Combined administration of 5-HT2 and thromboxane A2 antagonists: effects on platelet aggregation and isolated cardiac muscle.

1. To investigate possible mechanisms underlying the ability of combined administration of a 5-hydroxytryptamine2 (5-HT2) antagonist and a thromboxane A2 antagonist to reduce reperfusion-induced arrhythmias, the effects of these drugs alone and in combination on platelet aggregation and on cardiac muscle were determined. 2. Platelet aggregation was measured in whole blood obtained from anaesthetized rats. Concentrations of 5-HT (10 microM) and the thromboxane A2 mimetic U46619 (1 microM) which did not cause aggregation themselves, enhanced the responses to ADP (0.1 microM) and to collagen (1 microgram ml-1). For example, the response of 1.0 +/- 0.5 omega to ADP alone was increased significantly to 6.4 +/- 1.0 omega by 5-HT, 15.5 +/- 2.8 omega by U46619, and 17.3 +/- 1.3 omega when U46619, 5-HT and ADP were added together. 3. In further experiments blood was obtained from rats which had received either the 5-HT2 antagonist, ICI 170,809 (1 mg kg-1), or the thromboxane A2 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). 4. 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 omega versus 10.9 +/- 1.2 omega in controls), and ICI 192,605 (1 mg kg-1 min-1) reduced the response to U46619 (6.8 +/- 2.5 omega versus 11.2 +/- 2.2 omega 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 omega compared to 14.2 +/- 1.7 omega 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 omega versus 15.0 +/- 0.5 omega in controls). 5. 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 microM 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 period. In the presence of 100 microM ICI 192,605, ICI 170,809 (30 microM) increased the effective refractory period from 38 +/- 7 to 100 +/- 30 ms. 6. These results indicate that the previously observed antiarrhythmic activity of combined administration of the higher doses of ICI 170,809 and ICI 192,605 is unlikely to be due to direct effects on cardiac muscle but could be a consequence of reduced platelet aggregation.