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1 Medical Research, UniversityDept Veterans Affairs Medical Center, Cleveland, OH, USA; Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
2 Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA
3 Department of Pharmacology, School of Medicine, Case Western Reserve, Cleveland, OH, USA
* To whom correspondence should be addressed. E-mail: Steve.bibevski{at}med.va.gov.
Parasympathetic control of the heart is attenuated in heart failure (HF). We investigated possible mechanisms and sites of altered vagal control in dogs with heart failure induced by rapid pacing. Muscarinic blockade reduced the RR interval by 308 msec in controls but only by 32 msec in heart failure, indicating low levels of resting vagal tone. Vagomimetic doses of atropine sulfate prolonged RR interval 109 msec in controls, and increased standard deviation of the RR interval by 66 msec but only 46 msec and 16 msec, respectively in HF. Bradycardia elicited by electrical stimulation of the vagus nerve was also attenuated in the HF group. Conversely, muscarinic receptor activation by bethanechol, and indirectly by neostigmine, elicited exaggerated RR interval responses in HF. To investigate possible mechanisms, we measured muscarinic receptor density (Bmax) and acetylcholinesterase activity in different areas of the heart. In sinoatrial nodes, Bmax was increased (230 ± 75% of control) and acetylcholinesterase decreased (80 ± 6% of control) in heart failure. We conclude that muscarinic receptors are upregulated, and acetylcholinesterase is reduced in the sinus node in heart failure. Therefore, reduced vagal control in heart failure is most likely due to changes of pre-synaptic function (ganglionic), since post-synaptic mechanisms augment vagal control in HF.
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