The studies outlined in the current proposal will determine the contribution of pre- and post-ganglionic mechanisms to abnormal vagal control in heart failure. Patients and animals with heart failure show attenuated vagal control of heart rate, which could be due to changes in nerve activity, ganglionic transmission, synthesis or release of acetylcholine, acetylcholinesterase activity, or muscarinic receptor density or function. Preliminary data suggest that despite reduced vagal control of heart rate, post-synaptic mechanisms are augmented in heart failure (likely due to a form of denervation hypersensitivity). The project will determine the sites and mechanisms of altered vagal control in heart failure. Studies will include experiments in intact animals, in isolated spontaneously beating right atria, on atrial strips to measure release of acetylcholine, and on tissue samples. Specific hypotheses to be tested are: 1. Cholinergic mechanisms become abnormal very early in developing cardiac dysfunction. 2. This reduction in vagal control leads to changes in muscarinic receptor density and function during early stages of cardiac dysfunction and contributes to preserved baroreflex control of RR interval. 3. As left ventricular dysfunction becomes more severe, the abnormalities of vagal control become so profound that even upregulation of muscarinic receptors cannot compensate, resulting in grossly abnormal vagal mechanisms in heart failure. 4. Attenuated efferent vagal control in heart failure is likely due to pre-synaptic mechanisms. These studies will lead to a detailed understanding of abnormal cholinergic mechanisms that are present in heart failure. Since low vagal tone portends increased mortality, understanding these mechanisms may lead to efforts to restore vagal control and blunt the sympathetic excitatory state that is present in heart failure.
| Bibevski, Steve; Dunlap, Mark E (2004) Prevention of diminished parasympathetic control of the heart in experimental heart failure. Am J Physiol Heart Circ Physiol 287:H1780-5 |
| Bibevski, S; Zhou, Y; McIntosh, J M et al. (2000) Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons. J Neurosci 20:5076-82 |
| Bibevski, S; Dunlap, M E (1999) Ganglionic mechanisms contribute to diminished vagal control in heart failure. Circulation 99:2958-63 |
