title: Role of nitric oxide resistance in erythropoietin-induced hypertension in rats with chronic renal failure.
abstract: We studied the mechanism of erythropoietin (EPO)-induced hypertension (HTN) in rats with chronic renal failure (CRF). After partial nephrectomy, rats were randomized into four groups. Group A received EPO, 150 U/kg, two times weekly for 6 wk to prevent anemia; group B received placebo injections and became anemic; group C received EPO but was kept anemic by dietary iron deficiency; and group D received placebo and regular transfusions to match hematocrit (Hct) in group A. Blood pressure (BP), Hct, platelet cytosolic calcium ([Ca2+]i) and magnesium concentration, and pressor and vasodilatory responses were determined. By design, Hct in groups A and D were comparable and significantly greater (P < 0.01) than in groups B and C. Despite divergent Hct values, the EPO-treated groups A and C showed a significant rise in BP compared with the placebo-treated groups B and D. HTN occurred whether EPO therapy was begun immediately or 4 wk after nephrectomy. EPO therapy augmented the elevation of basal [Ca2+]i and restored the defective thrombin-mediated rise of platelet [Ca2+]i in CRF animals. EPO therapy did not alter caudal artery contraction in response to either 68 mM K(+)-induced depolarization, angiotensin II or alpha 1-agonist, methoxamine in vitro, or the pressor response to angiotensin II in vivo. However, EPO therapy impaired the hypotensive response to nitric oxide (NO) donors, sodium nitroprusside and S-nitroso-N-acetyl-D,L-penicillamine, and reversed the CRF-induced upregulation of guanosine 3',5'-cyclic monophosphate production by thoracic aorta in vitro. Thus EPO-induced HTN in CRF rats is Hct independent and is associated with and perhaps causally related to increased basal and stimulated [Ca2+]i and impaired vasodilatory response to NO.
authors: Department of Medicine, University of California, Irvine 92717, USA.
authors: N D
authors: ND
authors: Vaziri
authors: X J
authors: XJ
authors: Zhou
authors: F
authors: F
authors: Naqvi
authors: J
authors: J
authors: Smith
authors: F
authors: F
authors: Oveisi
authors: Z Q
authors: ZQ
authors: Wang
authors: R E
authors: RE
authors: Purdy
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000096:biosynthesis; D004351:Drug Resistance; D004921:Erythropoietin; D006400:Hematocrit; D006973:Hypertension / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009994:Osmolar Concentration; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026423:S-Nitroso-N-Acetylpenicillamine; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D014665:Vasodilator Agents; D004921:Erythropoietin; D000804:Angiotensin II; D009599:Nitroprusside; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D010396:Penicillamine; D006152:Cyclic GMP; D002118:Calcium