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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotension II (ANG II) increases the generation of vasoconstrictor prostaglandin endoperoxides (PGH2) and thromboxane A2 (TxA2). Two-kidney, one-clip (2K,1C) Goldblatt hypertensive rats have an increased plasma renin activity (PRA) and ANG II level during the early, but not the late, phases of hypertension. Therefore, the aim of these studies was to compare the antihypertensive efficacy of an ANG II type I (AT1) and a TxA2/PGH2 receptor antagonist during different phases of 2K,1C hypertension. Rats were maintained on a fixed sodium intake for 3 days before and throughout the period of drug administration. These studies assessed the antihypertensive response to administration of the AT1 receptor antagonist losartan (20 mg.kg-1.day-1), the TxA2/PGH2 receptor antagonist ifetroban (20 mg.kg-1.day-1) or vehicle given for 3 days to rats with early (2-4 wk postclip), intermediate (10-12 wk postclip), and late (36-42 wk post-clip) 2K,1C hypertension and to two control groups of rats corresponding in age to the early or intermediate and the late 2K,1C groups. The mean arterial pressure (MAP) was measured directly with indwelling arterial cannulas. The MAP of sham-operated rats was 109 +/- 5 mmHg. In the early phase of 2K,1C hypertension, the MAP was increased to 143 +/- 6 mmHg, and it was increased further to 162 +/- 5 mmHg during the intermediate and to 179 +/- 4 mmHg during the late phase. The PRA, compared with age-matched controls, was increased during early and intermediate, but not late phase 2K,1C hypertension. Neither drug lowered blood pressure in control rats. However, both drugs significantly reduced the blood pressure in the early, intermediate, and late phases of 2K, 1C hypertension. At the end of 3 days of administration, blood pressure in early 2K, 1C rats given losartan was reduced to levels of control rats, but remained slightly elevated in other groups and in those receiving ifetroban. In conclusion, AT1 and TxA2/PGH2 receptors maintain hypertension throughout the evolution of 2K, 1C hypertension in the rat, despite changes in PRA.
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PMID:AT1 and TxA2/PGH2 receptors maintain hypertension throughout 2K,1C Goldblatt hypertension in the rat. 889 78

We investigated the selectivity of a nonpeptide angiotensin II AT1 receptor antagonist losartan for the vascular thromboxane A2 (TxA2)/prostaglandin endoperoxide (PGH2) receptor in canine coronary arteries. Isometric tension was measured in canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2. The TxA2 analog, U46619, produced dose-dependent vasoconstdction in coronary rings (EC50, 10.6 +/- 0.9 nmol/l). Pretreatment with losartan (10(-8)-10(-5) mol/l) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in dose-dependent manner. The EC50 of U46619 was increased 3- and 13-fold in the presence of both 1 and 10 micromol/l of losartan without a change in maximal contraction. The selective TxA2/PGH2 receptor antagonist SQ29548 blocked U46619-induced contraction with greater potency than losartan in isolated coronary arteries. The active metabolite of losartan EXP3174 at 1 micromol/l did competitively block U46619-induced contractions in canine coronary rings. In contrast, the contractile responses produced by U46619 were unaffected by exposure to the nonpeptide AT1 receptor antagonist CV11974, the AT2 receptor antagonist PD123319 or the nonselective peptide angiotensin II antagonist Sar1Thr8-Ang II, each at 1 micromol/l concentration. These data indicate that losartan and its active metabolite EXP3174 are antagonists to the TxA2/PGH2 receptor in canine coronary arteries. The antagonistic effect of losartan and EXP3174 on the vascular TxA2/ PGH2 receptor may contribute to the long-term blood pressure-lowering effects of angiotensin antagonists in hypertension.
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PMID:Nonpeptide angiotensin II antagonist losartan inhibits thromboxane A2-induced contractions in canine coronary arteries. 919 Aug 37

Our recent studies have shown that the nonpeptide angiotensin II (Ang II) antagonist losartan interacts with thromboxane A2/prostaglandin H2 receptors and inhibits the thromboxane A2 (TxA2) analog U46619-induced vasoconstriction in canine coronary arteries. In this study, we further investigated whether losartan prevents TxA2-induced platelet aggregation and vasoconstriction in spontaneously hypertensive rats (SHRs). Pretreatment with losartan (10 microM) significantly reduced U46619-induced, concentration-dependent washed platelet aggregation. The inhibition is specific for losartan, because another Ang II AT1-receptor antagonist, CV11974 (10 microM), an active metabolite of TCV116, did not block the platelet aggregation caused by U46619. In addition, losartan (10 microM) augmented acetylcholine (ACH)-induced nitric oxide (NO)-dependent vasodilation and abolished the ACH-induced endothelium-derived contracting factor (EDCF)-mediated vasoconstriction in the aortic rings from adult SHRs. U46619 produced dose-dependent vasoconstriction in aortic vessels of SHRs, which was demonstrated to be blocked by the potent, selective TxA2/PGH2 receptor antagonist SQ29,548. Pretreatment with losartan (10(-6)-10(-5) M) inhibited the contractile response of U46619 and shifted the concentration-response curve to the right in a dose-dependent manner. The effective concentration at half maximal contraction (EC50) of U46619 was increased 2.5- and 7.6-fold in the presence of 1 and 10 microM losartan, respectively, without changes in maximal contraction. The active metabolite of losartan, EXP3174, at 1 microM also competitively inhibited U46619-induced contractions in aortic rings of SHRs. In contrast, neither the AT1-receptor antagonist CV11974, the AT2 antagonist PD123319, nor the angiotensin-converting enzyme inhibitor lisinopril, each at concentrations of 1 microM, had any effect on the U46619-induced constriction in aortic rings. In conclusion, losartan, acting as both AT1- and TxA2/PGH2-receptor antagonists, may enhance its therapeutic profile in the treatment of hypertension and cardiovascular disease.
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PMID:Losartan inhibits thromboxane A2-induced platelet aggregation and vascular constriction in spontaneously hypertensive rats. 970 Sep 80

In addition to its AT1-receptor antagonist activity, losartan has been shown to antagonize thromboxane A2 (TXA2)-induced contraction of animal vessels. We investigated for the first time in human isolated gastroepiploic artery (GEA) and saphenous vein (SV) the TXA2/PGH2-receptor antagonist activity of losartan in the presence of indomethacin (1 microM) and N(omega)-nitro-L-arginine (100 microg). Losartan at concentrations of > or =1 microM on GEA and from 10 microM on SV significantly shifted U46619-induced contractions to the right. In addition, 100 microM losartan decreased by 34% the amplitude of the contraction to U46619 on both GEA and SV. The potency of losartan for the TXA2 receptor was 50- and 80-fold lower than that for the AT1 receptor on human GEA and SV, respectively. This inhibitory effect of losartan appeared selective for angiotensin II and TXA2-induced contractions because 100 microM losartan did not modify either endothelin-1- or KCl-induced contraction in human SV, although a reduction of norepinephrine- and 5-hydroxytryptamine-induced contraction was observed in human GEA and SV, respectively. In conclusion, losartan is an antagonist of TXA2 receptor on human GEA and SV. However, this antagonist activity occurred for a relative high dose of losartan, suggesting that it contributes at a low level, if any, to its antihypertensive effect.
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PMID:Antagonistic effects of losartan on thromboxane A2-receptors in human isolated gastroepiploic artery and saphenous vein. 1054 91

Various AT1 receptor antagonists including losartan are known to inhibit human platelet activation by antagonising TXA2/PGH2 receptors (TP receptors). Presently, we check a hypothesis that losartan, an imidazole derivative in contrast with valsartan, a non-imidazole compound, may inhibit human platelet activation also through inhibition of TXA2 synthesis. Inhibitory action of losartan (2-n butyl-4-chloro-5-hydroxymethyl-1-beta(2'-(1H-tetrazol-5yl)biphenyl-4-yl)methyl] imidazole), its active metabolite EXP 3174 (2-n-butyl-4-chloro-1-beta (2-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl]imidazole-5-carboxylic acid) and valsartan ((S)-N-valeryl-N-(beta2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]valine), on collagen-induced platelet aggregation and TXA2 generation was compared to effects achieved by each compound on U46619-induced aggregation in aspirinized platelets. Losartan and aspirin inhibited collagen-induced platelet aggregation with approximately the same potency, whereas EXP 3174 and valsartan showed much weaker antiplatelet effects. Interestingly, losartan, EXP 3174 and valsartan displayed similar potencies as inhibitors of U46619-induced aggregation in asprinized platelets as in collagen-induced aggregation in non-aspirinized platelets. None of the above three AT1 antagonists, up to a concentration of 300 microM, did influence collagen-induced TXA2 synthesis in human platelets. In conclusion, antiplatelet effects of AT1 antagonists, irrespective of the presence or absence of non-condensed imidazole in their chemical structure, involve antagonism of TP receptors but not inhibition of TXA2 synthesis in platelets.
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PMID:Antiplatelet action of losartan involves TXA2 receptor antagonism but not TXA2 synthase inhibition. 1119 44

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.
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PMID:Angiotensin II AT(1) receptor antagonists and platelet activation. 1136 20