Direct vasopressor effect of recombinant human erythropoietin on renal resistance vessels

Abstract

The contractile properties of recombinant human erythropoietin (rHuEPO) on isolated resistance vessels of renal and mesenteric vascular beds were studied in an in vitro model using a small vessel myograph. Under isometric conditions, rHuEPO caused a contraction of this vasculature in a concentration range between 10 U/ml and 200 U/ml. A maximal active wall tension of 1.52 +/- 0.19 mN/mm was obtained under a rHuEPO dose of 200 U/ml. In Ca2+ free solution, the pressor response to high rHuEPO-concentrations was attenuated, and the response to low rHuEPO concentrations was abolished. In the presence of verapamil, phentolamine and saralasin, rHuEPO-induced contractions were not affected significantly. A dose-dependent vasodilatation of mounted vasculature to acetylcholine (ACh) indicated that endothelium remained intact in our preparations. rHuEPO-induced vessel contraction was not abrogated after an enzymatical removal of endothelium by collagenase, confirming that the described contractile responses are endothelial independent. These findings suggest that a direct vasopressor effect of rHuEPO on proximal resistance vessels may contribute to development of hypertension seen in rHuEPO-treated hemodialysis patients.

Role of erythropoietin in cortisol-induced hypertension

“…Recombinant human EPO (rHuEPO) causes contraction of isolated resistance vessels of the renal and mesenteric vascular beds. 7 These effects are endothelium independent and are not abolished by calcium antagonists or angiotensin II (AII) receptor antagonists. In cultured human coronary artery cells EPO causes dosedependent inhibition of basal and acetylcholine stimulated nitric oxide (NO) production and eNOS protein expression suggesting that EPO may also alter vascular reactivity by endothelium dependent mechanisms.…”

“…1,3 Cortisol treatment also causes suppression of the nitric oxide system as evidenced by reduced plasma nitrate/nitrite concentrations. 5 In the context of these observations, Correspondence 6,7 EPO-induced hypertension has also been demonstrated to be due in part to nitric oxide resistance. 8 The aim of the current study was to examine the role of EPO as a possible mediator of cortisolinduced hypertension.…”

The Effects of Intrarenal Infusion of Recombinant Human Erythropoietin on Mean Arterial Pressure and Renal Hemodynamics in Anesthetized Rabbits.

“…The mechanism by which rHuEPO induces hypertension has been in the past explained by an increase of blood viscosity strongly related to the hematocrit (Mayer et al 1988 ;Raine 1988), or vasoconstriction elicited by improvement of hypoxia (Eschbach et al 1987 ;Kamata et al 1991). Recently, Heidenreich et al (1991) have reported that rHuEPO has a direct vasopressor effect on renal and mesenteric resistance vessels of normotensive Wistar-Kyoto rats in vitro and that threshold concentration for a pressor response to rHuEPO is 10 U/ml. They suggest that the vasopressor capacity of rHuEPO may contribute to the development of hypertension seen in rHuEPO-treated dialysis patients and may amplify or aggravate other relevant pathomechanisms of hypertension.…”

“…Recently, Heidenreich et al (1991) have reported that rHuEPO has a direct vasopressor effect on proximal resistance vessels taken from Wistar-Kyoto rats without renal failure, which may contribute to the development of hypertension seen in rHuEPO-treated dialysis patients. Therefore, the present study was designed to determine whether rHuEPO has direct effects on mean arterial pressure (MAP) or renal hemodynamics in anesthetized rabbits without renal failure.…”

The influence of erythropoietin on levels of endothelin‐1 and nitric oxide in patients on hemodialysis

“…However, complications such as newly originated hypertension, worsening of previous hypertension, thrombosis of arteriovenous fi stula, and hyperkalemia can be caused by the use of rhEPO. [1][2][3][4] Hypertension induced with the use of erythropoietin in therapy is a complication which affects prognosis in patients treated with dialysis. 5,6 The exact mechanism of hypertension caused by rhEPO is not yet known.…”