Blunted sympathoinhibitory responses in obesity‐related hypertension are due to aberrant central but not peripheral signalling mechanisms

• Published in: The Journal of physiology Vol. 592; no. 7; pp. 1705 - 1720
• Main Authors: How, Jackie M. Y., Wardak, Suhail A., Ameer, Shaik I., Davey, Rachel A., Sartor, Daniela M.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.04.2014; BlackWell publishing Ltd
• Subjects: Animals; Arterial Pressure; Baroreflex; Cholecystokinin - pharmacology; Disease Models, Animal; Hypertension - etiology; Hypertension - metabolism; Hypertension - physiopathology; Male; Medulla Oblongata - drug effects; Medulla Oblongata - metabolism; Medulla Oblongata - physiopathology; Neural Inhibition - drug effects; Neuroscience: Neurobiology of Disease; Nodose Ganglion - metabolism; Nodose Ganglion - physiopathology; Obesity - complications; Obesity - metabolism; Obesity - physiopathology; Proto-Oncogene Proteins c-fos - metabolism; Rats, Sprague-Dawley; Receptor, Cholecystokinin A - genetics; Receptor, Cholecystokinin A - metabolism; Signal Transduction; Sympathetic Nervous System - drug effects; Sympathetic Nervous System - metabolism; Sympathetic Nervous System - physiopathology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2013.269670

Key points Using a diet‐induced obese rat model, we examined two sympathoinhibitory reflexes: the baroreflex and the reflex induced by the gastrointestinal hormone cholecystokinin (CCK). The change in neuronal discharge of presympathetic vasomotor neurons in the rostroventrolateral medulla (RVLM) to both sympathoinhibitory stimuli was significantly blunted in obesity‐prone (OP) hypertensive animals when compared to obesity‐resistant (OR) animals or controls on a low fat diet, at the single neuronal level. CCK1 receptor expression in the nodose ganglia, and subdiaphragmatic vagal afferent responses to CCK were not significantly different between OP, OR or control animals. OP hypertensive animals had significantly reduced Fos‐like immunoreactivity in the nucleus of the soliltary tract and the caudal ventrolateral medulla in response to CCK when compared to controls and/or OR animals, indicative of impaired signalling pathways in the brainstem within the reflex circuit between vagal afferents and presympathetic RVLM neurons. Blunted sympathoinhibitory responses in obesity‐related hypertension are associated with blunted responses in RVLM neurons as a result of aberrant central but not peripheral signalling mechanisms. The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular‐controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet‐induced obesity model, male Sprague–Dawley rats exhibited either an obesity‐prone (OP) or obesity‐resistant (OR) phenotype when placed on a medium high fat diet for 13–15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos‐like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity‐related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension.