Analysis Of Mechanisms To I-/α₂-receptor Agonists On Rabbit Sinoatrial Node And Vascular Purinergic Nerve

Moxonidine (Mox), a centrally acting antihypertensive drug, elicits less side effects (such as sedation or dry mouth) than clonidine (Clo). In radioligand binding experiments using membranes of the bovine rostral ventrolateral medulla, the affinity ratio of I1 site / α₂ site was reported to be 4 for Clo and even about 30 for Mox. It has been reported that Mox offers significant protection against the development of arrhythmias induced by regionally myocardial ischemia in the conscious rat. However, its mechanism as an antiarrhythmic agent is not clear. Though imidazoline receptors (IR) and α₂-adrenoceptors were reported to exist on hearts, however, the agonists or antagonists acting on IR also have higher affinity to α₂-adrenoceptors, so it is difficult to analyze the physiological and pharmacological effects regulated by IR and α₂-adrenoceptors in the heart. On the other hand, very little is known regarding the effects of Mox and Clo on action potentials (APs) of the rabbit sinoatrial node (SAN) pacemaker cells. Consequently, the present study was designed to investigate the effects of Mox, Clo, agmatine (Agm, an endogenous ligand for I-/α₂-receptors) and xylazine (Xyl, a non-imidazolines selective α₂-adrenoceptor agonist) on APs of the rabbit SAN pacemaker cells using intracellular microelectrode technique, and to compare their (Mox, Clo, Agm and Xyl) potency order for producing vasoconstriction in the rabbit isolated thoracic aorta (α₁-adrenoceptor preparation) and rabbit isolated ear vein (α₂-adrenoceptor preparation) to elucidate the contribution of IR and α_-adrenoceptors to the cardiac electrophysiological action induced by the four agonists. Inhibition of the release of noradrenaline (NA) from sympathetic neurons is a typical response to the imidazoline derivatives Clo and Mox.Originally, this effect was thought to be mediated exclusively by presynaptic α₂-adrenoceptors. However, it has recently been established that presynaptic IR mediating inhibition of NA release from postganglionic sympathetic nerve fibers have been identified in several tissues of various species including human beings. On the other hand, adenosine triphosphate (ATP) has been widely considered as the purinergic cotransmitter released together with the classical transmitter of NA induced vasconstrictive responses, indicated that the sympathetic purinergic neurotransmitter holds an important action in the control of vasoconstriction. However, the modulation effects of imidazoline compounds on the vasoconstrictive responses to purinergic transmitters have not been reported. To investigate the modulating effects on cardiovascular functions by peripheral ?R and α₂-adrenoceptors, in the present study, we observed the effects of Mox and Clo on neurogenic vasoconstriction induced by electrical field stimulation in the rabbit isolated saphenous artery. We simultaneously compared the effects of Xyl (a non-imidazolines agonist of α₂-adrenoceptors) and Agm (an endogenous ligand for I-/α₂-receptors) on neurogenic vasoconstriction in the rabbit isolated saphenous artery to clarify the presynaptic modulation effects of presynaptic IR on the purinergic vasoconstrictive responses. Part I Electrophysiologic effect of moxonidine on action potential in rabbit sinoatrial node pacemaker cellsMox is a second-generation, centrally acting antihypertensive drug, which activates imidazoline-1 receptors (I1-R) more strongly than ??2-adrenoceptors. Mox decreased the incidence of arrhythmias of the myocardial ischemia induced by coronary artery occlusion or reperfusion in the rat. It has been suggested that the antiarrhythmic effects of Mox are mediated by acting on the central ??2-adrenoceptors and I1-R, thereby reducing the activity of sympathetic nervous system. Antiarrhythmiceffects of Mox and other agonists of IR have also supported this hypothesis. In the rabbit isolated working heart, Mox facilitated spontaneous defibrillation of the ventricular fibrillation during ischemia. IR...