the hypothesis that preeclampsia is at least partially caused by an increase in thromboxane A2, some studies attempted to correct this pathologic condition by pharmacologic manipulation with low-dose aspirin. The current literature suggests that the use of low-dose aspirin during pregnancy is safe with regard to congenital anomalies and fetal, neonatal, and maternal cardiovascular physiologic state and hemostasis. Aspirin at least partially corrects the pathologic increase in angiotensin II sensitivity that precedes the clinical development of preeclampsia. In addition, some clinical trials have demonstrated that low-dose aspirin is effective in reducing the incidence of preeclampsia and/or fetal growth retardation in selected high-risk women. Currently, large clinical trials are in progress to evaluate the effectiveness and side effects of the use of low-dose aspirin in preventing preeclampsia and/or fetal growth retardation. Until these studies have been completed, it will remain unclear whether antiplatelet therapy, such as low-dose aspirin, should be adopted for the prevention of either preeclampsia or fetal growth retardation.

Plasma and Saliva Levels of PGI2 and TXA2 in the Headache‐Free Period of Classical Migraine Patients. The Effects of Nicardipine

The levels of Prostacyclin (PGI2) and Thromboxane A2 (TXA2) were assayed simultaneously (RIA) in the plasma and saliva of 9 patients suffering from classical migraine attacks. The assays were done during an attack-free period. In relation to the control group we observed a significant decrease in the plasma levels of PGI2 together with a sharp increase in TXA2 in saliva. When the patients were treated with nicardipine, a calcium antagonist, the TXA2 increase in saliva did not occur. These results suggest both a systemic and local effect in the classical migraine attacks. We explain and discuss our results by referring to the PGI2: TXA2 equilibrium system. Nicardipine action might be related to its ability to reduce the calcium entry into the cell induced by thromboxane.

Effect of in vivo coal dust exposure on arachidonic acid metabolism in the rat alveolar macrophage

Oxygenated metabolites of arachidonic acid (AA) are produced by the alveolar macrophage (AM) and have been shown to mediate inflammatory reactions. We therefore assessed the production of eicosanoids by AM harvested from the lungs of rats exposed to a bituminous coal dust for 2 wk in an inhalation chamber in order to determine if AA metabolism was altered in a manner that may promote an inflammatory response in the lung. Exposure to coal dust resulted in a 66% increase in the number of AM harvested, an increase in thromboxane A2 (TxA2) and leukotriene B4 (LTB4) production to 222% and 181% of control values, respectively, and a decrease in prostaglandin E2 (PGE2) production to 62% of control values. In AM harvested from rats allowed to breath clean air for 2 wk following coal dust exposure, PGE2 production returned to control levels but TxA2 and LTB4 production remained elevated. The TxA2 synthesis inhibitor UK 38,485 reduced TxA2 production in dust-exposed AM both immediately and 2 wk following exposure. Thus, exposure of rats to coal dust significantly alters the metabolism of AA in AM, with potentially important aspects of AA metabolism remaining altered even after a 2-wk recovery period. Based on the established role of eicosanoids in inflammatory and fibrotic processes, these results suggest that the alteration of AM eicosanoid production as a result of the inhalation of coal mine dust may be an important factor in the pathophysiology of coal workers' pneumoconiosis.

Effect of OKY 046, a thromboxane synthase inhibitor, on lung vascular permeability after pulmonary embolism in sheep.

OKY 046, a specific thromboxane synthase inhibitor, was used to investigate whether large pulmonary emboli, like microemboli, cause an increase in thromboxane A2 and an associated increase in vascular permeability in sheep. Nineteen sheep were anaesthetised and had cannulas inserted into the afferent lymphatic of the caudal mediastinal lymph node and pulmonary and carotid arteries. Several days later the animals were pretreated with placebo or OKY 046 0.4 mg/kg one hour before being given clotted blood 0.5 g/kg intravenously. After embolisation in the control animals mean pulmonary artery pressure (MPAP) rose from 12 to 34 mm Hg and pulmonary artery wedge pressure (PAWP) fell from 4.4 to 1.5 mm Hg; the cardiac index did not change but the physiological shunt (QS/QT) rose from 17% to 50%. One hour after embolisation the platelet count fell from 76 to 32 x 10(6)/l whereas at 15 minutes thromboxane B2 rose from 116 to 560 pg/ml in plasma and from 324 to 795 pg/ml in lymph (p less than 0.05). By 2 hours the concentration of thromboxane B2 was higher in lymph than in plasma. Lymph flow rose from 8.7 to a maximum of 27.3 ml/h at 15 minutes but despite the increase in flow the lymph:plasma (L:P) protein ratio did not fall, indicating an increased permeability of the blood vessels to protein. Pretreatment with OKY 046 inhibited the rise in plasma and lymph thromboxane B2, and limited the rise of QS/QT. The changes in MPAP, PAWP, cardiac index, platelet count, lymph flow, and L:P protein ratio, however, were no different from those in untreated sheep. These results indicate that a large pulmonary embolus leads to an increase in plasma and lung lymph thromboxane A2, which moderates the rise in QS/QT in part but not the increase in vascular permeability.