The cholinergic anti-inflammatory pathway in resistant hypertension treated with renal denervation

Abstract

Background Renal denervation (RDN) reduces sympathetic tone and may alter the sympathetic-parasympathetic balance. The autonomic nervous system is partly a regulator of innate immunity via the cholinergic anti-inflammatory pathway (CAP) which inhibits inflammation via the vagus nerve. Placental Growth Factor (PlGF) influences a neuro-immunological pathway in the spleen which may contribute to hypertension. The aim of this study was to investigate if modulation of renal sympathetic nerve activity affects CAP in terms of cytokine release as well as levels of PlGF. Methods Ten patients treated with RDN (Medtronic Inc), were analyzed for TNF, IL-1b and IL-10 and Lipopolysaccharide (LPS)-stimulated cytokine release before RDN, 1 day after and at 3- and 6-months follow-up. Four patients who underwent elective coronary angiography served as disease controls (DC). Results Baseline TNF was significantly lower 1 day after RDN ( p = 0.03). LPS-stimulated (0, 10 and 100 ng/mL) TNF and IL-1b were significantly lower 1 day after RDN (TNF p = 0.0009, p = 0.0009 and p = 0.001, IL-1b; p = 0.0001, p = 0.002 and p = 0.005). IL-10 was significantly higher one day after RDN (p = ns, p = 0.02 and p = 0.01). These differences however declined during follow up. A more marked TNF reduction was achieved with a cholinergic analogue, GTS-21, in LPS-stimulated whole blood as compared with samples without GTS-21. Cytokine levels in controls did not differ before and 1 day after coronary angiography. PlGF was significantly higher in RDN patients and DC compared with healthy controls but did not change during follow-up. Conclusion RDN has an immediate effect on TNF in vivo and cytokine release ex vivo but seems to wane over time suggesting that current RDN techniques may not have long-lasting immunomodulatory effect. Repeated and extended stimulation of CAP in resistant hypertension by targeting neural circuits may be a potential therapeutic strategy for treatment of both hypertension and inflammation. Electronic supplementary material The online version of this article (10.1186/s10020-019-0097-y) contains supplementary material, which is available to authorized users.

Long-term outcomes of renal denervation and related sex characteristics: data from a three-year follow-up

“…Безусловно, в реализации всех вышеописанных эффектов играет роль снижение интенсивности иммуновоспалительных процессов на фоне уменьшения симпатической активности. Наиболее доступным методом оценки интенсивности воспаления является определение циркулирующих про-и противовоспалительных цитокинов, краткосрочная динамика которых после РДН ранее уже описана в литературе [14]. Настоящее исследование впервые демонстрирует сохранение тенденции к снижению провоспалительных маркеров на протяжении трехлетнего периода.…”

Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective

“…[248][249][250] The effect of renal denervation on immune activation in humans is less clear. One trial demonstrated reductions in TNF-α and IL-1 and upregulation of IL-10 one day after RDN, however this did not persist to day three 251 , and was not corroborated elsewhere. 252,253 An alternative approach to sympathetic denervation is augmentation of parasympathetic activity through vagus nerve stimulation (VNS).…”

COVID-19-related myocarditis and cholinergic anti-inflammatory pathways

“…Extending the seminal finding that the CAP inhibits acute inflammation, researchers have assessed the therapeutic potential of VNS and have reported promising therapeutic results for many diseases including sepsis, 29 , 30 , 37 dementia, [38] , [39] , [40] , [41] arthritis, 35 , 36 and cerebro- and cardio-vascular diseases. 81 , 82 Koopman has found that the serum levels of TNF-α, IL-1β, and IL-6 significantly decrease, and the clinical symptoms improve, in patients with rheumatoid arthritis after 3 months of treatment with an implantable VNS device. 83 In patients undergoing off-pump surgical revascularization, the peripheral blood production of TNF-α and IL-6 significantly decreases after 6 hours of VNS treatment.…”