sq-29548 and Cardiovascular-Diseases

It had already showed that several thromboxane A(2) receptor (TP receptor) antagonists might be utilized in the treatment of cardiovascular diseases. In addition, recent reports suggested that TP receptor antagonism may be able to restrict vascular inflammation in atherosclerotic vessels. In particular, S18886 has been developed as a non-prostanoid TP receptor antagonist derived from sulotroban that is characterized by a tetrahydronaphthalene ring as a spacer between the 4-cholophenylsulfonamide group and carboxylic acid. Several reports using experimental animal models of atherosclerosis indicated that S18886 caused a regression of advanced atherosclerosis. More recently, several studies and patents showed that new thromboxane modulators combined with another pharmacological activities have been developed. Ohtake et al. discovered TRA-418 (a benzene-condensed heterocyclic derivative) having a TP receptor antagonistic activity and a prostaglandin I(2) receptor agonistic activity. Cesagrande found that 4-methyl-N- (4-trans-nitrooxycyclohexyl)-N-(3-pyridinylmethyl)-1,3- benzenedicarboxamide is endowed with anti-thromboxane and NO-donor actions. Oketani et al. discovered that E3040, a novel benzothiazole derivative, inhibited TXA(2) synthase and 5-LO activities. EK112, a combined angiotensin II and TP receptor antagonist, was developed. These new compounds may be able to restrict further infiltration of inflammatory cells in atherosclerotic vessels, thus stabilizing vulnerable plaques in the related cardiovascular diseases.

Topics: Animals; Atherosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Fatty Acids, Unsaturated; Humans; Hydrazines; Lipoxygenase Inhibitors; Naphthalenes; Oxidative Stress; Propionates; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction

1. The aim of this study was to establish how thromboxane receptors (TP) respond to the increase in levels of plasma thromboxane observed in both cardiac (cardiomyopathy, ischaemic heart disease and pulmonary hypertension) and vascular disease (atherosclerosis of coronary artery disease and accelerated atherosclerosis of saphenous vein grafts). 2. The agonist radioligand [(125)I]-BOP, bound rapidly to TP receptors in normal human cardiovascular tissue, displaying high affinity in left ventricle (K(D) 0.23 +/- 0.06 nM, B(max) 28.4 +/- 5.7 fmol mg(-1) protein) and reversibility with a t(1/2) of 10 min (n = five individuals +/- s.e.mean). 3. In the heart, TP receptor density in the right ventricle of primary pulmonary hypertensive patients were significantly increased (66.6 +/- 6 fmol mg(-1) protein) compared to non-diseased right ventricle (37.9 +/- 4.1 fmol mg(-1) protein, n = six individuals +/- s.e.mean, P<0.05). 4. In diseased vessels, TP receptor densities were significantly increased (3 fold in the intimal layer) in atherosclerotic coronary arteries, saphenous vein grafts with severe intimal thickening (n = 8-12 individuals, P<0.05) and aortic tissue (n=5 - 6 individuals, P<0.05), compared with normal vessels. 5. Losartan, tested at therapeutic doses, competed for [(125)I]-BOP binding to human vascular tissue, suggesting that some of the anti-hypertensive effects of this AT(1) receptor antagonist could also be mediated by blocking human TP receptors. 6. The differential distribution of TP receptors in the human cardiovascular system and the alteration of receptor density, accompanying the increase in endogenous thromboxane levels in cardiovascular disease, suggest that TP receptors represent a significant target for therapeutic interventions and highlights the importance for the development of novel selective antagonist for use in humans.

Topics: Adult; Angiotensin Receptor Antagonists; Binding, Competitive; Blood Vessels; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular Diseases; Fatty Acids, Unsaturated; Female; Heart Atria; Heart Ventricles; Humans; Hydrazines; In Vitro Techniques; Kinetics; Losartan; Male; Middle Aged; Radioligand Assay; Receptor, Angiotensin, Type 1; Receptors, Thromboxane