Angiotensin II receptor activation in youth triggers persistent insulin resistance and hypertension—a legacy effect?

Abstract

Although the involvement of angiotensin II (Ang II) in insulin resistance and hypertension has been established, the temporal relationships between Ang II receptor activation and changes in insulin sensitivity and blood pressure are not clear. To better understand this issue, we infused rats with Ang II (200 ng kg À1 min À1 ) or vehicle for 4 weeks and assessed the residual effects after the discontinuation of the infusion on blood pressure, insulin sensitivity and tissue parameters of inflammation. Four weeks after the discontinuation of the Ang II infusion, the blood pressure was higher by 12.8 mm Hg, and insulin sensitivity as determined by a euglycemic hyperinsulinemic glucose clamp was reduced (glucose infusion rate: 11.1 ± 0.7 vs. 17.6±0.5 mg kg À1 min À1 ) in the Ang II-treated group compared with controls. The persistent hypertension and insulin resistance were associated with greater than two-fold increases in macrophage chemoattractant protein-1, tumor necrosis factor-a and thiobarbituric acid-reactive substrates in the soleus muscle. Furthermore, total and activated forms of Rac-1, a regulatory subunit of the NADPH oxidase complex, were increased by 144 ± 14% and 277 ± 82%, respectively, in the skeletal muscle of Ang II-treated rats. These residual effects after Ang II infusion were all attenuated by the co-administration of tempol, a free radical scavenger, or candesartan with Ang II. The effects of candesartan were not mimicked by hydralazine at an equidepressant dose. These findings suggest that Ang II receptor activation in youth triggers the upregulation of inflammatory cytokines and the production of reactive oxygen species, thereby inducing later insulin resistance and hypertension. INTRODUCTIONEvidence from patients and animal models has indicated that the angiotensin II (Ang II) type 1 receptor (AT 1 receptor) has a major role in the development of insulin resistance and hypertension. 1-4 However, the relationship between timing of the AT 1 receptor activation and the development (and persistence) of changes in insulin sensitivity and blood pressure has not been fully elucidated. Interestingly, the Trial of Preventing Hypertension Study showed that the treatment of prehypertensive patients with the AT 1 receptor blocker (ARB) candesartan for 2 years significantly delayed the progression from pre-hypertension to stage 1 hypertension during the following 2 years. 5 This finding suggests long-lasting effects of transitory activation of the AT 1 receptor in the development of hypertension. The results of the Trial of Preventing Hypertension Study bear certain similarities to those of a study by Holman et al. 6 (United Kingdom Prospective Diabetes Study), indicating the so-called 'legacy effect' . These authors found that the reduction of microvascular events continued for 10 years, in spite of the loss of differences in glycemic control after 10 years of intensive glycemic control had been discontinued. Furthermore, such 'legacy

Apelin/APJ system: a promising therapy target for hypertension

“…(2) IR broke the balance between NO and ET-1 by impairing PI3K-dependent signaling to induce endothelial dysfunction, present serum NO decreased, ET levels over-expressed, also thickened the vessel wall and narrowed arteriolar lumen, demonstrated that IR could impaired NO dependent vasodilation and enhanced the effect of ET on vascular contraction [69]. (3) IR-induced hypertension may be associated with Ang-II as well, upregulates AT1 receptor to aggravate the adverse effect of Ang-II on the cardiovascular system, also increases the production of oxygen free and radical inflammatory cytokiness in endothelial cells, which may be involved in activation of the nuclear factor kappa B (NF kappa B) inflammatory pathway, ultimately causing hypertension and endothelial dysfunction [70]. (4) Insulin acts on almost all nephron segments' sodium transport and it is a strong enhancer of sodium reabsorption, yet hyperinsulinemia may induce the renal sodium reabsorption then lead to vascular resistance and BP increased [71].…”

Legacy in Cardiovascular Risk Factors Control: From Theory to Future Therapeutic Strategies?

“…A month after the end of infusion of a hypertensive dose of Ang II, blood pressure remained higher and insulin sensitivity was decreased in previously treated rats compared to saline-infused controls. These residual effects were attenuated by the co-administration of tempol, a free radical scavenger, or of candesartan together with Ang II during the infusion period, and the effects of candesartan were not mimicked by hydralazine at a dose producing a similar decrease in blood pressure; the data suggested a link with oxidative stress and an Ang II receptor specificity for this effect [ 76 ]. In another study on mice, a sustained vascular and heart injury was observed up to 1 week after withdrawal of an initial Ang II infusion with persistent activation of multiple signaling pathways (JNK1/2, STAT3, and NF-κB) and an increase in ROS production; as the sustained effect was attenuated with apocynin, a NOX inhibitor, the data suggested a link with persistent NADPH oxidase activation.…”

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“…In hypertension models, the overproduction of ROS by NADPH oxidase upregulation due to renin-angiotensin system activation appeared to persist after cessation of the hypertensive period and was related to deleterious effects. Otherwise, the intensive blocking of the renin-angiotensin system showed a long-term reduction in the overproduction of ROS [14]. thrombogenic reactions via interaction with their receptors (RAGEs), which promote endothelial dysfunction and atherosclerosis [5,15,16].…”