Renal sympathoinhibitory and regional vasodilator responses to cholecystokinin are altered in obesity‐related hypertension

Abstract

New Findings r What is the central question of this study?The renal and splanchnic circulations command >50% of cardiac output postprandially, and the gut hormone cholecystokinin promotes renal and splanchnic sympathoinhibition and regional vasodilatation. Animals fed a high-fat diet have blunted splanchnic sympathoinhibitory responses to cholecystokinin, but the role of gut peptides has not previously been considered in the aetiology of obesity-related hypertension. r What is the main finding and its importance? Obese, hypertensive animals had blunted renal sympathoinhibitory and renal and mesenteric vasodilator responses to cholecystokinin. These changes may impact cardiovascular homeostasis and lead to increased regional vascular resistance after a meal. Future therapies to treat this condition may include drugs that target the gut.The gut and kidney command >50% of cardiac output postprandially, highlighting the importance of these vascular beds in cardiovascular homeostasis. The gastrointestinal peptide cholecystokinin (CCK) induces vagally mediated splanchnic sympathoinhibition that is attenuated in animals fed a medium high-fat diet (MHFD); therefore, our aim was to determine whether renal sympathetic nerve discharge (RSND) responses to CCK are also affected by this diet, and whether these changes are associated with obesity and hypertension. Another aim was to determine whether regional vasodilator responses to CCK are affected in obesityrelated hypertension. In two separate studies, Sprague-Dawley rats were fed either a low-fat diet (LFD; control) or a MHFD for 13 weeks, after which MHFD animals were classified as obesity prone (OP) or obesity resistant (OR) based on their weight gain falling into the upper or lower tertile, respectively. Arterial pressure and heart rate were monitored in isofluraneanaesthetized, artificially ventilated animals, and either RSND or regional vascular responses to CCK (0.1-8 μg kg −1 ) were evaluated. The OP rats had higher baseline arterial pressure compared with control/OR rats (P < 0.05). Administration of CCK inhibited RSND and increased renal vascular conductance in control/OR rats, and these responses were significantly blunted in OP rats (P < 0.05 for all). Baseline arterial pressure was positively correlated with weight gain and inversely correlated with CCK-induced vasodilatation (P < 0.05 for both). We hypothesize that in obesity-related hypertension, disruption of the sympathoinhibitory signals elicited by CCK reduces vasodilatation in the splanchnic/renal regions, leading to increased postprandial vascular resistance.

Development of attenuated baroreflexes in obese Zucker rats coincides with impaired activation of nucleus tractus solitarius

“…However, significant differences in MAP cannot be reliably detected in conscious undisturbed OZR and LZR until 10 wk of age (28), with a clear separation of MAP levels by 12 wk of age (35). In agreement, rats made obese by a high-fat diet develop impaired baroreflexes within 4 wk on the diet (63), prior to the onset of elevated MAP that is present after 13 wk (21,49). Just as animal models of obesity show a separation of baroreflexes and elevated MAP, obese patients can have significantly impaired baroreflexes in the absence of hypertension (18).…”

“…In obese rats, the arterial baroreflex is not the only impaired sympathoinhibitory reflex that occurs by vagal activation of the NTS. Rats made obese by a high-fat diet with impaired arterial baroreflexes also show blunted sympathoinhibitory responses to gastric CCK, a reflex that is initiated by gastric vagal afferents to the NTS (21). Thus, it appears that metabolic syndrome differentially affects the processing of functionally diverse vagal inputs to distinct NTS neurons that regulate autonomic function to cardiovascular targets.…”

Physiology and Pathophysiology of Arterial Flow

“…Cholecystokinin causes a vagus-mediated splanchnic sympathoinhibition, hence a postprandial vasodilation in the splanchnic and renal territories (How et al 2013). It is also involved in the control of multiple functions in the central nervous system, where it acts as a neurotransmitter.…”

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

“…; How et al . ). The subpopulation of RVLM neurons inhibited by CCK is barosensitive and generally fast firing, fast conducting and predominantly non‐catecholaminergic (Sartor & Verberne, ).…”

“…Furthermore, in a model of diet‐induced obesity (DIO), we have also demonstrated that the sympathoinhibitory and vasodilator effects of gastrointestinal (GI) hormones involved in blood pressure regulation are attenuated or abolished in obese, hypertensive Sprague–Dawley rats (How et al . ; ,b; Sartor, ).…”