The role of the paraventricular nucleus of the hypothalamus in the regulation of cardiac and renal sympathetic nerve activity in conscious normal and heart failure sheep

Authors


R. Ramchandra: Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria 3010, Australia.  Email: rohit.ramchandra@florey.edu.au

Key points

  • • Heart failure is associated with large increases in sympathetic nerve activity to organs like the heart and kidney and this increase is detrimental to patients.
  • • We explored the role played by the paraventricular nucleus of the hypothalamus (PVN), a central brain region, in mediating the increase in sympathetic drive during heart failure.
  • • We show that neurons in the PVN selectively mediate changes in sympathetic drive to the kidney, but not to the heart when blood volume is increased.
  • • In addition, neurons in the PVN do not contribute to the resting levels of sympathetic drive to the heart during normal conditions or in heart failure.
  • • Our data demonstrates striking differences in the central mechanisms that control sympathetic drive to the heart and kidney during heart failure.

Abstract  The paraventricular nucleus of the hypothalamus (PVN) plays a major role in central cardiovascular and volume control, and has been implicated in controlling sympathetic nerve activity (SNA) during volume expansion and in heart failure (HF). The objectives were to determine the role of the PVN on cardiac and renal SNA (CSNA and RSNA) in conscious normal sheep and sheep with pacing-induced heart failure. In normovolaemic sheep in the normal state and in HF, bilateral microinjection of the GABA agonist muscimol (2 mm, 500 nl), had no effects on resting mean arterial pressure (MAP), heart rate (HR), CSNA or RSNA. In addition, neither chemical inhibition of the PVN using the inhibitory amino acid glycine (0.5 m, 500 nl), nor electrolytic lesion of the PVN reduced the elevated level of CSNA in HF. Dysinhibition of the PVN with bilateral microinjection of bicuculline (1 mm, 500 nl) in normal sheep increased MAP, HR and CSNA, but decreased RSNA, whereas in HF bicuculline had no effects on MAP, HR or CSNA, but inhibited RSNA. During volume expansion in normal sheep, muscimol reversed the inhibition of RSNA, but not of CSNA. In summary, removal of endogenous GABAergic inhibition to the PVN indicated that CSNA is normally under inhibitory control. Although this inhibition was absent in HF, the responses to pharmacological inhibition, or lesion of the PVN, indicates that it does not drive the increased CSNA in HF. These findings indicate the PVN has a greater influence on RSNA than CSNA in the resting state in normal and HF sheep, and during volume expansion in normal sheep.

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