Background/Aims: A recent observation that antiplatelet-aggregation drugs, including ticlopidine hydrochloride, may prevent erythropoietin (EPO)-induced rise in blood pressure in hemodialysis (HD) patients remains a subject of particular interest. The aim of the present study was to determine the effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure of HD patients with special reference to blood levels of vasoactive substances. Methods: HD patients who showed hypertension or aggravation of preceding hypertension with EPO treatment were selected for this study. Ticlopidine hydrochloride was administered at a dose of 200 mg daily for 4 weeks. Blood pressure and serum levels of nitric oxide (NO), atrial natriuretic peptide (ANP) and endothelin (ET) were determined before and after drug administration. Patients were divided into two groups, one of which showed a drop in mean blood pressure (MBP) of >10 mm Hg (group I) and one which did not (group II), and a comparison was made between them with respect to the blood parameters. Results: Five of 15 patients showed a drop of MBP of >10 mm Hg (group I), and 10 patients did not show any change in MBP (group II). In group I, there was a significant increase in blood NO levels compared to the concentrations before ticlopidine administration, while there was no change in group II. With respect to ANP and ET, there was no significant change in either of the groups. Conclusion: The findings suggest that the preventive effect of ticlopidine hydrochloride on EPO-induced rise in blood pressure may partly be related to the enhancement of NO production in patients on maintenance HD.

Keywords:
Ticlopidine hydrochloride, Nitric oxide, Erythropoietin, Hypertension, Hemodialysis
1.
Eschbach JW, Egrie JC, Dowing MR, Browne JK, Adamson JW: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med 1987;316:73–78.
2.
Raine AEG: Hypertension, blood viscosity, and cardiovascular morbidity in renal failure: Implications of erythropoietin therapy. Lancet 1988;i:97–100.
3.
Sundal E, Kaeser U: Correction of anaemia of chronic renal failure with recombinant human erythropoietin: Safety and efficacy of one year’s treatment in a European multicentre study of 150 haemodialysis-dependent patients. Nephrol Dial Transplant 1989;4:979–987.
4.
Steffen HM, Brunner R, Muller R, Degenhardt S, Pollok M, Lang R, Baldamus CA: Peripheral hemodynamics, blood viscosity, and the renin-angiotensin system in hemodialysis patients under therapy with recombinant human erythropoietin. Contrib Nephrol. Basel, Karger, 1989, vol 76, pp 292–298.
5.
Naruse M, Nakamura N, Naruse K, Kubo K, Kato M, Hagiwara H, Sugino N, Demura H: Plasma immunoreactive endothelin levels are increased in hemodialysis patients with hypertension following erythropoietin therapy. Hypertens Res 1992;15:11–16.
6.
Jandeleit K, Heintz B, Kristen R, Nelson K: Increased activity of the autonomic nervous system and increased sensitivity to angiotensin II infusion after recombinant human erythropoietin. Nephron 1990;56:220–221.
7.
London GM, Zins B, Pannier B, Naret C, Berthlot JM, Jacquot C, Safer M, Drüke TB: Vascular change in hemodialysis patients in response to recombinant human erythropoietin. Kidney Int 1989;36:878–882.
8.
Kuriyama S, Hopp L, Yoshida H, Hikata M, Tomonari H, Hashimoto T, Sakai O: Evidence for amelioration of endothelial cell dysfunction by erythropoietin therapy in predialysis patients. Am J Hypertens 1996;9:426–431.
9.
Ishimitsu T, Tsukada H, Ogawa Y, Numabe A, Yagi S: Genetic predisposition to hypertension facilitates blood pressure elevation in hemodialysis patients treated with erythropoietin. Am J Med 1993;94:401–406.
10.
Caravaca F, Pizarro JL, Arrobas M, Cubero JJ, Garcia MC, Perez-Miranda M: Antiplatelet therapy and development of hypertension induced by recombinant human erythropoietin in uremic patients. Kidney Int 1994;45:845–851.
11.
Caravaca F, Lopez-Minguez JR, Arrobas M, Cubero JJ, Pizarro JL, Cid MC, Sanchez-Casado E, Perez-Miranda M: Hemodynamic changes induced by the correction of anaemia by erythropoietin: Role of antiplatelet therapy. Nephrol Dial Transplant 1995;10:1720–1724.
12.
Iimura O, Kusano E, Amemiya M, Muto S, Ikeda U, Shimada K, Asano Y: Dipyridamole enhances interleukin-1β-stimulated nitric oxide production by cultured rat vascular smooth muscle cells. Eur J Pharmacol 1996;296:319–326.
13.
Inoue M, Kusano E, Amemiya M, Nemoto J, Muto S, Asano Y: Ticlopidine enhances interleukin-1β-stimulated nitric oxide production by cultured rat vascular smooth muscle cells (abstract). J Am Soc Nephrol 1996;7:1564.
14.
Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR: Analysis of nitrate, nitrite, and [15N]nitrate in biological fluids. Anal Biochem 1982;126:131–138.
15.
Kuriyama S, Tomonari H, Hosoya T: Antiplatelet therapy decreases the incidence of erythropoietin-induced hypertension in predialysis patients. Clin Exp Hypertens 1999;21:213–222.
16.
Kusano E, Akimoto T, Inoue M, Masunaga Y, Umino T, Ono S, Ando Y, Homma S, Muto S, Komatsu N, Asano Y: Human recombinant erythropoietin inhibits interleukin-1β-stimulated nitric oxide and cyclic guanosine monophosphate production in cultured rat vascular smooth muscle cells. Nephrol Dial Transplant 1999;14:597–603.
17.
Akimoto T, Kusano E, Muto S, Fujita N, Okada K, Saito T, Komatsu N, Ono S, Ebata S, Ando Y, Homma S, Asano Y: The effect of erythropoietin on interleukin-1β-mediated increase in nitric oxide synthesis in vascular smooth muscle cells. J Hypertens 1999;17:1249–1256.
18.
Kusano E, Akimoto T, Sasaki N, Ando Y, Asano Y: Hemodialysis and nitric oxide. J Artif Organs 2001;4:23–29.
19.
De-Lorgeril M, Burdet J, Salen P, Durbin S, Defreyn G, Delaye J, Boissonnat P: Ticlopidine increases nitric oxide generation in heart-transplant recipients: A possible novel property of ticlopidine. J Cardiovasc Pharmacol 1998;32:225–230.
20.
Mills RMJ, Billett JM, Nichols WW: Endothelial dysfunction early after heart transplantation. Assessment with intravascular ultrasound and doppler. Circulation 1992;86:1171–1174.
21.
Noris M, Benigni A, Boccardo P, Aiello S, Gaspari F, Todeschini M, Figliuzzi M, Remuzzi G: Enhanced nitric oxide synthesis in uremia: Implications for platelet dysfunction and dialysis hypotension. Kidney Int 1993;44:445–450.
22.
Pulkki KJ: Cytokines and cardiomyocyte death. Ann Med 1997;29:339–343.
23.
Van Geet C, Van Damme-Lombaerts R, Vanrusselt M, De Mol A, Proesmans W, Vermylen J: Recombinant human erythropoietin increases blood pressure, platelet aggregability and platelet-free calcium mobilization in uraemic children: A possible link? Thromb Haemost 1990;64:7–10.
24.
Fukuo K, Hata S, Suhara T, Nakahashi T, Shinto Y, Tsujimoto Y, Morimoto S, Ogihara T: Nitric oxide induces upregulation of fas and apoptosis in vascular smooth muscle. Hypertension 1996;27:823–826.
25.
Pollman MJ, Yamada T, Horiuchi M, Gibbons GH: Vasoactive substance regulates vascular smooth muscle cell apoptosis-countervailing influences of nitric oxide and angiotensin II. Circ Res 1996;79:748–756.
26.
Akimoto T, Kusano E, Inaba T, Iimura O, Takahashi H, Ikeda H, Ito C, Ando Y, Ozawa K, Asano Y: Erythropoietin regulates vascular smooth muscle cell apoptosis by a phosphatidylinositol-3-kinase-dependent pathway. Kidney Int 2000;58:269–282.
© 2002 S. Karger AG, Basel
2002
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