we exclude the probability that the antiarrhythmic action of ketanserin and ritanserin which we observed previously is associated to their capability to act as antagonists at a adrenoceptors. The existing benefits, on the other hand, do suggest that actions at a I adrenoceptors TGF-beta are unlikely to be involved with the antiarrhythmic results of some 5 HT receptor antagonists. Despite the fact that we located that I mg kg methiothepin abolished phenylephrine induced pressor responses, precisely the same dose of ICI 170,809 had no impact. As a result on the dose of ICl 170,809 which had antiarrhythmic exercise in our experiments we could not detect any a| adrenoceptor blockade. ICI 170,809 continues to be reported by some others to possess much less affinity to get a adrenoceptors than ketanserin and was inactive towards noradrenaline induced pressor responses in pithed rats.

One more possible explanation for the reductions in arrhythmias observed with all the 5 HT GDC-0068 ic50 receptor antagonists is the fact that the medicines are only obtaining a membrane stabilising result on cardiac cells. Ketanserin has become reported to possess Class 1 and Class 111 antiarrhythmic actions. We now have identified that ketanserin minimizes greatest driving frequency in rat isolated atrial and ventricular muscle preparations. This effect was shared by ritanserin and inside the existing research ICI 169,369 and ICI 170,809 also diminished optimum driving frequency, but methiothepin had no important result. The lack of the direct impact of methiothepin on isolated cardiac muscle regardless of its capability to lower ischaemia induced arrhythmias casts doubt around the suggestion the antiarrhythmic activity from the 5 HT receptor antagonists is simply as a result of a membrane stabilising result on cardiac muscle.

Also, the lack of antiarrhythmic activity of ICI 169,369 suggests that the capacity with the 5 HT receptor antagonists to reduce the maximum driving frequency of cardiac muscle might be a non unique effect happening at larger concentrations Metastasis than those that can be attained in vivo. During the cardiovascular procedure 5 HT2 receptors are usually not only observed on vascular smooth muscle but additionally on platelets. Stimulation of those receptors on platelets might bring about platelet aggregation or boost aggregation induced by other agents. In citrated rat platelet wealthy plasma we have now observed only the latter phenomenon. Platelet aggregation was measured ex vivo during the existing research.

Blood was eliminated 10 min after drug adminstration, the time at Doxorubicin Topoisomerase inhibitor which the coronary artery would be occluded from the arrhythmia experiments. Only ICI 169,369 and also the lower dose of ICI 170,809 failed to avoid the effect of 5 HT on platelet aggregation and these were also the sole drug interventions devoid of sizeable antiarrhythmic exercise. ICI 169,369 is much less potent than ICI 170,809, ritanserin and ketanserin at 5 HT2 receptors. It is actually achievable that if larger doses of ICI 169,369 could are actually offered it could have had precisely the same profile of exercise as the other S HTj receptor antagonists.