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5-Hydroxytryptamine dominates over thromboxane A2 in reducing collateral blood flow by activated platelets
1Department of Cardiovascular Pharmacology, Janssen Research Foundation, Beerse, Belgium.
Insights
Platelet-derived serotonin (5-HT) significantly reduces blood flow in feline hindlimb collaterals after collagen infusion. Blocking 5-HT2 receptors largely prevented this effect, suggesting serotonin
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Hemostasis
Background:
- Collagen infusion in feline hindlimbs causes platelet activation, reduced blood flow, and increased vascular resistance.
- These effects are more pronounced in collateral arterial beds compared to normal ones.
Purpose of the Study:
- To investigate the roles of serotonin (5-HT) and thromboxane A2 (TxA2) in collagen-induced hemodynamic changes in feline hindlimb collateral circulation.
- To determine which mediator, 5-HT or TxA2, plays a dominant role in reducing blood flow in collateral-dependent tissues.
Main Methods:
- Intra-aortic collagen infusion in feline hindlimbs.
- Pharmacological blockade of 5-HT2 receptors (ketanserin, ritanserin) or amine depletion (reserpine, parachlorophenylalanine).
- Inhibition of cyclooxygenase (indomethacin), TxA2/prostaglandin endoperoxide receptor antagonism (sulotroban), or TxA2 synthase inhibition (dazoxiben, ridogrel).
- Measurement of blood flow, vascular resistance, platelet activation, and mediator release (5-hydroxyindoles, TxB2, prostacyclin).
Main Results:
- Blockade of 5-HT2 receptors or amine depletion largely prevented collagen-induced perfusion defects without significantly affecting platelet activation.
- Cyclooxygenase inhibition or TxA2/prostaglandin endoperoxide receptor antagonism did not prevent the perfusion defect.
- TxA2 synthase inhibition partially reduced the perfusion defect and mediator release, while increasing prostacyclin levels.
Conclusions:
- Platelet-derived serotonin (5-HT) is the primary mediator responsible for reducing blood flow in collateral-dependent feline hindlimb tissue following collagen infusion.
- Serotonin's effect on blood flow in this model is more significant than that of thromboxane A2.
- Targeting 5-HT pathways may be a therapeutic strategy for improving blood flow in collateral-dependent tissues.
Abstract:
Intra-aortic infusion of collagen (100 micrograms/kg in 1 min) elicited an extensive platelet activation and transient but marked reductions of blood flow and increases of peripheral vascular resistance, both responses being more pronounced in collaterals than in normal arterial beds in feline hind legs. Blockade of 5-hydroxytryptamine (5-HT) subtype 2 (5-HT2) receptors for 5-HT (ketanserin or ritanserin, 0.63 mg/kg iv, -10 min) or amine depletion (reserpine, 0.1 mg/kg im, -10 days, + parachlorophenylalanine 100 mg/kg sc daily for 3 days), but not cyclooxygenase inhibition (indomethacin, 5 mg/kg iv) or thromboxane (Tx) A2/prostaglandin endoperoxide receptor antagonism (sulotroban, 2.5 mg/kg iv), largely prevented the collagen-induced perfusion defect without interfering substantially with the platelet activation process. TxA2 synthase inhibition, alone (dazoxiben, 5 mg/kg iv) or combined with TxA2-prostaglandin endoperoxide receptor antagonism (ridogrel, 2.5 mg/kg iv), partially reduced the collagen-induced perfusion defect and limited to a similar extent the initial platelet aggregation and release of 5-hydroxyindoles and TxB2 while increasing plasma levels of prostacyclin. These results suggest that platelet-derived 5-HT dominates over TxA2 in reducing blood flow in collateral-dependent tissue of the cat hindlimb.