Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-α - PubMed (original) (raw)

Comparative Study

Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-α

Megan E Bardgett et al. Hypertension. 2014 Mar.

Abstract

Development of angiotensin II (Ang II)-dependent hypertension involves microglial activation and proinflammatory cytokine actions in the hypothalamic paraventricular nucleus (PVN). Cytokines activate receptor signaling pathways that can both acutely grade neuronal discharge and trigger long-term adaptive changes that modulate neuronal excitability through gene transcription. Here, we investigated contributions of PVN cytokines to maintenance of hypertension induced by subcutaneous infusion of Ang II (150 ng/kg per min) for 14 days in rats consuming a 2% NaCl diet. Results indicate that bilateral PVN inhibition with the GABA-A receptor agonist muscimol (100 pmol/50 nL) caused significantly greater reductions of renal and splanchnic sympathetic nerve activity (SNA) and mean arterial pressure in hypertensive than in normotensive rats (P<0.01). Thus, ongoing PVN neuronal activity seems required for support of hypertension. Next, the role of the prototypical cytokine tumor necrosis factor-α was investigated. Whereas PVN injection of tumor necrosis factor-α (0.3 pmol/50 nL) acutely increased lumbar and splanchnic SNA and mean arterial pressure, interfering with endogenous tumor necrosis factor-α by injection of etanercept (10 μg/50 nL) was without effect in hypertensive and normotensive rats. Next, we determined that although microglial activation in PVN was increased in hypertensive rats, bilateral injections of minocycline (0.5 μg/50 nL), an inhibitor of microglial activation, failed to reduce lumbar or splanchnic SNA or mean arterial pressure in hypertensive or in normotensive rats. Collectively, these findings indicate that established Ang II-salt hypertension is supported by PVN neuronal activity, but short term maintenance of SNA and arterial blood pressure does not depend on ongoing local actions of tumor necrosis factor-α.

Keywords: blood pressure; cytokines; inflammation.

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Figures

Figure 1

Figure 1

Summary data of MAP and HR in NT and Ang II-salt HT rats at baseline and during 14 days of Ang II or saline infusion. Baseline MAP and HR were similar across groups despite HT rats consuming a high salt (2% NaCl) diet. Within 2 days of Ang II infusion, MAP increased significantly and remained elevated throughout the infusion period. HR did not change in either group throughout the infusion. *P<0.05 vs. NT.

Figure 2

Figure 2

(A) Representative examples of RSNA (left), SSNA (right), and ABP responses during PVN microinjection of muscimol in separate HT rats. (B) Peak changes in RSNA, SSNA, and MAP after bilateral microinjection of muscimol into the PVN of NT and HT. Note that PVN muscimol caused significantly greater reductions of RSNA, SSNA, and MAP in HT than NT rats. *P<0.05 vs. NT.

Figure 3

Figure 3

(A) Representative LSNA, SSNA, and ABP responses to PVN microinjection of aCSF (left), TNF-α alone (center), and etanercept followed by TNF-α (right). (B) Corresponding summary data. Note that prior injection of etanercept significantly blunted sympathoexcitatory responses to TNF-α. *P<0.05 vs aCSF. (C) Representative LSNA, SSNA, and ABP responses to PVN microinjection of etanercept alone in an NT (left) and an HT (right) rat. (D) Corresponding summary data. *P<0.05 vs. NT, #P<0.05 vs baseline.

Figure 4

Figure 4

(A) Digital photomicrographs of OX-42 staining of PVN sections from an NT (left, top) and an HT rat (right, top). Also shown is a section from a positive control rat in which LPS was injected unilaterally into PVN (left, bottom) and a control for non-specific staining (no 1° Ab, right, bottom). Scale bar = 25 µM. Note: Higher magnification (400x) images in NT and HT panels show characteristic morphology of activated microglia. (B) Quantification of relative OX-42 staining across NT, HT, PVN LPS and PVN LPS without 1° Ab. *P<0.05 vs. NT. 3V, third ventricle.

Figure 5

Figure 5

(A) Representative LSNA, SSNA, and ABP responses to PVN microinjection of aCSF (left), TNF-α alone (center), and minocycline followed by TNF-α (right). (B) Corresponding summary data. Note that minocycline significantly blunted the sympathoexcitatory responses to TNF-α. *P<0.05 vs. aCSF. (C) Representative LSNA, SSNA, and ABP responses to PVN microinjection of minocycline alone in an NT (left) and an HT (right) rat. (D) Corresponding summary data. *P<0.05 vs. NT, #P<0.05 vs baseline.

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