PROSTACYCLIN (PGI<sub>2</sub>) INHIBITS THE FORMATION OF PLATELET THROMBI IN ARTERIOLES AND VENULES OF THE HAMSTER CHEEK POUCH

Higgs, E. A.; Higgs, G. A.; Moncada, Salvador; Vane, John R.

doi:10.1111/j.1476-5381.1978.tb07809.x

Cited by 75 publications

(19 citation statements)

References 16 publications

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“…It can be seen (Fig. 1E) that PGI 2 caused a dose-dependent inhibition of 10 M ADP-induced aggregation, which is consistent with previous reports in human platelets (20). In order to measure the amount of cAMP that was associated with these different levels of inhibition, cAMP analysis was next performed.…”

Section: Dose-response Inhibition Of Adp-induced Human Plateletsupporting

confidence: 71%

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

Srinivasan¹,

Mir

Huang

et al. 2009

Journal of Biological Chemistry

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ADP plays an integral role in the process of hemostasis by signaling through two platelet G-protein-coupled receptors, P2Y 1 and P2Y 12 . The recent use of antagonists against these two receptors has contributed a substantial body of data characterizing the ADP signaling pathways in human platelets. Specifically, the results have indicated that although P2Y 1 receptors are involved in the initiation of platelet aggregation, P2Y 12 receptor activation appears to account for the bulk of the ADP-mediated effects. Based on this consideration, emphasis has been placed on the development of a new class of P2Y 12 antagonists (separate from clopidogrel and ticlopidine) as an approach to the treatment of thromboembolic disorders. The present work examined the molecular mechanisms by which two of these widely used adenosine-based P2Y 12 antagonists (2-methylthioadenosine 5 -monophosphate triethylammonium salt (2MeSAMP) and ARC69931MX), inhibit human platelet activation. It was found that both of these compounds raise platelet cAMP to levels that substantially inhibit platelet aggregation. Furthermore, the results demonstrated that this elevation of cAMP did not require G i signaling or functional P2Y 12 receptors but was mediated through activation of a separate G protein-coupled pathway, presumably involving G s . However, additional experiments revealed that neither 2MeSAMP nor ARC69931MX (cangrelor) increased cAMP through activation of A2a, IP, DP, or EP 2 receptors, which are known to couple to G s . Collectively, these findings indicate that 2MeSAMP and ARC69931MX interact with an unidentified platelet G protein-coupled receptor that stimulates cAMP-mediated inhibition of platelet function. This inhibition is in addition to that derived from antagonism of P2Y 12 receptors.Upon damage to the endothelial layer of the blood vessel wall, the underlying subendothelium is exposed to platelets in the blood, initiating a cascade of signaling events resulting in the transformation of "resting" platelets into "activated" platelets (1). One significant characteristic associated with these signaling events is the secretion of ADP from the platelet-dense granules (2). This released ADP acts to further amplify the platelet activation response by interacting with its G-protein-coupled receptors on the platelet surface, namely P2Y 1 (coupled to G q ) and P2Y 12 (coupled to G i ) (3-5). The consequence of platelet activation through ADP is a conformational change in the platelet membrane glycoprotein ␣IIb␤3 (6, 7), which then binds to fibrinogen present in the plasma. The binding of fibrinogen with ␣IIb␤3 on the surface of adjacent platelets results in fibrinogen-platelet cross-linking and the formation of a hemostatic plug at the site of vascular injury (8).Consequently, ADP is thought to play an integral role in the normal process of hemostasis. Of the two ADP-receptor signaling pathways in platelets, evidence has indicated that ADPmediated P2Y 12 signaling appears to play a more prominent role in platelet activation than ADP-media...

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Section: Dose-response Inhibition Of Adp-induced Human Plateletsupporting

confidence: 71%

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

Srinivasan¹,

Mir

Huang

et al. 2009

Journal of Biological Chemistry

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“…PGE 2 and prostacyclin (PGI 2 ) are products of cycloxygenase and they have properties of vasodilation and anti‐inflammation. PGI 2 reduces platelet aggregation, leukocyte adherence, and thus, cytoprotective effects [21, 22]. However, protacyclin is highly unstable with variable biologic actions.…”

Section: Discussionmentioning

confidence: 99%

Melatonin reduces pancreatic prostaglandins production and protects against caerulein‐induced pancreatitis in rats

Chen¹,

Chen

et al. 2005

Journal of Pineal Research

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Melatonin has been used to treat experimental pancreatitis, although not all the drug's therapeutic mechanisms of melatonin have been defined. Prostaglandins (PGs) are proinflammatory mediators that exert their effects mainly locally during inflammatory diseases. The present study was undertaken to examine whether treatment with melatonin influences local PG production. An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuously infusing caerulein (15 mg/kg/hr). Mean arterial pressure and pancreatic perfusion were monitored continuously. Melatonin was delivered via the intraperitoneal route at doses of either 2 or 10 mg/kg, 30 min after caerulein injection. Malondialdehyde and glutathione levels of the pancreas and liver and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hr after infusion of caerulein). Intraperitoneal injection of melatonin (2 and 10 mg/kg) reduced the reduction in systemic arterial pressure and decreased pancreatic perfusion in the rat model of caerulein pancreatitis. Moreover, melatonin treatment changed local PG production toward control level. Higher dose of melatonin was somewhat more effective in preventing the caerulein-induced alterations than was the lower dose.

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“…Subsequently, Begent and Born provided quantitative data on direct application of ADP on hamster cheek pouch venules and arterioles ( 5 ). ADP is typically applied locally to the microvessels of interest by iontophoresis from a micropipette (concentration in the pipette of 10 −2 –10 −3 M, ( 5 , 40 , 71 )). This results in platelet adhesion to endothelial cells, which appear normal by transmission electron microscopy ( 5 ).…”

Section: Biochemical Injurymentioning

confidence: 99%

Microvascular Thrombosis Models in Venules and Arterioles In Vivo

2005

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Platelets are intimately involved in hemostasis and thrombosis. Under physiological conditions, circulating platelets do not interact with microvascular walls. However, in response to microvascular injury, platelet adhesion and subsequent thrombus formation may be observed in venules and arterioles in vivo. Numerous intravital video microscopy techniques have been described to induce and monitor the formation of microvascular thrombi. The mechanisms of microvascular injury vary widely among different models. Some models induce platelet activation with minimal effects on endothelium, others induce endothelial inflammation or injury, while other models lead to thrombus formation associated with endothelial denudation. The molecular mechanisms mediating platelet-vessel wall adhesive interactions differ among various models. In some instances, differences in responses between venules and arterioles are described that cannot be explained solely by hemodynamic factors. Several models for induction of microvascular thrombosis in vivo are outlined in this review, with a focus on the mechanisms of injury and thrombus formation, as well as on differences in responses between venules and arterioles. Recognizing these characteristics should help investigators select an appropriate model for studying microvascular thrombosis in vivo.

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PROSTACYCLIN (PGI₂) INHIBITS THE FORMATION OF PLATELET THROMBI IN ARTERIOLES AND VENULES OF THE HAMSTER CHEEK POUCH

Cited by 75 publications

References 16 publications

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

Melatonin reduces pancreatic prostaglandins production and protects against caerulein‐induced pancreatitis in rats

Microvascular Thrombosis Models in Venules and Arterioles In Vivo

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PROSTACYCLIN (PGI2) INHIBITS THE FORMATION OF PLATELET THROMBI IN ARTERIOLES AND VENULES OF THE HAMSTER CHEEK POUCH

Cited by 75 publications

References 16 publications

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

The P2Y12 Antagonists, 2-Methylthioadenosine 5′-Monophosphate Triethylammonium Salt and Cangrelor (ARC69931MX), Can Inhibit Human Platelet Aggregation through a Gi-independent Increase in cAMP Levels

Melatonin reduces pancreatic prostaglandins production and protects against caerulein‐induced pancreatitis in rats

Microvascular Thrombosis Models in Venules and Arterioles In Vivo

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Product

Resources

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PROSTACYCLIN (PGI₂) INHIBITS THE FORMATION OF PLATELET THROMBI IN ARTERIOLES AND VENULES OF THE HAMSTER CHEEK POUCH