title: Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-α.
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.
authors: Department of Physiology, MC7756, University of Texas Health Science Center-San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229. bardgett@uthscsa.edu.
authors: Megan E
authors: ME
authors: Bardgett
authors: Walter W
authors: WW
authors: Holbein
authors: Myrna
authors: M
authors: Herrera-Rosales
authors: Glenn M
authors: GM
authors: Toney
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D058785:GABA-A Receptor Agonists; D017673:Sodium Chloride, Dietary; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; D009118:Muscimol
keywords: blood pressure; cytokines; inflammation