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3 It inhibited ET-1, ET-2 and ET-3-induced vasoconstriction of porcine isolated coronary arteries in a competitive (ET-1, ET-2) and a non-competitive (ET-3) manner. 4 In the rat in vivo, the ET-1-induced blood pressure changes including transient hypotension followed by sustained hypertension, were inhibited by TAK-044 (0.1-10 mg kg-', i.v.) in a dose-dependent manner.5 Acute myocardial infarction induced by 1 h coronary occlusion followed by 24 h reperfusion in rats caused an infarct size of 60 + 2% (n = 12) of the area-at-risk by weight. 6Intravenous injection of TAK-044 10 min before coronary occlusion reduced the infarct size in a dose-dependent manner: 32% and 54% reductions at 1 and 3 mg kg-', respectively. 7 TAK-044 administered 10 min before or I h after reperfusion (1 mg kg-', i.v.) showed similar inhibitory effects: 34% and 23% reductions, respectively. 8 We conclude that TAK-044 is an ETA/ETB receptor antagonist which shows strong inhibitory effects on the extension of myocardial infarct size after coronary artery occlusion-reperfusion in rats.

The conformation in solution of porcine brain natriuretic peptide was determined by combined use of NMR spectroscopy and distance geometry. A set of 157 inter-proton-distance constraints was derived from the twodimensional NOE spectra, and further a set of three hydrogen bond constraints was obtained from analysis of the temperature dependence of labile protons. The five structures with minimal violations were selected after performing distance-geometry calculations starting from 40 random initial conformations. The distance-geometry structures were further refined by the use of restrained energy minimization and restrained molecular dynamics. This structure shows a compact conformation with the carboxy-terminal region, Am21 -Tyr26, folded back to the disulfide-linked loop region, Cys4 -Cys20. The characteristics of the conformation determined are as follows: conformations of the three segments interposed by glycine residues, which are Arg7 -Ile12, Serl4 -Leu18 and Cys20 -Arg25, were well defined and the segments Arg7 -Ile12 and Cys20 Porcine brain natriuretic peptide (pBNP) was identified from acid extracts of porcine brain and was classified as a member of the atrial natriuretic peptide (ANP) family [l]. pBNP consists of 26 amino-acid residues and forms a monocyclic structure with a disulfide between Cys4 and Cys2O. The region Cys7 -Tyr28 of human ANP(hANP) exhibits full biological activities, such as natriuretic/diuretic and hypotensive effects. pBNP is distinguished from hANP by possessing six substitutions and one insertion in the corresponding region, Cys4-Tyr26 (Fig. 1) 121. ANP and BNP are both secreted from atrium cordis, so it is supposed that the homeostatic balances of body fluid and blood pressure are under dual regulation involving both ANP and BNP [I].The advances in both NMR methodology and computational techniques over the past few years have made it possible to determine the three-dimensional structures of polypeptides in solution 131. A number of peptide conformations have been resolved by the combined use of two-dimensional (2D) NMR and distance-geometry algorithm [4 -71. ConforCorrespondence to H. Inooka, Wadai 7, Tsukuba, Ibaraki, Japan Abbreviations. BNP, brain natriuretic peptide; pBNP, porcine BNP; ANP, atrial natriuretic peptide; hANP, human ANP; 2D, twodimensional; RMSD, root-mean-square distance; DADAS, distance analysis in dihedral angle space; cHx, cyclohexyl; MeOBzl, pmethoxybenzyl; Pme, pentamethylbenzenesulfonyl; HONB, Nhydroxy-5-norbornene-2,3-dicarboximide; Boc, t-butoxycarbonyl; OcHx, cyclohexyl ester; HOHAHA, 2D homonuclear HartmannHahn spectroscopy; NOESY, 2D nuclear Overhauser enhancement spectroscopy; DQF-COSY, 2D double-quantum-filtered correlated spectroscopy; REM, restrained energy minimization; RMD, restrained molecular dynamics. 300-42mational studies of hANP using 2D NMR techniques have been reported [8 -111. A defined conformation could not be found in most of these studies due to the flexibility of the peptide molecule in solution. Kobayashi et al. reported a defin...

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