Interaction between the effects of 5‐hydroxytryptamine and adrenaline on the growth of platelet thrombi in the coronary artery of the anaesthetized dog

McAuliffe, S.J.G.; Snow, H. M.; Cox, B.; Smith, C. C. T.; Noble, Mark I. M.

doi:10.1111/j.1476-5381.1993.tb13583.x

Cited by 23 publications

(25 citation statements)

References 22 publications

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“…This is reinforced by the fact that all present anti-thrombotic drugs used in this disease cause increased bleeding. There is unpublished data showing that, in humans, the 5HT 2A antagonist used in the study of McAuliffe [28] had no effect on haemostasis, which is consistent with the serotonin theory of Noble and Drake-Holland [25]. This drug, at least, could provide protection from thrombosis during surgical operations without affecting operative bleeding.…”

Section: Resultssupporting

confidence: 64%

“…The serotonin theory [25] supposes that this serotonin mediation is essential for thrombotic occlusion of diseased coronary arteries, owing to the fact that such occlusions are abolished by antagonism of the platelet 5HT 2A receptor [26,27], even when the major stimulus of adrenaline is applied [28] and also in the circumstances where thrombolysis has failed to clear a complete thrombotic occlusion [29].…”

Section: The Importance Of Platelet Serotonin Positive Feedbackmentioning

confidence: 99%

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Commentary: On the Pathophysiology of Coronary Heart Disease

Noble¹

2017

J Med Surg Pathol

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This article highlights some important aspects of the pathophysiology of coronary artery disease, namely:• The distribution of lesions within the arterial tree at sites of low wall shear stress.• The potential role of low flow-mediated arterial dilatation at sites of low wall stress.• Low flow-mediated dilatation leads to low nitric oxide production by the arterial endothelium and consequent reduced protection against lesion formation.• Flow-mediated dilatation is reduced by high lumenal glucose concentration.• The role of the glycocalyx dysfunction in mediating flow-mediated dilatation and consequent reduced NO production by the arterial endothelium and cell adhesion.• Stenoses cause convective acceleration of blood velocity and a consequent increase in platelet shear stress.• Increased platelet shear stress activates platelets with release of serotonin.• Serotonin activates more platelet activation via the 5HT 2A platelet receptor causing a positive feedback and thrombus growth.• Arterial thrombus growth is abolished by 5HT 2A receptor antagonists, the key to improved treatment of the disease.• One 5HT 2A receptor antagonist has been shown in humans to be safe and to cause no excess bleeding from wounds.

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Section: Resultssupporting

confidence: 64%

Section: The Importance Of Platelet Serotonin Positive Feedbackmentioning

confidence: 99%

Commentary: On the Pathophysiology of Coronary Heart Disease

Noble¹

2017

J Med Surg Pathol

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“…We tested serotonin, although a weak agonist by itself, because it may have an important role in thrombosis through its potentiation of the effects of other platelet agonists [18,26]. ADP, released by activated platelets or from damaged endothelium, may also be important with respect to the growth of mural thrombi on exposed sub-endothelial collagen [27,28].…”

Section: Discussionmentioning

confidence: 99%

The potentiation of adrenaline‐induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.

Alarayyed

Graham

Prichard

et al. 1995

Brit J Clinical Pharma

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1. Aggregation in platelet‐rich plasma from normotensive men was induced by adrenaline (0.25‐16 microM), ADP (0.25‐16 microM), collagen (0.25‐8 micrograms ml‐1) or serotonin (10 microM) alone, or by previously sub‐threshold concentrations of adrenaline (0.03‐1 microM) in combination with sub‐threshold concentrations of serotonin (2.5 microM), ADP (0.5 microM) or collagen (0.125 micrograms ml‐1). The effects of the alpha 1‐adrenoceptor blockers naftopidil and doxazosin on platelet aggregation were investigated. 2. The dose‐response curves for collagen and ADP were unaffected by either drug. However, naftopidil (40 microM) inhibited serotonin‐induced platelet aggregation (23.9%, 95% confidence interval (CI) 10.7 to 37.1%; P < 0.01) and caused a slight shift to the right of the adrenaline dose‐response curve with a mean increase in the EC50 value of 0.5 microM (95% CI 0.07 to 0.93 microM; P < 0.05). Doxazosin had no effect on serotonin or adrenaline‐induced aggregation. 3. A marked potentiation of the aggregation induced by subthreshold concentrations of adrenaline resulted from the prior addition of low concentrations of ADP, collagen or serotonin. 4. These potentiated responses were inhibited in a dose‐ dependent manner by naftopidil and to a lesser extent doxazosin. The maximum inhibitions (%) produced by naftopidil (40 microM) on the responses of adrenaline potentiated by ADP were 58.3% (95% CI 36.8 to 79.8%; P < 0.001), serotonin 58.9% (95% CI 40.0 to 77.8%; P < 0.001), and collagen 70.9% (95% CI 52.5 to 89.3%; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

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“…The serotonin theory [8] supposes that this serotonin mediation is essential for thrombotic occlusion of diseased coronary arteries, owing to the fact that such occlusions are abolished by antagonism of the platelet 5HT 2A receptor [9,19] even when the major stimulus of adrenaline is applied [20] and also in the circumstances where thrombolysis has failed to clear a complete thrombotic occlusion [21].…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

“…These problems are not due to the receptor blockade, but have precluded their application to human arterial thrombosis. However, Th001 (Arteclere TM ) formerly known as ICI170809 [23], or AZ170809, has proved extremely potent as an inhibitor of intracoronary thrombus growth [20]. This drug appeared to be safe in a number of trials of toxicity, which are detailed in an Investigator's Brochure.…”

Section: Serotonin Dependence Of Acute Arterial Thrombosis and Its Inmentioning

confidence: 99%

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

Mi¹

2017

J Hematol Clin Res

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An enquiry into the lack of attention awarded to serotonin antagonism in the treatment of arterial thrombosis revealed that the mode of action of serotonin and its platelet receptor antagonists was an action upon thrombus growth, and not, as with other anti-platelet drugs upon the initiation of thrombosis. This lack of effect could explain why this approach has been considered not to be effective. However under conditions of arterial stenosis in which there is platelet activation by increased shear stress, and during the growth phase of arterial thrombi, serotonin 5HT 2A antagonism has been demonstrated to have great potentcy in dispersing thrombotic obstruction to blood fl ow. This mode of action, the lack of participation of serotonin in haemostasis, and the absence of serotonin in wounds accounts for the proven lack of effect of effect of pure specifi c 5HT 2A antagonists (i.e., not those with other actions) on operative bleeding and skin bleeding times. This lack of effect on haemostasis solves the dosing problem encountered with other anti-thrombotic drugs, with which drug concentration cannot be controlled with single fi xed doses, leading to the association between increased antithrombotic effi cacy and increased bleeding complications. Thus 5HT 2A antagonism appears to be the preferred approach, from the point of view of safety and lack of bleeding risk; this consideration applies particularly to thrombosis therapy in the context of traumatic accidents, surgical operations and invasive procedures such as angioplasty.

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Interaction between the effects of 5‐hydroxytryptamine and adrenaline on the growth of platelet thrombi in the coronary artery of the anaesthetized dog

Cited by 23 publications

References 22 publications

Commentary: On the Pathophysiology of Coronary Heart Disease

Commentary: On the Pathophysiology of Coronary Heart Disease

The potentiation of adrenaline‐induced in vitro platelet aggregation by ADP, collagen and serotonin and its inhibition by naftopidil and doxazosin in normal human subjects.

Preservation of Haemostasis with Anti-thrombotic Serotonin Antagonism

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