de la Cruz-Lynch Arthur, Dailey-Krempel Brianna, Dayton Alex, Nguyen Duc T, Tyshynsky Roman, Van Helden Dusty, Lahti Matthew, Carney John, Evans Louise, Vulchanova Lucy, Osborn John
Department of Surgery, University of Minnesota, Minneapolis, MN, 55455, USA.
Department of Integrative Biology & Physiology, University of Minnesota, Minneapolis, MN, 55455, USA.
Cardiovasc Eng Technol. 2025 May 6. doi: 10.1007/s13239-025-00786-x.
Catheter-based total renal denervation (TRDN) has recently gained FDA approval to lower blood pressure in patients with treatment-resistant hypertension. Current TRDN technologies indiscriminately destroy efferent (sympathetic) and afferent (sensory) renal nerves. However, preclinical studies suggest that the beneficial effects of TRDN may be due to ablation of afferent, rather than efferent, renal nerves. We developed a novel method for chemical ablation of afferent renal nerves by periaxonal application of capsaicin which has been employed in mouse and rat models of hypertension. In certain rodent models afferent-specific renal denervation (ARDN) has been shown to lower arterial pressure to the same degree as TRDN. The objective of the present study was to develop a catheter-based method for ARDN in a large animal model with the long-term goal of translating this treatment to humans. We tested the feasibility of using the Peregrine™ catheter infusion system, currently used to perform TRDN in humans by injection of ethanol, to perform catheter-based afferent renal denervation in sheep by periaxonal application of capsaicin.
Castrated, adult, male, Friesen sheep underwent Sham RDN (saline, n = 2), TRDN (ethanol, n = 4), or ARDN (capsaicin, n = 4) with the Peregrine™ catheter before termination > 2 weeks after the procedure. Denervation of renal efferents was verified by measurement of renal cortical norepinephrine (NE) content and anti-tyrosine hydroxylase (TH) staining; denervation of renal afferents was verified with anti-calcitonin gene-related peptide (CGRP) staining.
There was a significant decrease in TH + and CGRP + fibers in TRDN kidneys and in CGRP + but not TH + fibers in ARDN kidneys. TRDN significantly reduced renal cortical norepinephrine (NE) content by 89% while ARDN had similar NE content to Sham RDN kidneys.
This study establishes the feasibility of performing catheter-based afferent renal denervation in a large animal model. Furthermore, this study provides a translational model to evaluate catheter-based ARDN as a potential treatment for hypertension.
基于导管的全肾去神经支配术（TRDN）最近已获得美国食品药品监督管理局（FDA）批准，用于降低顽固性高血压患者的血压。目前的TRDN技术会不加区分地破坏传出（交感）和传入（感觉）肾神经。然而，临床前研究表明，TRDN的有益效果可能归因于传入肾神经而非传出肾神经的消融。我们开发了一种通过轴周应用辣椒素来化学消融传入肾神经的新方法，该方法已应用于高血压小鼠和大鼠模型。在某些啮齿动物模型中，传入特异性肾去神经支配术（ARDN）已被证明能将动脉血压降低到与TRDN相同的程度。本研究的目的是在大型动物模型中开发一种基于导管的ARDN方法，其长期目标是将这种治疗方法应用于人类。我们测试了使用目前通过注射乙醇在人类中进行TRDN的Peregrine™导管输注系统，通过轴周应用辣椒素来在绵羊中进行基于导管的传入肾去神经支配术的可行性。
在手术后>2周处死前，对去势的成年雄性弗里斯兰绵羊进行假RDN（生理盐水，n = 2）、TRDN（乙醇，n = 4）或ARDN（辣椒素，n = 4），使用Peregrine™导管。通过测量肾皮质去甲肾上腺素（NE）含量和抗酪氨酸羟化酶（TH）染色来验证肾传出神经的去神经支配；通过抗降钙素基因相关肽（CGRP）染色来验证肾传入神经的去神经支配。
TRDN肾脏中TH +和CGRP +纤维显著减少，而ARDN肾脏中CGRP +纤维减少，但TH +纤维未减少。TRDN使肾皮质去甲肾上腺素（NE）含量显著降低89%，而ARDN的NE含量与假RDN肾脏相似。
本研究确立了在大型动物模型中进行基于导管的传入肾去神经支配术的可行性。此外，本研究提供了一个转化模型，以评估基于导管的ARDN作为高血压潜在治疗方法的效果。
