I 82 Volume 3 . Number 2 . 1992 Effect of Erythropoietin on Hematocrit and Blood Pressure in Normotensive and Hypertensive Rats1 Martin Muntzel,2 Thierry Hannedouche, Bernard Lacour, and Tilman DrUeke M. Muntzel, T. Hannedouche, B. Lacour, T. Dr#{252}eke, INSERM Unit 90, Department of Nephrology, H#{244}pital Necker, Paris, France (J. Am. Soc. Nephrol. 1992; 3:182-187) ABSTRACT Treatment with recombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic pa- tients. Of major concern, however, are blood pres- sure (BP) increases during rHuEPO therapy, observed particularly in persons with a history of hypertension. To determine whether preexisting hypertension enhances BP increases to rHuEPO, BP responses to 2 wk of rHuEPO or placebo were observed in sponta- neously hypertensive rats (SHR) and their normoten- sive genetic controls (Wistar-Kyoto (WKY) rats). In ad- dition, the role of endothelial-released nitric oxide (NO) in BP alterations caused by rHuEPO through i.v. infusions of endothelium-dependent and independ- ent vasoactive agents were indirectly examined. At trial completion, rHuEPO elevated hematocrit, he- moglobin, and mean cell volume more in SHR than in WKY rats (P < 0.001). Despite the considerable increase in hematocril, rHuEPO did not alter BP in either strain. An infusion of NGmonomethyILarginmne (L-NMMA). a specific inhibitor of NO formation, ele- vated BP more in rHuEPO-treated SHR than in identi- cally treated WKY rats (P< 0.05). Further, the admin- istration of L-arginmne caused a greater decrease in blood pressure in SHR than in WKY rats, independent of treatment condition (P< 0.01). Because changes in BP with endothelium-independent agents were similar across groups, responses to i-NMMA and L- argmnine were specific to the endothelium and prob- ably independent of basal BP. Thus, rHuEPO provoked greater erythropoiesis in SHR than in WKY rats but did not elevate BP. i-NMMA stimulated higher BP in SHR treated with rHuEPO, suggesting a compensatory in- I Received February 1 1. 1992. Accepted April 30. 1992. 2 Correspondence to Dr. M. Muntzel, Department of Psychology and the Car- diovascular Center, University of Iowa. Iowa City. IA 52242. 1046-6673/0302-0 182$03.00/0 Journal of the American Society of Nephrology Copyright C 1992 by the American Society of Nephrology crease in vasodilatory NO synthesis to protect against a hypertensive effect of the drug in SHR. The hypertensive effect may be ascribed to the exag- gerated increase in hematocrit and perhaps viscos- ity in the SHR strain. Key Words: Erythropoiesis. L-arginlne, Afr-monomethy/-L-argi- n/ne, spontaneously hypertensive rats. Wistar-Kyoto rats R ecombinant human erythropoietin (rHuEPO) successfully reverses anemia in uremic hemo- dialysis patients (1 ). A major side effect, however, has been the development of hypertension in 20 to 30% of rHuEPO-treated patients, requiring the insti- tution or augmentation of antihypertensive medica- tion (1 ,2). Elevations in blood pressure by rHuEPO are not limited to the reversal of anemia, because 2 wk of rHuEPO treatment increased blood pressure in normal, nonanemic rats (3,4). A determinant of hypertensive episodes with rHuEPO therapy may be the presence of preexisting hypertension (2). Consistent with this possibility. both blood transfusion and isotonic saline loading increased blood pressure in anemic patients with a history of hypertension but did not alter pressure in anemics with normotension (5,6). In addition, rHuEPO treatment necessitated the reinforcement of antihypertensive medication in eight hypertensive dialysis patients, yet did not influence pressure in six normotensive dialysis subjects (7). Laboratory studies supported these findings. because experi- mental manipulations that reduced hematocrit bow- ered blood pressure in spontaneously hypertensive rats (SHR), but similar alterations in hematocrit had no effect on blood pressure in normotensive Wistar- Kyoto (WKY) rats (8). The mechanism of blood pressure elevation with rHuEPO is incompletely understood but has been ascribed to increased blood viscosity consequent to increasing hematocrit, to a boss of hypoxic vasodila- tion, and to direct vasoconstrictor actions of the drug (1 .2,9). An additional explanation, proposed by Mar- tin and Moncada (10), implicates alterations in nitric oxide (NO), recently identified as one of the endothe- blab-derived relaxing factors (1 1). According to those authors, increases in hemoglobin after rHuEPO ther- apy may bind NO, thereby favoring the contraction of vascular smooth muscle and the elevation of ar- terial pressure (10). To determine whether the blood pressure-raising