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(Hypertension. 2000;36:83.)
© 2000 American Heart Association, Inc.

Scientific Contributions

Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism

Masataka Sata; Masao Kakoki; Daisuke Nagata; Hiroaki Nishimatsu; Etsu Suzuki; Teruhiko Aoyagi; Seiryo Sugiura; Hirotatsu Kojima; Tetsuo Nagano; Kenji Kangawa; Hisayuki Matsuo; Masao Omata; Ryozo Nagai; Yasunobu Hirata

From the Department of Internal Medicine, Graduate School of Medicine (M.S., M.K., D.N., H.N., E.S., T.A., S.S., M.O., R.N., Y.H.) and Graduate School of Pharmaceutical Sciences (H.K., T.N.), University of Tokyo, Tokyo, Japan; and National Cardiovascular Center Research Institute (K.K., H.M.), Osaka, Japan.

Correspondence to Dr Yasunobu Hirata, Department of Cardiovascular Medicine, University of Tokyo Graduate School of Medicine, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail hirata-2im{at}h.u-tokyo.ac.jp

Abstract—Adrenomedullin, which was discovered as a vasodilating peptide, has been reported to be produced in various organs, in which adrenomedullin regulates not only vascular tone but also cell proliferation and differentiation in an autocrine/paracrine manner. We evaluated the effect of adrenomedullin on endothelial cell apoptosis. Human umbilical vein endothelial cells underwent apoptosis when cultured in serum-free medium. Treatment with adrenomedullin reduced the number of cells with pyknotic nuclei (Hoechst 33258 staining) and inhibited cell death (dimethylthiazol-diphenyltetrazolium bromide assay) in a dose-dependent manner. The administration of adrenomedullin did not alter the expression levels of Bcl-2 family proteins. Experiments with analogs of cAMP or a cAMP-elevating agonist demonstrated that elevation of the intracellular cAMP concentration does not mediate the antiapoptotic effect of adrenomedullin. The coadministration of N-nitro-L-arginine methyl ester (2 mmol/L), an inhibitor of nitric oxide synthase, abrogated the effect of adrenomedullin. Lower doses of sodium nitroprusside (1 to 10 µmol/L), a nitric oxide donor, mimicked the antiapoptotic effect of adrenomedullin. The antiapoptotic effect of sodium nitroprusside was not attenuated by the inhibition of soluble guanylyl cyclase with 1 µmol/L oxadiazolo-quinoxalin-1-one nor could apoptosis be inhibited by the incubation of human umbilical vein endothelial cells with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analog. These results indicate that adrenomedullin and nitric oxide inhibit endothelial cell apoptosis via a cGMP-independent mechanism.

Key Words: endothelium • adrenomedullin • apoptosis • nitric oxide • cyclic AMP

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