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Abstract

Heart failure is characterized by an elevation in sympathetic tone. The mechanisms responsible for this sympatho-excitation of heart failure are not completely understood. Several studies from this laboratory have compared differences in the cardiac "sympathetic afferent" reflex between sham dogs and dogs with pacing-induced heart failure. We found 1) that the cardiac sympathetic afferent reflex is augmented in heart failure, 2) tonic cardiac sympathetic afferent inputs play an important role in the elevated sympathetic tone in heart failure, 3) cardiac sympathetic afferents are sensitized in heart failure and 4) the central gain of the cardiac sympathetic afferent reflex in heart failure is sensitized and that this sensitization may be related to augmented central Ang II and blunted NO mechanisms. These studies integrate into the regulation of sympathetic outflow in heart failure which is likely to be mediated by a variety of peripheral inputs modulated by central substances. If the cardiac sympathetic afferent reflex is one of the excitatory reflexes which contribute to sympathetic activation in heart failure, a comprehensive understanding of neuro-humoral regulation of this reflex may result in more definitives and rational therapy targeted to the sympathetic nervous system in this disease state.

Cardiac Sympathetic Afferent Denervation Attenuates Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats With Heart Failure

“…One potential explanation is an increased CSAR control of cardiac sympathetic efferent outflow (also called the “cardiac-cardiac reflex”) in CHF. It is well known that myocardial ischemia releases large amounts of metabolites including bradykinin, ATP, prostaglandins and protons that stimulate cardiac sympathetic afferent nerve endings and cause an excitatory response of MAP, HR and sympathetic nerve activity 1, 3, 4 . Previous studies from this laboratory 1, 2 demonstrated that acute epicardial application of lidocaine, which blocked cardiac sympathetic afferent input, decreased baseline MAP, HR and RSNA in anesthetized CHF dogs and rats but not in sham animals, indicating that the CSAR is tonically activated and contributes to the elevated renal sympathetic nerve activity in CHF.…”

“…It is well known that myocardial ischemia causes the production and release of several metabolites including bradykinin, prostaglandins and protons that stimulate sympathetic afferent nerve endings leading to increases in arterial pressure (AP), heart rate (HR) and sympathetic nerve activity 1, 3, 4 . In CHF, the CSAR is sensitized and cardiac sympathetic afferents are tonically activated 1-3 .…”

“…In CHF, the CSAR is sensitized and cardiac sympathetic afferents are tonically activated 1-3 . Recent evidence indicates that transient receptor potential vanilloid 1 (TRPV1)-expressing cardiac afferent fibers are necessary for sensing and triggering the activation of the CSAR and that desensitization of these afferents by systemic administration of resiniferatoxin (RTX), an ultrapotent analogue of capsaicin capable of inducing rapid degeneration of TRPV1-expressing afferent neurons and fibers 5-7 , can almost completely abolish CSAR activation in adult rats 5 .…”

ASICs and cardiovascular homeostasis

“…In contrast to ASIC channels in skeletal muscle afferents, we have demonstrated that the ASIC channel in mouse cardiac afferents is a heteromer composed of ASIC2a and −3 subunits (Hattori et al, 2009). Besides serving as pain sensors during myocardial ischemia or infarction, cardiac sympathetic afferents trigger sympathoexcitation (Malliani et al, 1969; Minisi and Thames, 1991), and there is evidence to support their contribution to the detrimental sympathetic activation associated with cardiovascular disease states (Wang and Ma, 2000; Wu et al, 2008). …”

Physiological regulation of pro-inflammatory cytokines expression in rat cardiovascular tissues by sympathetic nervous system and angiotensin II

“…Interaction between SNS and ANG II was demonstrated by several functional studies which showed that ANG II stimulates sympathetic neurotransmitter (NE) release by activation of its specific AT1 receptor (AT1R) located on presynaptic SNS terminal axon reaching cardiovascular tissues (Saxena, 1992;Cox et al 1995;Dendorfer et al 1998;Wang and Ma 2000). Moreover, the blockage of ANG II receptor AT1R with losartan reduces NE release and enhances its reuptake by SNS terminal axon (Raasch et al 2004).…”