PANEL DE DISCUSION
Dissociation of the pressor and erythropoetic effects of erythropoetin.
N.D. Vaziri, M.D., MACP
Division of Nephrology and Hypertension
University of California, Irvine. USA
David H. Tang, Pharm.D.
Cardiovascular Medical Information Scientist
Recombinant human erythropoietin has transformed the treatment of anemia in patients with end-stage renal disease. It has long been hypothesized that the site of action of erythropoietin was not limited exclusively to the erythroid progenitor cells. Subsequently, several studies have demonstrated that erythropoietin has potential targets on a wide array of cell types and organ systems. This article will review the mechanism of erythropoietin-induced hypertension and its effects on the production and action of vasoactive substances.
Arterial pressure often rises in patients undergoing maintenance EPO therapy for chronic renal failure. This EPO-induced hypertension is usually evident within weeks to months of the onset of therapy. Often the increase in blood pressure corresponds to the improvements in hematocrit of patients treated with EPO.(1-4) The temporal relationship between the rise of erythrocyte mass and blood pressure has led many clinicians to believe that EPO-induced hypertension may simply be the result of an increase in erythrocyte mass and hematocrit. It was proposed that the return of blood viscosity to near normal values as the anemia was corrected served as the major causal factor in EPO-induced hypertension.(5,6) It was also hypothesized that the expansion of blood volume due to increased erythrocyte mass and binding of endogenous nitric oxide by hemoglobin and loss of hypoxic vasodilation also contributed to the increase in blood pressure.(7,8) However, careful evaluation of the original clinical data and subsequent studies have raised doubts about the proposed causal relationship with increased hematocrit. (9-11)
In order to study the relationship between EPO-induced hypertension and the correction of anemia, we conducted an animal study that would separate the effects of chronic EPO administration from hematocrit increases.(10) The rats used in this study were subjected to 5/6 nephrectomy to produce chronic renal failure (CRF) and were then randomized into four groups. The groups consisted of CRF animals treated with the following regimen:
This study showed that treatment with EPO resulted in severe hypertension of equal magnitude in both iron-replete and iron-depleted CRF rats despite widely different hematocrits. In addition, no increase in arterial blood pressure was seen in the CRF animals receiving multiple transfusions. The results of this study showed that the pressor effects of chronic EPO therapy are distinct from its erythropoietic action in the CRF animals.(10) Similar results were found in a study using normal animals.(11) These findings supported the results of our studies on a group of dialysis patients with iron-deficiency anemia treated with a maintenance dosage of EPO for several weeks before and after iron repletion with intravenous iron dextran administration.(12) Iron repletion increased hematocrit but not blood pressure in these patients. The studies cited above provide a strong argument against the hypothesis that EPO-induced hypertension is due to the correction of anemia in the treated patients.
Effect of EPO on Vasodilatory System
Several recent studies have shown that an impaired vasodilatory system plays a role in the genesis of hypertension with EPO therapy. Studies by Vaziri et al. have demonstrated an attenuated response to NO donors in EPO-treated rats.(11,12) In vitro studies using arterial ring preparations supported these in vivo findings. The in vitro experiments indicate that the impaired response to NO was not due to differences in hematocrit or circulating vasoactive factors. The results of these studies strongly suggest that EPO may induce resistance to the vasodilatory action of NO. Impaired vasodilatory response to NO in these experiments occurred despite normal generation of cGMP hence placing the defect at a point distal to the production of cGMP.(10,11) Since the cGMP-induced smooth muscle relaxation is mediated by a reduction in cytosolic [Ca++], elevation of cytosolic [Ca++] can account for NO resistance caused by EPO treatment. In fact, dihydropyridine calcium channel antagonists which lower cytosolic [Ca++] have been shown to ameliorate EPO-induced hypertension and improve NO metabolism in rats.(13)
In addition to causing NO resistance, EPO has been shown to lower NO synthase (NOS) expression in cultured endothelial cells.(14) Despite these findings, chronic administration of EPO has not been found to significantly alter NO production or NOS isotype expression in intact animals with chronic renal insufficiency.(13) This is because direct inhibition of NOS expression is cancelled by the indirect stimulation of NOS expression caused by EPO-induced hypertension. EPO has not been shown to adversely affect atrial natriuretic peptide (ANP) production or plasma levels.(15) In summary, the available literature suggests that EPO therapy may decrease vasodilatory tone by promoting NO and possibly ANP resistance, thereby increasing vascular resistance and blood pressure.
Effects of EPO on Vasopressors
Several studies have shown that EPO can increase plasma endothelin-1 (ET-1) concentration in humans and in cultured endothelial cells and isolated perfused rat limb.(16-19) However, other studies have not shown a significant rise in plasma ET-1 concentration when EPO was administered to either patients or in experimental animals.(15,20-22)
EPO has been shown to enhance the gene expressions of renin and renin substrate in both the kidney and vascular tissue.(23) However, studies have shown that treatment with EPO does not raise plasma renin activity or angiotensin II concentration in rats.(23) In addition, other studies have shown that the administration of EPO does not alter the vasopressor response to angiotensin in either intact animals or isolated vascular preparations.(10,11) Regardless, it is possible that increased tissue renin-angiotensin system activity may contribute to the development of EPO-induced hypertension.
Catecholamine concentrations have demonstrated a variable response to EPO exposure. Theoretically, EPO therapy can reverse the high catecholamine levels seen in patients with severe anemia. However, uncontrolled EPO-induced hypertension can raise catecholamine levels by promoting heart failure. However, EPO therapy usually does not affect circulating catecholamine measurements.(24) Data on the effect of EPO therapy on the pressor response to catecholamines have been contradictory. EPO therapy has been shown to increase norepinephrine-induced vasoconstrictive response in dialysis patients and vascular rings from EPO-treated animals.(21,25) However, in other studies pressor response to a –1 adrenergic stimulation with methoxamine was not increased with EPO therapy in the rats or tissue preparation in vitro.(10,11)
Studies using cultured human umbilical vein endothelial cells exposed to EPO have demonstrated an increase in the production of vasoconstrictive prostaglandins (thomboxane B2 and PGF2a ) and a decrease in the production of vasodilatory prostaglandins (prostacyclin).(18,25) This may play a partial role in the pathogenesis of EPO-induced hypertension and enhanced platelet reactivity with this drug.
Basal cytoplasmic concentration of ionized calcium ([Ca++]i) plays a major role in the modulation of vascular tone. Contractile proteins such as actin and myosin are in relaxed conformation at low [Ca++] and a tense conformation at high cellular [Ca++]. [Ca++]i is also involved in the final pathway of contraction in vascular smooth muscle and other contractile cells. It has been shown that elevated basal [Ca++]i is associated with increased vascular tone and is a hallmark of various hypertensive disorders.(26-28) Through its effects on Ca++ uptake, EPO elevates cytosolic [Ca++] and expands the releasable intracellular calcium stores. These events result in increased vascular tone and contractility.
Direct Vasopressor Action of EPO
The onset of EPO-induced hypertension is usually apparent within several weeks in humans and after a few days in rats.(1-4,10) EPO does not appear to have a rapid-onset pressor effect in either humans or experimental animals. Studies utilizing a single bolus intravenous injection of EPO in rats and dialysis-dependent patients with end-stage renal failure have failed to show an immediate change in arterial pressure.(11,20) However, in vitro studies using rat mesenteric artery resistance vessels (29) and rat tail artery preparations (11) have shown a dose-dependent vascular contraction, corresponding with increased cytosolic Ca++. The absence of a rapid-onset pressor response in vivo despite the presence of a fast-acting vasoconstrictive response in vitro suggests a concurrent activation of a vasodilatory mechanism in vivo, but not in vitro.
Patients and animals receiving chronic EPO therapy experience a hematocrit-independent elevation of the arterial blood pressure. This phenomenon has been observed in both human and animal experiments and is believed to be mediated by increased activation of the tissue renin angiotensin system, enhanced endothelin-1 production, modulation of the production of vasoactive prostaglandins, elevations in cytosolic [Ca++]i and the development of NO resistance.
Buckner FS, Eschbach JW, Haley NR, et al: Hypertension following erythropoietin therapy in anemic hemodialysis patients. Am J Hypertens 3:947-955, 1990
Abraham PA, Macres MG: Blood pressure in hemodialysis patients during amelioration of anemia with erythropoietin. J Am Soc Nephrol 2:927-936, 1991
Raine AE, Roger SD: Effects of erythropoietin on blood pressure. Am J Kidney Dis 33:76-83, 1991
Vaziri ND: Mechanism of erythropoietin-induced hypertension. Am J Kidney Dis 33:821-828, 1999
Raine AE: Hypertension, blood viscosity and cardiovascular morbidity in renal failure: Implications of erythropoietin therapy. Lancet 1:97-100, 1988
Steffen HM, Brunner R, Muller R, et al: Peripheral hemodynamics, blood viscosity and the renin-angiotensin system in hemodialysis patients under therapy with recombinant human erythropoietin. Contrib Nephrol 76:292-298, 1989
Martin J, Moncada S: Blood pressure, erythropoietin and nitric oxide [letter]. Lancet 1:644, 1988
Neff MS, Kim KE, Persoff M, et al: Hemodynamics of uremic anemia. Circulation 43:876-883, 1971
Samtleben W, Baldamus CA, Bommer J, et al : Blood pressure changes during treatment with recombinant human erythropoietin. Contrib Nephrol 66:114-122, 1988
Vaziri ND, Zhou XJ, Naqvi F, et al: Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure. Am J Physiol 271:E113-E122, 1996
Vaziri ND, Zhou XJ, Smith J, et al: In vivo and in vitro pressor effects of erythropoietin in rats. Am J Physiol 269:F838-F845, 1995
Kaupke CJ, Kim S, Vaziri ND: Effect of erythrocyte mass on arterial blood pressure in dialysis patients receiving maintenance erythropoietin therapy. J Am Soc Nephrol 4:1874-1878, 1994
Ni Z, Wang XQ, Vaziri ND: Nitric oxide metabolism in erythropoietin-induced hypertension: Effect of calcium channel blockade. Hypertension 32: 724-729, 1998
Wang XQ, Vaziri ND: Erythropoietin depresses nitric oxide synthase expression by cultured human endothelial cells. Hypertension (in press)
Zhou XJ, Pandian D, Vaziri ND, et al: Erythropoietin-induced hypertension in rat is not mediated by alterations of plasma endothelin, vasopressin or atrial natriuretic peptide levels. J Am Soc Nephrol 8:901-905, 1997
Takahashi K, Totsune K, Imai Y, et al: Plasma concentrations of immunoreactive-endothelin in patients with chronic renal failure treated with recombinant human erythropoietin. Clin Sci 84:47-50, 1993
Carlini RG, Dusso AS, Obialo CI, et al: Recombinant human erythropoietin (rHuEPO) increases endothelin-1 release by endothelial cells. Kidney Int 43:1010-1014, 1993
Bode-Boger SM, Boger RH, Kuhn M, et al: Recombinant human erythropoietin enhances vasoconstrictor tone via endothelin-1 and constrictor prostanoids. Kidney Int 50:1255-1261, 1996
Katoh K, Mizuno K, Hashimoto S, et al: Direct evidence for erythropoietin-induced release of endothelin from peripheral vascular tissue. Life Sci 54:L253-L259, 1994
Hon G, Vaziri ND, Kaupke CJ, et al: Lack of a fast-acting effect of erythropoietin on arterial blood pressure and endothelin level. Artif Organs 19:188-191, 1995
Hand MF, Haynes WG, Johnstone HA, et al: Erythropoietin enhances vascular responsiveness to norepinephrine in renal failure. Kidney Int 48:806-813, 1995
Lai KN, Lui SF, Leung JC, et al: Effect of subcutaneous and intraperitoneal administration of recombinant human erythropoietin on blood pressure and vasoactive hormones in patients on continuous ambulatory peritoneal dialysis. Nephron 57:394-400, 1991
Eggena P, Willsey P, Jamgotchian N, et al: Influence of recombinant human erythropoietin on blood pressure and tissue renin-angiotensin systems. Am J Physiol 261:E642-E646, 1991
Lebel M, Kingma I, Grose JH, et al: Hemodynamic and hormonal changes during erythropoietin therapy in hemodialysis patients. J Am Soc Nephrol 9:97-104, 1998
Bode-Boger SM, Boger RH, Kuhn M, et al: Endothelin release and shift in prostaglandin balance are involved in the modulation of vascular tone by recombinant erythropoietin. J Cardiovasc Pharmacol 20:S25-S28, 1992
Resnick LM: Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. Am J Med 93:S11-S20 (suppl 2A), 1992
Vasdev S, Thompson P, Triggle C, et al: Fura-2 used as a probe to show elevated intracellular free calcium in platelets of Dahl-sensitive rats fed a high salt diet. Biochem Biophys Res Commun 154:380-86, 1988
Krzcsinski JM, Du F, Pequeux ML, et al: Plasma Na-K ATPase inhibitor activity and intracellular ions during hemodialysis. Int J Artif Organs 16:23-30, 1993
Heidenreich S, Rahn KH, Zidek W: Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels. Kidney Int 39:259-265, 1991