Effects Of Histamine Receptor Agonists And Antagonists On Ion Channels In Guinea Pig Ventricular Myocytes And Effect Of H₂ Receptor Agonist On Left Ventricle Functions In Guinea Pig And Rat Hearts

Histamine is one of the aminergic neurotransmitters which exists in many tissues. It plays many important physiological roles, such as immediating hypersensitivity reactions, alterations in vascular permeability, activation of smooth muscle contraction, regulation of gastrointestinal mobility and gastric acid secretion, as well as in the modification of various leukocyte subset activities. These various effects of histamine are mediated by histamine receptors on the plasma membrane with subclasses as H1, H2H3 receptors. In heart, histamine receptors express on sinoatrial node, right atria, the near end of coronary artery, and so on. Early reports showed that over 50% of patients with allergy had cardiac symptoms or electrocardiogram (ECG) changes. This suggests that histamine over-released under pathological state do harm to the heart. Well, the physiological roles of histamine in cardiac tissue and the pathological effects of histamine on heart in allergic diseases remain to be rectified.Histamine H1 antagonists are antiallergic drugs while H2 antagonists are widely used in peptic ulcer. The first generation of H1 antagonists had been reported to have a beneficial effect on allergic arrhythmias. But others argued that they could induce lethal arrhythmias such as torsade de point (TdP). The use of the first generation antihistamines, such as diphenhydramine, hydroxyzine, chlorpheniramine, is limited by their anticholinergic and sedative properties. The second generation of antihistamines, so-called non-sedatingantihistamines such as terfenadine, astemizole, et al, are freeof these side-effects. However, the cardiac side-effects of the second generation antihistamines had been reported since the 1990s, mainly from lerfenadine. It was considered that serious proarrhythmic effect of the second generation antihistamines was due to the blockade on delayed rectifier potassium channel (Ik) which results in the prolongation of action potential duration and dispersion of the repolarization duration, which allows re-entry and induces an abnormality in the terminal repolarization, resulting in an early after-depolarization (BAD), and triggered activity, thus provoked a specific form of polymorphic ventricular tachydysrhythmia, i.e. torsade de pointes (TdP). The class III antiarrhythmic agents, however, which target on the Ik, can also prolong the action potential duration and QT interval but rarely lead to arrhythmias. Then, the ion mechanism of HI antihistamine in proarrhythmias should be studied further. Does differences of the effects on cardiac electrophysiological features between the two generation of antihistamines exist? Why does the second generation ofantihistamines tend to cause lethal arrhythmias? At the same time, little was know about the ion basis of H2 antagonists on allergic arrhythmias. In order to make these questions clear, we used whole-cell patch clamp technique to study the effects of agonists and antagonists of HI and H2 receptors on cardiac sodium current, delayed rectifier potassium current, and L-type calcium current which are the main ion currents in cardiac electrical activities, then analyzed the ionic mechanism of histamine and its antagonists on cardiac electrical activities.Part OneEffects of Histamine H1 Receptor Agonists andAntagonists on Ion Channel in Guinea PigVentricular MyocytesMaterials and MethodsEnzymatic method was to get single ventricular myocytes from guinea pig hearts. Whole-cell patch clamp technique was used to record the sodium current (iNaX delayed rectifier potassium current (Ik) and L-type calcium current(ICa-L) and the influences of HI1 receptor agonist betahistine, the first generation H1 antagonist prothamize and the second generation H1 antagonist terfenadine on these ion currents. A drop of the isolated cell suspension was placed into a small chamber (volume 1.5ml) on the stage of an inverted microscope. 2-5min was allowed for the cells to adhere to the bottom of the chamber. Then the cells were constantlyperfused with n...