thromboxane-a2 and Cardiomegaly

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

Topics: Animals; Blood Platelets; Cardiomegaly; Cardiovascular Diseases; Dinoprost; Epoprostenol; Hemodynamics; Humans; Hypertension, Renovascular; Inflammation Mediators; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Prostaglandins; Receptors, Prostaglandin; Sepsis; Signal Transduction; Tachycardia; Thromboxane A2

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

To determine the influence of experimental hypertension on the structure and function of porcine coronary small arteries.. Miniature pigs underwent partial left renal artery constriction and contralateral nephrectomy. Blood pressures were recorded, using indwelling carotid artery catheters. After 4 weeks the pigs were killed, the heart was removed and subepicardial third-order branches of the left anterior descending artery were dissected and mounted in a myograph for morphological and functional assessment.. Final mean +/- SEM systolic and diastolic blood pressures were, respectively, 197 +/- 9 and 142 +/- 7 mmHg (n = 21) for the hypertensive pigs and 125 +/- 4 and 80 +/- 4 mmHg (n = 11) for the sham-operated control pigs. Hypertension was associated with significant left ventricular hypertrophy. The media thickness: lumen diameter ratio was increased significantly in hypertensive intramyocardial small arteries, caused mainly by remodelling (remodelling index 92%) rather than by medial growth. Maximal contractile responses to potassium and acetycholine were significantly depressed in the arteries from hypertensive pigs, whereas endothelium-dependent relaxation responses to bradykinin, substance P and serotonin were not significantly influenced by hypertension.. These results demonstrate that even short-term hypertension induces both structural and functional changes in left ventricular intramyocardial small arteries.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Cardiomegaly; Coronary Vessels; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Hypertension, Renovascular; Male; Prostaglandin Endoperoxides, Synthetic; Swine; Swine, Miniature; Thromboxane A2; Vasoconstriction

Rats were killed after 6 weeks of continuous ingestion of the pneumotoxic alkaloid monocrotaline (2.2 mg/kg/day), the neutrophil elastase inhibitor SC39026 (60 mg/kg/day), or both. Pulmonary reactions were evaluated by light and electron microscopy. Lung endothelial function was monitored by angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) and thromboxane (TXA2) production. Lung hydroxyproline content was measured as an index of interstitial fibrosis. Cardiac right ventricular hypertrophy was determined by the right ventricle to the left ventricle plus septum weight ratio (RV/LV + S). Rats receiving SC39026 alone did not differ significantly from untreated control animals with respect to any of the quantitative endpoints, although rarefaction of Type I pneumocytes was observed in the electron micrographs of these animals. Monocrotaline-treated rats, in contrast, developed a significant increase in RV/LV + S, and exhibited pulmonary edema, inflammation, fibrosis, and muscularization and occlusive mural thickening of the pulmonary small arteries and arterioles. These monocrotaline-induced structural changes were accompanied by decreased lung ACE and PLA activities, and increased PGI2 and TXA2 production, and by an increase in lung hydroxyproline content. Cotreatment with SC39026 ameliorated the monocrotaline-induced pulmonary vascular wall thickening and the cardiac right ventricular hypertrophy. These data suggest that inappropriate neutrophil elastase activity contributes to monocrotaline pulmonary vasculopathy and hypertension. On the other hand, cotreatment with SC39026 had no significant effect on the severity of the monocrotaline-induced lung inflammatory reaction, the pulmonary endothelial dysfunction, or the increase in lung hydroxyproline content.

Topics: Animals; Cardiomegaly; Chlorobenzoates; Epoprostenol; Hydroxyproline; Lung Diseases; Male; Monocrotaline; Organ Size; Pancreatic Elastase; Peptidyl-Dipeptidase A; Pyrrolizidine Alkaloids; Rats; Rats, Inbred Strains; Thromboxane A2; Tissue Plasminogen Activator