Altered regulation of the rostral ventrolateral medulla in hypertensive obese Zucker rats

Domitila A. Huber and Ann M. Schreihofer
American Journal of Physiology - Heart and Circulatory Physiology 301: H230-H240, 2011

Fat rats!

Obese Zucker rats (OZR) are a genetic model of obesity and differ from lean Zucker rats (LZR) in that they lack leptin receptors.  Because leptin is a key signaler of satiety, these rats eat much more and become obese.  They also have increased sympathetic nerve activity (SNA) and increased mean arterial pressure (MAP).  It has been seen that, in human subjects, eliminating SNA causes greater decreases in MAP in obese subjects than in lean subjects, suggesting that the increased SNA contributes to the increased MAP.  In rats, this increased sympathetic tone has been traced back to the RVLM.  In some models, this is at least partially explained by increases in tonic glutamate and angiotensin II activation and decreased tonic GABA inhibition of the RVLM.

Huber and Schreihofer did recordings from the left greater splanchnic nerve, brain stem microinjections, and histological analysis to further study the source of the differences between the OZRs and LZRs.  When muscimol (a GABAA agonist) was injected into the RVLM, the SNA dropped almost to zero and the MAP and heart rate (HR) both decreased significantly, with the MAP decreasing more in the OZR than in the LZR.  In the NTS, muscimol injections caused increases in SNA, HR, and MAP, but the OZR had smaller increases than the LZR.  Injection of losartan (an AT1 antagonist) into the RVLM produced a decrease in SNA, MAP, and HR in the OZR but only a decrease in HR in the LZR.  Kynurenate (an ionotropic glutamate receptor antagonist) injection eliminated the reflex decreases in all three variables in response to stimulation of the sciatic nerve.  In the CVLM, kynurenate injections evoked smaller increases in SNA and HR in the OZR than in the LZR.  Gabazine (a GABAA antagonist) injected into the RVLM caused a reduction of the reflex decreases in SNA, HR, and MAP in response to stimulation of vagal afferents, but less so in the OZR than in the LZR.  Finally, injecting GABA into the RVLM caused similar decreases in SNA, HR, and MAP in both OZR and LZR.

To summarize the results, drug injections into the RVLM showed that the RVLM in the OZR is probably receiving less GABA than in the LZR (because the GABAA agonist caused a greater response and the GABAA antagonist caused a lesser response) and that the NTS is exerting less control in the OZR than in the LZR (because inhibiting is caused a lesser response).  The AT1 antagonist caused a greater response in the OZR, indicating that the OZR RVLM is being activated more by angiotensin II than the LZR RVLM is.  Knocking out glutamate signalling in the CVLM of the OZR had less of an effect than in the LZR, implying that the CVLM is less active in the OZR (which agrees with the NTS data).  In short, the OZR RVLM is receiving less tonic GABA input from the CVLM, receiving more tonic angiotensin II input, and receiving similar tonic glutamate input.  The OZR CVLM receives less tonic glutamate (which explains the lower tonic GABA release in the RVLM), and the NTS is also less active (because inhibiting it has a lesser effect).

Huber and Schreihofer suggest several reasons for these differences, but the experiments in this paper assessed only the differences and not their causes.  One potential problem with comparing a leptin-receptor deficient rat to a normal rat is that the leptin-receptor deficient rat has higher levels of leptin, which is known to cause increased SNA and MAP.  However, it has been shown that the OZR still have higher SNA and MAP and attenuated baroreflexes even when leptin's effects are absent.  Also, the MAP and baroreflexes are normal in juvenile OZR, even though they lack the leptin receptor.  Experiments in other animal models of hypertension show differences similar to those seen in these rats, as well.