| Background Hypertension is a major risk factor for various cardiovascular diseases, such as atherosclerosis, myocardial infarction, stroke and heart failure. A comprehensive meta-analysis shows that aerobic endurance training significantly reduces blood pressure in hypertensive participants. However, the mechanisms involved in blood pressure lowering effects of physical exercise are still largely unknown. Accumulating studies have demonstrated that vascular insulin resistance is a common pathophysiological change observed in hypertension as well as many other diabetic cardiovascular diseases. Vascular insulin resistance, characterized by impaired insulin-stimulated production of endothelial-derived vasodilator nitric oxide(NO) or/and enhanced insulin-stimulated production of the vasoconstrictor endothelin-1(ET-1),contributes to elevated peripheral vascular resistance and subsequent hypertension. Lifestyle modi?cations or drug interventions that can improve vascular insulin sensitivity would benefit the prevention and treatment of hypertension. Insulin resistance is associated with altered balance of the parasympathetic and sympathetic nervous activity, especially attenuated parasympathetic activity. Recently, the reduced parasympathetic tone throws a new light on the study of hypertension. Suppression of parasympathetic tone and resultant impairment of cholinergic anti-inflammatory pathway, namely α7 nicotinic acetylcholine receptor(α7n ACh R)-mediated activation of the janus kinase 2(Jak2)/signal transducer and activator of transcription 3(STAT3) pathway contributes to runaway cytokine-mediated inflammation in hypertension. Experimental studies and clinical observations have demonstrated that exercise is effective to improve cardiovascular autonomic dysfunction by reducing sympathetic activity and/or enhancing parasympathetic activity. However, the role of cholinergic anti-inflammatory pathway in exercise-induced blood pressure-lowering effects in hypertension has not been previously reported.Aims This study was aimed to 1) investigate whether exercise may improve cholinergic anti-inflammatory pathway in resistance vessels in hypertension and 2) assess the effect of such alteration on vascular insulin resistance and blood pressure.Methods 1. Male SHRs and Wistar-Kyoto(WKY) rats at 8 weeks of age were subjected to an eight-week free-of-loading swim training session(1 hour/day, 5 days/week, n=8). 2. From 8 weeks of age, SHRs and WKY rats in the PNU-282987 treatment groups were treated daily for 4 weeks by peritoneal injection with PNU-282987(0.50 mg/kg/day), while rats in the vehicle treatment groups were given saline alone(n=8). 3. Blood pressure was measured noninvasively with a tail-cuff system every two weeks.4. The vasodilator response to insulin of mesenteric arterioles was measured using a myograph. 5. The expression and phosphorylation of proteins in insulin signaling and cholinergic anti-inflammatory pathways were measured by western blot analysis. 6. The levels of TNF-α and IL-1β in serum and tissues were measured with commercial ELISA kits. 7. The in situ production of ROS in mesenteric arterioles was measured by dihydroethidium(DHE).Results 1. Exercise training reduced blood pressure(190±3 mm Hg vs. 212±4 mm Hg, P<0.05,n=8) and increased systemic insulin sensitivity(P<0.05, n=8) in SHRs. 2. Exercise training improved insulin-induced vasorelaxation of mesenteric arterioles(P<0.05, n=8)and increased insulin-evoked phosphorylation of both Akt(Ser473) and e NOS(Ser1177) in mesenteric arterioles(P<0.01, n=8) in SHRs. 3. Exercise training decreased TNF-α and IL-1β levels in the serum, mesenteric arterioles and heart in SHRs(P<0.05, n=8). 4. Exercise training improved expression of VACh T, α7n ACh R and phosphorylation of Jak2 in mesenteric arterioles and heart of SHRs(P<0.05, n=8). 5. PNU-282987, a selective a7 n ACh R agonist, decreased TNF-α and IL-1β levels in the serum and mesenteric arterioles in SHRs(P<0.05, n=8). 6. PNU-282987 reduced blood pressure(173±4 mm Hg vs. 191±5 mm Hg, P<0.05, n=8) and enhanced systemic insulin sensitivity(P<0.05, n=8) in SHRs. 7. PNU-282987 improved insulin-induced vasorelaxation of mesenteric arterioles and increased insulin-evoked phosphorylation of both Akt(Ser473) and e NOS(Ser1177) in mesenteric arterioles in SHRs(P<0.05, n=8). 8. PNU-282987 reduced gp91 phox and SOD2 expression and attenuated ROS production in mesenteric arterioles in SHRs(P<0.05, n=8).Conclusions 1. Aerobic exercise alleviates vascular insulin resistance in resistance vessels, which delays the progression of hypertension. 2. Exercise-induced beneficial effect on vascular insulin sensitivity is partly mediated by activating α7n ACh R-mediated cholinergic anti-inflammatory pathway. |
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