thromboxane-a2 and candesartan

Topics: Acrylates; Angiotensin II; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Growth Hormone; Humans; Hypertension; Imidazoles; Irbesartan; Losartan; Models, Molecular; Receptor, Angiotensin, Type 1; Tetrazoles; Thiophenes; Thromboxane A2

Multiple factors are involved in thrombus formation and require complex and highly therapeutic strategies. Platelet activation plays a critical role in the genesis of acute coronary syndromes involving not only platelets but also endothelial cells, leucocytes and erythrocytes. Angiotensin II (Ang II) is a vasoconstrictor that could participate in the thrombotic process. Platelets also express Ang II AT1 type receptors on their surface. Losartan is a non-peptidic inhibitor of AT1 receptors. It has been demonstrated that losartan reduced platelet aggregation induced by the thromboxane A2 (TXA2) analogue U46619. This effect was not observed with the losartan metabolite EXP 3174. The effect of losartan was assessed in binding studies in which losartan competitively inhibited the binding of [3H]U46619 to platelets in a dose-dependent manner. Irbesartan also inhibits the TXA2 receptor in platelets, an effect that was not obtained with the active form of candesartan, CV11974, and with valsartan. These results suggest that the structural requirements necessary to antagonize the TXA2/PGH2 platelet receptor may be different from those involved in AT1 receptor antagonism. The in vivo relevance of the in vitro findings has been confirmed by the fact that in vivo administration of losartan decreases P-selectin expression in platelets obtained from stroke-prone spontaneously hypertensive rats.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Angiotensin Receptor Antagonists; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Coronary Disease; Coronary Thrombosis; Humans; Losartan; P-Selectin; Platelet Activation; Platelet Aggregation; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Thromboxane; Tetrazoles; Thrombosis; Thromboxane A2; Valine; Valsartan

In vitro studies have suggested that losartan interacts with the thromboxane (TxA2)/ prostaglandin H2 (PGH2) receptor in human platelets, reducing TxA2-dependent platelet activation. The aim of this study was to evaluate the effect of different angiotensin II type 1 receptor antagonists in stroke-prone spontaneously hypertensive rats (SHRSP). The level of platelet activation was assessed by determining P-selectin expression in platelets by flow cytometry. The ex vivo adhesion of platelets was also analyzed. The number of platelets that expressed P-selectin in SPSHR was significantly increased (% P-selectin expression: WKY 4 +/- 0, 4%; SHRSP 15.5 +/- 0, 8% [n = 8], p < 0.05). In SHRSP receiving losartan (20 mg/kg body weight per day) the percentage of platelets expressing P-selectin fell to levels close to that observed in WKY. The number of platelets from SHRSP treated with valsartan and candesartan (20 mg/kg body weight per day for 14 days) that expressed P-selectin was not significantly different from those from untreated SPRHR. Only losartan treatment reduced ex vivo platelet adhesion to a synthetic surface. The antiplatelet effect of losartan does not appear to be related to the level of blood pressure reduction. In ex vivo experiments, losartan significantly reduced the binding of the radiolabeled TxA2 agonist U46619 to platelets obtained from SHRSP in a dose-dependent manner. Treatment with losartan reduced the number of activated platelets in SHRSP independently of its blood pressure effects. TxA2-receptor blockade is proposed as a mechanism by which losartan can prevent platelet activation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Platelets; Blood Pressure; Humans; Hypertension; Losartan; P-Selectin; Platelet Activation; Platelet Adhesiveness; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stroke; Tetrazoles; Thromboxane A2; Valine; Valsartan

Enhanced platelet activity and platelet endothelial interaction are hallmarks of different vascular and metabolic diseases with subsequent thrombus formation. In atherosclerosis, coronary artery disease, congestive heart failure, nitrate tolerance, chronic inflammation, or diabetic states, platelet activation may in part be due to a stimulation of the renin-angiotensin-aldosteron system, which also contributes to enhanced oxidant stress in these conditions.. We examined the putative role of the angiotensin receptor (AT1) and of phospholipase A2 (PLA2) in mediating platelet activation under defined in vitro conditions using the AT1 receptor antagonists losartan, EXP 3174, candesartan, and the PLA2 inhibitor arachidonyltrifluoromethyl ketone (AACOCF3), respectively.. In washed human or canine platelet suspensions, losartan (10(-4)-10(-6) mol/L) dose-dependently suppressed thrombin-induced calcium transients as well as thromboxane (TxA2) release. In both species, aggregation of washed platelets in response to thrombin or ADP was substantially diminished by different doses of losartan. This inhibition of platelet aggregation was even maintained in ADP-stimulated platelet-rich plasma. While the PLA2 inhibitor AACOCF3 effectively inhibited thrombin-induced TxA2 release from washed human or canine platelets (similar to the effects observed with losartan), the AT1 agonist angiotensin II elicited platelet TxA2 release only at high supra-physiological doses (e.g., at 10(-4) mol/L). The AT1 specific antagonist candesartan did not diminish stimulated platelet aggregation, TxA2 formation, or calcium transients. By contrast, the active losartan metabolite EXP 3174 dose-dependently inhibited stimulated platelet calcium transients as well as TxA2 release at 1-100 micromol/L.. Losartan significantly counteracts ex vivo platelet activation, probably via the blockade of TxA2 receptor-dependent signaling (e.g. implying activation of phospholipase A2) rather than acting at the AT1 receptor itself. This implies that the TxA2 signaling pathway plays a significant role during platelet activation, which may be successfully antagonized in vivo under different pathological states with enhanced thrombus formation or platelet-endothelium interactions.

Topics: Angiotensin Receptor Antagonists; Animals; Arachidonic Acids; Benzimidazoles; Biphenyl Compounds; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Humans; Imidazoles; Losartan; Phospholipases A; Phospholipases A2; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Receptors, Thromboxane; Renin-Angiotensin System; Signal Transduction; Tetrazoles; Thromboxane A2

A recent study has shown that losartan, an AT-1-receptor antagonist, interacts with thromboxane A2 (TxA2)/prostaglandin H2 (PGH2) receptors in human platelets. The aim of this study was to analyze the ability of different angiotensin II (Ang II) AT-1-receptor antagonists to inhibit TxA2-dependent human platelet activation. Platelets were obtained from healthy volunteers. Platelets were stimulated with the TxA2 analogue, U46619 (10(-6) M). U46619-stimulated platelet activation was significantly reduced by both losartan and irbesartan in a dose-dependent manner. Only maximal doses of valsartan (5 x 10(-6) M) and the main metabolite of losartan, EXP3174 (5 x 10(-6) M), reduced U46619-induced platelet activation. Whereas the active form of candesartan cilexetil (candesartan, CV-11974) failed to modify platelet activation involved by TxA2, telmisartan showed a higher effect than valsartan and EXP3174 but lower than either losartan and irbesartan. Losartan or irbesartan reduced the binding of [3H]-U46619 to platelets, an effect that was observed with lower ability with the other AT-1 antagonists. Although platelets expressed AT-1-type receptors, exogenous Ang II did not modify platelet activation. This effect was not modified by blocking the AT-2 receptor with PD123319. These results suggest that some AT-1-receptor antagonists reduce TxA2-dependent activation independent of Ang II involvement.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adenosine Diphosphate; Adult; Angiotensin II; Angiotensin Receptor Antagonists; Antibodies, Monoclonal; Benzimidazoles; Benzoates; Binding, Competitive; Biphenyl Compounds; Blood Platelets; Dose-Response Relationship, Drug; Humans; Imidazoles; Irbesartan; Losartan; Platelet Activation; Pyridines; Radioligand Assay; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Telmisartan; Tetrazoles; Thromboxane A2; Time Factors; Valine; Valsartan

A recent study has shown that losartan, an AT(1)-receptor antagonist, interacts with thromboxane A(2) (TxA(2))/prostaglandin H(2) (PGH(2)) receptors in human platelets. The aim of the present study was to analyse the ability of different angiotensin II (Ang II) AT(1)-receptor antagonists to inhibit TxA(2)-dependent human platelet activation. Platelets were obtained from healthy volunteers and were stimulated with the thromboxane A(2) analogue, U46619 (10(-6) mol/L). U46619-stimulated platelet activation was significantly reduced by losartan in a dose-dependent manner. Only maximal doses of valsartan (5x10(-6) mol/L), reduced U46619-induced platelet activation. The active form of candesartan cilexetil, candesartan (CV-11974), failed to modify platelet activation. Losartan reduced the binding of [(3)H]-U46619 to platelets, an effect that was observed to a lesser extent with valsartan but not with CV-11974. These results suggest that, whilst some AT(1)-receptor antagonists reduce TxA(2)-dependent human platelet activation, it is not a feature common to all AT(1) antagonists.

Topics: Adenosine Diphosphate; Adult; Angiotensin Receptor Antagonists; Benzimidazoles; Biphenyl Compounds; Blood Platelets; Cells, Cultured; Drug Interactions; Humans; Losartan; Male; Platelet Activation; Platelet Aggregation Inhibitors; Receptor, Angiotensin, Type 1; Tetrazoles; Thromboxane A2; Valine; Valsartan

The present study describes the influence of carbocyclic thromboxane A2 on the proliferative effects of angiotensin II on vascular smooth muscle cells. Angiotensin II (10(-7) M) and carbocyclic thromboxane A2 (10(-6) M) per se caused an increase in [3H]thymidine incorporation and cell number. The exposure of cells to both agonists resulted in a 2.5-fold elevation of the angiotensin II dependent effect on DNA synthesis and a 1.6-fold increase in cell number. 2-Ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid (CV-11974), the active metabolite of the specific non-peptide angiotensin AT1 receptor antagonist (+/-)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate (TCV-116, Candesartan) suppressed the effect of angiotensin II on cell growth as well as reduced the synergistic effect of carbocyclic thromboxane A2. Simultaneous cell stimulation with carbocyclic thromboxane A2 and angiotensin II for 30 min resulted in a 26 +/- 9% elevation of the angiotensin II-induced increase of c-fos mRNA (100%).

Topics: Angiotensin II; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Cell Division; Cells, Cultured; DNA; Muscle, Smooth, Vascular; Platelet Aggregation Inhibitors; Proto-Oncogene Proteins c-fos; Rats; Rats, Inbred WKY; RNA, Messenger; Tetrazoles; Thromboxane A2; Vasoconstrictor Agents