15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Cardiomegaly

To investigate the molecular mechanisms and cellular signaling pathways involved in the activation of TP receptors and the consequent induction of contractile responses in coronary arteries of renal hypertensive (2K-1C) rats.. The coronary perfusion pressure (CPP) was lower in 2K-1C rats during increased coronary flow as measured by the Langendorff technique. The coronary contraction and relaxation were evaluated by vascular reactivity studies, and the molecular mechanisms were investigated on the basis of the protein expression of TP receptors, Cav-1, eNOS, COX-1, and COX-2, as measured by Western blot. The levels of eicosanoids were determined by ELISA immunoassay and analyzed by reverse-phase HPLC coupled to electrospray ionization mass spectrometry (HPLC-MS/MS). The metabolites from NO production were evaluated by the Griess reaction. The coronary arteries of 2K-1C rats expressed COX-2 to a larger extent and TP receptors to a lesser extent than the coronary arteries of normotensive (2K) rats. Selective COX-1 and non-selective COX inhibitors reversed the reduction in the contraction induced by TP receptors in the coronary arteries of 2K-1C rats. U46619, an agonist of TP receptors, induced a contractile response that was relaxed by acetylcholine (ACh). In the coronary arteries of 2K-1C rats, this ACh-induced relaxation depended on COX. The activation of TP receptors increased the production of PGI. Activation of TP receptors increases production of PGI

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Blood Pressure; Cardiomegaly; Chromatography, Reverse-Phase; Coronary Vessels; Cyclooxygenase 1; Cyclooxygenase 2; Disease Models, Animal; Epoprostenol; Hypertension, Renovascular; Male; Membrane Proteins; Nitric Oxide; Rats; Rats, Wistar; Receptors, Thromboxane; Spectrometry, Mass, Electrospray Ionization; Thromboxanes; Vasodilation

We have previously shown that the thromboxane (TXA2) receptor agonist, U46619, can directly induce ventricular arrhythmias that were associated with increases in intracellular calcium in cardiomyocytes. Since TXA2 is an inflammatory mediator and induces direct calcium changes in cardiomyocytes, we hypothesized that TXA2 released during ischemia or inflammation could also cause cardiac remodeling.. U46619 (0.1-10 μM) was applied to isolated adult mouse ventricular primary cardiomyocytes, mouse ventricular cardiac muscle strips, and cultured HL-1 cardiomyocytes and markers of hypertrophy and cell death were measured.. We found that TXA2 receptors were expressed in ventricular cardiomyocytes and were functional via calcium imaging. U46619 treatment for 24 h did not increase expression of pathological hypertrophy genes (atrial natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin) and it did not increase protein synthesis. There was also no increase in cardiomyocyte size after 48 h treatment with U46619 as measured by flow cytometry. However, U46619 (0.1-10 μM) caused a concentration-dependent increase in cardiomyocyte death (trypan blue, MTT assays, visual cell counts and TUNEL stain) after 24 h. Treatment of cells with the TXA2 receptor antagonist SQ29548 and inhibitors of the IP3 pathway, gentamicin and 2-APB, eliminated the increase in cell death induced by U46619.. Our data suggests that TXA2 does not induce cardiac hypertrophy, but does induce cell death that is mediated in part by IP3 signaling pathways. These findings may provide important therapeutic targets for inflammatory-induced cardiac apoptosis that can lead to heart failure.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Boron Compounds; Cardiomegaly; Cell Death; Cell Line; Cells, Cultured; Gentamicins; Male; Mice; Muscle Proteins; Myocardium; Myocytes, Cardiac; Receptors, Thromboxane A2, Prostaglandin H2; RNA, Messenger

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

We recently described the early appearance of pulmonary hypertension in the fawn-hooded rat (FHR), an animal with platelet storage pool disease also known to develop systemic hypertension at later ages. Since mediators released from aggregating platelets influence vascular tone, we hypothesized that platelet-mediated pulmonary vascular responses in FHR may be abnormal and potentially linked to the mechanism of pulmonary hypertension. To test this we examined reactivity of isolated pulmonary arteries (PA) and thoracic aortas (Ao) from young FHR with moderately severe pulmonary hypertension but normal systemic pressures. These vessels were compared with PA and Ao from control Sprague-Dawley rat (SDR). Aggregating platelets (1,000-40,000 platelets/mm3) from FHR caused dilation of SDR PA and Ao but constriction of FHR PA and Ao. Qualitatively similar responses were also observed with platelets isolated from SDR implying that abnormal responses were not simply due to the storage pool deficiency in FHR. Response to the platelet-derived endothelium-dependent vasodilator ADP was markedly impaired in FHR PA and mildly impaired in FHR Ao. Endothelium-dependent dilation to acetylcholine, but not to A23187, was mildly impaired in FHR PA while responses to both dilators were normal in FHR Ao. Endothelium-independent dilation to sodium nitroprusside was normal in both FHR PA and Ao. Constrictor sensitivity to serotonin, but not to the thromboxane A2 mimetic U-46619, was increased in FHR PA while responses to both constrictors were normal in FHR Ao. In summary, PAs from FHR with spontaneous pulmonary hypertension exhibit paradoxical constriction to both normal and storage pool deficient platelets.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Acetylcholine; Adenosine Diphosphate; Animals; Aorta; Blood Platelets; Calcimycin; Cardiomegaly; Endothelium, Vascular; Hypertension, Pulmonary; Male; Meclofenamic Acid; Nitroprusside; Platelet Aggregation; Platelet Storage Pool Deficiency; Prostaglandin Endoperoxides, Synthetic; Pulmonary Artery; Rats; Rats, Inbred Strains; Serotonin; Vasoconstriction; Vasodilation