Nitric Oxide Metabolism in Erythropoietin-Induced Hypertension: Effect of Calcium Channel Blockade

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 32; no. 4; pp. 724 - 729
• Main Authors: Ni, Zhenmin, Wang, Xiu Q, Vaziri, Nosratola D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.1998; Hagerstown, MD Lippincott
• Subjects: Animals; Biological and medical sciences; Blood Pressure - drug effects; Blotting, Western; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Drug Interactions; Drug toxicity and drugs side effects treatment; Erythropoietin - therapeutic use; Erythropoietin - toxicity; Felodipine - pharmacology; Hypertension - chemically induced; Hypertension - metabolism; Kidney Failure, Chronic - drug therapy; Kidney Failure, Chronic - metabolism; Male; Medical sciences; Nephrectomy; Nitric Oxide - biosynthesis; Nitric Oxide - metabolism; Nitric Oxide - urine; Nitric Oxide Synthase - drug effects; Nitric Oxide Synthase - metabolism; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Toxicity: cardiovascular system; Vasodilator Agents - metabolism; Hypertension; Erythropoietin; Rat; Toxicity; Rodentia; Calcium antagonist; Cardiovascular disease; Glycoprotein hormone; Metabolism; Vertebrata; Mammalia; Treatment; Animal; Nitric oxide; Recombinant protein
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.32.4.724

Long-term administration of erythropoietin (EPO) frequently causes hypertension in humans and animals with chronic renal failure (CRF). We recently demonstrated that EPO-induced hypertension is hematocrit independent and accompanied by elevated cytosolic [Ca]i and nitric oxide (NO) resistance. This study was undertaken to examine the effects of therapy with EPO alone or together with calcium channel blockade on NO metabolism. Urinary excretion of NO metabolites (NOx) and thoracic aorta and kidney endothelial and inducible NO synthases (eNOS and iNOS) were studied in 4 groups of 6 nephrectomized rats treated with either placebo, EPO, the calcium channel blocker felodipine, or EPO plus felodipine for 6 weeks. A group of sham-operated placebo-treated animals served as control. The placebo-treated CRF group exhibited moderate hypertension, elevated basal and depressed stimulated platelet [Ca]i, reduced urinary NOx excretion, and diminished vascular and renal eNOS and iNOS proteins. EPO therapy further raised blood pressure and increased resting and stimulated [Ca]i but did not change NOx excretion or NOS proteins. Concurrent administration of felodipine abrogated EPO-induced hypertension, normalized resting and stimulated [Ca]i, and increased NOx excretion and eNOS and iNOS proteins. Thus, EPO therapy leads to marked increases in blood pressure and resting and stimulated [Ca]i. These abnormalities are ameliorated by calcium channel blockade, which restores [Ca]i to normal and increases vascular and renal NOS expression. (Hypertension. 1998;32:724-729.)