Vascular endothelial function masks increased sympathetic vasopressor activity in rats with metabolic syndrome

Abstract

Sympathetic hyperactivation, a common feature of obesity and metabolic syndrome, is a key trigger of hypertension. However, some obese subjects with autonomic imbalance present a dissociation between sympathetic activity-mediated vasoconstriction and increased blood pressure. Here, we aimed to determine in a rat model of metabolic syndrome whether the endothelium endothelial nitric oxide (NO) synthase (eNOS)-NO pathway contributes to counteract the vasopressor effect of the sympathetic system. Rats were fed a high-fat and high-sucrose (HFS) diet for 15 wk. Sympathovagal balance was evaluated by spectral analysis of heart rate variability and plasmatic catecholamine measurements. Blood pressure was measured in the presence or absence of N-nitro-l-arginine methyl ester (l-NAME) to inhibit the contribution of eNOS. Vascular reactivity was assessed on isolated aortic rings in response to α-adrenergic agonist. The HFS diet increased sympathetic tone, which is characterized by a higher low on the high-frequency spectral power ratio and a higher plasmatic concentration of epinephrine. Despite this, no change in blood pressure was observed. Interestingly, HFS rats exhibited vascular hyporeactivity (-23.6%) to α-adrenergic receptor stimulation that was abolished by endothelial removal or eNOS inhibition (l-NAME). In addition, eNOS phosphorylation (Ser) was increased in response to phenylephrine in HFS rats only. Accordingly, eNOS inhibition in vivo revealed higher blood pressure in HFS rats compared with control rats (147 vs. 126 mmHg for mean blood pressure, respectively). Restrain of adrenergic vasopressor action by endothelium eNOS is increased in HFS rats and contributes to maintained blood pressure in the physiological range. NEW & NOTEWORTHY Despite the fact that prohypertensive sympathetic nervous system activity is markedly increased in rats with early metabolic syndrome, they present with normal blood pressure. These observations appear to be explained by increased endothelial nitric oxide synthase response to adrenergic stimulation, which results in vascular hyporeactivity to α-adrenergic stimulation, and therefore blood pressure is preserved in the physiological range. Listen to this article's corresponding podcast at http://www.physiology.org/doi/10.1152/ajpheart.00217.2017 .

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“…Recent findings suggest that the increase in sympathetic activity is generally known as a pathophysiological mechanism in hypertension [15] and insulin resistance [16,17]. Insulin resistance is broadly observed in patients with visceral obesity, and it was reported to be a common feature in OSA whether or not obesity is associated [18,19,20,21,22,23].…”

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“…This mechanism has been proposed to explain the ‘‘pro-hypertensive’’ effect of insulin in susceptible individuals [ 10 , 11 ], where hypertension could represent the unwanted consequence of a compensatory mechanism recruited in the obese to restore energy balance and limit further weight gain (i.e., IR) ( Figure 2 ). In other words, obese subjects, while resistant to the effects of insulin on peripheral glucose uptake, should not be resistant to the effect of insulin on the SNS, although this is not invariably associated with increased blood pressure due to a counterbalance of vascular compensatory mechanisms [ 12 ]. Obese subjects of the normative aging study were shown to be sensitive to the effects of insulin on sympathetic activity despite resistance to the effects of insulin on glucose uptake and displayed an increased 24-h urinary norepinephrine excretion [ 13 ], the amounts of norepinephrine excreted being related to the degree of obesity [ 14 ].…”