thromboxane-a2 and Myocardial-Ischemia

One of major complications of ischemic heart disease is myocardial infarction, which develops as a result of thrombosis at the site of ruptured atherosclerotic plaque. Platelets activation and aggregation are the key events of this process. The efficiency of aspirin and/or clopidogrel use is limited by residual platelet reactivity what indicates the need to explore its mechanisms. This review covers intracellular signaling systems involved in realization of effects of the main platelet agonists in order to specify new molecules for the target therapy in case of aspirin resistance.

Topics: Humans; Myocardial Infarction; Myocardial Ischemia; Plaque, Atherosclerotic; Platelet Aggregation; Platelet Aggregation Inhibitors; Signal Transduction; Thromboxane A2

Aspirin is an antiplatelet drug, inhibiting the cyclooxygenase activity of platelet prostaglandin H synthase-1 and almost complete suppressing platelet capacity to generate the prothrombotic and proatherogenic thromboxane A2. Antiplatelet therapy with aspirin reduces the risk of serious vascular events by about a quarter in patients who are at high risk because they already have occlusive vascular disease. However, the inhibition of thromboxane-dependent platelet function by aspirin is effective for the prevention of thrombosis, but is also associated with excess bleeding, although the absolute increase in major gastrointestinal or other major extracranial bleeds is an order of magnitude smaller. For secondary prevention of vascular events, the benefits of aspirin therapy substantially exceed the risks. Therefore, aspirin is a cornerstone of antithrombotic therapy in acute coronary syndromes, in chronic ischemic heart disease and in percutaneous coronary intervention. On the other hand, the role of aspirin in primary prevention remains uncertain and it is still debated, because the absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis and the reduction in vascular events needs to be weighed against any increase in major bleeds. Future data from ongoing studies will help us to identify people at high vascular risk who take advantage from aspirin therapy for primary prevention or will indicate if specific category of high risk patients, like patients with diabetes, could be better protected from an increase in the frequency of aspirin administration.

Topics: Animals; Aspirin; Blood Platelets; Cyclooxygenase 1; Cyclooxygenase Inhibitors; Hemorrhage; History, 20th Century; History, 21st Century; Humans; Myocardial Ischemia; Patient Selection; Platelet Aggregation Inhibitors; Primary Prevention; Risk Factors; Secondary Prevention; Thromboxane A2; Treatment Outcome

The early period following an acute coronary syndrome (ACS) is characterised by atherosclerotic plaque destabilisation and a pro-coagulant state, and is when patients are at highest risk for recurrent cardiovascular events and mortality. Statins decrease thrombus formation and increase fibrinolysis, inhibit platelet reactivity and aggregation, improve endothelial function in patients with coronary artery disease and have a major role in plaque stabilisation. Several studies showed that initiation of early statin therapy in these settings may have beneficial effects. This review summarises the current data on statins in the setting of ACSs. Known and other possible mechanisms of action are described. The pathophysiological mechanisms, histological features and biochemical characteristics of ACS are different than those with stable coronary disease, thereby suggesting that the mechanisms whereby statins exert their benefits in ACS may be distinct from those for stable CHD. Initiation of the therapy during hospitalisation rather than at the time of hospital discharge may provide protection against early recurrent cardiovascular events and also improve patients' compliance.

Topics: C-Reactive Protein; Cholesterol, LDL; Clinical Trials as Topic; Coronary Artery Disease; Dose-Response Relationship, Drug; Endothelium, Vascular; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myocardial Ischemia; Platelet Aggregation Inhibitors; Risk Factors; Syndrome; Thromboxane A2

This report reviews the author's involvement in the growth of ideas and basic concepts in myocardial ischemia resulting in the histological changes of myocardial infarction. Concepts arising from the study of myocardial substrate utilization, activation of the inducible form of nitric oxide synthase and production of prostacyclin and thromboxane in the infarcted heart are presented. New approaches are discussed dealing with the effects of nonsteroidal anti-inflammatory drugs on myocardial production of nitric oxide and prostanoids, and with the relevance of the inducible form of cyclooxygenase. The review also records a number of significant similarities between angiogenesis in the ischemic heart and some cancers. Angiogenesis in both instances originates from inflammatory reactions, illustrating how different tissues and organs such as ischemic heart muscle and cancer react to similar pathological stimuli in an identical manner. This multifocal approach opens new concepts on myocardial ischemia and cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Colonic Neoplasms; Cyclooxygenase Inhibitors; Endothelial Growth Factors; Epoprostenol; Gene Transfer Techniques; Genetic Therapy; Humans; Lymphokines; Myocardial Infarction; Myocardial Ischemia; Myocardium; Neovascularization, Pathologic; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Prostaglandin-Endoperoxide Synthases; Thromboxane A2; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

This review presents a comprehensive discussion on the chemistry, pharmacokinetics, and pharmacodynamics of ifetroban sodium, a new thomboxane A2/prostaglandin H2 receptor antagonist. Thromboxane A2 is an arachidonic acid product, formed by the enzyme cyclooxygenase. In contrast to other cyclooxygenase products, thromboxane A2 has been shown to be involved in vascular contraction and has been implicated in platelet activation. In general, results of clinical studies and animal experiments indicate that hypertension is associated with hyperaggregability of platelets and increased thomboxane A2 levels in blood, urine, and tissues. The precursors to thromboxane A2, prostaglandin G2, and prostaglandin H2, also bind and activate the same receptors. Thus, a receptor antagonist was thought to be an improved strategy for reversing the actions of thromboxane A2/prostaglandin H2, rather than a thromboxane synthesis inhibitor. This review describes new methods for the synthesis and analysis of ifetroban, its tissue distribution, and its actions in a variety of animal models and disease states. We describe studies on the mechanisms of how ifetroban relaxes experimentally contracted isolated vascular tissue, and on the effects of ifetroban on myocardial ischemia, hypertension, stroke, thrombosis, and its effects on platelets. These experiments were conducted on several animal models, including dog, ferret, and rat, as well as on humans. Clinical studies are also described. These investigations show that ifetroban sodium is effective at reversing the effects of thromboxane A2- and prostaglandin H2-mediated processes.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypertension; Muscle Contraction; Muscle, Smooth, Vascular; Myocardial Ischemia; Oxazoles; Platelet Aggregation Inhibitors; Prostaglandin H2; Prostaglandins H; Randomized Controlled Trials as Topic; Receptors, Prostaglandin; Receptors, Thromboxane; Stroke; Thrombosis; Thromboxane A2

Daily life cardiac ischaemia is defined as reversible myocardial cellular hypoxia that occurs during activities of daily living, without artificial provocation. Most of these daily life ischaemic episodes are not associated with symptoms. However, it is not practical to distinguish silent versus symptomatic daily life ischaemia as both are associated with haemodynamic abnormalities and future adverse outcomes. Daily life cardiac ischaemia is best detected using ambulatory electrocardiogram (ECG) monitoring; however, there are other diagnostic tools (e.g. exercise treadmill) that can be used. Once detected, the optimal therapy for daily life myocardial ischaemia has yet to be identified. However, it does appear that usual antianginal medications including nitrates, beta-blockers, calcium antagonists and antiplatelet drugs are effective in reducing the incidence and severity of daily life myocardial ischaemia. Medical therapy and revascularisation should be utilised to obliterate all episodes of daily life cardiac ischaemia to prevent future cardiac events. Moreover, the efficacy of the chosen therapeutic regimen for each patient should be documented with follow-up objective testing. The diagnosis and management of daily life myocardial ischaemia is continually evolving. Future research as well as economic considerations will shape future management strategies.

Topics: Activities of Daily Living; Adrenergic beta-Antagonists; Aspirin; Calcium Channel Blockers; Drug Therapy, Combination; Humans; Myocardial Ischemia; Myocardial Revascularization; Nitrates; Outcome Assessment, Health Care; Risk Factors; Thromboxane A2

The causes of ventricular arrhythmias in the acute setting of coronary artery disease (myocardial ischaemia and reperfusion) may be approached using two paradigms. One, the electrophysiological paradigm (disturbance of ionic homeostasis, electrogenesis, and conduction) has not been addressed in detail here. Instead, we have focused on the concept of a chemical paradigm of arrhythmogenesis. Many endogenous chemical substances (derived from the myocardium, nerves, blood plasma, platelets, leucocytes, and endothelium) accumulate in the ischaemic tissue or are produced during reperfusion and many of these have been suggested to modulate ventricular arrhythmias. Some substances may be arrhythmogenic and others may be antiarrhythmic. Together they determine whether or not arrhythmias occur. Potentially arrhythmogenic substances include potassium, catecholamines, cAMP, histamine, 5-HT, lysophosphatidylcholine, palmitylcarnitine, platelet activating factor, prostaglandins, leukotrienes, thromboxane A2, angiotensin II, endothelin, opioids, protons, calcium, and free radicals. We have considered each of these, with the objective of evaluating which are important in arrhythmogenesis in acute ischaemia and reperfusion. Two alternative models of arrhythmogenesis are possible in the context of the chemical paradigm: a series model (where one substance or its effects determines the arrhythmogenicity of another) and a parallel model (where numerous substances operate independently to cause ventricular arrhythmias). It is not yet clear which model is most appropriate; a combination of the two is possible, so a working prototype has been constructed which accommodates both. A set of criteria (hitherto lacking) for establishing whether a substance is sufficient and necessary for arrhythmogenesis is proposed. Some generalisations are given on approaches to establishment of these criteria for putative arrhythmogenic substances. Finally, we have considered how arrhythmogenic drug development may be influenced by using the chemical paradigm as an alternative to the electrophysiological paradigm of arrhythmogenesis.

Topics: Acute Disease; Arrhythmias, Cardiac; Calcium; Endothelins; Free Radicals; Humans; Myocardial Ischemia; Myocardial Reperfusion Injury; Potassium; Thromboxane A2

Topics: Angina, Unstable; Aspirin; Coronary Thrombosis; Humans; Myocardial Ischemia; Platelet Activation; Prostaglandins; Thrombolytic Therapy; Thromboxane A2

To investigate the effects of electro-acupuncture (EA) combined general anesthesia on myocardial injury of high blood sugar patients with coronary heart disease (CHD) in the perioperative phase.. Recruited were 40 senile patients with glycosylated hemoglobin (HbA1c) more than 6.5%. They were more than 60 years old. They received post-traumatic fracture reduction surgery of four limbs. They were randomly assigned to two groups, Group N (treated by general intravenous anesthesia) and Group D (treated by EA combined with general intravenous anesthesia), 20 in each group. All patients were maintained anesthesia by propofol, fentanyl, and vecuronium. Prior to the induction of anesthesia, patients in Group D received induction of EA at Neiguan (PC6) and Baihui (DU20) for 20 min, which lasted to the end of the surgery. At before intubation (T0), immediately after intubation (T1), 5 min (T2), immediately after extubation (T3), 5 min (T4), 60 min (T5), 180 min (T6), the fast blood glucose (FBG), plasma vasoactive substance TXB2 and 6-K-prostacycline (6-K-PGF1alpha) were detected in the two groups. The glucose coefficient of variation (GluCV) and the ratio of TXB2/6-K-PGF1alpha were calculated. The changes of ST-segment elevation (mV, sampling 1 min after each time point, and the mean calculated) was recorded.. There was no statistical difference in all the tested values between the two groups at T0 (P>0.05). The FBG, ST elevation, and the ratio of TXB2/6-K-PGF1alpha were significantly higher at each time point than at T0 in Group N (P<0.05), while there was no statistical difference in Group D (P>0.05). The ratio of TXB2/6-K-PGF1alpha and ST elevation were significantly higher in Group N than in Group D (P<0.01). The TXB2 and 6-K-PGF1alpha were significantly higher at each time point than at T0 in the two groups (P<0.05). The increment of TXB2 was obviously lower in Group D than in Group N (P<0.05), but the increment of 6-K-PGF1alpha was obviously higher in Group D than in Group N (P<0.05).. EA could reduce the perioperative stress response to the injury of coronary vascular endothelial cells, and improve myocardial ischemia and CHD patients' prognosis by regulating the central nervous system, the cardiovascular active substances, and anti-oxygen free radicals.

Topics: Acupuncture Analgesia; Aged; Anesthesia, General; Blood Glucose; Coronary Disease; Electroacupuncture; Epoprostenol; Female; Glycated Hemoglobin; Humans; Intraoperative Period; Male; Middle Aged; Myocardial Ischemia; Myocardium; Thromboxane A2

PSVT attack of >20min and frequency >160 is well-recognized model of myocardial dysfunction. We measured 6-keto-PGF1alpha and TXB(2) before and after adenosine administration to assess its cardioprotective potential. A total of 64 patients were randomly assigned as having acute episode of PSVT to adenosine or verapamil group. A bolus of 6mg of adenosine up to the maximum dose of 12 or 5mg of verapamil up to the maximum dose of 10mg were given, until the sinus rhythm was restored. The levels of PGI(2), TXA(2) and TAS were measured in three different time intervals. In adenosine group all parameters were normalized after 20min of conversion to sinus rhythm. The ratio of PGI(2)/TXA(2) increased after 5min of conversion to SR (P<0.01). Also, the ratio of TXA(2)/TAS was decreased for ADO (P<0.01). This is the first study to demonstrate that adenosine exerts cardioprotective effect.

Topics: 6-Ketoprostaglandin F1 alpha; Adenosine; Adult; Cardiotonic Agents; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Prostaglandins; Tachycardia, Paroxysmal; Tachycardia, Supraventricular; Thromboxane A2; Thromboxane B2; Verapamil

To evaluate whether aspirin reduces the incidence and frequency of daily life myocardial ischaemia in a cohort of patients with chronic stable coronary artery disease.. Tertiary referral centre.. 60 patients with chronic stable coronary artery disease underwent 48 hour Holter monitoring to assess the incidence and frequency of daily life myocardial ischaemia. Those with myocardial ischaemia (40/60) entered a double blind, crossover trial of aspirin (300 mg/day for three weeks) versus placebo. After each treatment arm, 48 hour Holter monitoring was repeated and urinary thromboxane (Tx) B2, 11-dehydro-TxB2, plasma prothrombin fragment F1+2, macrophage colony stimulating factor (MCSF), and interleukin (IL)-6 were measured.. Aspirin reduced the total number and duration of ischaemic episodes from 339 to 251 and from 1765 to 1365 minutes, respectively (p < 0.01 for both). TxB2 was also reduced from 0.2 to 0.1 ng/mg creatinine, 11-dehydro-TxB2 from 3.3 to 1.3 ng/mg creatinine, F1+2 from 1.5 to 1.2 nmol/l, MCSF from 991 to 843 pg/ml, and IL-6 from 3.5 to 2.9 pg/ml (p < 0.05 for all). 11-dehydro-TxB2 excretion with and without aspirin was related to MCSF concentrations (p < 0.01), and the percentage reduction of MCSF by aspirin was related to the reduction of 11-dehydro-TxB2 (p < 0.05) and the reduction of the ischaemic burden compared with placebo (p < 0.05).. In patients with daily life ischaemia, aspirin reduces the incidence and frequency of ischaemic episodes as well as the systemic concentrations of haemostatic/inflammatory markers. Aspirin may prevent transient coronary flow reductions through platelet, thrombin, and cytokine inhibition.

Topics: Adult; Aged; Aspirin; Biomarkers; Cohort Studies; Coronary Artery Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography, Ambulatory; Female; Humans; Interleukin-6; Macrophage Colony-Stimulating Factor; Male; Middle Aged; Myocardial Ischemia; Peptide Fragments; Platelet Aggregation Inhibitors; Prothrombin; Thromboxane A2; Thromboxane B2

To compare a thromboxane antagonist (GR3219) with aspirin in patients with prolonged chest pain and ST segment depression to see if the frequency of attacks of chest pain was reduced.. The trial was part of a study comparing GR3219 with aspirin, and streptokinase with placebo and comprised the GR3219/aspirin leg. Thirty one patients were randomly assigned to GR3219 80 mg twice daily and 28 to aspirin 300 mg daily. The patients were under the age of 76 and admitted to a coronary care unit within 6 hours of continuous chest pain. The ECG showed at least 1 mm of flat or down-going ST segment. The patients kept diaries of their pain over the subsequent 31 days.. Seventy percent of patients developed further chest pain. There was no difference between the pattern of recurrent chest pain according to which drug was used.. The hypothesis that specific thromboxane A blockade with GR3219 would be more efficacious than aspirin was not supported by these results.

Topics: Aged; Aspirin; Biphenyl Compounds; Coronary Care Units; Double-Blind Method; Electrocardiography; Female; Heptanoic Acids; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Platelet Aggregation Inhibitors; Recurrence; Streptokinase; Thromboxane A2

The role of thromboxane A2 (TxA2) in unstable angina has not yet been defined. TxA2 receptor antagonists may be of value in studying this role.. To investigate whether TxA2 has a pathogenetic effect on the occurrence of myocardial ischemia and from what source TxA2 originates, we studied TxA2 formation by unstimulated monocytes from patients with unstable angina (n = 40), stable effort angina (n = 20), and controls (n = 20). We also compared the effects of picotamide (1200 mg/day), a TxA2-synthase inhibitor and TxA2-receptor antagonist, with those of aspirin (325 mg/day) on myocardial ischemia and TxA2 formation by monocytes and platelets. The double-blind randomized study was performed on patients with unstable angina on continuous Holter monitoring.. In the presence of autologous lymphocytes, unstimulated monocytes from patients with unstable angina formed significantly (P < 0.001) more TxA2 than those from controls or from patients with effort angina. Although TxA2 formation by circulating monocytes and platelets was inhibited to a greater degree by aspirin than by picotamide (88 +/- 6 and 98 +/- 2%, respectively, versus 65 +/- 2 and 74 +/- 1%, P < 0.001), aspirin failed to affect the occurrence of myocardial ischemia whereas picotamide significantly (P < 0.001) reduced the number of anginal attacks (84.8%), silent ischemic episodes (64.2%), and overall duration of ischemia (69.8%), in comparison to the run-in period.. These results indicate that TxA2 formed by monocytes contributes to the pathogenesis of myocardial ischemia in unstable angina. TxA2 formation occurs mainly in extravascular spaces, probably within the coronary vascular wall. Picotamide appears to control myocardial ischemia effectively in patients with unstable angina.

Topics: Aged; Angina Pectoris; Angina, Unstable; Aspirin; Double-Blind Method; Female; Follow-Up Studies; Humans; Leukocytes, Mononuclear; Lymphocytes; Male; Middle Aged; Myocardial Ischemia; Phthalic Acids; Placebos; Platelet Aggregation Inhibitors; Prospective Studies; Thromboxane A2

Thromboxane A2 (TXA2) induces platelet adhesion through thromboxane prostanoid (TP) receptor. Platelets contain many pro-angiogenic factors and are recruited to the site of vascular injury. However, the cellular and molecular mechanisms of platelet-dependent angiogenesis, especially the involvement of TP signalling, have not been fully elucidated. The present study hypothesized that TP-dependent platelet adhesion would contribute to angiogenesis in a mouse hindlimb ischaemic model.. Blood flow recovery was suppressed by the TXA2 receptor antagonist (S-1452) and the TXA2 synthase inhibitor (OKY-046) compared with control mice. TP knockout mice (TP(-/-)) showed delayed blood flow recovery from ischaemia and impaired angiogenesis compared with wild-type (WT) mice and prostacyclin receptor knockout mice (IP(-/-)). Selective platelet adhesion to ischaemic endothelial cells (ECs) via P-selectin was identified in WT and IP(-/-), but not in TP(-/-), via in vivo microscopy. IF analysis showed that P-selectin glycoprotein ligand-1 (PSGL-1) co-localized with endothelial CD31 in ischaemic muscle in WT and IP(-/-) but not diminished in TP(-/-). Platelet-rich plasma levels of stromal cell-derived factor-1 and VEGF were increased after ischaemia in WT, and suppressed by antibody against P-selectin in WT but not in TP(-/-). Furthermore, the blood flow recovery was suppressed by neutralizing antibodies against VEGF or C-X-C chemokine receptor type 4 in WT and IP(-/-) but not in TP(-/-).. These results indicated that TP signalling facilitates ischaemia-induced angiogenesis via P-selectin-mediated platelet adhesion to PSGL-1 on the ECs at ischaemic sites and the supply of pro-angiogenic factors by the adherent platelets.

Topics: Animals; Blood Platelets; Endothelial Cells; Male; Membrane Glycoproteins; Mice, Knockout; Myocardial Ischemia; Platelet Adhesiveness; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thromboxane A2

Topics: Animals; Blood Platelets; Endothelial Cells; Male; Myocardial Ischemia; Platelet Adhesiveness; Thromboxane A2

Levels of fatty acids in platelets of ischemic heart disease (IHD) patients (n = 39) has been compared with those in healthy subjects (n = 12). Increased content of arachidonic acid and thromboxane A2 in platelets of IHD patients forms thrombogenic picture of IHD. High level of fibrinogen and decrease in heparin and antithrombin III in IHD patients facilitates formation of blood clots. Morphological examination of platelets in IHD patients has demonstrated an increase of levels of discocytes and spherocytes as well as appearance of small and large platelet-erythrocyte aggregates promoting blood slot formation.

Topics: Antithrombins; Arachidonic Acid; Blood Coagulation Factors; Blood Platelets; Erythrocyte Aggregation; Erythrocyte Deformability; Humans; Myocardial Ischemia; Platelet Adhesiveness; Platelet Aggregation; Thrombosis; Thromboxane A2

Myocardial ischemia is a complex process leading to the simultaneous release of a number of mediators, including thromboxane A(2) (TxA(2)) and bradykinin (BK), that activate cardiac spinal afferents. The present study tested the hypothesis that TxA(2) and BK reciprocally interact to excite ischemically sensitive cardiac afferents. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) of anesthetized cats. Fifty-two ischemically sensitive afferents (conduction velocity = 0.27-3.35 m/s, 7 Adelta-fibers and 45 C-fibers) were identified. Repeated injections (1 microg) of BK into the left atrium (LA) 4 min after the administration of U-46619 (5 microg into the LA), a TxA(2) mimetic, induced a significantly larger cardiac afferent response than the first response to BK (0.61 +/- 0.14 to 1.95 +/- 0.29 vs. 0.66 +/- 0.09 to 2.75 +/- 0.34 impulses/s, first injection vs. second injection, n = 8). Conversely, blockade of TxA(2) receptors with BM-13,177 (30 mg/kg iv) attenuated the responses of eight other afferents to BK (1 microg into the LA) by 45%. In contrast, repeated BK (1 microg into the LA) induced consistent discharge activity in six separate afferents. We then observed that the coadministration of U-46619 (5 microg) and BK (1 microg into the LA) together caused a total response that was significantly higher than the predicted response by the simple addition of the individual responses. BK (1 microg) facilitated eight cardiac afferent responses to U-46619 (5 microg into the LA) by 64%. In contrast, repeated U-46619 (5 microg into the LA) without intervening BK stimulation evoked consistent responses in seven other ischemically sensitive afferents. Finally, inhibition of cyclooxygenase with indomethacin (5 mg/kg iv) eliminated the potentiating effects of BK on the cardiac afferent response to U-46619 (5 microg into the LA) but did not alter the afferent response to U-46619. These data suggest that BK and TxA(2) reciprocally interact to stimulate ischemically sensitive cardiac afferent endings leading to synergistic afferent responses and that the BK sensitization effect is mediated by cyclooxygenase products.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Cats; Cyclooxygenase Inhibitors; Drug Synergism; Female; Heart; Indomethacin; Male; Myocardial Ischemia; Neurons, Afferent; Prostaglandin-Endoperoxide Synthases; Spinal Cord; Thromboxane A2; Vasoconstrictor Agents

Clinical and experimental evidence has shown that myocardial ischemia activates cardiac spinal afferents that mediate sympathoexcitatory reflex responses. During myocardial ischemia, thromboxane A2 (TxA2) is released in large quantities by activated platelets in the coronary circulation of patients with coronary artery disease. We hypothesized that endogenous TxA2 contributes to sympathoexcitatory reflexes during myocardial ischemia through stimulation of TxA2/prostaglandin endoperoxide (TP) receptors. Regional myocardial ischemia was induced by occlusion of a diagonal branch of left anterior descending coronary artery of anesthetized cats. Hemodynamic parameters and renal sympathetic nerve activity were recorded after sinoaortic denervation and bilateral vagotomy. Regional myocardial ischemia evoked significant increases in mean blood pressure (122+/-10 vs. 139+/-12 mmHg, before vs. ischemia), aortic flow (153+/-18 vs. 167+/-20 ml/min), first derivative of left ventricular pressure at 40-mmHg developed pressure (2,736+/-252 vs. 2,926+/-281 mmHg/s), systemic vascular resistance (0.6+/-0.1 vs. 0.9+/-0.12 peripheral resistance units), and renal sympathetic nerve activity (by 22%). The reflex nature of the excitatory responses was confirmed by observing its disappearance after blockade of cardiac nerve transmission with intrapericardial 2% procaine treatment. Moreover, application of U-46619 (2.5-10 microg), a TxA2 mimetic, on the heart caused graded increases in mean arterial pressure and renal nerve activity, responses that were abolished 3 min after local blockade of cardiac neural transmission with intrapericardial procaine. BM 13,177 (30 mg/kg iv), a selective TP receptor antagonist, eliminated the reflex responses to U-46619 and significantly attenuated the excitatory responses during brief (5 min) regional myocardial ischemia. The sympathoexcitatory reflex responses to U-46619 were unchanged by blockade of histamine H1 receptors with pyrilamine and serotonin 5-HT3 receptors with tropisetron, indicating specificity of this TP receptor agonist. These data indicate that endogenous TxA2 participates in myocardial ischemia-mediated sympathoexcitatory reflex responses through a TP receptor mechanism.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Anesthetics, Local; Animals; Cats; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Heart; Hemodynamics; Histamine H1 Antagonists; Indoles; Kidney; Male; Myocardial Ischemia; Pressoreceptors; Procaine; Pyrilamine; Receptors, Thromboxane; Reflex; Serotonin Antagonists; Sulfonamides; Sympathetic Nervous System; Thromboxane A2; Tropisetron; Vagotomy

Myocardial ischaemia activates blood platelets, which in turn stimulate cardiac sympathetic afferents, leading to chest pain and sympathoexcitatory reflex cardiovascular responses. Previous studies have shown that activated platelets stimulate ischaemically sensitive cardiac sympathetic afferents, and that thromboxane A(2) (TxA(2)) is one of the mediators released from activated platelets during myocardial ischaemia. The present study tested the hypothesis that endogenous TxA(2) stimulates cardiac afferents during ischaemia through direct activation of TxA(2) (TP) receptors coupled with the phospholipase C-protein kinase C (PLC-PKC) cellular pathway. Nerve activity of single unit cardiac sympathetic afferents was recorded from the left sympathetic chain or rami communicantes (T(2)-T(5)) in anaesthetized cats. Single fields of 39 afferents (conduction velocity = 0.27-3.65 m s(-1)) were identified in the left or right ventricle initially with mechanical stimulation and confirmed with a stimulating electrode. Five minutes of myocardial ischaemia stimulated all 39 cardiac afferents (8 Adelta-, 31 C-fibres) and the responses of these 39 afferents to chemical stimuli were further studied in the following four protocols. In the first protocol, 2.5, 5 and 10 microg of the TxA(2) mimetic, U46619, injected into the left atrium (LA), stimulated seven ischaemically sensitive cardiac afferents in a dose-dependent manner. Second, BM13,177, a selective TxA(2) receptor antagonist, abolished the responses of six afferents to 5 microg of U46619 injected into the left atrium and attenuated the ischaemia-related increase in activity of seven other afferents by 44%. In contrast, cardiac afferents, in the absence of TP receptor blockade responded consistently to repeated administration of U46619 (n = 6) and to recurrent myocardial ischaemia (n = 7). In the fourth protocol, administration of PKC-(19-36), a selective PKC inhibitor, attenuated the responses of six other cardiac afferents to U46619 by 38%. Finally, using an immunohistochemical staining approach, we observed that TP receptors were expressed in cardiac sensory neurons in thoracic dorsal root ganglia. Taken together, these data indicate that endogenous TxA(2) contributes to the activation of cardiac afferents during myocardial ischaemia through direct stimulation of TP receptors probably located in the cardiac sensory nervous system and that the stimulating effect of TxA(2) on cardiac afferents is dependent, at least

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic Fibers; Afferent Pathways; Animals; Cats; Dose-Response Relationship, Drug; Female; Heart; Immunohistochemistry; Male; Myocardial Ischemia; Peptide Fragments; Protein Kinase C; Receptors, Thromboxane; Thromboxane A2

Inhibition of erythrocyte (RBC) promotion of platelet reactivity could improve the antiplatelet effect of aspirin (ASA). We tested different ASA regimens for optimal inhibition of platelets and the effects of RBC in patients with a history of vascular diseases. Collagen-induced platelet activation (14C-5HT, TXA2 release) and platelet recruitment (proaggregatory activity of cell-free releasates from activated platelets) were measured in PRP, platelet-RBC (Hct 40%), and whole blood (WB) in 206 patients initially on 200-300-mg ASA/day. Their regimen was modified to biweekly 500 mg (loading dose, L) plus daily or twice-daily low-dose ASA (50 or 100 mg). TXA2 was inhibited with all regimens. Percentage of patients with suboptimal inhibition of platelet recruitment in WB was 200-300 ASA/day (41%), L-50/day (87%), L-100/day (58%), L-50/twice-daily (39%), and L-100/twice-daily (20%; P < 0.05 vs other regimens). 14C-5HT release was inhibited to the greatest extent with L-100/twice-daily in PRP + RBC or WB (P < 0.05 vs other regimens) due to greater inhibition of the RBC prothrombotic effect. Compared with other ASA regimens, L-100 twice-daily (equivalent to 221-mg ASA/day in the 14-day cycle), reduced by >50% the proportion of patients with suboptimal inhibition of platelet recruitment in WB and inhibited 14C-5HT release to the greatest extent.

Topics: Adult; Aged; Aged, 80 and over; Aspirin; Blood Platelets; Brain Ischemia; Collagen; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythrocytes; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Platelet Aggregation Inhibitors; Serotonin; Thromboxane A2

Licofelone is an analogue of arachidonic acid that inhibits 5-lipoxygenase (LOX), cyclooxygenase (COX)-1 and COX-2. We investigated the effects of licofelone on cardiovascular derangements and production of thromboxane (Tx)A(2) induced by the inflammatory agonist n-formyl-methionyl-leucyl-phenylalanine (fMLP) in the rabbit, in comparison with those of aspirin or rofecoxib, inhibitors of COX-1 and COX-2, respectively. In control rabbits, injection of fMLP (30 nmol/kg) in the jugular vein evokes ischemic electrocardiographic (ECG) changes in the first 1-5 min, i.e. a profound depression of the ST segment and inversion of the T wave. Simultaneously, fMLP induces bradycardia and hypotension and increases TxB(2) blood levels. All changes are transient. Licofelone (60 mg/kg/5 days, p.os) prevented fMLP-induced ECG ischemic changes in all treated animals, reverted bradycardia and hypotension, and significantly reduced TxB(2). Aspirin (10 mg/kg/5 days, p.os) prevented ischemic ECG alterations in 2 out of 5 treated animals and did not modify either bradycardia or hypotension. One rabbit died two min after fMLP. In 2 rabbits, aspirin reduced TxB(2) levels by more than 80% respect to mean control values; the remaining two rabbits produced an amount of TxB(2) similar to controls. These two rabbits also showed ischemic ECG changes. Rofecoxib (10 mg/kg/5 days, p.os) did not prevent fMLP-induced ischemic ECG alteration, bradycardia and hypotension, and did not significantly modify the increase of TxB(2). These results indicate that the capacity of licofelone to efficiently suppress TxA(2) production, is responsible for the protection from the cardiovascular derangement triggered by an inflammatory stimulus.

Topics: Acetates; Animals; Aspirin; Blood Pressure; Cyclooxygenase Inhibitors; Disease Models, Animal; Electrocardiography; Heart Rate; Inflammation; Lactones; Leukotriene B4; Lipoxygenase Inhibitors; Male; Myocardial Ischemia; N-Formylmethionine Leucyl-Phenylalanine; Pyrroles; Rabbits; Sulfones; Thromboxane A2; Time Factors

It has been proven that nicotine contributes to cardiovascular diseases, although its precise mechanism of action is still unclear. The purpose of this study is to find how nicotine may complicate myocardial ischemia by affecting the thromboxane/prostacyclin (TXA(2)/PGI(2)) balance. We used four groups (n=7 each) of isolated and perfused rabbit hearts according to Langendorff method: (i) control group; (ii) group submitted to 1 microM nicotine perfusion during 60 min; (iii) group submitted to a regional ischemia by ligation of the left descending coronary artery during 60 min and (iv) group submitted to nicotine perfusion during ischemia. Levels of TXB(2) and 6-keto PGF(1alpha), the stable metabolites of TXA(2) and PGI(2) were then determined in the microsomes of the hearts by radioimmunoassay. The results showed that (1) a TXA(2) synthetase activity is present in the myocardium, and this activity, as well as that of PGI(2) synthetase, is decreased by a 60min ischemia; (2) TXA(2) and PGI(2) activities are not affected by nicotine in the normal myocardium and (3) nicotine infusion during ischemia contributes to the increase of TXA(2)/PGI(2) ratio further by decreasing PGI(2). Therefore, these results provide one explanation on how nicotine might worsen myocardial ischemia.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Enzyme Inhibitors; Epoprostenol; Heart; In Vitro Techniques; Intramolecular Oxidoreductases; Male; Microsomes; Myocardial Ischemia; Myocardium; Nicotine; Perfusion; Rabbits; Smoking; Thromboxane A2; Thromboxane B2

Epidemiological studies link acute infection of the respiratory tract to a transient increased risk of acute myocardial infarction. The underlying mechanisms remain unknown. We hypothesized that vasoactive mediators produced by inflammatory cells in the lungs and drained in the coronary circulation may trigger acute myocardial ischemia. To test this hypothesis we used an experimental model in the rabbit. Injection of the bacterial-derived peptide N-formyl-Met-Leu-Phe (or N-formyl-Methionyl-Leucyl-Phenylalanine)(fMLP) in the jugular vein induced massive recruitment of both polymorphonuclear leukocytes (PMN) and platelets in the microcirculation of the lungs, accompanied by rapid and marked increase of leukotriene B4, cysteinyl leukotrienes and thromboxane (Tx) A2 in the aortic blood. In all animals, fMLP evoked ischemic electrocardiographic changes: within the first minute of infusion a profound depression of the ST segment and inversion of the T wave were observed. Mean aortic pressure and heart rate fell to 64.0 +/- 6.9 and 83.5 +/- 3.1% of the basal levels at 3 and 10 min, respectively. All these alterations were transient. Aspirin, prevented electrocardiographic ischemic changes, reverted bradycardia and hypotension but did not significantly modify either PMN or platelet recruitment nor leukotriene synthesis. Ridogrel, a Tx-synthase and receptor inhibitor, prevented ECG alterations and bradycardia, but did not prevent and even worsened hypotension; it blocked platelet, but not PMN, sequestration. Pretreatment of animals with intravenous high dose of aspirin prevented ridogrel-dependent hypotension and platelet inhibition, suggesting that PGI2 contributes to the effects of Tx-synthase and receptor inhibitor. In hypercholesterolemic rabbits, ECG alterations persisted longer than in normal controls. In summary, our results indicate that acute activation of PMN and platelets in the lungs provokes transient myocardial ischemia, in normal animals that is exacerbated in hypercholesterolemic rabbits. TxA2 appears to be the major mediator of this phenomenon. Moreover the data suggest that a balance between TxA2 and PGI2 plays a pivotal role in platelet activation and recruitment in our model.

Topics: Acute Disease; Animals; Arteriosclerosis; Disease Models, Animal; Electrocardiography; Epoprostenol; Inflammation Mediators; Male; Myocardial Ischemia; N-Formylmethionine Leucyl-Phenylalanine; Platelet Activation; Pneumonia; Rabbits; Thromboxane A2

Inhibition of cyclooxygenase (COX) might favour non-enzymatic formation of cardiodepressive isoprostanes from arachidonic acid by radicals generated during reperfusion. This could explain deleterious effects of acetylsalicylic acid (ASA) on cardiac function. We examined the influence of COX inhibition on myocardial function after low-flow ischaemia and reperfusion, employing either ASA (100 micromol/l), the partially selective COX-2 inhibitor meloxicam (0.3 micromol/l and 3.0 micromol/l), or the highly selective COX-2 inhibitor SC 58125 (1.0 micromol/l and 3.0 microgmol/l). Isolated, buffer-perfused guinea pig hearts, performing pressure-volume work before and after consecutive low-flow ischaemia and reperfusion, were used for the study. Measurement of coronary and aortic flow, ejection time and heart rate served to calculate external heart work (EHW), before and after ischaemia. Additionally, release of prostacyclin and thromboxane A2, production of lactate, consumption of pyruvate and tissue concentration of the isoprostane 8-iso-PGF2alpha were measured. ASA significantly reduced recovery of EHW (46+/-18% vs. 82+/-15% for controls), whereas meloxicam and SC 58125 did not (64+/-15% and 74+/-13% recovery, respectively). Paradoxically, ASA increased reactive hyperaemia and consumption of pyruvate in the early reperfusion phase in comparison to all other groups, while lactate production did not differ. Prostacyclin production did not increase during reperfusion and was not significantly different between groups at any time point. In contrast, thromboxane A2 release increased about fivefold in the 2nd min of reperfusion under control conditions and in the presence of SC 58125, but was inhibited by ASA and by meloxicam in both concentrations. Isoprostane content of heart tissue was not detectably influenced under the mild reperfusion conditions used here. We conclude that ASA can aggravate postischaemic cardiac dysfunction, independent of COX inhibition. The deleterious effect in the present model might be due to uncoupling of mitochondrial oxidative phosphorylation rather than to direct effects of reduced eicosanoid release or radical induced formation of isoprostanes.

Topics: Animals; Aspirin; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprost; Eicosanoids; F2-Isoprostanes; Guinea Pigs; Heart; Hemodynamics; Isoenzymes; Male; Meloxicam; Myocardial Ischemia; Myocardial Reperfusion Injury; Prostaglandin-Endoperoxide Synthases; Pyrazoles; Thiazines; Thiazoles; Thromboxane A2

Prostaglandin (PG) I(2) and thromboxane (TX) A(2), the most common prostanoids in the cardiovascular system, are produced abundantly during cardiac ischemia/reperfusion (I/R); their roles in I/R injury, however, remain undetermined. We intended to clarify these roles of PGI(2) and TXA(2) using mice lacking the PGI(2) receptor, IP(-/-) mice, or the TXA(2) receptor, TP(-/-) mice.. The left anterior descending coronary artery was occluded for 1 hour and then reperfused for 24 hours. The size of myocardial infarct in IP(-/-) mice was significantly larger than that in wild-type mice, although the size of the area at risk was similar between the 2 groups of mice. In contrast, there was no such difference between TP(-/-) and wild-type mice. To further determine whether PGI(2) and TXA(2) act directly on the cardiac tissue or indirectly through their action on blood constituents, we perfused excised heart according to the Langendorff technique. The isolated heart was then subjected to global ischemia followed by reperfusion. In IP(-/-) mice, developed tension and coronary flow rate during reperfusion were significantly lower and release of creatine kinase was significantly higher than those in wild-type mice. There were no such differences, however, between TP(-/-) and wild-type mice.. PGI(2), which was produced endogenously during cardiac I/R, exerts a protective effect on cardiomyocytes independent of its effects on platelets and neutrophils. In contrast, TXA(2) has little role in the cardiac I/R injury.

Topics: Adenosine Triphosphate; Animals; Blood Flow Velocity; Blood Pressure; Coronary Circulation; Creatine Kinase; Cytoprotection; Disease Models, Animal; Electrocardiography; Epoprostenol; Heart; Heart Rate; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Receptors, Epoprostenol; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2

Eicosanoids and volatile anesthetics can influence cardiac reperfusion injury. Accordingly, we analyzed the effects of sevoflurane and isoflurane applied in clinically relevant concentrations on the myocardial production of prostacyclin and thromboxane A2 (TxA2) and on heart function. Isolated guinea pig hearts, perfused with crystalloid buffer, performed pressure-volume work. Between two working phases, hearts were subjected to 15 min of global ischemia followed by reperfusion. The hearts received no anesthetic, 1 minimum alveolar anesthetic concentration (MAC) isoflurane (1.2 vol%), or 0.5 and 1 MAC sevoflurane (1 vol% and 2 vol%), either only preischemically or pre- and postischemically. In additional groups, cyclooxygenase function was examined by an infusion of 1 microM arachidonic acid (AA) in the absence and presence of sevoflurane. The variables measured included the myocardial production of prostacyclin, TxA2 and lactate, consumption of pyruvate, coronary perfusion pressure, and the tissue level of isoprostane 8-iso-PGF2alpha. External heart work, determined pre- and postischemically, served to assess recovery of heart function. Volatile anesthetics had no impact on postischemic recovery of myocardial function (50%-60% recovery), perfusion pressure, lactate production, or isoprostane content. Release of prostacyclin and TxA2 was increased in the early reperfusion phase 5-8- and 2-4-fold, respectively, indicating enhanced AA liberation. Isoflurane and sevoflurane did not augment the eicosanoid release. Only 2 vol% sevoflurane applied during reperfusion prevented the increased eicosanoid formation in this phase. Infusion of AA increased prostacyclin production approximately 200-fold under all conditions, decreased pyruvate consumption irreversibly, and markedly attenuated postischemic heart work (25% recovery). None of these effects were mitigated by 2 vol% sevoflurane. In conclusion, only sevoflurane at 2 vol% attenuated the increased liberation of AA during reperfusion. Decreased eicosanoid formation had no effect on myocardial recovery in our experimental setting while excess AA was deleterious. Because eicosanoids influence intravascular platelet and leukocyte adhesion and activation, sevoflurane may have effects in reperfused tissues beyond those of isoflurane.. In an isolated guinea pig heart model, myocardial eicosanoid release was not increased by isoflurane or sevoflurane, either before or after ischemia. Sevoflurane (2 vol%) but not isoflurane attenuated the increased release of eicosanoids during reperfusion.

Topics: Anesthetics, Inhalation; Animals; Coronary Circulation; Dinoprost; Eicosanoids; Guinea Pigs; Hemodynamics; In Vitro Techniques; Isoflurane; Lactic Acid; Male; Methyl Ethers; Myocardial Ischemia; Myocardium; Pyruvic Acid; Sevoflurane; Thromboxane A2; Time Factors

Pretreatment with tetramethylpyrazine (TMP, 12 mg/kg/day), a drug originally derived from the rhizomes of Ligusticum wallichii, significantly reduced the incidence of ischemia-induced ventricular tachycardia (VT) and fibrillation (VF) from 100% and 50% of control hearts to 41% (p < 0.05) and 0% (p < 0.05), respectively, in the ischemic rat heart. TMP also diminished the incidence of reperfusion-induced VT and VF from 100% and 100% of control hearts to 33% (p < 0.05) and 41% (p < 0.05), respectively. Pretreatment with TMP produced a slight, but significant increase of 6-keto-PGF1 alpha and a decrease of TXB2 production during aerobic perfusion. Ischemia and reperfusion markedly increased the release of 6-keto-PGF1 alpha and TXB2. Pretreatment with TMP significantly enhanced the release of 6-keto-PGF1 alpha and diminished TXB2 outflow following left coronary artery occlusion and reperfusion.

Topics: Animals; Arrhythmias, Cardiac; Epoprostenol; Heart; Male; Myocardial Ischemia; Pyrazines; Rats; Rats, Sprague-Dawley; Thromboxane A2

1. Myocardial thromboxane A2 production increases in patients with pacing-induced ischaemia and correlates with a decrease in myocardial lactate extraction. The release of myocardial thromboxane A2 before any lactate production was observed in patients with unstable angina. This study was proposed to clarify whether the early thromboxane A2 release contributed to the ongoing myocardial ischaemia and to determine which metabolites can be attributed to the thromboxane A2 release. Thirty-five patients with chest pain and positive treadmill exercise test underwent atrial pacing to the predicted maximal heart rate. The pacing was maintained at this peak rate for 10 min, then ceased. Blood samples of the ascending aorta and coronary sinus were drawn simultaneously at rest, at 2 and 10 min of peak-pacing, and 5 and 10 min after termination of the pacing; samples were used for analyses of lipid profiles, prostacyclin, thromboxane A2, lactate and lipid peroxides on plasma and low-density lipoprotein particles. 2. Twenty out of 35 patients who displayed pacing-induced ischaemia were documented by electrocardiographic evidence of ST depression > 2 mm developing after 2 min of peak-pacing [ischaemic group, ST delta(+)]. They had (i) negative fractional lactate extraction; (ii) pacing-induced decreases of plasma thromboxane A2 levels in the coronary sinus blood (564 +/- 57 versus 479 +/- 47 ng/l, P < 0.05) at 2 min of peak-pacing; the data increased at 10 min of peak-pacing (564 +/- 57 versus 620 +/- 60 ng/l, P < 0.05), then returned to baseline levels at 5 and 10 min post-pacing; (iii) significantly increased lipid peroxides on low-density lipoprotein of the coronary sinus blood at 2 and 10 min of peak-pacing (each P < 0.001), as well as at 5 min post-pacing (P < 0.05); (iv) significant correlation between thromboxane A2 levels and lipid peroxides on low-density lipoprotein of the coronary sinus blood samples. 3. In ST delta(+) patients, myocardial thromboxane synthesis changed before lactate production and correlated with the increase of lipid peroxides on low-density lipoprotein of the coronary venous blood. This implies that lipid peroxides on low-density lipoprotein participate in thromboxane production and play a determinative role in pacing-induced ischaemia.

Topics: Analysis of Variance; Cardiac Pacing, Artificial; Electrocardiography; Female; Humans; Lactic Acid; Lipid Peroxides; Lipoproteins, LDL; Male; Middle Aged; Myocardial Ischemia; Myocardium; Thromboxane A2; Time Factors

Efficacy of aspirin (Acetylsalicylic acid, ASA) antiaggregatory prevention was demonstrated in a series of clinical trials. The recommended ASA doses decreased gradually and doses 50-30 mg ASA/d are intensively studied at the present time. A group of 42 patients with coronary heart disease was evaluated: (1) Basal TXB2 production during spontaneous blood clotting was 360 +/- 37.6 ng/ml; (2) Two initial doses were tested: while 200 mg ASA inhibited, during spontaneous blood clotting, median TXB2 production by 99.9% (serum TXB2 concentration 1.35 ng/ml), 30 mg ASA median inhibition was just 42.0% (serum TXB2 151 ng/ml); (3) 30 mg ASA/d maintenance dose was evaluated for 3 months. The median TXB2 production inhibition was 98.5% (serum TXB2 3.75 ng/ml, first month) and 94.0% (serum TXB2 14.2 ng/ml, third month); (4) Four patients did not respond sufficiently, because of noncompliance verified by the determination of salicyluric acid urinary excretion, the lower limit of excretion being <3 micromol/2 h; (5) Both initial and maintenance ASA dose decreased metabolic TXA2 endproducts in urine; (6) 5HT platelet release did not decrease; (7) Potential changes of 5HT metabolic elimination were excluded by the simultaneous determination of 5-hydroxyindoleacetic acid (5HIAA). In conclusion, 200 mg initial dose and 30 mg ASA/d maintenance dose are suggested to be maximally inhibitory for TXB2 production without influence on 5HT release.

Topics: Aspirin; Blood Coagulation; Coronary Disease; Dose-Response Relationship, Drug; Humans; Myocardial Ischemia; Serotonin; Thromboxane A2; Thromboxane B2

The platelet products thromboxane A2 and serotonin have been shown to cause constriction of well-developed coronary collateral vessels. This study was performed to determine whether intravascular platelet activation produced with platelet activating factor (PAF) can cause a decrease in coronary collateral blood flow.. Collateral vessel growth was induced by embolization of a hollow stainless steel plug into the left anterior descending coronary artery (LAD) of adult dogs. The animals were returned to the laboratory 3 to 6 weeks later for surgical instrumentation and measurement of collateral blood flow. Collateral flow was assessed by measuring retrograde blood flow from the cannulated collateral-dependent artery. PAF (10 nmol) was injected into the left main coronary artery to allow products of platelet activation to reach collateral vessels arising from the left coronary system. PAF caused a vasoconstrictor response, which became maximal 3 minutes after injection and resulted in a 40.3+/-7.4% decrease in retrograde blood flow (32.1+/-2.1 to 19.6+/-3.2 mL/min; P<0.05). By 15 minutes after the PAF injection, both retrograde blood flow and transcollateral resistance had returned to normal. After pretreatment with the thromboxane A2 receptor antagonist SQ30, 741, the vasoconstrictor response to PAF was abolished and, in contrast to the decrease in retrograde blood flow from PAF alone, a weak vasodilator effect was unmasked.. PAF caused a decrease in coronary collateral blood flow. This vasoconstrictor response required the participation of thromboxane A2.

Topics: Animals; Blood Platelets; Collateral Circulation; Coronary Circulation; Dogs; Myocardial Ischemia; Platelet Activating Factor; Platelet Activation; Thromboxane A2; Vasoconstriction

The effects of thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor blockade on myocardial infarct size and cardiac dynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetized open-chest dogs were subjected to left anterior descending (LAD) coronary artery occlusion. Twenty minutes post-occlusion the dogs were given i.v. saline (0.9% NaCl solution) (n = 12) or the TXA2 receptor antagonist SQ 29548 (0.2 mg/kg i.v. loading dose +0.2 mg/kg/h i.v. for 4 h) (n = 10). SQ 29548 treatment resulted in a significant (P < 0.01) reduction in infarct size. Heart rate (HR) and systolic blood pressure (SAP) were not markedly affected by the drug. The sharp rise in the left ventricular end diastolic pressure (LVEDP) in the saline-treated animals was significantly lowered by SQ 29548 treatment and the correction of this variable was maintained till 24 h post-occlusion. The lowered maximal rate of rise of left ventricular pressure (LVdP/dt max) in the saline-treated animals was corrected albeit non-significantly by the drug treatment. Thus, SQ 29548 treatment resulted in a significant salvage of myocardial tissue and marked alterations in left ventricular dynamics. The study suggests a deleterious role for thromboxane A2 in ischemia; indicating that TXA2 blockade may have potential as a mode of therapy for ischemic heart disease.

Topics: Animals; Blood Pressure; Bridged Bicyclo Compounds, Heterocyclic; Dogs; Fatty Acids, Unsaturated; Female; Heart Rate; Hemodynamics; Hydrazines; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Necrosis; Receptors, Thromboxane; Thromboxane A2

1. The effects of the 5-HT2 antagonist, ICI 170,809 and the thromboxane A2 antagonist, ICI 192,605, given alone and in combination (n = 12 per group), were examined in anaesthetized rats. Haemodynamics and arrhythmias induced by permanent coronary artery occlusion or by reperfusion after 5 min of ischaemia were monitored. 2. In a study on reperfusion-induced arrhythmias, the only significant effect of ICI 170,809 (1 mg kg-1, i.v.) was a reduction in the number of ventricular premature beats (VPBs). ICI 192,605 (1 mg kg-1 min-1, i.v.) did not alter reperfusion-induced arrhythmias. However, in combination, when compared with controls, these drugs caused significant reductions in the incidence of ventricular tachycardia (VT), 100% to 58%; ventricular fibrillation (VF), 92% to 33%; and the mortality due to sustained VF, 67% to 17%. There was also a significant reduction in the number of VPBs following reperfusion. 3. In a second study with lower doses of drugs, ICI 170,809 (0.3 mg kg-1) and ICI 192,605 (0.3 mg kg-1 min-1) had no significant effects on reperfusion-induced arrhythmias either alone or in combination. 4. A third study examined the effects of the higher doses of the drugs on ischaemia-induced arrhythmias. Neither drug alone, nor in combination, altered the incidence of ischaemia-induced VT, VF, the mortality, or the number of VPBs. 5. These results indicate that, in contrast to the administration of either drug alone, combined administration of a 5-HT2 antagonist and a thromboxane A2 antagonist caused marked suppression of reperfusion-induced but not ischaemia-induced arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Dioxanes; Drug Combinations; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Quinolines; Rats; Rats, Wistar; Serotonin Antagonists; Thromboxane A2

We investigated the effects of (2R)-2-amino-N-(2,6-dimethylphenyl)-N-[3-(3-pyridyl)propyl]propionamide D-tartrate (Ro 22-9194), a novel class I antiarrhythmic agent, on myocardial ischemia- and reperfusion-induced arrhythmias in dogs. The incidence of ventricular fibrillation induced by reperfusion after a 30-min coronary ligation was significantly reduced by an i.v. infusion of Ro 22-9194 (10 mg/kg for 5 min before and an additional 20 mg/kg for 30 min during coronary ligation: total, 30 mg/kg) from 73% in the vehicle-treated group to 13%. Ro 22-9194 (20 and 30 mg/kg) also dose-dependently reduced the incidence of ventricular arrhythmias, including ventricular tachycardia and ventricular fibrillation, after coronary reperfusion. Other class I antiarrhythmic agents, mexiletine (15 mg/kg) and disopyramide (7.5 mg/kg), did not inhibit the development of ventricular fibrillation. In in vitro studies, Ro 22-9194, but neither mexiletine nor disopyramide (approximately 10(-3) M), inhibited thromboxane A2 synthase and arachidonic acid-induced aggregation of human platelets (IC50: 1.2 x 10(-5) M and 3.4 x 10(-5) M, respectively). Furthermore, Ro 22-9194 (30 mg/kg) attenuated the increase in venous thromboxane B2 concentrations in the local coronary vein during coronary ligation in dogs. A thromboxane A2 synthase inhibitor, OKY-046 (2.5 mg/kg administered for 5 min before coronary ligation) also showed no evident increases in thromboxane B2 concentrations as well as an antifibrillatory effect. Venous 6-keto-prostaglandin F1 alpha concentrations were not affected by either Ro 22-9194 or OKY-046. These results demonstrate that, unlike mexiletine and disopyramide, Ro 22-9194 protects against reperfusion-induced fatal ventricular arrhythmias in dogs. They also suggest that, in addition to the class I antiarrhythmic effect, the thromboxane A2 synthase inhibitory activity may contribute to the antiarrhythmic properties of Ro 22-9194.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclooxygenase Inhibitors; Disopyramide; Dogs; Enzyme Inhibitors; Female; Humans; Male; Methacrylates; Mexiletine; Myocardial Ischemia; Myocardial Reperfusion Injury; Platelet Aggregation; Pyridines; Thromboxane A2; Thromboxane-A Synthase

Oestrogen-replacement therapy is associated with a reduced incidence of cardiovascular disease. The acute administration of oestrogen improves myocardial ischemia in women with coronary heart disease. In this study we investigated the relaxing effect of oestradiol-17 beta on human coronary arteries in vitro and determined the role of endothelial modulation in this relaxation by using isolated human coronary arteries.. Atherosclerosis-free epicardial arteries from men and women were removed from patients undergoing heart or combined heart and lung transplantation. The arteries were cut into ring segments and placed into organ baths containing Tyrode's solution. Changes in isometric tension were measured. The relaxing response to oestradiol-17 beta (10(-10) - 10(-5) mol/l) was investigated and the effects of endothelium, NGmonomethyl-L-arginine and indomethacin on the response of oestradiol-17 beta were assessed.. Oestradiol-17 beta (10(-10) - 10(-5) mol/l) induced significant relaxation in coronary arteries pre-contracted with the thromboxane A2 analog (U46619; 3 x 10(-8) mol/l). Relaxation was significantly greater in coronary arteries from female patients. No significant differences were observed between arteries with or without endothelium nor after nitric oxide synthase or cyclo-oxygenase inhibition. These results indicate that oestradiol-17 beta induces human coronary artery relaxation via an endothelium-independent mechanism in vitro. The sex of the patients significantly affects sensitivity of the coronary arterial rings to oestrogen.. Oestradiol-17 beta-induced coronary relaxation may play an important role in regulation of coronary tone, and may partly explain why oestrogen improves myocardial ischemia in women and why it protects postmenopausal women from the risk of developing coronary heart disease.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Arginine; Child; Child, Preschool; Coronary Vessels; Endothelium, Vascular; Enzyme Inhibitors; Estradiol; Estrogen Replacement Therapy; Female; Humans; In Vitro Techniques; Indomethacin; Infant; Male; Middle Aged; Myocardial Ischemia; omega-N-Methylarginine; Prostaglandin Endoperoxides, Synthetic; Sex Factors; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

1. The objectives of the present experiments were to assess the role of ETA receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of platelet-activating factor (PAF) and thromboxane A2 (TxA2) in these actions of ET-1 in rats. 2. Intravenous bolus injection of ET-1 (0.1-2 nmol kg-1) into anaesthetized rats induced ST segment elevation of the electrocardiogram in a dose-dependent manner without causing arrhythmias. ST segment elevation developed within 20-90 s and persisted for at least 10-20 min following administration of ET-1. 3. Pretreatment of the animals with the selective endothelin ETA receptor antagonist, FR 139317 (2.5 mg kg-1, i.v.) inhibited by 86% the ST segment elevation elicited by ET-1 (1 nmol kg-1). Pretreatment with intravenous administration of BM 13505 (1 mg kg-1), a TxA2 receptor antagonist, OKY-046 (10 mg kg-1), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1) markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg-1 bolus plus 2 mg kg-1 h-1) did not significantly affect ET-1-induced ST segment elevation. 4. Bolus injection of ET-1 (1 nmol kg-1, i.v.) to conscious rats resulted in a prolonged pressor effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia. ET-l enhanced albumin leakage by 87 and 120% in the left ventricle and right atrium, respectively, as measured by the extravasation of Evans blue dye.5. The selective ETA receptor antagonist, FR 139317 (2.5 mg kg-1) significantly blunted the pressor action of ET-1 and the accompanying bradycardia without affecting the depressor response. Furthermore,FR 139317 almost completely abolished the permeability effect of ET-l in both vascular beds studied.6. Pretreatment of the animals with BM 13505 (1 mg kg-1), OKY-046 (10mg kg-1), WEB 2086(1 mg kg-1) or BN 52021 (10mg kg-1) significantly reduced ET-1 (1 nmol kg-1)-induced albumin extravasation both in the left ventricle and right atrium. The PAF receptor antagonists, WEB 2086 and BN 52021 were equally potent inhibitors in the left ventricle, whereas BN 52021 appeared to be a more potent inhibitor than WEB 2086 in the right atrium. Pretreatment with indomethacin (3 mg kg-1 plus 2 mg kg-1 h-1) did not modify the permeability response to ET-1. None of these compounds af

Topics: Anesthesia; Animals; Blood Pressure; Capillary Permeability; Edema; Electrocardiography; Endothelin Receptor Antagonists; Endothelins; Heart Rate; In Vitro Techniques; Male; Myocardial Ischemia; Platelet Activating Factor; Platelet Membrane Glycoproteins; Rats; Rats, Wistar; Receptors, Cell Surface; Receptors, Endothelin; Receptors, G-Protein-Coupled; Receptors, Thromboxane; Thromboxane A2

Reperfusion of the ischemic myocardium is a cornerstone of current therapy for acute coronary syndromes. Experiments show that reperfusion is associated with injury to the coronary artery. Such injury may manifest as augmented vasospasm or impaired vasodilation, and in this study we assessed whether such coronary responses to serotonin do occur.. Left anterior descending arteries (LAD) were occluded in 12 open-chested dogs for 1 h, then reperfused for 1 h. Vasoreactivity to serotonin was measured in isolated rings from the LAD and circumflex arteries (Cx), both at basal resting tension and after preconstriction with U-46619. Endothelium was removed in half of the rings.. In the basal state, LAD rings displayed increased initial constriction and decreased dilation in response to serotonin (maximum dilation: LAD, -4.5 +/- 1.7% versus Cx, -7.6 +/- 1.4%, P < 0.05). With endothelium removed, peak constrictions of the LAD and Cx were significantly augmented, and LAD dilations remained slightly impaired compared with the Cx. After U-46619, dilation in response to serotonin was impaired in the LAD compared with Cx rings (maximum dilation: LAD, -18.3 +/- 11.4% versus Cx, -44.0 +/- 8.4 LAD, P < 0.05). Endothelium removal diminished, but did not abolish, this relationship. De-endothelialized Cx, but not LAD, rings displayed slightly impaired dilations in response to serotonin compared with their respective controls.. After ischemia-reperfusion, coronary arteries respond to serotonin with enhanced constriction and impaired dilation. Changes in both the endothelium and the smooth muscle may determine these responses to serotonin.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Coronary Vasospasm; Coronary Vessels; Dogs; Endothelium, Vascular; Male; Muscle, Smooth, Vascular; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Reperfusion Injury; Potassium Chloride; Prostaglandin Endoperoxides, Synthetic; Serotonin; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

The anti-anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11-dideoxy-11 alpha,9 alpha-epoxymethano-PGF2 alpha (U-46619), a stable thromboxane A2 agonist, in anaesthetized rats. The ST elevation induced by U-46619 (5-20 micrograms kg-1, i.c.a.) was dose-dependent and reproducible. U-46619-induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0.01 micrograms kg-1), and to a lesser extent by nitroglycerin (0.3 mg kg-1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U-46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0.1 microgram kg-1, i.v.), but not by nitroglycerin (0.3 mg kg-1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U-46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Platelets; Blood Pressure; Coronary Vessels; Disease Models, Animal; Electrocardiography; Epoprostenol; Heart Rate; Injections, Intra-Arterial; Injections, Intravenous; Male; Myocardial Ischemia; Nitroglycerin; Platelet Aggregation; Platelet Count; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

Antianginal effects of monatepil ([(+-)-N-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-(4-fluor ophenyl)-1-piperazinebutanamide]monomaleate, AJ-2615, CAS 10337-41-9), a new calcium antagonist, were evaluated in experimentally induced myocardial ischemia in anesthetized rats and compared with those of diltiazem. Ischemic electrocardiogram change (ST elevation) and reduction of myocardial tissue oxygen tension were induced by intracoronary arterial administration of U-46619 ((5Z,9a,11a,13E,15(S))-9,11-(methano-epoxy)prosta-5,13-di en-1-oic acid) (10 micrograms/kg), a stable thromboxane A2 agonist. The ST elevation induced by U-46619 was significantly prevented by monatepil pretreatment (0.1 mg/kg i.v.), and to a lesser extent by diltiazem (0.3 mg/kg i.v.). Moreover, the decrease in myocardial tissue oxygen tension at the time of ST elevation after U-46619 was inhibited by monatepil pretreatment (0.3 mg/kg i.v.). These results indicate that monatepil exerts a more potent preventive effect against U-46619-induced myocardial ischemic changes than diltiazem and suggest that monatepil has potential for treating vasospastic angina.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Calcium Channel Blockers; Dibenzothiepins; Diltiazem; Electrocardiography; Heart Rate; Male; Myocardial Ischemia; Myocardium; Oxygen Consumption; Piperazines; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

We investigated the possible protective effects of benidipine (Coniel), a calcium antagonist, on mechanical dysfunction, metabolic damage and changes in vascular reactivity during ischemia and reperfusion in the Langendorff-perfused rat heart. The responses of perfusion pressure to U-46619, a vasoconstrictor, and acetylcholine, an endothelial-dependent vasodilator, were also determined as indices of the vascular function. Thirty min of reperfusion following 30 min of global ischemia produced contractile failure and the marked release of lactate dehydrogenase (LDH) and creatine phosphokinase (CPK). Additionally, the ischemia and reperfusion augmented the vasoconstrictor response to U-46619, and depressed the endothelium-dependent vasodilator response to acetylcholine. These hearts were treated with 1 or 10 nM benidipine from 20 min before ischemia to the beginning of ischemia. While benidipine at 10 nM had a modest negative inotropic action, 1 nM of this drug had minimal depressant effects on the preischemic function. The depressed contractile function after the ischemia was improved, and the increased releases of LDH and CPK were significantly ameliorated by benidipine. Also, benidipine restored the augmented contractile response to U-46619 and preserved the vasodilator response to acetylcholine. These results demonstrate that pretreatment with benidipine prevents myocardial injury following ischemia and reperfusion. The cardioprotective effects of benidipine may in part be due to the protection of vascular reactivity by this drug.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Calcium Channel Blockers; Dihydropyridines; Disease Models, Animal; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Thromboxane A2; Vascular Resistance; Vasoconstrictor Agents

We examined whether subtotal coronary artery occlusion and reperfusion alter coronary flow reserve and regional myocardial function.. Total coronary artery occlusion followed by reperfusion results in decreased coronary flow reserve and regional myocardial dysfunction.. Thirteen anesthetized dogs were subjected to subtotal occlusion of the left anterior descending coronary artery for 1 h, followed by reperfusion for 1 h. During subtotal left anterior descending occlusion, heart rate was increased by atrial pacing. After reperfusion, coronary flow reserve, indicated by reactive hyperemia, as well as coronary flow responses to acetylcholine and nitroglycerin, regional myocardial function and myocardial leukocyte accumulation were measured.. After reperfusion, coronary flow reserve was decreased in the ischemic left anterior descending but not the nonischemic circumflex coronary artery region. Myocardial function was also depressed in the left anterior descending coronary region and did not improve on reperfusion. Histologic study showed no leukocyte infiltration in the ischemic left anterior descending coronary region. Myeloperoxidase, an index of myocardial leukocyte accumulation, was similar in the left anterior descending and circumflex coronary regions. Sensitivity of epicardial left anterior descending coronary artery rings to the thromboxane A2 analog U46,619 was enhanced, and relaxation of these rings in response to endothelium-dependent relaxants was decreased.. Coronary flow reserve is reduced and regional myocardial function depressed after subtotal coronary artery occlusion and increased heart rate. A decreased synthesis or increased breakdown of endothelium-derived relaxing factor may be related to a decrease in coronary flow reserve. However, the reduction in coronary flow reserve appears to be unrelated to leukocyte accumulation in the reperfused region.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Animals; Cardiac Pacing, Artificial; Constriction; Coronary Circulation; Coronary Vessels; Dogs; Female; Heart; Heart Rate; Leukocytes; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Nitric Oxide; Nitroglycerin; Oxygen; Peroxidase; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents; Vasodilation

The thromboxane A2 receptor agonist, U-46619 ((5Z, 9 alpha, 11 alpha, 13E, 15(S))-9,11-(methanoepoxy)prosta-5,13-dien-1-oic acid) (10 micrograms/kg), induced a typical ischemic change (ST elevation) in the electrocardiogram on intracoronary arterial administration in the rat. The elevation of the ST segment induced by U-46619 was significantly reduced by pretreatment with anti-endothelin-1 rabbit serum. The plasma concentration of endothelin-1 dose dependently increased at the time of ST segment elevation after U-46619. These results indicate that endogenous endothelin-1 partly contributes to coronary spasmodic angina induced by thromboxane A2 in rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angina Pectoris; Animals; Electrocardiography; Endothelins; Injections, Intra-Arterial; Male; Myocardial Ischemia; Prostaglandin Endoperoxides, Synthetic; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Thromboxane A2; Vasoconstrictor Agents

The myocardial salvage efficacy of a thromboxane A2/prostaglandin endoperoxide (TP) receptor antagonist has not been previously determined in a ferret model of ischemia and reperfusion. Assessments of the reproducibility of infarct size resulting from a 90 min period of occlusion followed by 5 hr of reperfusion of the left anterior descending coronary artery in saline-treated control ferrets revealed a consistent mean level of tissue damage representing 23.1 +/- 1.4% of the left ventricle. In subsequent studies, ferrets were given the thromboxane receptor antagonist SQ 30,741 (1 mg/kg bolus and 1 mg/kg/hr infusion, i.v.) or vehicle. At this dose, SQ 30,741 significantly reduced infarct size from that measured in control ferrets by 44%. Concurrently, the drug produced a 97% inhibition of platelet TP receptors as measured by inhibition of the ex vivo platelet shape change response to U-46,619. Drug administration was not associated with measurable alterations in mean blood pressure, heart rate or the rate-pressure-product. The importance of this finding to clinical utility and the mechanism of the observed cardioprotective action, however, remain unclear. These data indicate that the ferret represents a useful model for the assessment of the myocardial salvage efficacy of TP receptor antagonists and are consistent with attenuation of ischemic myocardial damage by doses of these agents which produce > 96% TP receptor blockade.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Platelets; Blood Pressure; Ferrets; Heart; Heart Rate; In Vitro Techniques; Male; Myocardial Infarction; Myocardial Ischemia; Myocardium; Orchiectomy; Prostaglandin Endoperoxides, Synthetic; Receptors, Thromboxane; Reperfusion; Thromboxane A2; Vasoconstrictor Agents

The coronary circulation has been shown to remain responsive to vasodilator and vasoconstrictor stimuli during myocardial ischaemia. The aim of this study was to investigate whether endogenous adenosine attenuates coronary vasoconstriction caused by the thromboxane A2 analogue, U46619.. Nine chronically instrumented dogs were studied during treadmill exercise in the presence of a coronary stenosis which resulted in distal left circumflex coronary artery hypoperfusion. Myocardial blood flow was assessed with radioactive microspheres during exercise prior to and during intracoronary infusion of U46619 (0.01 microgram.kg-1 x min-1), in the absence and the presence of adenosine receptor blockade with intravenous 8-phenyltheophylline (5 mg.kg-1) and intracoronary adenosine deaminase (50 units.kg-1). Distal coronary pressure was maintained constant during the control stenosis and the three interventions, at 49(SEM 3), 50(3), 50(3), and 50(3) mm Hg.. During control exercise mean myocardial blood flow was 0.91(0.09) ml.min-1 x g-1 in the stenosis region and 2.54(0.28) in the normal region. With no change in distal coronary pressure, U46619 decreased mean myocardial blood flow to 0.70(0.10) ml.min-1 x g-1 (p < 0.05). Adenosine blockade alone decreased myocardial blood flow in the stenosis region to 0.60(0.07) ml.min-1 x g-1 (p < 0.05 v control stenosis), indicating that endogenous adenosine contributed to coronary vasodilatation in the ischaemic region. However, adenosine blockade did not augment the vasoconstriction in response to U46619 [mean myocardial blood flow 0.49(0.05) ml.min-1 x g-1], indicating that endogenous adenosine did not attenuate the vasoconstriction caused by U46619.. Endogenous adenosine contributed to dilatation of resistance vessels in hypoperfused myocardium of exercising dogs in the absence as well as in the presence of U46619. However, endogenous adenosine did not attenuate the magnitude of the vasoconstrictor response to U46619. These findings are best explained by observations that thromboxane A2 and adenosine act on coronary vascular segments of different size.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine; Animals; Coronary Vessels; Dogs; Myocardial Contraction; Myocardial Ischemia; Physical Exertion; Prostaglandin Endoperoxides, Synthetic; Regional Blood Flow; Theophylline; Thromboxane A2; Vasoconstriction; Vasoconstrictor Agents

We investigated the effect of BAY u3405, a thromboxane A2 receptor antagonist in pentobarbital anaesthetized rats subjected to left main coronary artery ligation (1 h) followed by reperfusion (1 h; MI/R). Sham operated rats were used as controls (Sham MI/R). Survival rate, myocardial necrosis, myocardial myeloperoxidase activity (investigated as an index of leukocyte adhesion and accumulation) and serum creatine phosphokinase activity were studied. Ischaemia-reperfusion injury significantly reduced the survival rate (45%), caused a marked myocardial necrosis, increased serum creatine phosphokinase activity (Sham MI/R = 26 +/- 10.2 U/ml; MI/R = 213 +/- 19 U/ml) and produced a rise in myocardial myeloperoxidase activity in the area-at-risk and in the necrotic area (6.1 +/- 0.4 U x 10(-3)/g tissue and 6.7 +/- 0.9 U x 10(-3)/g of tissue, respectively). The administration of BAY u3405 (30 and 60 mg/kg/i.v., 30 min before occlusion) significantly increased survival rate, lowered the area of myocardial necrosis, blunted the increase in serum creatine phosphokinase activity and reduced the increase in myeloperoxidase activity in both the area-at-risk and the necrotic area. Furthermore, the protective effect of BAY u3405 was dose-dependent. These data are consistent with an involvement of TXA2 in myocardial ischaemia-reperfusion injury and suggest that BAY u3405 may represent a novel therapeutic approach to the treatment of acute ischaemia-reperfusion injury.

Topics: Animals; Carbazoles; Creatine Kinase; Hemodynamics; Leukocytes; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Peroxidase; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane; Sulfonamides; Thromboxane A2

In 26 patients with coronary heart disease, transesophageal atrial pacing was used to study cerebral hemodynamics from brain tomoscintigraphic findings as compared to the severity of induced of myocardial ischemia, echocardiographic parameters of left ventricular function and prostacyclin-thromboxane balance. In angina pectoris, the lower rate of cerebral blood flow was found to be correlated with the integral parameter of myocardial ischemia, deteriorated cardiac contractile and pump function, and higher plasma thromboxane A2 levels.

Topics: Cardiac Pacing, Artificial; Cerebrovascular Circulation; Electrocardiography; Epoprostenol; Esophagus; Heart Atria; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Myocardial Ischemia; Thromboxane A2

Several attempts have been undertaken to reduce the severity of ischemic myocardial injury by exogenous administration of eicosanoids and by modification of endogenous eicosanoid production. The present study investigates whether defibrotide, a compound that stimulates endogenous prostacyclin (PGI2), has a beneficial effect in experimental ischemic myocardial injury. Anesthetized, open-chest minipigs were subjected to 1 h of coronary artery occlusion, followed by 3 h of reperfusion. Defibrotide (32 mg/kg x h) or its vehicle were infused i.v. throughout the experiment. Defibrotide increased cardiac PGI2 formation 3- to 4-fold greater than control (P < .05). Thromboxane levels remained unchanged. Irreversible ischemic injury, as identified by negative tetrazolium staining, amounted to 44 +/- 6% of the area at risk in pigs receiving vehicle but was reduced to 23 +/- 4% by defibrotide (P < .05). This reduced tissue injury in defibrotide-treated pigs was associated with improved functional recovery (left ventricular pressure, + dP/dtmax), during early reperfusion. Recovery did not occur in vehicle-treated pigs. Collagen (2 micrograms/ml)-induced platelet aggregation ex vivo was increased in vehicle-treated pigs during ischemia and reperfusion, but not in animals treated with defibrotide. Polymorphonuclear neutrophil leukocyte accumulation in the ischemic border zone was reduced from 59 +/- 17 cells/mm2 in vehicle-treated pigs to 17 +/- 9 cells/mm2 by defibrotide (P < .05). Pretreatment of the animals with indomethacin (3 mg/kg) prevented the reduction of infarct size and polymorphonuclear neutrophil leukocyte infiltration by defibrotide. Indomethacin increased infarct size in vehicle- and defibrotide-treated pigs by 71 and 59%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Blood Platelets; Cyclooxygenase Inhibitors; Disease Models, Animal; Epoprostenol; Female; Granulocytes; Indomethacin; Leukocyte Count; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Neutrophils; Platelet Count; Polydeoxyribonucleotides; Prostaglandins; Stimulation, Chemical; Swine; Swine, Miniature; Thromboxane A2; Ventricular Function, Left

We have shown earlier that prostacyclin (PGI2) and its stable analogue: 7-oxo-prostacyclin(7-OXO) may induce a prolonged, late appearing (24-48 h after drug administration), dose dependent protection of the heart from harmful consequences of a subsequent severe ischaemic stress, such as myocardial ischaemia, life-threatening ventricular arrhythmias and early ischaemic morphological changes. In an other study we observed that a similar but shortlived (less than 1 h) cardioprotection, induced by 'preconditioning' brief coronary artery occlusions, is greatly reduced by blockade of the cyclooxygenase pathway, suggesting that prostanoids might play a role in this shortlasting protection. Objective of our present study was to elucidate the importance of some arachidonic acid (AA) metabolites, such as PGI2 and thromboxane A2 (TXA2) in the mechanism of the late appearing, prolonged cardioprotection. Estimation of the metabolites: 6-keto-PGF1 alpha (6-KETO) and thromboxane B2 (TXB2) was made from the perfusate of isolated Langendorff hearts of guinea-pigs pretreated with 50 micrograms/kg 7-OXO, 24 and 48 h before preparation. Pretreatment alone produced a slight, but significant elevation of 6-KETO (from 206 +/- 11 to 284 +/- 19 pg/ml/min after 24 h, and to 261 +/- 18 pg/ml/min after 48 h). No change was seen in TXB2 production. Global ischaemia for 25 min (followed by 25 min reperfusion) markedly increased the release of both AA metabolites; maximal values were observed in the third min of reperfusion (6-KETO from 206 +/- 11 to 1275 +/- 55 pg/ml/min and TXB2 from 29 +/- 4 to 172 +/- 12 pg/ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Epoprostenol; Guinea Pigs; Heart; Male; Myocardial Ischemia; Thromboxane A2; Thromboxane B2

After crystalloid cardioplegic arrest, cardiac-derived thromboxane A2 may be an important initiating mediator of no-reflow and hemodynamic deterioration during reperfusion because of its potent vasoactive properties. Although previous studies have already documented the increased release of cardiac thromboxane A2 after ischemia, none have studied the effects of cardiac thromboxane A2 on hemodynamics. We therefore tested the ability of cardiac thromboxane A2 to mediate deterioration of coronary flow and functional recovery during reperfusion after global ischemia. Crystalloid-perfused rat hearts that had undergone Langendorff preparation (n = 30) were subjected to 2 hours of global ischemia at 15 degrees C under cardioplegic protection with (n = 15) or without (n = 15) thromboxane A2 receptor antagonist SQ29548. In eight of 15 hearts in each group, preischemic and postischemic aortic flow, coronary flow, cardiac output, heart rate, and stroke work were determined. In the remaining seven hearts in each group, preischemic and postischemic coronary effluent levels of the stable hydrolysis product of thromboxane A2 and thromboxane B2 were determined with radioimmunoassay through the use of nonrecirculating perfusate. At the completion of the experiment, water content was determined by wet weight/dry weight calculations. In a separate group (n = 7) preischemic myocardial water content was determined. Within the group protected by cardioplegic solution alone, postischemic aortic flow, coronary flow, cardiac output, and stroke work were all significantly decreased (p < 0.05) compared with preischemic values (aortic flow, 50.8 +/- 2.7 versus 29.4 +/- 3.3 ml/min; coronary flow, 13.2 +/- 1.3 versus 8.5 +/- 1.3 ml/min; cardiac output, 64.0 +/- 3.8 versus 38.0 +/- 4.4 ml/min; stroke work, 12.5 +/- 0.7 versus 7.1 +/- 0.8 cm H2O.ml). In relation to the group with cardioplegic solution alone, postischemic aortic flow, coronary flow, cardiac output, and stroke work were all significantly greater (p < 0.05) in the group with the receptor antagonist (aortic flow: 49.5 +/- 2.4 versus 29.4 +/- 3.3 ml/min; coronary flow; 12.4 +/- 1.2 versus 8.5 +/- 1.3 ml/min; cardiac output, 62.0 +/- 2.8 versus 38.0 +/- 4.4 ml/min; stroke work, 12.6 +/- 0.8 versus 7.1 +/- 0.8 cm H2O.ml). Overall, postischemic coronary effluent thromboxane B2 levels were greater than preischemic values (105.6 +/- 12.4 versus 69.6 +/- 9.8, p < 0.05) and treatment with the receptor antagonist did not significant

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cardiac Output; Cardioplegic Solutions; Coronary Circulation; Fatty Acids, Unsaturated; Hydrazines; In Vitro Techniques; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Sprague-Dawley; Stroke Volume; Thromboxane A2; Thromboxane B2

Platelets are a source of vasoactive mediators that regulate vascular tone. Platelets also play a role in intravascular thrombus formation and dynamic coronary constriction that result in myocardial ischemia. However, effects of platelets on myocardial function after ischemia and reperfusion are unknown. In this study, we examined the effects of platelets on myocardial dysfunction caused by ischemia/reperfusion. Buffer-perfused isolated rat hearts, after global ischemia (15 minutes) and reperfusion (10 minutes), developed marked myocardial dysfunction, indicated by a 65 +/- 4% decrease in the force of cardiac contraction (FCC) and a 26 +/- 7% increase in coronary perfusion pressure (CPP). Ischemia/reperfusion was also associated with release of creatine kinase (CK) and ATP metabolites in the coronary effluents. Perfusion of hearts with buffer containing washed rat platelets (3-8 x 10(7) cells/ml) protected hearts against dysfunction from ischemia/reperfusion, indicated by minimal changes in CPP (-1 +/- 1%) and FCC (-1 +/- 3%). Release of CK in the coronary effluent was also reduced, as was the release of ATP metabolites in the platelet-perfused hearts. Perfusion of hearts with serotonin receptor antagonist LY53,857 (10(-6) M), thromboxane A2 receptor antagonist SQ29,548 (10(-6) M), adenine nucleotide scavenger apyrase (0.4 units/ml), or nitric oxide synthetase inhibitor NG-monomethyl-L-arginine (2 x 10(-4) M) attenuated (p < 0.05) the platelet-mediated cardioprotective effects. Perfusion of the hearts with L-arginine (2 x 10(-4) M) instead of platelets also showed modest protective effects on FCC (-4.3 +/- 13%), CPP (+18 +/- 7%), and CK release. Prolongation of the ischemic period to 30 minutes and reperfusion to 20 minutes also demonstrated marked cardiac dysfunction (FCC, -58 +/- 10%; CPP, +36 +/- 8%) in buffer-perfused hearts. Perfusion of hearts with platelets in this setting of prolonged ischemia/reperfusion also exhibited protective effects on FCC (-24 +/- 10%), CPP (+12 +/- 6%), and CK release. Thus, platelets protect myocardium from ischemia/reperfusion-induced injury, and these protective effects of platelets are evident regardless of the duration of ischemia/reperfusion. Furthermore, these cardioprotective effects of platelets seem to be related to the release of serotonin, thromboxane A2, and adenine nucleotides. These substances most likely elicit release of endothelium-derived relaxing factor, with its attendant tissue-protective effects, fro

Topics: Adenosine Triphosphate; Animals; Arginine; Blood Platelets; Creatine Kinase; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Myocardial Reperfusion Injury; Nitric Oxide; Perfusion; Rats; Rats, Sprague-Dawley; Serotonin; Thromboxane A2

To assess the potential role of vasoactive cardiac eicosanoids in the modulation of coronary flow, we measure thromboxane(TX)B2, 6-keto-prostaglandin(PG)F1 alpha, PGE2 and sulphido-peptide leukotrienes (LTC4, D4, E4) in the coronary effluent of isolated perfused rat heart in both baseline and post-ischaemic conditions. Leukotrienes were undetectable. The order of production rate for the other eicosanoids was 6-keto-PGF1 alpha > TXB2 > PGE2. Production of such substances was increased about seven-fold over control after 5 min. global ischaemia; experiments with hypoxia showed that this was due to an actual increase in synthesis and not to a washout effect. A platelet source for TXB2 was excluded by 111In platelet labelling experiments. We assessed relative sensitivity to inhibition of cardiac TX synthesis relative to production of 6-keto-PGF1 alpha to inhibition by aspirin, ibuprofen, diclofenac and the specific thromboxane synthase inhibitor OKY-046. Aspirin, ibuprofen and diclofenac decreased 6-keto-PGF1 alpha production at a concentration always greater than required for a similar extent of TX inhibition. On the other hand a selective inhibition (> 90%) of TX was observed in the presence of OKY-046. Regression analysis of various 6-keto-PGF1 alpha/TXB2 ratios, as obtained in these different conditions, vs coronary flow, showed no correlation in baseline conditions, but a significant positive correlation (r = 0.59, P < 0.01) for post-ischaemic values. These data suggest a role for cardiac eicosanoids, including a non-platelet, cardiac-derived TX, in modulating the hyperaemic response in the isolated rat heart.

Topics: Animals; Blood Platelets; Coronary Circulation; Eicosanoids; Heart; Heart Rate; Hyperemia; Hypoxia; In Vitro Techniques; Indium Radioisotopes; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Rats; Rats, Wistar; Thromboxane A2; Thromboxanes