Thromboxane A2 and prostaglandin endoperoxide receptors in platelets and vascular smooth muscle.

Saussy, David L.; Mais, Dale E.; Knapp, Daniel R.; Halushka, Perry V.

doi:10.1161/01.cir.72.6.1202

Cited by 35 publications

(9 citation statements)

References 44 publications

(6 reference statements)

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“…One interpretation of these findings is that in mesenteric arteries the vasoconstrictor effect of bradykinin is mainly mediated by endoperoxides. The application of exogenous prostaglandin endoperoxides causes contraction of isolated vascular smooth muscle via an interaction with receptors which are shared with thromboxane A2 (Coleman et al, 1981;Saussy et al, 1985). As suggested by the results of the present study, prostaglandin endoperoxides formed endogenously by bradykinin may stimulate the contraction of vascular smooth muscle.…”

Section: Discussionsupporting

confidence: 61%

Bradykinin‐induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline

Fasciolo

Vargas

Lama

et al. 1990

British J Pharmacology

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1 Administration of bradykinin caused dose-dependent vasoconstriction in rat isolated perfused mesenteric arteries precontracted with noradrenaline.2 The vasoconstrictor response was not mediated by BK1-bradykinin receptors.3 Inhibition of cyclo-oxygenase with indomethacin, aspirin or meclofenamate abolished the vasoconstrictor effect of bradykinin, showing that a member of the arachidonic acid cascade may be involved. 4 Inhibitors of thromboxane synthesis (imidazole and UK 38485) did not affect or only reduced the bradykinin-induced vasoconstriction. 5 The endoperoxide H2/thromboxane A2 receptor antagonist SQ 29548 significantly reduced the vasoconstrictor effect of bradykinin, but did not affect the vasoconstrictor response to noradrenaline, adrenaline, vasopressin, 5-hydroxytryptamine or prostaglandins. 6 The eicosanoid(s) that mediate bradykinin-induced vasoconstriction appear to be synthesized outside the arterial endothelium. 7 The data suggest that the vasoconstrictor effect of bradykinin in the rat isolated mesenteric artery is mediated by vasoconstrictor arachidonic acid metabolites including the cyclic endoperoxides and/or the thromboxanes.

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Section: Discussionsupporting

confidence: 61%

Bradykinin‐induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline

Fasciolo

Vargas

Lama

et al. 1990

British J Pharmacology

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“…The TP receptor, the first to be isolated and cloned (from human platelets) [76], is a Gprotein-coupled receptor with seven transmembrane domains. Two subtypes of TP receptors have been identified and designated as TP α (responsible for platelet aggregation) and TP β (responsible for smooth-muscle contraction) [77][78][79]. The EP receptor has been classified into four subtypes: EP 1 , EP 2 , EP 3 , and EP 4 , all of which recognize PGE 2 but differ in their pharmacology and responses to various PGE analogs.…”

Section: Pg Receptors and Receptor Subtype Classificationsmentioning

confidence: 99%

“…PGF 2α , however, causes vasoconstriction. TXA 2 produced by aggregating platelets is a potent vasoconstrictor and prothrombotic agent [6,77]. Inhibition of the proaggregatory effect of TXA 2 on platelets is the pharmacological basis for low-dose aspirin therapy in cardiovascular prophylaxis.…”

Section: Cardiovascular and Renal Pg Actionsmentioning

confidence: 99%

Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers

Khanapure¹,

Garvey²,

Janero³

et al. 2007

CTMC

280

188

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In mammalian cells, eicosanoid biosynthesis is usually initiated by the activation of phospholipase A2 and the release of arachidonic acid (AA) from membrane phospholipids. The AA is subsequently transformed by cyclooxygenase (COX) and lipoxygenase (LO) pathways to prostaglandins, thromboxane and leukotrienes collectively termed eicosanoids. Eicosanoid production is considerably increased during inflammation. Both COX and LO pathways are of particular clinical relevance. The COX pathway is the major target for non-steroidal anti-inflammatory drugs (NSAIDs), the most popular medications used to treat pain, fever and inflammation. Although their anti-inflammatory effects are well known, their long-term use is associated with gastrointestinal (GI) complications such as ulceration. In 1991, it was discovered that COX exists in two distinct isozymes, COX-1 and COX-2, of which COX-2 is primarily expressed at sites of inflammation and produces pro-inflammatory eicosanoids. For this reason, COX-2 selective inhibitors (COXIBs) have been developed recently as anti-inflammatory agents to minimize the risk of GI toxicity. Recently, some COX-2 selective inhibitors have shown adverse cardiovascular side effects, resulting in the withdrawal of rofecoxib and valdecoxib from the market. Selective inhibition of COX-2 without reducing COX-1-mediated thromboxane production could alter the balance between prostacyclin and thromboxane and promote a prothrombotic state, thereby explaining the observed COX-2 cardiovascular risk. In this review, we describe mechanisms for the production of pro-inflammatory eicosanoid mediators contributing to inflammation and summarize promising options for the prevention of inflammatory mediator formation and the therapeutic inhibition of pain and inflammation.

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“…First, the TP receptor may present conformational differences between species used in the test (human, rat, and guinea pig). Second, several authors initially stated in the 1980s that at least two pharmacological subtypes of TP receptor existed Saussy et al, 1985). The first subtype was thought to be present at the platelet surface (Takahara et al, 1990), responsible for platelet aggregation.…”

Section: Bm-613 An Original Antiplatelet and Antithrombotic Agent 297mentioning

confidence: 99%

In Vitro and in Vivo Pharmacological Characterization of BM-613 [N-n-Pentyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a Novel Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist

Hanson

Rolin²,

Reynaud³

et al. 2004

J Pharmacol Exp Ther

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Thromboxane A 2 (TXA 2 ) is a key mediator of platelet aggregation and smooth muscle contraction. Its action is mediated by its G protein-coupled receptor of which two isoforms, termed TP␣ and TP␤, occur in humans. TXA 2 has been implicated in pathologies such as cardiovascular diseases, pulmonary embolism, atherosclerosis, and asthma. This study describes the pharmacological characterization of BM-613 [N-n-pentyl-NЈ-[2-(4Ј-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a new combined TXA 2 receptor antagonist and TXA 2 synthase inhibitor. It exhibits a strong affinity for human platelet TP receptors (IC 50 ϭ 1.4 nM), TP␣ and TP␤ expressed in COS-7 cells (IC 50 ϭ 2.1 and 3.1 nM, respectively), and TPs expressed in human coronary artery smooth muscle cells (IC 50 ϭ 29 M). BM-613 shows a weak ability to prevent contraction of isolated rat aorta (ED 50 ϭ 1.52 M) and guinea pig trachea (ED 50 ϭ 2.5 M) induced by TXA 2 agonist U-46619 (9.11-dideoxy-9.11-methanoepoxy-prostaglandin F 2 ). Besides, BM-613 antagonizes TP␣ (IC 50 ϭ 0.11 M) and TP␤ (IC 50 ϭ 0.17 M) calcium mobilization induced by U-46619 and inhibits human platelet aggregation induced by U-46619 (ED 50 ϭ 0.278 M), arachidonic acid (ED 50 ϭ 0.375 M), and the second wave of ADP. BM-613 also dose dependently prevents TXA 2 production by human platelets (IC 50 ϭ 0.15 M). In a rat model of ferric chloride-induced thrombosis, BM-613 significantly reduces weight of formed thrombus by 79, 49, and 28% at 5, 2, and 1 mg/kg i.v., respectively. In conclusion, BM-613 is a dual and potent TP receptor antagonist and TXA 2 synthase inhibitor characterized by a strong antiplatelet and antithrombotic potency. These results suggest that BM-613 could be a potential therapeutic drug for thrombotic disorders.Thromboxane A 2 (TXA 2 ) is a key lipid mediator characterized by several implications in physiological homeostasis, including platelet aggregation and vascular and bronchial smooth muscle constriction (Hamberg et al., 1975;Moncada and Vane, 1978). An overproduction of TXA 2 has been associated with many pathological states such as myocardial infarction, thrombosis and thrombotic disorders, unstable angina, pulmonary embolism, shock, atherosclerosis, preeclampsia, and asthma (Dogné et al., 2004a).TXA 2 is a metabolite of arachidonic acid (AA), a 20-carbon

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Thromboxane A2 and prostaglandin endoperoxide receptors in platelets and vascular smooth muscle.

Cited by 35 publications

References 44 publications

Bradykinin‐induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline

Bradykinin‐induced vasoconstriction of rat mesenteric arteries precontracted with noradrenaline

Eicosanoids in Inflammation: Biosynthesis, Pharmacology, and Therapeutic Frontiers

In Vitro and in Vivo Pharmacological Characterization of BM-613 [N-n-Pentyl-N′-[2-(4′-methylphenylamino)-5-nitrobenzenesulfonyl]urea], a Novel Dual Thromboxane Synthase Inhibitor and Thromboxane Receptor Antagonist

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