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

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.

Figure 1. Effects of bilateral microinjection of muscimol (2 mm, 500 nl) into the PVN on mean arterial blood pressure, heart rate, cardiac SNA and renal SNA in conscious normal (n= 5, continuous line) and HF sheep (n= 5, dashed lines)

The distribution of all injection sites is shown in the schematic drawing adapted from coronal sections from 1 animal. The dots show the centre of injection sites as visualized by the distribution of blue dye. Dots indicate the paraventricular nucleus of the hypothalamus (PVN) muscimol injection sites in the normal (open circles) and heart failure animals. IC, optic chiasm.

Figure 2. Arterial baroreflex curves for cardiac SNA and heart rate (HR) during the control period (continuous line, filled circles) and after microinjection of glycine (1 mm) (dashed line, open circles) in normal and HF sheep

CSNA is presented as percentage of baseline activity measured. Resting points were taken from 5 min of recording during control periods. Values are means ± SEM (n= 6 in the normal and n= 5 in the HF group). The bottom panel indicates the distribution of microinjection sites in normal and HF sheep, dots show centre of injection sites as visualized by the distribution of blue dye in the normal (open circles) and heart failure animals. OC, optic chiasm.

Figure 3. Changes in levels of mean arterial pressure, heart rate, cardiac sympathetic nerve activity and baroreflex control of heart rate and CSNA pre- and post-lesion of the PVN in 5 HF sheep

Data are means ± SEM; *P < 0.05 pre- vs. post-lesion. The straight lines represent the pre-lesion and the dotted lines represent the post-lesion baroreflex curves. The common area of lesion in all five sheep with HF is denoted below in the first 4 panels on the left. The panels on the right represent sections from one animal showing the lesioned area.

Figure 4. Changes in mean arterial pressure, central venous pressure, cardiac SNA and renal SNA during volume expansion with infusion of gelofusine over 30 min in conscious sheep (n= 6)

At an infused volume of 300 ml, sheep were treated with bilateral PVN microinjections of muscimol (2mM, 500 nL) (dashed line) or artificial CSF (continuous line). The dotted line signifies when the microinjection into the PVN was conducted. #Significant difference, P > 0.05 between treatments. The circles show the centre of injection sites as visualized by the distribution of bue dye. Circles indicate the paraventricular nucleus of the hypothalamus (PVN) muscimol injection sites in the normal (open circles) and heart failure animals. IC, optic chiasm.

Figure 5

Original data showing changes in arterial pressure, cardiac SNA and renal SNA in normal (upper panels) and HF animals (lower panels) before (left panels) and 25 min post-bilateral microinjection of bicuculline (1 mM) into the PVN (right panels).

Figure 6. Effects of microinjection of bicuculline into the PVN on mean arterial blood pressure, heart rate, cardiac SNA and renal SNA in conscious normal (n= 5, continuous line) and HF sheep (n= 5, dashed lines)

*Significant effect of time within group, P < 0.05; #significant difference between treatments, P < 0.05. The distribution of all injection sites is shown in the schematic drawing adapted from coronoal sections from 1 animal. The circles show the centre of injection sites as visualized by the distribution of bue dye. Circles indicate the paraventricular nucleus of the hypothalamus (PVN) muscimol injection sites in the normal (open circles) and heart failure animals. IC, optic chiasm.