Published online before print May 27, 2003, doi: 10.1161/01.HYP.0000074702.06466.27
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(Hypertension. 2003;42:82.)
© 2003 American Heart Association, Inc.
Scientific Contribution |
Methylation of 2-Hydroxyestradiol in Isolated Organs
From the Center for Clinical Pharmacology (L.C.Z., R.K.D., Z.M., E.K.J.), Departments of Medicine (L.C.Z., R.K.D., Z.M., E.K.J.) and Pharmacology (E.K.J.), University of Pittsburgh Medical Center, Pittsburgh, Penn; and Clinic for Endocrinology, Department of Obstetrics and Gynecology, University Hospital Zurich (R.K.D.), Zurich, Switzerland.
Correspondence to Dr Edwin K. Jackson, University of Pittsburgh Medical Center, Center for Clinical Pharmacology, 623 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261. E-mail edj+{at}pitt.edu
Vascular smooth muscle and glomerular mesangial cells in culture express a biochemical pathway that methylates 2-hydroxyestradiol (17ß-estradiol metabolite) to produce 2-methoxyestradiol, a cell growth inhibitor that may mediate the cardiorenal protective effects of 17ß-estradiol. Whether this pathway exists in intact organ systems is currently unclear. Accordingly, the purpose of the present investigation was to characterize the methylation of 2-hydroxestradiol in intact organs from both male and female rats. No significant differences were detected in the ability of male and female tissues to methylate 2-hydroxyestradiol. In isolated hearts, kidneys, and mesenteries perfused with Tyrode’s solution, Km values for 2-hydroxyestradiol methylation were 0.175±0.021, 0.387±0.054, and 0.495±0.089 µmol/L, respectively, and Vmax values were 21.0±1.58, 24.9±1.49, and 1.01±0.148 pmol 2-methoxyestradiol · min-1 · ml-1 per gram, respectively. The catalytic efficiency (Vmax/Km) was greatest in the heart compared with the kidney and mesentery (132±14.3, 78.4±15.1, and 2.30±0.263 pmol 2-methoxyestradiol · min-1 · mL-1 · µmol/L-1 per gram, respectively). In the kidney, the catechol-O-methyltransferase inhibitor quercetin and norepinephrine (10 µmol/L) reduced methylation of 2-hydroxyestradiol by approximately 90% and 41%, respectively. Importantly, methylation in the kidney was inhibited by an average of 16.6±1.80% by endogenous norepinephrine released by renal artery nerve stimulation. Our results indicate that a robust 2-hydroxyestradiol methylation pathway exists in the kidney and heart, but not in the mesentery, and that this pathway is mediated by catechol-O-methyltransferase. Our findings also suggest that catecholamines may interfere with 2-hydroxyestradiol methylation and thereby attenuate the cardiorenal protective effects of 17ß-estradiol.
Key Words: vascular diseases • coronary artery disease • sympathetic nervous system • renal disease • catecholamines
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