Abstract
Exercise performance declines in heart failure (HF). Reduced blood flow to active muscle has been thought to contribute to the abnormal responses in HF. Thus it is important to understand the mechanisms that regulate the autonomic responses during exercise in normal subjects and in patients with HF. Sympathetic nervous activity (SNA) is increased with exercise in normal subjects and is increased in HF subjects at rest and in response to exercise. Heightened peripheral SNA and the resultant increased neurovascular levels of norepinephrine (NE) evoke vasoconstriction. The NE response is accentuated in HF and this results in an increase in prominent vasoconstriction. Interstitial concentrations of NE ([NE]i) provide an outstanding index of NE concentrations at the neurovascular junction. Microdialysis methods allow us to collect interstitial NE samples from resting and active muscles of healthy control rats and rats with HF induced by myocardial infarctions. The completed experiments from this laboratory have shown that NEi rises in active muscle. Several muscle metabolites can alter the interstitial concentration of NE and in turn influence blood flow. For example, elevated interstitial ATP evoked by muscle stretch is linked to the rise in [NE]i. A purinergic P2X receptor is a family of cation-permeable ligand gated ion channels that open in response to extracellular ATP. The elevated NE induced by muscle stimulation is attenuated by a P2X receptor blocker, and is augmented by a nucleotidase inhibitor. This suggests a mechanism by which NEi is increased via P2X receptors on the sympathetic nerve terminals. K+ is also a stimulant of NE exocytosis from the sympathetic nerve. Interstitial K+ concentration increases with muscle contraction and K+ infused into the arterial blood supply of the hindlimb muscle increases [NE]i. In HF, an increase in the concentration of interstitial K+ is augmented. In addition, we have also examined NE response to sympathetic nerve stimulation and activity of NE uptake 1, a pathway by which NE is reabsorpted by presynaptic sympathetic nerves. Given level of sympathetic nerve stimulation leads to a greater NEi response in HF as compared with healthy control. This effect is due, in part, to reduced NE uptake 1 in HF. Our experimental results suggest that 1) ATP and P2X receptors; 2) muscle metabolite K+; and 3) the SNA and NE uptake 1 pathway play an important role in regulating neurovascular NE levels in HF.
Keywords: Sympathetic nerve, muscle metabolite, vasoconstriction, norepinephrine, heart failure
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