Journal
HYPERTENSION
Volume 67, Issue 1, Pages 163-170Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/HYPERTENSIONAHA.115.06263
Keywords
angiotensin II; blood pressure; high-fat diet; proinflammatory cytokine; sensitization
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Funding
- National Institutes of Health (NIH) [HL-14388, HL-98207, MH-80241, HL-096671, HL-073986]
- Department of Veterans Affairs
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL096671, R01HL073986, R01HL098207, P01HL014388] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [R01MH080241] Funding Source: NIH RePORTER
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Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor- synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor- mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines.
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