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Chronic inhibition of endoplasmic reticulum (ER) stress attenuates cardiovascular but not appetite responses to MC3/4R antagonism in SHR
Author(s) -
Carmo Jussara Marcia,
Silva Alexandre A.,
Wang Zhen,
Hall John E.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.959.3
Subject(s) - medicine , melanocortin , endocrinology , blood pressure , tauroursodeoxycholic acid , antagonist , sympathetic nervous system , antagonism , appetite , endoplasmic reticulum , melanocortin 4 receptor , ventricle , heart rate , spontaneously hypertensive rat , unfolded protein response , chemistry , hormone , receptor , biochemistry
We previously demonstrated that activation of the central nervous system (CNS) melanocortin system plays a key role in modulating sympathetic nerve activity (SNA) and blood pressure (BP) in spontaneous hypertensive rats (SHR). Previous studies also suggest that endoplasmic reticulum (ER) stress may contribute to cardiovascular pathophysiology and hypertension in SHR. However, whether there is a major interaction of ER stress and melanocortin‐4 receptor (MC4R) activation in contributing to hypertension and appetite regulation in SHR is still unknown. In this study we examined the role of ER stress alone or in combination with MC3/4R antagonism in controlling BP and metabolic functions in SHR. Male SHR (n=7) were implanted with BP telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the lateral ventricle at 12 weeks of age. After 10 days of recovery, food intake, BP and heart rate (HR) were measured 24‐hrs/day. After stable baseline measurements for 5 days, tauroursodeoxycholic (TUDCA, 100 mg/kg, IP) was injected daily for 22 consecutive days to inhibit ER stress, which was followed by a 10‐day combined treatment with the MC3/4R antagonist (SHU‐9119, 1 nmol/h, ICV) for 10 days. Chronic ER stress inhibition alone did not alter food intake (16±1 vs. 14±3g), body weight (293±4 vs. 301±4 g), MAP (166±2 vs. 169±3 mmHg) or HR (335±6 vs. 338±2 bpm). Combined treatment with MC3/4R antagonist significantly increased food intake by 120% and body weight by 19%, while reducing BP by 9±2 mmHg and HR by 28±5 bpm when compared to −25 mmHg and −45 bpm with MC3/4R antagonist alone. No changes were observed in blood glucose levels. These results indicate that chronic inhibition of ER stress did not alter appetite, HR or BP, but attenuated BP and HR responses to MC3/4R antagonist in SHR. Support or Funding Information (NHLBI‐PO1HL51971, NIGMS‐P20GM104357 and AHA SDG5680016)