Protein Kinase C Epsilon Contributes to the Exaggerated Mechanoreflex in Rats with Heart Failure
Authors: Butenas Alec L. E. , Parr Shannon K. , Hammond Stephen T. , Ade Carl J. , Hageman K. S. , Musch Timothy I. , Copp Steven W. 
Published: May 2022

Background

During exercise, skeletal muscle contraction stimulates mechanically sensitive channels on the sensory endings of thin fiber muscle afferents. Stimulation of these mechanically sensitive channels initiates a reflex, termed the mechanoreflex, which contributes importantly to reflex increases in sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). In patients and animals with heart failure with reduced ejection fraction (HF‐rEF), mechanoreflex activation contributes to exaggerated increases in SNA and is linked to decreased exercise tolerance and increased mortality. The exaggerated mechanoreflex in HF‐rEF is partially attributed to an increased responsiveness of thin fiber skeletal muscle afferents to mechanical stimulation. Several lines of evidence demonstrate that signaling within sensory neurons mediated by the non‐traditional protein kinase c epsilon (PKCε) isoform augments mechanically activated channel function and produces mechanical hyperalgesia. Whether PKCε‐mediated signaling within sensory neurons contributes the exaggerated mechanoreflex in HF‐rEF is unknown.

Purpose & Hypothesis

We determined the role played by PKCε within sensory endings of thin fiber muscle afferents in evoking the mechanoreflex in rats with HF‐rEF and healthy control rats. We tested the hypothesis that injection of the selective PKCε inhibitor PKCε141 (44μg) into the arterial supply of the hindlimb would reduce the reflex increase in renal SNA (RSNA) and MAP evoked during 30 seconds of 1 Hz dynamic hindlimb muscle stretch (a model of mechanoreflex activation) in HF‐rEF rats, but not in healthy control rats.

Methods

Experiments were performed on Sprague‐Dawley rats subjected to coronary artery ligation surgery to produce myocardial infarction and HF‐rEF or a sham ligation. At least six weeks after the initial surgery, in decerebrate, unanesthetized rats we compared (Student’s t‐tests) the mechanoreflex evoked by hindlimb skeletal muscle stretch before and after injection of PKCε141 into the arterial supply of the hindlimb.

Results

Ejection fraction (determined via echocardiography) was significantly reduced in HF‐rEF rats (48±1%) compared to sham rats (80±2%, P<0.01). Intra‐arterial PKCε141 injection reduced the pressor and RSNA response to hindlimb muscle stretch in HF‐rEF rats (n=6, 4M/2F, peak ΔMAP pre: 34±8; post: 19±7 mmHg; P=0.04; peak ΔRSNA pre: 121±32; post: 70±24%; P=0.04), but not SHAM rats (n=4, 3M/1F, peak ΔMAP pre: 14±4; post: 14±3 mmHg; P=0.87; peak ΔRSNA pre: 62±32; post: 58±26%; P=0.80) rats. In control experiments (n=3 HF‐rEF rats, 2M/1F), injection of PKCε141 into the jugular vein had no effect on the pressor or RSNA response to muscle stretch demonstrating a lack of central nervous system effects.

Conclusions

These data suggest that that PKCε signaling within the sensory neuron endings contributes to the exaggerated mechanoreflex in HF‐rEF and enhance the understanding of the sympathetic and cardiovascular adjustments to exercise in the ~6 million Americans with HF‐rEF.