thromboxane-a2 and Heart-Failure

The aim of this study was to evaluate whether thromboxane inhibition can favorably affect renal perfusion and clinical conditions in patients affected by severe heart failure.. The renal formation of the vasoconstrictor thromboxane A(2) (TxA(2)) is increased during cardiac failure.. By oral administration of picotamide (a renal TxA(2) synthase and TxA(2)/prostaglandin H(2) receptor inhibitor), we blocked renal TxA(2). Fourteen patients in New York Heart Association functional class IV were studied according to a randomized, double-blinded, cross-over design. Each of the two eight-day periods of testing was preceded by a three-day period during which certain vasoactive medications were stopped.. Daily 24-h total urinary thromboxane B(2) (TxB(2)), the stable metabolite of TxA(2), dropped at the end of picotamide treatment (p < 0.01 vs. baseline). Compared with placebo, effective renal plasma flow and the glomerular filtration rate increased (p < 0.01 and p < 0.05, respectively), thus leading to a significant decrease in the filtration fraction (p < 0.01). Renal vascular resistance decreased consistently (p < 0.01). In all patients, picotamide treatment was associated with an increase in diuresis and natriuresis (p < 0.001 vs. baseline). Plasma creatinine decreased (p < 0.05 vs. baseline). Patients also showed improvement in several clinical parameters, including a significant decrease in both pulmonary and venous pressure (p < 0.01 vs. baseline).. These results indicate that renal thromboxane formation plays an important role in renal vascular resistance in patients with severe heart failure, such as those described in the present study. Inhibition of TxA(2) improves renal hemodynamics and kidney function and favorably affects indexes of cardiac performance.

Topics: Aged; Cross-Over Studies; Double-Blind Method; Female; Heart Failure; Humans; Kidney; Male; Phthalic Acids; Regional Blood Flow; Thromboxane A2; Thromboxane B2; Vascular Resistance

The prostaglandin-thromboxane system, platelet hemostasis and central hemodynamics were evaluated in 51 patients with heart failure-complicated acute myocardial infarction during aspirin, roxicam and basic (nitrates + cardiac glycosides + diuretics) therapies. The new non-steroidal antiinflammatory agent roxicam was shown to selectively inhibit thromboxane, without affecting prostacyclin levels. The agent may be regarded as the drug of choice in using antiaggregatory therapy in patients with myocardial infarction concurrent with heart failure.

Topics: 6-Ketoprostaglandin F1 alpha; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Cardiac Glycosides; Diuretics; Epoprostenol; Heart Failure; Humans; Myocardial Infarction; Nitrates; Piroxicam; Thromboxane A2; Thromboxane B2; Thromboxanes

Endothelial dysfunction can lead to congestive heart failure and the activation of endothelial ATP-sensitive potassium (K(ATP)) channels may contribute to endothelial protection. Therefore, the present study was carried out to investigate the hypothesis that natakalim, a novel K(ATP) channel opener, ameliorates post-infarction left ventricular remodeling and failure by correcting endothelial dysfunction. The effects of myocardial infarction were assessed 8 weeks following left anterior descending coronary artery occlusion in male Wistar rats. Depressed blood pressure, cardiac dysfunction, evidence of left ventricular remodeling and congestive heart failure were observed in the rats with myocardial infarction. Treatment with natakalim at daily oral doses of 1, 3 or 9 mg/kg/day for 8 weeks prevented these changes. Natakalim also prevented the progression to cardiac failure, which was demonstrated by the increase in right ventricular weight/body weight (RVW/BW) and relative lung weight, signs of cardiac dysfunction, as well as the overexpression of atrial and brain natriuretic peptide mRNAs. Our results also demonstrated that natakalim enhanced the downregulation of endothelium-derived nitric oxide, attenuated the upregulation of inducible nitric oxide synthase-derived nitric oxide (NO), inhibited the upregulated endothelin system and corrected the imbalance between prostacyclin and thromboxane A(2). Overall, our findings suggest that natakalim prevents post-infarction hypertrophy and cardiac failure by restoring the coordinated balance between endothelial function and cardiac hypertrophy.

Topics: Administration, Oral; Allyl Compounds; Animals; Blood Pressure; Cardiomegaly; Dose-Response Relationship, Drug; Endothelins; Endothelium, Vascular; Epoprostenol; Heart Failure; Heart Ventricles; Hydroxyproline; Immunohistochemistry; Male; Microscopy, Electron, Transmission; Myocardial Infarction; Myocardium; Natriuretic Peptide, Brain; Nitric Oxide; Propylamines; Rats; Rats, Wistar; Thromboxane A2; Ventricular Remodeling

The clinical history of patients with heart failure (HF) is complicated by arterial thromboembolism. Platelet activation is reported in this population, but the underlying mechanism has not been clarified. Forty-two patients with HF scored according to New York Heart Association (NYHA) classification had higher levels of collagen-induced platelet aggregation, platelet tumor necrosis factor-alpha (TNF-alpha) receptor expression, and serum thromboxane B2 and higher circulating levels of TNF-alpha than 20 healthy subjects. Coincubation of platelets from HF patients with an inhibitor of TNF-alpha receptors significantly reduced collagen-induced platelet aggregation. In vitro study demonstrated that TNF-alpha amplified the platelet response to collagen; this effect was inhibited by TNF-alpha receptor antagonist and inhibitors of arachidonic acid metabolism. This study showed that TNF-alpha behaves as a trigger of platelet activation through stimulation of the arachidonic acid pathway.

Topics: Aged; Arachidonic Acid; Blood Platelets; Case-Control Studies; Cells, Cultured; Collagen; Female; Heart Failure; Humans; Male; Middle Aged; Platelet Activation; Receptors, Tumor Necrosis Factor; Thromboxane A2; Tumor Necrosis Factor-alpha

Although it is known that endothelin (ET-1) is elevated in heart failure (HF), it remains unclear if chronic ET(A/B) receptor antagonism affects the progression of HF, particularly by affecting coronary vasoactivity and left ventricular (LV) diastolic function.. We examined the effects of an ET(A/B) receptor antagonist, L-753,037 (oral bid for 6 weeks, n=7), and vehicle (n=8) in conscious dogs with previously implanted aortic, coronary sinus and left atrial catheters, LV pressure gauge, aortic flow probe, LV dimension crystals and pacers.. Baseline hemodynamics were similar in the two groups. During the development of rapid pacing-induced HF, treatment with the ET(A/B) antagonist significantly reduced total peripheral resistance and increased cardiac output compared to vehicle. After 2 weeks of pacing, LV diastolic function (tau) was improved (P<0.05) in the ET(A/B) antagonist group (+6+/-2 ms) compared to the vehicle group (+12+/-2 ms). In addition, ET(A/B) antagonist treatment attenuated the increase in mean left atrial pressure and LV end-diastolic pressure that occurred during heart failure in vehicle-treated animals. However, LV systolic function (LV dP/dt, fractional shortening and Vcfc) neither at rest nor in response to dobutamine was altered by ET(A/B) antagonist treatment. Also, ET(A/B) antagonist treatment did not affect the progressive increases in LV dimension. After 6 weeks of pacing, maximal Ca(2+) transport in isolated cardiac sarcoplasmic reticulum (SR) was reduced (P<0.02) in the vehicle-treated compared to the ET(A/B) antagonist-treated dogs (1.34+/-0.09 vs. 1.60+/-0.06 micromol/mg/min, respectively). The improvement in SR function in the ET(A/B) antagonist-treated dogs was associated with a significant attenuation of the reduction in protein expression of SERCA2a and calsequestrin observed in the vehicle-treated dogs. Coronary arteries isolated from the dogs treated with the ET(A/B) antagonist exhibited enhanced (P<0.01) coronary endothelium-dependent relaxation compared to the vehicle group, while coronary responses to an NO donor were identical in the two groups. Plasma NO levels in the coronary sinus during the late stage of HF were higher (P<0.05) in the ET(A/B) antagonist group (40+/-2 microM) compared to the vehicle group (18+/-2 microM).. We conclude that in conscious dogs during the development of HF induced by rapid pacing, chronic inhibition of ET(A/B) receptors does not affect resting myocardial contractile function nor reserve, but reduces vascular resistance and improves LV diastolic function. After 6 weeks of pacing, the reduction in intracellular Ca(2+) regulation by the SR is also attenuated, and endothelium-dependent coronary relaxation is improved, which appears to be related to the preservation of coronary NO levels.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Analysis of Variance; Animals; Calcium; Cardiac Pacing, Artificial; Coronary Vessels; Dogs; Endothelin Receptor Antagonists; Heart Failure; In Vitro Techniques; Myocardial Contraction; Nitric Oxide; Pyridines; Receptor, Endothelin A; Receptor, Endothelin B; Sarcoplasmic Reticulum; Sodium Nitrite; Stroke Volume; Thromboxane A2; Vascular Resistance; Vasoconstriction

Renal formation of the vasoconstrictor prostaglandins thromboxane A2 (TXA2) and prostaglandin F2 alpha (PGF2 alpha) was investigated in 25 patients with cardiac failure, divided into New York Heart Association functional classes I to IV, and in eight healthy control subjects. Plasma renin activity (PRA) and hemodynamic parameters were also investigated. Renal vasoconstrictor eicosanoid formation, measured in urinary daily excretion, was not different between patients in class I and control subjects. Class II to IV patients showed progressively increasing production of PGF2 alpha (F = 49.8, p < 0.001, analysis of variance) and TXA2 (F = 37.8, p < 0.002). PGF2 alpha excretion peaked in class IV (+ 1266% vs class I, p < 0.001). Compared with class I, urinary excretion of thromboxane B2 was + 816% in class III and + 1561% in class IV (both p < 0.001). PRA was significantly increased only in class IV (+ 1558%, p < 0.001). The current results indicate a progressive increase in renal production of vasoconstrictor eicosanoids directly related to New York Heart Association class and suggest that these prostanoids may have a role in deterioration of renal function.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analysis of Variance; Case-Control Studies; Dinoprost; Female; Heart Failure; Hemodynamics; Humans; Kidney; Middle Aged; Severity of Illness Index; Thromboxane A2

There is little, if any, good evidence in the literature to indicate a role for cardiovascular PG in congestive heart failure, either in its pathogenesis or as a consequence of and defense against its manifestations. Usually congestive heart failure is considered to develop as a vicious cycle in which impaired cardiac output, increased peripheral resistance, decreased renal blood flow, increased renin release and further increased peripheral resistance and decreased cardiac output are important constituents. Increased sympathetic activity may promote cardiovascular PG formation through the sympathetic neurotransmitter noradrenaline; such an action has, however, not been documented hitherto. Furthermore, increased plasma renin activity may promote PG formation via increased circulating levels of angiotensin; even such an action remains, however, to be demonstrated. If the heart failure leads to local tissue ischemia the hypoxia as such, or the subsequent increase in adenosine production, may also facilitate cardiovascular PG formation. All these mechanisms, if operative, would counteract the increased peripheral resistance, by promoting the formation of vasodilator PG. On the other hand PGI2 stimulates renal formation of renin, which would act to elevate the peripheral resistance. These contradictory effects of endogenously formed PG focus on the need for more careful studies on their involvement in the hemodynamic consequences of congestive heart failure: until more data are available it is impossible to know whether an activated synthesis of PG should be regarded as advantageous and worth therapeutical support, or negative and subject to inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Dinoprost; Dinoprostone; Epoprostenol; Heart Failure; Humans; Indomethacin; Kidney; Prostaglandin Antagonists; Prostaglandins; Prostaglandins E; Prostaglandins F; Thromboxane A2

Topics: Arachidonic Acid; Arachidonic Acids; Blood Platelets; Cardiovascular Diseases; Coronary Disease; Eicosanoic Acids; Endothelium; Heart Failure; Humans; Leukocytes; Lipoxygenase; Muscle, Smooth, Vascular; Myocardial Infarction; Myocarditis; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Thrombosis; Thromboxane A2