Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure

Abstract

Lataro RM, Silva CA, Fazan R Jr, Rossi MA, Prado CM, Godinho RO, Salgado HC. Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure. Am J Physiol Regul Integr Comp Physiol 305: R908 -R916, 2013. First published August 28, 2013 doi:10.1152/ajpregu.00102.2013.-Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

Increase in cholinergic modulation with pyridostigmine induces anti-inflammatory cell recruitment soon after acute myocardial infarction in rats

“…Our group (8,27) and others (9,18) have demonstrated that baroreflex dysfunction, reduction in parasympathetic modulation, and increased sympathetic response identified after MI may be restored with physiological and pharmacological interventions that act on the cholinergic anti-inflammatory pathway.…”

“…Administration of PY improves the autonomic profile (8,9,18,27) and decreases left ventricular (LV) dysfunction following MI in some experimental studies (8,9,18). Two to four weeks of PY administration may ameliorate cardiac remodeling induced by MI via multiple mechanisms, including by increasing mediators of angiogenesis (41), by decreasing proinflammatory cytokine production, and via cardiac fibrosis of the surviving myocardium (21).…”

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

“…Furthermore, vagus nerve stimulation in animal studies and in patients with heart failure has shown improvement in cardiac function, suggesting that cholinergic-pathway activation may provide therapeutic benefit (5,18,45,53,). Other studies using drugs to augment the parasympathetic nervous system or influence vagal tone, including acetylcholinesterase inhibitors such as donepezil or pyridostigmine, show evidence of improved ventricular remodeling and autonomic function in animal models of heart failure or after myocardial infarction (13,26,32,37,42). Studies of patients treated with these drugs for Alzheimer's dementia have reported reduced adverse cardiac events, including myocardial infarction and death (31).…”

Midodrine and Pyridostigmine; Novelties in Heart Failure Therapy

“…In another animal study by Lataro et al, the use of Pyridostigmine in heart failure models was associated with decrease in myocyte diameter, increase in stroke volume, cardiac output and contractility. 20 At 4 weeks of treatment, Pyridostigmine group had an EF of 25% compared to 15% in the control group. Pyridostigmine group had a higher level of vascular endothelial growth factor expression (suggesting angiogenesis) and a higher collagen density in cardiac myocytes.…”

“…17 None of the studies involving pro-cholinergic agents in the treatment of heart failure have reached clinical application yet. [18][19][20][21][22] Pyridostigmine is a reversible acetylcholine esterase inhibitor, it augments the effect of the parasympathetic system. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] It is currently used in the treatment of myasthenia gravis.…”