Inhibition of cyclic strain-induced endothelin-1 secretion by tetramethylpyrazine.

1. Chuanxiong is a Chinese herb that has been used widely in China to treat vascular disorders. 2,3,5,6-Tetramethylpyrazine (TMP) is one of the major components purified from chuanxiong. Many studies have demonstrated that TMP is effective in the treatment of cardiovascular diseases. However, the mechanism of action by which TMP exerts relaxation in vascular vessels remains unclear. 2. Endothelin (ET)-1 is a potent vasopressor synthesised by endothelial cells both in culture and in vivo. The aims of the present study were to test the hypothesis that TMP may alter strain-induced ET-1 secretion and to identify the putative underlying signalling pathways in endothelial cells. 3. We showed that TMP inhibits strain-induced ET-1 secretion. 2,3,5,6-Tetramethylpyrazine also inhibits the strain-induced formation of reactive oxygen species (ROS) and phosphorylation of extracellular signal-regulated kinases (ERK) 1/2. Furthermore, pretreating cells with TMP or the anti-oxidant N-acetyl-cysteine decreased strain-induced increases in ET-1 secretion and ERK1/2 phosphorylation. Using a reporter gene assay, TMP and N-acetyl-cysteine were demonstrated to also attenuate the strain-induced activity of the activator protein-1 reporter. 4. In summary, we have demonstrated, for the first time, that TMP inhibits strain-induced ET-1 gene expression, in part by interfering with the ERK1/2 pathway via attenuation of ROS formation. Thus, the present study provides important new insights into the molecular pathways that may contribute to the proposed beneficial effects of TMP in the vascular system.

The autoantibody expression against different source of oxidized low density lipoprotein in patients with acute myocardial infarction.

The aim of this study was to examine the expression of antibodies against two different sources of low density lipoprotein (LDL) that were oxidized by CuSO(4), in patients with early stage of acute myocardial infarction (AMI). When LDL purified from sera with high level of LDL was used as a modified antigen, the results indicated that the titers of antibodies against the oxidized LDL in 30 patients were increased by 135% compared to those in normal subjects; however, the titers of antibody against modified LDL purified from normal-range LDL in the same patients were only slightly increased by 52%. Comparing the levels of autoantibody expressed in the high LDL sera group, high triglyceride sera group, and AMI patients sera group (total of 41; in addition to 30 AMI patients, 11 more sera of AMI patients were collected), the amount of autoantibody against the oxLDL purified from high LDL sera in AMI patients sera group was significantly increased up to 195%. In contrast to AMI patients, the sera titers against the same antigen in two subject groups with either high LDL or high triglyceride are only 50% higher than normal subjects. Moreover, the ratio of thromboxane B(2) over 6-keto-prostaglandin F(1alpha) (6-keto-PG F(1alpha)) in the acute myocardial infarction patients was 1.79, which is much lower than the normal subjects, 4.19. Concluding from the above observations, we suggest that the expression level of anti-oxidized LDL antibody may play a role on the pathogenesis of acute myocardial infarction disease, but is independent with the levels of thromboxane A(2) and prostacyclin in the examined sera.

Fosinopril improves left ventricular diastolic function in young mildly hypertensive patients without hypertrophy.

To clarify whether fosinopril monotherapy can improve left ventricular diastolic function (LVDF) in young mildly hypertensives without hypertrophy, we studied 66 patients (pts) with diastolic blood pressure 90-100 mmHg, aged <45 years, with normal 2-dimensional echocardiography (2-D echo), and impaired DF. Impaired DF was defined as a Doppler transmitral early (E) to atrial (A) filling velocity ratio (E/A ratio) <1. Thirty-eight pts were selected for fosinopril monotherapy. Mean age was 36 years. Duration of documented hypertension was 5.4 years. Mean daily dose of fosinopril was 20 mg. Twenty-eight controls were treated with hydrochlorothiazide and hydralazine combination. Sixty-six age- and sex-matched healthy subjects served to establish normal reference values of 2-D and Doppler echo measurements. All hypertensives were treated for 30 months and re-examined 4 weeks after cessation of treatment. The fosinopril-treated group showed improvements in transmitral E (52 +/- 8 cm/s, vs. 61 +/- 9 cm/s, p < 0.01), A (56 +/- 9 cm/s, vs. 47 +/- 6 cm/s, p < 0.05), and E/A ratio (0.93 +/- 0.16, vs. 1.29 +/- 0.18, p < 0.01). Moreover, the early to atrial velocity-time integral ratio (1.31 +/- 0.10, vs. 2.24 +/- 0.10, p < 0.001) improved. The pulmonary venous flow pattern normalized after fosinopril therapy. LV mass index, relative wall thickness, LV dimension, left atrial dimension, fractional shortening, heart rate, and body mass index did not change. The hydrochlorothiazide-hydralazine combination-treated group did not show an improved diastolic function. It is concluded that long-term fosinopril monotherapy leads to an improvement of impaired LVDF in young mildly hypertensives without hypertrophy.