Hypertensive Young Adult Female Obese Zucker Rats (OZR) Do not Develop the Impaired Baroreflexes or Reduced Activation of the NTS Observed in Male OZR

Abstract

Obese Zucker rats (OZR) have dysfunctional leptin receptors, which fosters excess food intake and the development of metabolic syndrome in comparison to lean Zucker rats (LZR) with functional leptin receptors. Adult male OZR and female OZR have excess weight gain, hyperinsulinemia, and hypertension compared to same sex, age‐matched LZR. Adult male OZR have also have blunted baroreflexes that emerge with the development of impaired activation the nucleus tractus solitarius (NTS). In contrast, female OZR do not have blunted baroreflexes at this age (12–14 weeks). This study determined whether fully functional baroreflexes in female OZR corresponded with a sustained ability to activate the NTS in comparison to age‐matched female LZR. Rats were instrumented with indwelling catheters run through a tether and swivel to measure mean arterial pressure (MAP) and heart rate (HR) through a femoral artery and infusion of drugs through a femoral vein while the rats were conscious and undisturbed. As expected, female OZR had elevated MAP compared to female LZR (135 ± 2 vs. 121 ± 2 mmHg in 9 OZR and 7 LZR, P<0.05), as observed in male rats (127± 2 vs. 115 ± 3 mmHg in 13 OZR and 10 LZR, P<0.05). Infusion of phenylephrine (PE) to raise MAP by 40 mmHg evoked the expected blunted bradycardia in male OZR (−52 ± 9 vs. −101 ± 9 bpm in 11 OZR and 10 LZR, P<0.05), whereas responses in female rats were comparable (−111 ± 13 vs. −129 ± 20 bpm in 9 OZR and 7 LZR). Likewise, PE‐induced c‐Fos expression in NTS was reduced in these male OZR compared to LZR (121 ± 18 and 199 ± 21 counts in P<0.05; bilateral counts of NTS at bregma levels −14.2, −13.8, −13.2, and −13.0 mm), but PE‐induced c‐Fos expression in NTS was comparable in female OZR and LZR (311 ± 38 and 390 ± 32 counts). At the age when impaired baroreflex‐mediated changes in sympathetic nerve activity begin to emerge in male OZR (in gain, but not yet in range), the NTS appeared to undergo dramatic neuroplasticity. Male OZR displayed a surge of ΔFosB expression in the NTS at 7–8 weeks of age (375 ± 59 vs. 146 ± 13 counts 4 OZR and 5 LZR, P<0.05), and this difference persisted into adulthood (132 ± 12 vs. 64 ± 10 counts in 6 OZR and 7 LZR, P<0.05). In 7–8 week old female OZR, this surge in ΔFosB expression in the NTS is absent (82 ± 13 and 56 ± 14 counts in 5 OZR and 4 LZR), with little change at 11–12 weeks of age (102 ± 8 and 68 ± 14 counts 5 OZR and 5 LZR). These data suggest that the preservation of NTS function in hypertensive, young adult female OZR with metabolic syndrome may underlie their sustained ability to respond to acute changes in MAP. The surge of ΔFosB expression in NTS of juvenile male OZR but not female OZR may provide important clues for mechanisms underlying the vulnerability of male OZR to the development of impaired NTS function and baroreflexes. These data also highlight the likelihood of differing mechanisms for the development of hypertension and impaired control of MAP by baroreflexes in the setting of metabolic syndrome. Further study is needed determine phenotypes of these NTS neurons, which attributes of metabolic syndrome alter NTS neuronal function and baroreflexes, and how female OZR are protected from these changes despite the development of other attributes of metabolic syndrome.Support or Funding InformationAHA GRNT18880005 to AMS, PRE27260088 to PC