Nitric oxide mediated the effects of nebivolol in cardiorenal syndrome

Document Type : Original Article


1 University of Health Sciences, Faculty of Pharmacy, Department of Pharmacology, Istanbul-Turkey

2 Istanbul University, Istanbul Medical Faculty, Department of Pathology, Istanbul-Turkey


Objective(s): Despite several proposed mechanisms for the pathophysiology of cardiorenal syndrome (CRS), the exact mechanism remains unclear. Nitrosative stress has been argued as a key mechanism recently. Nebivolol is a beta-blocker with nitric oxide (NO)-releasing effect. In the present study, NO-mediated effects of two different treatment regimes of nebivolol in CRS were studied.
Materials and Methods: Rats were divided into: sham-operated (sham-control), myocardial infarction (MI)-induced, (MI-control) early nebivolol-treated (MI-neb1) and late nebivolol-treated (Mı-neb2) groups. The effects of nebivolol were assessed both in the early and late period of MI by histologic, hemodynamic and biologic studies.
Results: Developed MI model was in line with the heart failure with preserved ejection fraction. Focal and total tubular damage findings were observed in MI-control group both in early and late period of MI. In parallel, subclinical functional damage was transformed into chronic renal dysfunction in this group.  Increased inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) together with decreased neuronal NOS (nNOS) levels were in parallel with the increased inflammation and nitrosative stress biomarkers. Nebivolol effectively prevented both subclinical and clinical nephropathy. There was no statistical difference between the nebivolol treatment regimes.
Conclusion: The beneficial effects of nebivolol were closely related to the reduction of nitrosative damages as well as hemodynamic alterations. The NO-mediated effects were: prevention of nitrosative damage by decreasing iNOS, preservation of nNOS in order to maintain glomerular filtration rate (GFR), and restoration of eNOS in the late period of MI. On contrary to our previous work, early nebivolol administration had a similar effect with delayed administration of nebivolol on CRS.


Main Subjects

1. Bight R. Cases and observations illustrative of renal disease accompanied by the secretion of albuminous urine. Guys Hosp Rep II 1836; 1: 338-400.
2. Ronco C, Cruz DN, Ronco F. Cardiorenal syndromes. Curr Opin Crit Care 2009; 15: 384–391.
3. Fabbian F, Pala M, De Giorgi AD, Scalone A, Molino C, Portaluppi F et al. Clinical features of cardio-renal syndrome in a cohort of consecutive patients admitted to an internal medicine ward. Open Cardiovasc Med J 2011; 5: 220–225.  

4. Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA et al. Transient nitric oxide reduction induces permanent cardiac systolic dysfunction and worsens kidney damage in rats with chronic kidney disease. IS J Physiol Regul Integr Comp Physiol 2010; 298: 815-823.
5. Sumayao RJ, Newsholme P, McMorrow T. Inducible nitric oxide synthase inhibitör 1400W increases Na+, K+-ATPase levels and activity and ameliorates mitochondrial dysfunction in Ctns null kidney proximal tubular epithelial cells. Clin Exp Pharmacol Physiol 2018; 45:1149-1160.
6. Mercanoğlu G, Güngör M, Safran N, Uzun H, Sezgin C, Mercanoğlu F, et al. The effects of nebivolol on cardiomyocyte apoptosis after myocardial infarction in rats. Circulation J 2008; 72:660-670. 

7. Fraccarollo D, Hu K, Galuppo P, Gaudron P, Ertl G. Chronic endothelin receptor blockade attenuates progressive ventricular dilation and improves cardiac function in rats with myocardial infarction: possible involvement of myocardial endothelin system in ventricular remodeling. Circulation 1997; 96:3963-3973.
8. Sutton JM, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR. et al. Quantitavive two- dimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction: the perotective effects of captopril. Circulation 1999; 89:68-75.
9. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ et al. American Society of Echocardiography Recommendations for Use of Echocardiography in Clinical Trials A Report from the American Society of Echocardiography’s Guidelines and Standards Committee and The Task Force on Echocardiography in Clinical Trials. J Am Soc Echocardiogr 2004; 17:1086-1119.
10. Bolukbas C, Bolukbas FF, Horoz M, Aslan M, Celik H, Erel O. Increased oxidative stress associated with the severity of the liver disease in various forms of hepatitis B virus infection. BMC Infect Dis 2005; 5:95.
11. Lowry OH, Rosebrough NJ, Farr ACC, Randall Ri. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193: 265-266.  

12. Chatterjee PK, Cuzzocrea S, Brown PA, Zacharowski K, Stewart KN, Mota FH. et al. Tempol, a membrane- permeable radical scavenger, reduces oxidant stress-mediated renal dysfunction and injury in the rat. Kidney Int 2000; 58:658-673.
13. Kingma JG, Simard D, Rouleau JR, Drolet B, Simard C.  The physiopathology of cardiorenal syndrome: a review of the potential contributions of inflammation. J Cardiovasc Dev Dis 2017; 4:21.  
14. Napoli C, Casamassimi A, Crudele V, Infante T, Abbondanza C. Kidney and heart interactions during cardiorenal syndrome: A molecular and clinical pathogenic framework. Future Cardiol 2011; 7: 485–497.
15. Adams KFJ, Fonarow GC, Emerman CL, Lejemtel TH, Abraham WT, Berkowitz RL et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005; 149:209-216.
16. Reddy YNV, Carter RE, Obokata M, Redfield MM, Borlaug BA. A simple, evidence-based approach to help guide diagnosis of heart failure with preserved ejection fraction. Circulation 2018; 138:861-870.
17. Molcan L, Vesela A, Zeman M. Radiotelemetry measurement of heart rate, blood pressure and locomotory activity of rats in physiological experiment. Slovak J Anim Sci 2009; 42:63-66.
18. Cho EK, Ko M, Lee YS, Song HYM, Kim MG, Kim HK et al. Role of inflammation in the pathogenesis of cardiorenal syndrome in a rat myocardial infarction model. Nephrol Dial Transplant 2013; 28: 2766–2778.
19. Kastner PR, Hall JE, Guyton AC. Renal hemodynamic responses to increased renal venous pressure: role of angiotensin II. Am J Physiol 1982; 43:260-264.
20. Damman K, Navis G, Smilde TD, Voors AA, Bij W, Veldhuisen DJ et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872-878.
21. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam, B. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 2005; 26:11–17.
22. Dong Z, Gong K, Huang D, Zhu W, Sun W, Zhang Y et al. Myocardial infarction accelerates glomerular injury and microalbuminuria in diabetic rats via local hemodynamic and immunity. Int J Cardiol  2015; 179: 397–408.
23. Nijst, P, Mullens, W. The acute cardiorenal syndrome: burden and mechanisms of disease. Curr Heart Fail Rep 2014; 11:453–462.
24. Ross EA. Congestive renal failure: the pathophysiology and treatment of renal venous hypertension. J Cardiac Failure 2012; 18:930–938.
25. Cops J, Mullens W, Verrbrugge FH, Swennen Q, Moor BD, Reynders C et al. Selective abdominal venous congestion induces adverse renal and hepatic morphological and functional alterations despite a preserved cardiac function. Scientific Reports 2018; 8:17757.
26. Fattah H, Vallon V. Tubuler recovery after acute kidney injury. Nephron 2018; 140:140-143.
27. Molitoris BA. Therapeutic translation in acute kidney injury: the epithelial/endothelial axis. J Clin Invest 2014; 124:2355-2363.  

28. Zuk A, Bonventre JV. Acute kidney injury. Annu Rev Med 2016; 67:293–307.  

29. Venkatachalam MA, Weinberg JM, Kriz W, Bidani AK: Failed tubule recovery, AKI-CKD transition, and kidney disease progression. J Am Soc Nephrol 2015; 26:1765–1776. 

30. Schumann BA, Schmitz J, Scheffner I, Schmitt R, Broecker V, Haller H et al. Distinct morphological features of acute tubular injury in renal allografts correlate with clinical outcome. Am J Physiol Renal Physiol 2018; 315:701-710.
31. Virzı  GM, Clementi A, Cal M, Brocca A, Day S, Pastori S et al. Oxidative stress: dual pathway induction in cardiorenal syndrome type 1 pathogenesis. Oxidative Medicine and Cellular Longevity 2015; 1-9.
32. Vicente AG, Garvin JL. Effects of reactive oxygen species on tubular transport along the nephron. Antioxidants 2017; 6:2-15.
33. Eitle E, Hiranyachattada S, Wang H, Harris PJ. Inhibition of proximal tubular fluid absorption by nitric oxide and atrial natriuretic peptide in rat kidney. Am J Physiol 1998; 274: 175-180. 

34. Wang T. Nitric oxide regulates HCO3 and Na+ transport by a cGMP-mediated mechanism in the kidney proximal tubule. Am J Physiol 1997; 272: 242–248.
35. Guzman NJ, Fang, MZ, Tang SS, Ingelfinger JR, Garg LC. Autocrine inhibition of Na+/K(+)-ATPase by nitric oxide in mouse proximal tubule epithelial cells. J Clin Investig 1995; 95: 2083-2088.
36. Vallon V, Traynor T, Barajas L, Huang YG, Briggs JP, Schnermann J. Feedback control of glomerular vascular tone in neuronal nitric oxide synthase knockout mice. J Am Soc Nephron 2001; 12:1599-1606.
37. Ichihara A, Hayashi M, Hirota N, Saruta T. Superoxide inhibits neuronal nitric oxide synthase influences on afferent arterioles in spontaneously hypertensive rats. Hypertension 2001; 37:630-634.
38. Virzı GM, Day S, Cal M, Vescovo G, Ronco C. Heart-kidney crosstalk and role of humoral signalling in critical illness.  Critical Care 2014; 18: 201. 

39. Li PL, Zhang Y. Crosstalk between ceramide and redox signalling: Implications for endothelial dysfunction and renal disease.  Handbook of Experimental Pharmacology 2013; 216:171-197.
40. Mandavia CH, Aroor AR, Demarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes.  Life Sciences 2013; 92:601-608.
41. Maack C, Bohm M. Targeting mitochondrial oxidative stress in heart failure: throttling the afterburner. J Am Coll Cardiol 2011; 58:83-86. 

42. Quoilin C, Mickalad AM, Lecart S, Aupart MPF, Hoebeke M. Evidence of oxidavite stresds and mitocondrial respiratory chain dysfunction in an in vitro model of sepsis induced kidney injury. Biochimica et Biophysica Acta 2014; 1837:1790-1800.
43. Brandes P. Triggering mitochondrial radical release: a new function for NADPH oxidases. Hypertension 2005; 45:847-848.
44. Halliwell B, Gutteridge J. Free Radicals in Biology and Medicine, Oxford University Press, New York, 1999.
45. Schnermann J, Wahl M, Liebau G, Fischbach H. Balance between tubular flow rate and net fluid reabsorption in the proximal convolution of the rat kidney: I. Dependency of reabsorptive net fluid flux upon proximal tubular surface area at spontaneous variations of filtration rate. Pflügers Arch 1968; 304:90-103.
46. Du Z, Yan Q, Duan Y, Weinbaum S, Weinstein AM, Wang T. Axial flow modulates proximal tubule NHE3 and H-ATPase activities by changing microvillus bending moments. Am J Physiol Renal Physiol 2006; 290:289-296.
47. Wang T. Flow-activated transport events along the nephron. Curr Opin Nephrol Hypertens 2006; 15:530-536.
48. Han KH, Lim JM, Kim WY, Kim H, Madsen KM, Kim J. Expression of endothelial nitric oxide synthase in developing rat kidney American Journal of Physiology-Renal Physiology 2005; 288:694-702.
49. Tojo A, Welch WJ, Bremer V, Kimoto M, Kimura K, Omata M, et al. Colocalization of demethylating enzymes and NOS and functional effects of methylarginines in rat kidney. Kidney Int 1997; 52: 1593-1601.
50. Mercanoglu G, Önder SY, Macit C, Mercanoglu F.  The effect of nebivolol on acute renal injury developed after myocardial ischemia: A preclinical study Med Bull Haseki 2018; 56:228-234.
51. Malinski T. Understanding nitric oxide physiology in the heart: a nanomedical approach. Am J Cardiol 2005; 76: 13-24.
52. Mercanoğlu GO, Pamukçu B, Safran N, Mercanoğlu F, Fici F, Güngör M. Nebivolol prevents remodeling in a rat myocardial infarction model: an echocardiographic study. Anatol J Cardiol  2010; 10:18-27.