on April 28, 2008
Published online before print April 28, 2008, doi: 10.1161/CIRCULATIONAHA.107.753467
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Submitted on November 18, 2007
From the Departments of Pharmacology (L.L., K.L.N., Y.C., S.W.L., R.B., P.K.M.), and Chemistry (Y.Y.G., Y.Z., C.T.), National University of Singapore, Singapore; Pharmaceutical Science Division, King's College, London, UK (L.L., P.K.M.); and Institute of Biomedical and Clinical Science, Peninsula Medical School, Universities of Exeter and Plymouth, Exeter, UK (M.W.). * To whom correspondence should be addressed. E-mail: phillip.moore{at}kcl.ac.uk.
Background—The potential biological significance of hydrogen sulfide (H2S) has attracted growing interest in recent years. The aim of this study was to characterize a novel, water-soluble, slow-releasing H2S compound [morpholin-4-ium 4 methoxyphenyl(morpholino) phosphinodithioate (GYY4137)] and evaluate its use as a tool to investigate the cardiovascular biology of this gas. Methods and Results—The acute vasorelaxant effect of drugs was assessed in rat aortic rings and perfused rat kidney in vitro and in the anesthetized rat in vivo. The chronic effect of GYY4137 on blood pressure in normotensive and spontaneously hypertensive rats was determined by tail-cuff plethysmography. GYY4137 released H2S slowly both in aqueous solution in vitro and after intravenous or intraperitoneal administration in anesthetized rats in vivo. GYY4137 caused a slow relaxation of rat aortic rings and dilated the perfused rat renal vasculature by opening vascular smooth muscle KATP channels. GYY4137 did not affect rat heart rate or force of contraction in vitro. GYY4137 exhibited antihypertensive activity as evidenced by ability to reduce NG-nitro-L-arginine methyl ester–evoked hypertension in the anesthetized rat and after chronic (14-day) administration in spontaneously hypertensive rats. Conclusions—These results identify GYY4137 as a slow-releasing H2S compound with vasodilator and antihypertensive activity. GYY4137 is likely to prove useful in the study of the many and varied biological effects of H2S. GYY4137 may also prove of therapeutic value in cardiovascular disease.
Accepted on March 14, 2008
Characterization of a Novel, Water-Soluble Hydrogen Sulfide–Releasing Molecule (GYY4137). New Insights Into the Biology of Hydrogen Sulfide
Ling Li BSc,
Key words: blood pressure • endothelium • hypertension • hydrogen sulfide
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