Cellular Ca mobilization and muscarinic relaxation in mammalian iris dilator muscle.

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The aim of this project is to elucidate the Ca mobilizing mechanism underlying changes in muscle tension when transmitters, autacoids and drugs are applied to iris dilator muscle of the rat and some other species. Special efforts were made to investigate the mechanisms of relaxation induced by muscarinic stimulation. First, it is found that the muscarinic relaxation is mediated by M_2-like receptor, whereas the conventional classification of muscarinic receptors into M_1 and M_2 does not fit well to characteristics of the receptor in the rat and pig iris dilator (J. Eye, 1988). Second, a striking finding was obtained that the relaxation induced not only by nerve stimulation but also by exogenously applied muscarinic agonist disappeared after parasympathectomy by ciliary ganglionectomy (E.J.P.,1988). This suggests that the muscarinic relaxation may not occur directly but mediate a release of relaxing substance from cells nearby. Therefore, substances which induce relaxation in dilator m … More uscle were widely surveyed. It was finally found that high K^+ solution induced marked relaxation when Ca, alpha- and beta- adrenergic, and muscarinic antagonists were simultaneously present (B.J.P., 1990). Since the high K^+-induced relaxation was also abolished after parasympathectomy (manuscript in preparation), an additional indirect evidence to the assumption was obtained. The relaxing substance is neither the endothelium derived relaxing factor in vascularture and probably nor a peptide. On the other hand, sympathectomy by superior ganglionectomy did not alter the muscarinic relaxation, whereas a specific increase in sensitivity to noradrenaline was observed. The supersensitivity is due to the abolishment of noradrenaline-uptake after degeneration of sympathetic nerve endings (J.J.P., 1989). Beta-adrenergic and some other relaxations were not affected by sympathectomy either (manuscript in preparation). The measurement of intracellular Ca concentration by fluorescent indicator, fura2, was considered to be one of the most effective approaches to clarify the cellular Ca mobilization, the success rate of concomitant measurements of [Ca]_i and tension was very low in the rat dilator tissue because of its small size. Sufficient results for publication have not been obtained. From the results mentioned above, it is highly possible that muscarinic agonists and high K^+ solution induce relaxation of dilator muscle via release of a relaxing substance somewhat relating to parasympathetic but not sympathetic innervation. Further study is required to determine the relaxing substance. Less