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Additive effects of cilnidipine and angiotensin II receptor blocker in preventing the progression of diabetic nephropathy in diabetic spontaneously hypertensive rats

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Abstract

Background

Cilnidipine (Cil) is an L/N-type calcium channel blocker (CCB) that is known to provide renal protection by decreasing the activity of the sympathetic nervous system and the renin-angiotensin system (RAS). However, very few studies have evaluated the renoprotective effects of Cil in hypertension complicated by diabetes mellitus. In this study, we compared the effects of cilnidipine and the L-type CCB, amlodipine (Aml), in combination with an angiotensin II receptor blocker (ARB) on diabetic nephropathy that developed as a result of inducing diabetes in hypertensive rats.

Methods

Diabetes was induced in 9-week-old male spontaneously hypertensive rats by intraperitoneally injecting them with streptozotocin (40 mg/kg twice) and the rats (8 per group) were randomly assigned to receive valsartan (Val), Cil + Val, Aml + Val, or vehicle for 8 weeks through a gastric tube.

Results

There were no significant differences in systolic blood pressure or plasma parameters between the two combination therapy groups. Blood pressure lowering by neither combination therapy significantly affected the glycemic variables. However, the increased glycogen levels in the kidney as a result of hyperglycemia were significantly suppressed in the groups that received combination therapy, and the increased proteinurea and glomerulosclerosis due to progression of the diabetic nephropathy were significantly suppressed in the Cil + Val group. In addition, a significant decrease in ED-1-positive cells was observed in the Cil + Val group alone.

Conclusion

The results of this study suggested that the L/N-type CCB, cilnidipine, had additive antihypertensive and proteinuria-lowering effects when administered in combination with an ARB, even in type-1 diabetic rats, and that the L-type CCB, amlodipine, did not. Furthermore, combination therapy with cilnidipine and valsartan significantly reduced glycogen accumulation and ED-1-positive cell infiltration, suggesting that cilnidipine suppressed the excessive increase in the activity of the sympathetic nervous system and RAS through N-type calcium channel blockade.

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References

  1. Sundkvist G, Lilja B. Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care. 1993;1993(16):773–9.

    Article  Google Scholar 

  2. Anderson S, Jung FF, Ingelfinger JR. Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations. Am J Physiol Renal Fluid Electrolyte Physiol. 1993;265:F477–86.

    CAS  Google Scholar 

  3. Henry DN, Busik JV, Brosius FC III, Heilig CW. Glucose transporters control gene expression of aldose reductase, PKC, and GLUT1 in mesangial cells in vitro. Am J Physiol Renal Physiol. 1999;277:F97–104.

    CAS  Google Scholar 

  4. Gnudi L, Viberti G., Raij L, Rodriguez V, Burt D, Cortes P, et al. GLUT-1 overexpression: link between hemodynamic and metabolic factors in glomerular injury? Hypertension. 2003; 42:19–24.

  5. Nose A, Mori Y, Uchiyama-Tanaka Y, Kishimoto N, Maruyama K, Matsubara H, et al. Regulation of glucose transporte (GLUT1) gene expression by angiotensin II in mesangial cells: involvement of HB-EGF and EGF receptor transactivation. Hypertens Res. 2003;26:67–73.

    Article  PubMed  CAS  Google Scholar 

  6. Linden KC, DeHaan CL, Zhang Y, Glowacka S, Cox AJ, Kelly DJ, et al. Renal expression and localization of the facilitative glucose transporters GLUT1 and GLUT12 in animal models of hypertension and diabetic nephropathy. Am J Physiol Renal Physiol. 2006;290:F205–13.

    Article  PubMed  CAS  Google Scholar 

  7. D’Agord Schaan B, Lacchini S, Bertoluci MC, Irigoyen MC, Machado UF, Schmid H. Impact of renal denervation on renal content of GLUT1, albuminuria and urinary TGF-beta1 in streptozotocin-induced diabetic rats. Auton Neurosci. 2003; 104: 88–94.

    Google Scholar 

  8. Vora JP, Dolben J, Dean JD, Thomas D, Williams JD, Owens DR, et al. Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int. 1992;41:829–35.

    Article  PubMed  CAS  Google Scholar 

  9. Takahara A. Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release. Cardiovasc Ther. 2009;27:124–39.

    Article  PubMed  CAS  Google Scholar 

  10. Shiga T, Yamada Y, Matsuda N, Tanaka T, Urae A, Hashiguchi M, et al. Influence of cilnidipine or nisoldipine on sympathetic activity in healthy male subjects. Heart Vessels. 2007;22:404–9.

    Article  PubMed  Google Scholar 

  11. Nagahama S, Norimatsu T, Maki T, Yasuda M, Tanaka S. The effect of combination therapy with an L/N-Type Ca(2+) channel blocker, cilnidipine, and an angiotensin II receptor blocker on the blood pressure and heart rate in Japanese hypertensive patients: an observational study conducted in Japan. Hypertens Res. 2007;30:815–22.

    Article  PubMed  CAS  Google Scholar 

  12. Varagic J, Susic D, Frohlich ED. Cilnidipine improves spontaneously hypertensive rat coronary hemodynamics without altering cardiovascular mass and collagen. J Hypertens. 2002;20:317–22.

    Article  PubMed  CAS  Google Scholar 

  13. Sakata K, Yoshida H, Tamekiyo H, Obayashi K, Nawada R, Doi O, et al. Comparative effect of clinidipine and quinapril on left ventricular mass in mild essential hypertension. Drugs Exp Clin Res. 2003; 29:117–23.

    Google Scholar 

  14. Takemori K, Ishida H, Dote K, Yamamoto K, Ito H. Prophylactic effects of an N- and L-type Ca2+ antagonist, cilnidipine, against cardiac hypertrophy and dysfunction in stroke-prone, spontaneously hypertensive rats. Can J Physiol Pharmacol. 2005;83:785–90.

    Article  PubMed  CAS  Google Scholar 

  15. Fujita T, Ando K, Nishimura H, Ideura T, Yasuda G, Isshiki M, et al. Cilnidipine versus Amlodipine Randomised Trial for Evaluation in Renal Desease (CARTER) Study Investigators. Antiproteinuric effect of the calcium channel blocker cilnidipine added to renin-angiotensin inhibition in hypertensive patients with chronic renal disease. Kidney Int. 2007;72:1543–9.

    Article  PubMed  CAS  Google Scholar 

  16. Zhou X, Ono H, Ono Y, Frohlich ED. N- and L-type calcium channel antagonist improves glomerular dynamics, reverses severe nephrosclerosis, and inhibits apoptosis and proliferation in an l-NAME/SHR model. J Hypertens. 2002;20:993–1000.

    Article  PubMed  CAS  Google Scholar 

  17. Kojima S, Shida M, Yokoyama H. Comparison between cilnidipine and amlodipine besilate with respect to proteinuria in hypertensive patients with renal diseases. Hypertens Res. 2004;27:379–85.

    Article  PubMed  CAS  Google Scholar 

  18. Dall’Ago P, Fernandes TG, Machado UF, Bello AA, Irigoyen MC. Baroreflex and chemoreflex dysfunction in streptozotocin-diabetic rats. Braz J Med Biol Res. 1997;30:119–24.

    PubMed  Google Scholar 

  19. Maeda CY, Fernandes TG, Timm HB, Irigoyen MC. Autonomic dysfunction in short-term experimental diabetes. Hypertension. 1995;26:1100–4.

    Article  PubMed  CAS  Google Scholar 

  20. Widdop RE, Verberne AJ, Jarrott B, Louis WJ. Impaired arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious spontaneously hypertensive rats. J Hypertens. 1990;8:269–75.

    Article  PubMed  CAS  Google Scholar 

  21. Farah VM, De Angelis K, Joaquim LF, Candido GO, Bernardes N, Fazan R Jr, et al. Autonomic modulation of arterial pressure and heart rate variability in hypertensive diabetic rats. Clinics. 2007;62:477–82.

    Article  Google Scholar 

  22. Takahara A, Dohmoto H, Hisa H, Satoh S, Yoshimoto R. Cilnidipine attenuates renal nerve stimulation-induced renal vasoconstriction and antinatriuresis in anesthetized dogs. Jpn J Pharmacol. 1997;75:27–32.

    Article  PubMed  CAS  Google Scholar 

  23. Aritomi S, Koganei H, Wagatsuma H, Mitsui A, Ogawa T, Nitta K, et al. The N-type and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-salt diet. Heart Vessels. 2010;25:549–55.

    Article  PubMed  Google Scholar 

  24. Konda T, Enomoto A, Matsushita J, Takahara A, Moriyama T. The N- and L-type calcium channel blocker cilnidipine suppresses renal injury in Dahl rats fed a high-sucrose diet, an experimental model of metabolic syndrome. Nephron Physiol. 2005;101:1–13.

    Article  Google Scholar 

  25. Katayama K, Nomura S, Ishikawa H, Murata T, Koyabu S, Nakano T. Comparison between valsartan and valsartan plus cilnidipine in type II diabetics with normo- and microalbuminuria. Kidney Int. 2006;70:151–6.

    Article  PubMed  CAS  Google Scholar 

  26. Konda T, Enomoto A, Aritomi S, Niinuma K, Koganei H, Ogawa T, et al. Different effects of L/N-Type and L-Type calcium channel blockers on the renin-angiotensin-aldosterone system in SHR/Izm. Am J Nephrol. 2009;30:155–61.

    Article  PubMed  CAS  Google Scholar 

  27. Takahara A, Nakamura Y, Wagatsuma H, Aritomi S, Nakayama A, Satoh Y, et al. A. long-term blockade of L/N-type Ca(2+) channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart. Br J Pharmacol. 2009;158:1366–74.

    Article  PubMed  CAS  Google Scholar 

  28. Konoshita T, Makino Y, Kimura T, Fujii M, Wakahara S, Arakawa K, et al. A new-generation N/L-type calcium channel blocker leads to less activation of the renin-angiotensin system compared with conventional L type calcium channel blocker. J Hypertens. 2010;28:2156–60.

    Article  PubMed  CAS  Google Scholar 

  29. Balt JC, Mathy MJ, Pfaffendorf M, van Zwieten PA. Sympatho-inhibitory properties of various AT1 receptor antagonists. J Hypertens. 2002;20:S3–11.

    Article  CAS  Google Scholar 

  30. Levy BI. How to explain the differences between renin angiotensin system modulators. Am J Hypertens. 2005;18:134S–41S.

    Article  PubMed  CAS  Google Scholar 

  31. Aritomi S, Niinuma K, Ogawa T, Konda T, Nitta K. Effects of an N-Type Calcium Antagonist on Angiotensin II-Renin Feedback. Am J Nephrol. 2011;33:168–75.

    Article  PubMed  CAS  Google Scholar 

  32. Klar J, Sigl M, Obermayer B, Schweda F, Krämer BK, Kurtz A Calcium inhibits renin gene expression by transcriptional and posttranscriptional mechanisms. Hypertension. 2005; 46: 1340–6.

    Google Scholar 

  33. Luippold G, Beilharz M, Mühlbauer B. Chronic renal denervation prevents glomerular hyperfiltration in diabetic rats. Nephrol Dial Transplant. 2004;19:342–7.

    Article  PubMed  Google Scholar 

  34. Schaan BD, Irigoyen MC, Lacchini S, Moreira ED, Schmid H, Machado UF. Sympathetic modulation of the renal glucose transporter GLUT2 in diabetic rats. Auton Neurosci. 2005;117:54–61.

    Article  PubMed  CAS  Google Scholar 

  35. Lehfeld LS, Silveira LA, Ghini B, Lopes de Faria JB. Early blood pressure normalization independent of the class of antihypertensive agent prevents augmented renal fibronectin and albuminuria in experimental diabetic nephropathy. Kidney Blood Press Res. 2004; 27: 114–20.

    Google Scholar 

  36. Mervaala EM, Müller DN, Park JK, Schmidt F, Lohn M, Breu V, Dragun D, Ganten D, Haller H, Luft FC. Monocyte infiltration and adhesion molecules in a rat model of high human renin hypertension. Hypertension. 1999;33:389–95.

    Article  PubMed  CAS  Google Scholar 

  37. Toba H, Yoshida M, Tojo C, Nakano A, Oshima Y, Kojima Y, et al. L/N-type calcium channel blocker cilnidipine ameliorates proteinuria and inhibits the renal renin-angiotensin-aldosterone system in deoxycorticosterone acetate-salt hypertensive rats. Hypertens Res. 2011;34:521–9.

    Article  PubMed  CAS  Google Scholar 

  38. Lassila M, Davis BJ, Allen TJ, Burrell LM, Cooper ME, Cao Z. Cardiovascular hypertrophy in diabetic spontaneously hypertensive rats: optimizing blockade of the renin-angiotensin system. Clin Sci (Lond). 2003;104(4):341–7.

    Article  CAS  Google Scholar 

  39. Benter IF, Yousif MH, Dhaunsi GS, Kaur J, Chappell MC, Diz DI. Angiotensin-(1–7) prevents activation of NADPH oxidase and renal vascular dysfunction in diabetic hypertensive rats. Am J Nephrol. 2008;28(1):25–33.

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Kosaku Nitta.

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Aritomi, S., Niinuma, K., Ogawa, T. et al. Additive effects of cilnidipine and angiotensin II receptor blocker in preventing the progression of diabetic nephropathy in diabetic spontaneously hypertensive rats. Clin Exp Nephrol 17, 41–50 (2013). https://doi.org/10.1007/s10157-012-0677-4

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  • DOI: https://doi.org/10.1007/s10157-012-0677-4

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