Sympathetic nerve response to optogenetic inhibition of PVN‐RVLM neurons in anesthetized rats with heart failure

Abstract

Central neuronal cell groups that underlie enhanced sympathetic nerve activity (SNA) in heart failure (HF) have not been identified. Here, we tested the hypothesis that paraventricular hypothalamic nucleus (PVN) neurons that send axonal projections to the rostral ventrolateral medulla (RVLM) mediate this abnormality by examining the effect of optogenetic inhibition of PVN‐RVLM neuron activity on renal SNA (RSNA) in anesthetized rats after myocardial infarction (MI). More than one week after left coronary artery ligation to induce MI, rats received bilateral microinjection into the PVN of an adeno‐associated virus (AAV) vector that encodes reporter protein mcherry (control‐MI rats, N=6) or the light‐activated inhibitory opsin Archaerhodopsin‐eYFP (ArchT‐MI rats, N=12). The AAV vector encoding ArchT‐eYFP was also bilaterally microinjected into the PVN of the sham‐operated rats (ArchT‐sham rats, N=6). More than three weeks later, intermittent bouts (1‐ to 4‐sec stimulation to non‐stimulation) of photostimulation (532 nm wavelength, 5 mW) for 1 min were bilaterally provided to the RVLM of rats anesthetized with a mixture of urethane and α‐chloralose. The RSNA responses to 12 optogenetic stimulations were superimposed on one another and averaged. The superimposing analysis showed that 1‐sec photostimulation significantly (P<0.05) changed RSNA from baseline in ArchT‐MI rats while this stimulation had no effect in control‐MI or ArchT‐sham rats. During the early 500‐msec period of 1‐sec photostimulation, the RSNA changes from baseline were not significant or did not differ among rat groups (+7 ± 6, +4 ± 15, and +14 ± 10% for ArchT‐MI, control‐MI, and ArchT‐sham rats, respectively). During the late 500‐msec period, on the other hand, a significant RSNA inhibition from baseline was detected in ArchT‐MI rats (−35 ± 10%), which was significantly different from the RSNA changes in control‐MI and ArchT‐sham rats (+6 ± 9 and +15 ± 11%). Left ventricular end‐diastolic pressure was increased in rats after MI [+7 ± 3 mmHg, 40 ± 5% of infarct size (IS)] as compared to sham‐operated rats (+2 ± 0 mmHg, 0 ± 0% of IS), indicating heart dysfunction in rats after MI. Taken together, we suggest that dysfunction of PVN‐RVLM neurons underlies enhanced SNA in HF.Support or Funding InformationSupported by JSPS KAKENHI 15H05367 (SK) & 16K15190 (SK), the Nakatomi Foundation grant (SK), and the Takeda Science Foundation grant (SK).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.