Stimulation of muscarinic receptors by acetylcholine induces a rapid and prolonged turnover of polyphosphoinositides (PPI) in cardiac atria and ventricles. In contrast to other tissues, the function associated with cholinergic activated PPI turnover is poorly understood in heart. Therefore, studies are proposed here to further investigate muscarinic receptor activation of the phospholipase C activity initiating PPI turnover an to further explore a hypothesis that PPI turnover may be involved in the regulation of voltage dependent Ca2+ channels. Muscarinic receptor inhibition of Ca2+ influx through these channels may be partially responsible for the negative inotropic and chronotropic effects of acetylcholine, particularly in the presence of sympathetic stimulation by beta adrenergic receptor agonists.
The specific aims of this proposal are: 1. To characterize the properties of muscarinic receptor regulation of 45Ca2+ influx in atrial and ventricular myocytes. 2. To further elucidate the mechanism coupling muscarinic receptors to polyphosphoinositide phospholipase C in sarcolemmal membranes isolated from atrial and ventricular tissue. 3. To study regulation of 45Ca2+ fluxes by protein kinase C and inositol phosphates in resealed cardiac sarcolemmal vesicles. Collectively, the results obtained from this investigation will provide a molecular basis for the actions of muscarinic receptor agonists on PPI turnover in both atrial and ventricular myocytes. In addition, further insights into the physiological role of cholinergic nerve stimulation on various regions of the heart may be provided.
