COMBINED ADMINISTRATION OF 5-HT2 AND THROMBOXANE A(2) ANTAGONISTS - EFFECTS ON PLATELET-AGGREGATION AND ISOLATED CARDIAC-MUSCLE

1 To investigate possible mechanisms underlying the ability of combine d administration of a 5-hydroxytryptamine(2) (5-HT2) antagonist and a thromboxane A(2) antagonist to reduce reperfusion-induced arrhythmias, the effects of these drugs alone and in combination on platelet aggre gation and on cardiac muscle were determined. 2 Platelet aggregation w as measured in whole blood obtained from anaesthetized rats. Concentra tions of 5-HT (10 mu M) and the thromboxane A(2) mimetic U46619 (1 mu M) which did not cause aggregation themselves, enhanced the responses to ADP (0.1 mu M) and to collagen (1 mu g ml(-1)). For example, the re sponse of 1.0+/-0.5 Ohm to ADP alone was increased significantly to 6. 4+/-1.0 Ohm by 5-HT, 15.5+/-2.8 Ohm by U46619, and 17.3+/-1.3 Ohm when U46619, 5-HT and ADP were added together. 3 In further experiments bl ood was obtained from rats which had received either the 5-HT2 antagon ist, ICI 170,809 (1 mg kg(-1)), or the thromboxane A(2) antagonist, IC I 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 result s were obtained with lower doses of ICI 170,809 (0.3 mg kg(-1)) and IC I 192,605 (0.3 mg kg(-1) min(-1)). 4 When collagen was used as the pri mary aggregating agent ICI 170,809 (1 mg kg(-1)) reduced the response to 5-HT (5.0+/-0.8 Ohm versus 10.9+/-1.2 Ohm in controls), and ICI 192 ,605 (1 mg kg(-1) min(-1)) reduced the response to U46619 (6.8+/-2.5 O hm versus 11.2+/-2.2 Ohm in control). The greatest reduction of platel et aggregation was seen in blood from rats which had received both ant agonists, with the response to U46619 plus 5-HT plus collagen being 2. 7+/-0.6 Ohm compared to 14.2+/-1.7 Ohm 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 m g kg(-1) min(-1)) reduced the response to U46619 plus 5-HT plus collag en (7.6+/-1.4 Ohm versus 15.0+/-0.5 Ohm 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 mu M to left papillary muscles. ICI 192,605 did not increase the e ffective refractory period itself and did not alter the ability of ICI 170,809 to prolong the effective refractory period. In the presence o f 100 mu M ICI 192,605, ICI 170,809 (30 mu M) increased the effective refractory period from 38+/-7 to 100+/-30 ms. 6 These results indicate that the previously observed antiarrhythmic activity of combined admi nistration of the higher doses of ICI 170,809 and ICI 192,605 is unlik ely to be due to direct effects on cardiac muscle but could be a conse quence of reduced platelet aggregation.