Acknowledgment. This study was supported by M.P.I. (Roma). We thank the supply Department of Zoological Station (Napoli) for collection of the animals. Mass spectra were provided by the "Servizio di Spettrometria di massa" of the CNR and the Universitá di Napoli. The assistance of the staff is gratefully acknowledged.

New nitro ester 3-[(nitrooxy)alkyl]-2H-1,3-benzoxazin-4(3H)-ones show marked inhibitory activity against ischemia-induced electrocardiographic changes, with only limited systemic hemodynamic effects, and are reported in the present study. These new nitro vasodilators are potent inhibitors of the electrocardiographic T-wave and S-T segment elevation induced by intravenous or intracoronary administration of Arg-vasopressin or methacholine in the anesthetized rat. The most active compounds are up to 300- and 600-fold more potent than glyceryl trinitrate or Nicorandil, respectively. These nitro esters relax in a concentration-dependent manner the isolated rabbit aorta, at higher concentrations (2-40-fold) than glyceryl trinitrate, and reduce the mean arterial blood pressure at doses 7-300-fold higher than those required by glyceryl trinitrate to exert a similar hypotensive effect. Remarkably, these compounds retain their anti-ischemic and hemodynamic profile after oral (po) administration. These new nitro ester derivatives, endowed with a marked antianginal activity, which is not associated with concurrent and pronounced falls in systemic blood pressure, represent the leads of a new class of selective nitrovasodilators having a preferential action on large coronary vessels, which could be clinically relevant in the treatment of coronary artery diseases.

The homolytic benzylation of protonated 4-cyanopyridine, quinoline, 2-methyl-and 4-methylquinoline, isoquinoline, and quinoxaline is investigated. The great influence of the polar effect and of the reversibility of the addition of the benzyl radical on the reaction selectivity is discussed. It is put forward the hypothesis that the HSAB principle can be extended to free-radical reactions when the polar effect is the dominant factor.

No abstract

IThe inflammatory response induced by poly-L-arginine in the rat hind-paw was studied both by measuring paw oedema and histologically. 2 The paw volume was measured with a hydroplethysmometer at 0.5, 1, 2, 4, 6 and 18 h after the subplantar injection of the polycation. Protein extravasation was evaluated with Evans' blue and the histology studied by light microscopy. 3 Poly-L-arginine (12, 24, 43 and 115 kD) caused dose-and molecular weight-dependent oedema which had a rapid onset and long duration. Evans' blue extravasation paralleled the oedema induced by poly-Larginine. Microscopic examination of the paws at early stages of oedema formation showed exuberant liquid exudate with no inflammatory cells. After 18 h, a cellular infiltrate was present, consisting mainly of mononuclear cells. 4 Indomethacin, dexamethasone, BW755c or the PAF-antagonist WEB 2086 caused no significant inhibition of the poly-L-arginine-induced oedema. Cyproheptadine had inhibitory effects only on the early stages of the polycation-induced oedema. Similar results were observed with rats depleted of histamine and 5-hydroxytryptamine. 5 Heparin, a polyanion, injected in the rat paw caused a marked inhibition of the polycation-induced oedema. NG-monomethyl-L-arginine (LNMMA), an inhibitor of EDRF synthesis, injected locally also produced a marked inhibition, but this inhibition was reversed by iloprost. 6 These results suggest that the oedema induced by polycations was due to their cationic charge. The inhibitory effect of LNMMA is probably due to a decrease in vascular flow rather than a decrease in vascular permeability.