Attenuated baroreflex control of sympathetic nerve activity in obese Zucker rats by central mechanisms

Abstract

Adult obese Zucker rats (OZRs) have reduced sympathetic responses to evoked changes in arterial pressure (AP) compared to lean Zucker rats (LZRs). This study examined whether attenuated sympathetic baroreflexes in OZRs may be due to altered sensory or central mechanisms. The OZRs had elevated baseline splanchnic sympathetic nerve activity (SNA) and mean AP (MAP) compared to age-matched LZRs under urethane anaesthesia (P < 0.05). Aortic depressor nerve activity (ADNA) was measured while AP was altered by infusions of phenylephrine or nitroprusside (+/-60 mmHg over 60-90 s) in rats treated with atropine and propranolol to eliminate changes in heart rate. Although baseline ADNA was higher in the hypertensive OZRs, the relationship between MAP and ADNA was comparable in OZRs and LZRs. In contrast, electrical stimulation of the ADN afferent fibres (5 s train, 2 ms pulses, 4 V, 0.5-48 Hz) produced dramatically smaller reductions in SNA and MAP in OZRs compared to LZRs (P < 0.05). After blockade of alpha-adrenergic receptors to prevent sympathetically mediated depressor responses, OZRs still had reduced sympathetic responses to stimulation of the ADN. In addition, stimulation of vagal afferent nerves electrically or with phenylbiguanide (1, 2, 4 and 8 microg, i.v.) produced smaller inhibitions of SNA in OZRs compared with LZRs (P < 0.05). These data suggest that attenuated sympathetic baroreflexes are the result of altered central mechanisms in OZRs, and not deficits in the responsiveness of aortic baroreceptors to AP. Furthermore, central deficits in the regulation of SNA in OZRs extend to other sympathoinhibitory reflexes initiated by vagal afferent nerves.

Figure 2. Typical baroreflex curves for ADNA and SNA in OZRs and LZRs

Representative sigmoidal analyses for adult LZRs (A and B) and OZRs (C and D). Upper plots depict mean AP (MAP) versus ADNA from one LZR (A) and one OZR (B). Lower plots depict MAP versus SNA from one LZR (C) and one OZR (D).

Figure 1. Typical responses of aortic depressor nerve and sympathetic nerve activity to evoked changes in arterial pressure

Representative recordings of aortic depressor nerve activity (ADNA), splanchnic sympathetic nerve activity (SNA) and pulsatile arterial pressure (PAP) from one lean Zucker rat (LZR, top) and one obese Zucker rat (OZR, bottom). Minimal ADNA is observed when AP is reduced by nitroprusside (A and D). At baseline AP, ADNA shows bursts with each pulse of AP in both OZR and LZR (B and E). When AP is increased by infusion of phenylephrine, the bursts of ADNA are increased in both groups (C and F). Here, SNA is readily silenced in the LZR (C), but is still present in the OZR (F).

Figure 3. Relationship between AP and ADNA after ganglionic blockade

Groups of LZRs (n= 7) and OZRs (n= 7) were treated with chlorisondamine to decrease AP and minimize ADNA. Then, AP was steadily raised by infusion of phenylephrine. The plot shows MAP versus ADNA (expressed in μV) fitted by four-parameters logistic sigmoidal regression.

Figure 4. Effects of ADN stimulation on SNA and AP in LZRs and OZRs

Frequency-dependent changes in SNA (A) and MAP (B) in response to electrical stimulation of the left ADN in LZRs (filled bars; n= 9) and in OZRs (open bars; n= 9). After sympathetically mediated changes in AP were clamped by injection of phentolamine, stimulation of the ADN still evoked reduced inhibitions of SNA (C) in OZRs compared to LZRs. There were no significant changes in MAP under these conditions (D). *Significant difference from LZRs at that stimulus intensity (P < 0.05).

Figure 5. Effects of vagal afferent nerve stimulation on SNA in LZRs and OZRs

Electrical stimulation of right vagal afferent nerves in LZRs (n= 11, filled bars) and OZRs (n= 10, open bars) after injection of phentolamine to prevent sympathetically mediated changes in AP. In the low frequency range (A) inhibition of SNA was attenuated in OZRs at the highest frequency of stimulus. In the high frequency range (B) increases in SNA were comparable in LZRs and OZRs. Data are means ±s.e.m. *Significant difference from LZRs at that stimulus intensity (P < 0.05).

Figure 6. Effects of bolus injection of phenylbiguanide (PBG) on SNA

Filled bars: LZRs (n= 10); open bars: OZRs (n= 11). *Significant difference from LZRs at that dose of PBG (P < 0.05).