Decreased Vagal Control Over Heart Rate in Rats With Right-Sided Congestive Heart Failure-Downregulation of Neuronal Nitric Oxide Synthase-

Abstract

ongestive heart failure (CHF) is associated with an augmentation of sympathetic nerve activity and a reduction in parasympathetic nerve activity. 1,2 This autonomic imbalance may underlie the increased risk of sudden cardiac death in CHF patients. 3 In normal individuals, parasympathetic impulses are transmitted from the solitary nucleus in the brain to the heart through efferent preand post-ganglionic vagal neurons. Upon vagal stimulation, acetylcholine (ACh) released from the nerve terminals binds to muscarinic (M2) receptors of the heart. Emerging evidence shows that the ACh release at both pre-and postganglionic levels is facilitated by nitric oxide (NO) generated by neuronal NO synthase (nNOS) at nerve terminals. 4,5 Stimulation of the M2 receptor in the sinoatrial (SA) node pacemaker cells results in a reduction of heart rate (HR) via increase of ACh-sensitive potassium channel current (IK,ACh) and decrease of hyperpolarization-activated cation channel current (If). 6 The level within the vagal cascade, at which a defect results in parasympathetic withdrawal, is unknown.In a dog model of CHF induced by rapid ventricular pacing, Bibevski and Dunlap demonstrated that although the HR response to pre-ganglionic vagal nerve stimulation was attenuated compared with controls, the HR response to post-ganglionic vagal nerve stimulation was significantly enhanced, suggesting a defect located within the parasympathetic ganglion. 7 However, these sparse data require confirmation in general, but especially in other animal models and human patients. Also, the anatomic site(s) and molecular mechanisms of parasympathetic withdrawal in failing hearts remains to be clarified. We investigated the effects of pre-and post-ganglionic vagal nerve stimulation (VS), and those of direct application of ACh on HR or spontaneous activity of the SA node in rats with right-sided CHF secondary to pulmonary hypertension, induced by monocrotaline (MCT, 60 mg/kg, sc). Our results point to vagal nerve dysfunction at both pre-and post-ganglionic levels despite enhanced sensitivity of the SA node to ACh. Downregulation of nNOS and upregulation of M2 receptor are associated with these changes in the right atria of CHF rats. Methods Animal ModelRight ventricular hypertrophy with CHF was produced in 5-week-old male Wistar rats by a single subcutaneous injection of MCT (60 mg/kg; Sigma Chemical Co, St. Louis, MO, USA). 8 As previously described, right ventricular hypertrophy and heart failure were completed 4 weeks after MCT injection. Rats injected with saline were used as controls. 8 The rats were killed for in vivo and in vitro experi- Background Parasympathetic drive is attenuated in heart failure, and resulting autonomic imbalance may increase the risk of sudden cardiac death. The anatomic site(s) and molecular mechanisms underlying this parasympathetic withdrawal are unknown. Methods and ResultsWe examined the effects of pre-and post-ganglionic vagal nerve stimulation (VS) and acetylcholine (ACh) application on the heart rate of rats with ri...

Alterations in Pharmacological Action of the Right Ventricle of Monocrotaline-Induced Pulmonary Hypertensive Rats

“…5) In contrast, M 2 receptors in the right atrium have been shown to be up-regulated. 34) The former appears to be incompatible to our findings and the latter might be compatible with our findings, but more close correlation should be elucidated for understanding of the mechanism responsible for the effect of ACh on the right ventricle of the MCT-administered rat. Furthermore, the reduced levels of cholinesterase activity in the RV muscle of the MCT rats are possible factor for the ACh hypersensitivity.…”

Evidence for impaired vagus nerve activity in heart failure

“…Thus, for a given cardiovascular insult, intact baroreflexes appear to be protective against ischemic events and worsening LV dysfunction. Potential mechanisms of this protection include lesser degrees of ischemia, reduced electrical instability, and direct myocardial protective effects, possibly mediated by the release of nitric oxide [33,34].…”

“…In parasympathetic neurons, NO serves to increase acetylcholine release via stimulation of soluble guanylate cylase [33,50], and direct modulation of vagal control of cardiac activity has been demonstrated [51] suggesting that NO modulation of parasympathetic activity may be important [34,52]. As described elsewhere in this issue, NO levels are known to be significantly altered in HF in complex patterns and could represent a significant component to vagal dysfunction in HF [34,53]. Angiotensin II is elevated in HF and has been demonstrated to modulate autonomic function in both central and peripheral locations.…”

Arrhythmia and neuronal/endothelial myocyte uncoupling in hyperhomocysteinemia

“…Constitutively, NO released from sympathetic and parasympathetic nerves moderate neuronal-myocyte coupling and cardiac rhythm (Nihei et al, 2005), and NO released from endothelium regulates E-M coupling and cardiac diastolic relaxation (Brady et al, 1994;Pinsky et al, 1997). Interestingly, Hcy decreases both neuronal (Kim, 1999) and endothelial NO (Chen et al, 2002) but increases inducible NO through iNOS (Welch et al, 1998).…”