Combined administration of 5‐HT 2 and thromboxane A 2 antagonists: effects on platelet aggregation and isolated cardiac muscle

• Published in: British journal of pharmacology 2009-02, Vol.121 (5), p.875-882
• Main Authors: Shaw, Linda A, Batey, Andrew J, Coker, Susan J
• Format: Article
• Language: English
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0701208

To investigate possible mechanisms underlying the ability of combined administration of a 5‐hydroxytryptamine 2 (5‐HT 2 ) antagonist and a thromboxane A 2 antagonist to reduce reperfusion‐induced arrhythmias, the effects of these drugs alone and in combination on platelet aggregation and on cardiac muscle were determined. Platelet aggregation was measured in whole blood obtained from anaesthetized rats. Concentrations of 5‐HT (10 μ M ) and the thromboxane A 2 mimetic U46619 (1 μ M ) which did not cause aggregation themselves, enhanced the responses to ADP (0.1 μ M ) and to collagen (1 μg ml −1 ). For example, the response of 1.0±0.5 Ω to ADP alone was increased significantly to 6.4±1.0 Ω by 5‐HT, 15.5±2.8 Ω by U46619, and 17.3±1.3 Ω when U46619, 5‐HT and ADP were added together. In further experiments blood was obtained from rats which had received either the 5‐HT 2 antagonist, ICI 170,809 (1 mg kg −1 ), or the thromboxane A 2 antagonist, ICI 192,605 (1 mg kg −1  min −1 ), or both in combination. When ADP was used as the primary aggregating agent, the ability of U46619 alone, or together with 5‐HT, to enhance responses was reduced significantly by ICI 192,605 alone and in combination with ICI 170,809. Similar results were obtained with lower doses of ICI 170,809 (0.3 mg kg −1 ) and ICI 192,605 (0.3 mg kg −1  min −1 ). When collagen was used as the primary aggregating agent ICI 170,809 (1 mg kg −1 ) reduced the response to 5‐HT (5.0±0.8 Ω versus 10.9±1.2 Ω in controls), and ICI 192,605 (1 mg kg −1  min −1 ) reduced the response to U46619 (6.8±2.5 Ω versus 11.2±2.2 Ω in control). The greatest reduction of platelet aggregation was seen in blood from rats which had received both antagonists, with the response to U46619 plus 5‐HT plus collagen being 2.7± 0.6 Ω compared to 14.2±1.7 Ω in controls. In contrast, there was no significant attenuation of platelet aggregation in blood from rats which had received the lower doses of each antagonist alone. Only the combination of ICI 170,809 (0.3 mg kg −1 ) and ICI 192,605 (0.3 mg kg −1  min −1 ) reduced the response to U46619 plus 5‐HT plus collagen (7.6±1.4 Ω versus 15.0±0.5 Ω in controls). In rat isolated ventricular muscle preparations, ICI 170,809 increased the effective refractory period; e.g. from 39±4 to 86±18 ms, 10 min after adding 30 μ M to left papillary muscles. ICI 192,605 did not increase the effective refractory period itself and did not alter the ability of ICI 170,809 to prolong the effective refractory