• I. TUDORANCEA “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania
  • F. MITU “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • A. O. PETRIS “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania
  • D. N. SERBAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania
  • Ionela Lacramioara SERBAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • R. ILIESCU “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • D. PIEPTU “Grigore T. Popa” University of Medicine and Pharmacy Iasi


THE IMPACT OF RENAL DENERVATION ON THE BAROREFLEX CONTROL OF HEART RATE IN AN EXPERIMENTAL MODEL OF REDUCED RENAL MASS, SALT SENSITIVE VOLUME-OVERLOAD HYPERTENSION (Abstract): Background. Beyond lowering arterial blood pressure in hypertensive patients, renal denervation (RDNx) has also been shown to improve the cardiac autonomic nervous system, particularly in sympathetically mediated cardiovascular disorders. Nevertheless, little is known about the efficiency of renal nerve ablation in non-mediated sympathetically diseases. Therefore, our aim was to investigate the influence of renal denervation on the cardiac autonomic nervous system in an experimental rat model of salt sensitive, volume-overload hypertension developed after surgical reduction of renal mass (RRM) by 75-80% and salt loading. Material and methods: The dynamic time-dependent cardiac autonomic system analyses such as the baroreflex sensitivity (BRS), the power of the fluctuations of the heart rate in high frequency range (0.75-3Hz, HF power) and both short and long-term beat-to-beat variability were calculated from continuously recorded cardiac cycles before and after surgical RRM by 80%, including here RDNx and central sympathoinhibition with clonidine. Results: The BRS decreased significantly throughout the entire 2 weeks of the development of salt-sensitive, volume overload hypertension induced after surgical RRM and high salt diet. After RDNx, the HF power decreased during the first 7 days, paralleling the alterations of both long and short-term heart rate variability. Global sympathoinhibition after clonidine administration significantly improved the cardiac autonomic nervous system as reflected by the substantial enhancement of the BRS, the HF power and both short and long-term heart rate variability. Conclusions: The present results indicate that in salt-sensitive, volume overload hypertension, the cardiac autonomic nervous system is impaired, and these alterations are not improved over the long term by RDNx. On contrary, central sympathoinhibition after clonidine administration following RDNx significantly improved BRS, the HF power and both short- and long-term beat-to-beat variability.

Author Biographies

I. TUDORANCEA, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania

Department of Medical Specialties (I)
CHRONEX-RD Biomedical Research Center

F. MITU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Medical Specialties (I)

A. O. PETRIS, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania

Department of Medical Specialties (I)

D. N. SERBAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi, Romania

Department of Morpho-Functional Sciences (II)

Ionela Lacramioara SERBAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-Functional Sciences (II)

R. ILIESCU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

CHRONEX-RD Biomedical Research Center
University of Mississippi Medical Center, Jackson, MS, USA
Department of Physiology & Biophysics
Regional Institute of Oncology Iasi, Romania
TRANSCEND Research Center

D. PIEPTU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Surgery (I)


1. Purves D, Augustine GJ, Fitzpatrick D, Katz LC, LaMantia A-S, McNamara JO, et al. Autonomic Regulation of Cardiovascular Function - Neuroscience - NCBI Bookshelf, 2001.
2. Tank J, Diedrich A, Szczech E, Luft FC, Jordan J. Baroreflex regulation of heart rate and sympathetic vasomotor tone in women and men. Hypertension 2005; 45: 1159-1164.
3. Robinson BF, Epstein SE, Beiser GD, Braunwald E. Control of heart rate by the autonomic nervous system. Studies in man on the interrelation between baroreceptor mechanisms and exercise. Circ Res 966; 19: 400-411.
4. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, et al. Hypertension: physiol-ogy and pathophysiology. Compr Physiol 2012; 2: 2393-2442.
5. Dojki FK, Bakris GL. Blood pressure control and cardiovascular/renal outcomes. Endocrinol Metab Clin North Am 2018; 47:175-184.
6. Oparil S, Acelajado MC, Bakris GL, Berlowitz DR, Cífková R, Dominiczak AF et al. Hypertension. Nat Rev Dis Primers 2018; 4: 18014.
7. Fernandez G, Lee JA, Liu LC, Gassler JP. The baroreflex in hypertension. Curr Hypertens Rep 2015; 17: 19.
8. La Rovere MT, Pinna GD, Raczak G. Baroreflex sensitivity: measurement and clinical implications. Ann Noninvasive Electrocardiol 2008; 13: 191-207.
9. Schwartz PJ, De Ferrari GM. Sympathetic-parasympathetic interaction in health and disease: abnor-malities and relevance in heart failure. Heart Fail Rev 2011; 16: 101-117.
10. Parati G, Di Rienzo M, Mancia G. Heart Fail Rev Dynamic modulation of baroreflex sensitivity in health and disease. Ann N Y Acad Sci 2001; 940: 469-487.
11. Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, et al. Reduced heart rate variability and mortality risk in an elderly cohort. The Framingham Heart Study. Circulation 1994; 90: 878-883.
12. Billman GE. Heart rate variability - a historical perspective. Front Physiol 2011; 2: 86.
13. Tsuji H, Larson MG, Venditti FJ, Manders ES, Evans JC, Feldman CL, et al. Impact of reduced heart rate variability on risk for cardiac events. The Framingham Heart Study. Circulation 1996; 94: 2850-2855.
14. Singh JP, Larson MG, Tsuji H, Evans JC, O’Donnell CJ, Levy D. Reduced heart rate variability and new-onset hypertension: insights into pathogenesis of hypertension: the Framingham Heart Study. Hypertension 1998; 32: 293-297.
15. Reed MJ, Robertson CE, Addison PS. Heart rate variability measurements and the prediction of ven-tricular arrhythmias. QJM. 2005; 98: 87-95.
16. Iliescu R, Tudorancea I, Irwin ED, Lohmeier TE. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol 2013; 305: H1080-1088.
17. Grassi G, Seravalle G, Brambilla G, Pini C, Alimento M, Facchetti R, et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol 2014; 177: 1020-1025.
18. Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circ Res 2014; 114: 1004-1021.
19. Ukena C, Mahfoud F, Spies A, Kindermann I, Linz D, Cremers B, et al. Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension. Int J Cardiol 2013; 167: 2846-2851.
20. Donazzan L, Mahfoud F, Ewen S, Ukena C, Cremers B, Kirsch C-M, et al. Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension. Clin Res Cardiol 2016; 105: 364-371.
21. Iliescu R, Lohmeier TE, Tudorancea I, Laffin L, Bakris GL. Renal denervation for the treatment of resistant hypertension: review and clinical perspective. Am J Physiol Renal Physiol 2015; 309: F583-594.
22. Kannan A, Medina RI, Nagajothi N, Balamuthusamy S. Renal sympathetic nervous system and the effects of denervation on renal arteries. World J Cardiol 2014; 6: 814-823.
23. Seravalle G, Brambilla G, Grassi G. Effects of renal denervation on sympathetic nervous system activity. In: Interventional therapies for secondary and essential hypertension. Tsioufis C, Schmieder RE, Mancia G (editors). Cham: Springer International Publishing; 2016, 303-319.
24. Hildebrandt DA, Irwin ED, Lohmeier TE. Prolonged Baroreflex Activation Abolishes Salt-Induced Hypertension After Reductions in Kidney Mass Novelty and Significance. Hypertension 2016; 68: 1400-1406.
25. Tudorancea I, Lohmeier TE, Alexander BT, Pieptu D, Serban DN, Iliescu R. Reduced Renal Mass, Salt-Sensitive Hypertension Is Resistant to Renal Denervation. Front Physiol 2018; 9: 455.
26. Himmel F, Weil J, Reppel M, Mortensen K, Franzen K, Ansgar L, et al. Improved heart rate dynamics in patients undergoing percutaneous renal denervation. J Clin Hypertension 2012; 14: 654-655.
27. Remo BF, Preminger M, Bradfield J, Mittal S, Boyle N, Gupta A, et al. Safety and efficacy of renal denervation as a novel treatment of ventricular tachycardia storm in patients with cardiomyopathy. Heart Rhythm 2014; 11: 541-546.
28. Schirmer SH, Sayed MMYA, Reil J-C, Ukena C, Linz D, Kindermann M, et al. Improvements in left ventricular hypertrophy and diastolic function following renal denervation: effects beyond blood pressure and heart rate reduction. J Am Coll Cardiol 2014; 63: 1916-1923.
29. Schlaich MP, Hering D, Sobotka PA, Krum H, Esler MD. Renal denervation in human hypertension: mechanisms, current findings, and future prospects. Curr Hypertens Rep 2012; 14: 247-253.
30. Iliescu R, Cazan R, McLemore GR, Venegas-Pont M, Ryan MJ. Renal blood flow and dynamic auto-regulation in conscious mice. Am J Physiol Renal Physiol. 2008; 295: F734-740.
31. Lohmeier TE, Iliescu R, Dwyer TM, Irwin ED, Cates AW, Rossing MA. Sustained suppression of sympathetic activity and arterial pressure during chronic activation of the carotid baroreflex. Am J Physiol Heart Circ Physiol 2010; 299: H402-409.
32. Özaykan B, Taskin E, Magemizoğlu A. Effect of salt loading on baroreflex sensitivity in reduced renal mass hypertension. Clin Exp Hypertens 2017; 39: 592-600.
33. Gao SA, Johansson M, Rundqvist B, Lambert G, Jensen G, Friberg P. Reduced spontaneous barore-ceptor sensitivity in patients with renovascular hypertension. J Hypertens 2002; 20: 111-116.
34. Pliquett RU, Benkhoff S, Jung O, Brandes RP. Sympathoactivation and rho-kinase-dependent barore-flex function in experimental renovascular hypertension with reduced kidney mass. BMC Physiol 2014; 14 :4.
35. Oliveira-Sales EB, Toward MA, Campos RR, Paton JFR. Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats. Auton Neurosci. 2014; 183: 23-29.
36. Spinelli L, Petretta M, Marciano F, Testa G, Rao MA, Volpe M, et al. Cardiac autonomic responses to volume overload in normal subjects and in patients with dilated cardiomyopathy. Am J Physiol 1999; 277(4 Pt 2): H1361-1368.
37. Creager MA, Roddy MA, Holland KM, Hirsch AT, Dzau VJ. Sodium depresses arterial baroreceptor reflex function in normotensive humans. Hypertension 1991;17(6 Pt 2): 989-996.
38. Miyajima E, Buñag RD. Dietary salt loading produces baroreflex impairment and mild hypertension in rats. Am J Physiol 1985; 249(2 Pt 2): H278-284.
39. Weinstock M, Schorer-Apelbaum D. Impaired baroreflex sensitivity in the etiology of salt hypertension in the rabbit. Clin Sci. 1985; 68: 489-493.
40. Diamond J, Gray JA, Inman DR. The relation between receptor potentials and the concentration of sodium ions. J Physiol (Lond). 1958; 142: 382-394.
41. Kunze DL, Saum WR, Brown AM. Sodium sensitivity of baroreceptors mediates reflex changes of blood pressure and urine flow. Nature 1977; 267: 75-78.
42. Saum WR, Ayachi S, Brown AM. Actions of sodium and potassium ions on baroreceptors of normo-tensive and spontaneously hypertensive rats. Circ Res 1977; 41: 768-774.
43. Simmonds SS, Lay J, Stocker SD. Dietary salt intake exaggerates sympathetic reflexes and increases blood pressure variability in normotensive rats. Hypertension 2014; 64: 583-589.
44. Adams JM, McCarthy JJ, Stocker SD. Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla. Hypertension 2008; 52: 932-937.
45. Adams JM, Bardgett ME, Stocker SD. Ventral lamina terminalis mediates enhanced cardiovascular responses of rostral ventrolateral medulla neurons during increased dietary salt. Hypertension 2009; 54: 308-314.
46. Adams JM, Madden CJ, Sved AF, Stocker SD. Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses from the rostral ventrolateral medulla. Hypertension 2007; 50: 354-359.
47. Yu L, Huang B, Wang Z, Wang S, Wang M, Li X, et al. Impacts of renal sympathetic activation on atrial fibrillation: the potential role of the autonomic cross talk between kidney and heart. J Am Heart Assoc. 2017; 6(3): e004716.
48. Yamada S, Lo L-W, Chou Y-H, Lin W-L, Chang S-L, Lin Y-J, et al. Beneficial effect of renal dener-vation on ventricular premature complex induced cardiomyopathy. J Am Heart Assoc. 2017; 6(3): pii: e004479.
49. Ukena C, Mahfoud F, Ewen S, Bollmann A, Hindricks G, Hoffmann BA, et al. Renal denervation for treatment of ventricular arrhythmias: data from an International Multicenter Registry. Clin Res Cardiol 2016; 105: 873-879.
50. Hoogerwaard AF, Elvan A. Novel insights into the mechanisms of renal sympathetic denervation-induced neuromodulation in controlling atrial arrhythmias in canines. Heart Rhythm. 2017; 14: 263-264.
51. Huang B, Yu L, He B, Lu Z, Wang S, He W, et al. Renal sympathetic denervation modulates ventric-ular electrophysiology and has a protective effect on ischemia-induced ventricular arrhythmia. Exp Physiol 2014; 99: 1467-1477.
52. Sleight P, West MJ, Korner PI, Oliver JR, Chalmers JP, Robinson JL. The action of clonidine on the baroreflex control of heart rate in conscious animals and man, and on single aortic baroreceptor dis-charge in the rabbit. Arch Int Pharmacodyn Ther 1975; 214: 4-11.
53. Tank J, Jordan J, Diedrich A, Obst M, Plehm R, Luft FC, et al. Clonidine improves spontaneous baroreflex sensitivity in conscious mice through parasympathetic activation. Hypertension 2004; 43: 1042-1047.