Recombinant Human Erythropoietin Inhibits the Cutaneous Vasodilatation Induced by Acetylcholine

Buemi, Michele; Denuzzo, Giulia; Allegra, Alessandro; Aloisi, Carmela; Squadrito, F.; Squadrito, G; Dattola, A.; Corica, Francesco; Vermiglio, G

doi:10.1159/000179076

Cited by 14 publications

(13 citation statements)

References 8 publications

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“…Additionally, a reduced effect of a selective NOS inhibitor (N G -nitro-L-arginine methyl ester; L-NAME) on acetylcholine-induced vasodilatation was observed in the Epo group, indicating that NOS activity had been inhibited or sensitivity of NOS to L-NAME was decreased in Epo-treated rabbits (180). Similar effects have been observed in healthy human cutaneous vessels, in which local infusion of high doses of Epo could revert endothelium-dependent vasodilatation induced by acetylcholine (22). Taken together, there are several indications that Epo can enhance and diminish NO release, which may depend on concentrations and perhaps the presence of high blood pressure or a uremic environment.…”

Section: How Does Epo Influence the Cardiorenal Connectors?mentioning

confidence: 61%

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Jie

Verhaar²,

Cramer³

et al. 2006

American Journal of Physiology-Renal Physiology

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We have recently proposed severe cardiorenal syndrome (SCRS), in which cardiac and renal failure mutually amplify progressive failure of both organs. This frequent pathophysiological condition has an extremely poor prognosis. Interactions between inflammation, the renin-angiotensin system, the balance between the nitric oxide and reactive oxygen species and the sympathetic nervous system form the cardiorenal connectors and are cornerstones in the pathophysiology of SCRS. An absolute deficit of erythropoietin (Epo) and decreased sensitivity to Epo in this syndrome both contribute to the development of anemia, which is more pronounced than renal anemia in the absence of heart failure. Besides expression on erythroid progenitor cells, Epo receptors are present in the heart, kidney, and vascular system, in which activation results in antiapoptosis, proliferation, and possibly antioxidation and anti-inflammation. Interestingly, Epo can improve cardiac and renal function. We have therefore reviewed the literature with respect to Epo and the cardiorenal connectors. Indeed, there are indications that Epo can diminish inflammation, reduce renin-angiotensin system activity, and shift the nitric oxide and reactive oxygen species balance toward nitric oxide. Information about Epo and the sympathetic nervous system is scarce. This analysis underscores the relevance of a further understanding of clinical and cellular mechanisms underlying protective effects of Epo, because this will support better treatment of SCRS. heart failure; renal failure; anemia; nitric oxide; reactive oxygen species COEXISTENCE OF RENAL AND cardiac disease is associated with high morbidity and mortality. This pathophysiological condition, in which combined cardiac and renal dysfunction amplifies a progression in the failure of the individual organ, has recently been denoted as severe cardiorenal syndrome (SCRS) (19,20).In patients with declined renal function measured by glomerular filtration rate (GFR), an independent increased risk for cardiovascular events has been found. The hazard ratio for cardiovascular events was 1.4 with a GFR Ͻ60 ml/min and increased with diminished renal function to 2.8 in patients with a GFR Ͻ30 ml/min (99). A 40% higher adjusted risk for adverse cardiovascular outcomes or death was observed in those with relatively minor degrees of renal dysfunction (120). The prevalence of chronic renal failure (CRF) is reportedly high in patients with congestive heart failure (CHF). Furthermore, the prevalence and severity of CRF correlate with the severity of CHF (44, 72). These data support that combined cardiac and renal failure is a profound problem, and a further understanding of the underlying pathophysiological and molecular mechanisms is needed to improve therapy.Our group proposed an interactive network of cardiorenal connectors, i.e., the renin-angiotensin system (RAS), nitric oxide and reactive oxygen species (NO-ROS) balance, the sympathetic nervous system (SNS), and inflammation, as the cornerstones of the pathophysiology o...

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Section: How Does Epo Influence the Cardiorenal Connectors?mentioning

confidence: 61%

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Jie

Verhaar²,

Cramer³

et al. 2006

American Journal of Physiology-Renal Physiology

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“…22,23 Infusion of EPO into the lower limbs of healthy volunteers suggested that EPO may impair synthesis of endothelial NO resulting in vasoconstriction. 24 Incubation with EPO of human coronary artery endothelial cells to 24 hours inhibited NO production and endothelial nitric oxide synthase (eNOS) expression while stimulating DNA synthesis. 25 However, short-term EPO stimulation of vascular endothelial cells in culture generally has not shown modification of NO synthesis or regulation of expression of endothelin-1 or nitric oxide synthase, data interpreted as suggesting that the hypertensive effect of EPO is not a direct effect on endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Beleslin-Čokić

Čokić²,

Yu³

et al. 2004

Blood

264

211

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Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell

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“…Using telethermography, it has been demonstrated that the acetylcholine-induced relaxation of the dorsal pedal subcutaneous artery of normal humans was blunted by graded doses of EPO [6], suggesting that EPO may impair the synthesis of endothelial NO in this vasculature. Moreover, EPO treatment (150 units:kg −" ; twice per week for 6 weeks) in rats raised the blood pressure and impaired the hypotensive response to sodium nitroprusside, a NO donor, but did not change caudal artery contraction in response to depolarization induced by 68 mM potassium [7], suggesting that EPO-induced hypertension may be associated with an impaired vasodilatory response to NO.…”

Section: Introductionmentioning

confidence: 99%

Relationship between erythropoietin and nitric oxide in the contraction of rat renal arcuate arteries and human umbilical vein endothelial cells

Johns

Richards

1999

Clinical Science

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We have investigated the effects of recombinant human erythropoietin (EPO) on the responses of rat renal arcuate arteries to dopamine, noradrenaline and acetylcholine and on the release of NO from human umbilical vein endothelial cells (HUVEC) in culture. Noradrenaline induced a concentration-dependent constriction and acetylcholine a concentration-dependent relaxation of the vessels. The effects of dopamine were concentration-dependent, leading to relaxation of the vessels at low concentrations and contraction of the vessels at high concentrations. N(G)-Nitro-L-arginine methyl ester (L-NAME; 0.1 mM) did not change the vasoconstrictor responses to noradrenaline and dopamine, but inhibited the acetylcholine- and dopamine-induced vasorelaxation. Neither 0.1 nor 20 units.ml(-1) EPO affected noradrenaline-induced constriction, or dopamine- or acetylcholine-induced relaxation, of the vessels. EPO at 20 units. ml(-1) attenuated dopamine-induced constriction of the vessels. This effect was blunted by application of L-NAME, suggesting that EPO may stimulate dopamine-mediated NO release from these vessels. EPO stimulated NO release from the resting HUVEC in a concentration- and time-dependent manner, an effect that was inhibited by the presence of N(G)-nitro-L-arginine. These data suggest that, in vitro, EPO is able to stimulate NO release from rat renal arcuate arteries and HUVEC in culture. Whether these acute short-term actions can be related to the longer-term actions of EPO remains to be resolved.

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Recombinant Human Erythropoietin Inhibits the Cutaneous Vasodilatation Induced by Acetylcholine

Cited by 14 publications

References 8 publications

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors

Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells

Relationship between erythropoietin and nitric oxide in the contraction of rat renal arcuate arteries and human umbilical vein endothelial cells

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