Hoe 140 (d‐Arg‐[Hyp3, Thi5, d‐Tic7, Oic8]bradykinin) is a new bradykinin (BK)‐antagonist. It was tested in several in vitro assays and compared with d‐Arg‐[Hyp2, Thi5,8,d‐Phe7]BK.
In receptor binding studies in guinea‐pig ileum preparations, Hoe 140 showed an IC50 of 1.07 × 10−9mol l−1 and a KI value of 7.98 × 10−10 mol l−1.
In isolated organ preparations Hoe 140 and d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK inhibited bradykinin‐induced contractions concentration dependently, with IC50‐values in the guinea‐pig ileum preparation of 1.1 × 10−8 mol l−1 and 3 × 10−5 mol l−1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 × 10−9 mol l−1 for Hoe 140. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK showed an IC50 of 4.0 × 10−6 mol l−1. The IC50 values in the guinea‐pig isolated pulmonary artery were 5.4 × 10−9 mol l−1 and 6.4 × 10−6 mol l−1, respectively. In the rabbit aorta no inhibitory effects on Des‐Arg9‐BK induced contractions were observed.
In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10−8 mol l−1) bradykinin‐induced endothelium‐derived relaxing factor (EDRF) release and the bradykinin‐induced increase in cytosolic free calcium (IC50 = 10−9 mol l−1).
Hoe 140 (10−7 mol l−1) totally suppressed the bradykinin‐induced (10−8 to 10−4mol l−1) prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK (10−7 mol l−1) showed a weaker antagonism.
Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK.
In conscious dogs, intravenous doses of 0.01 and 0.1 mgkg-1 of Hoe 140 and D-Arg-[Hyp2, Thi5'8, D-Phe7]BK were well tolerated. At doses of 1 mg kg-adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. 6 Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.
SummaryRice (Oryza sativa L.) produces ent-copalyl diphosphate (ent-CDP) and syn-CDP as precursors for several classes of phytoalexins and the phytohormones, gibberellins (GAs). It has recently been shown that a loss-offunction mutation of OsCPS1, a gene encoding a putative ent-CDP synthase, results in a severely GA-deficient dwarf phenotype in rice. To clarify the biological functions of the ent-and syn-CDP synthases involved in the biosynthesis of phytoalexins and/or GAs, we isolated two cDNAs, OsCyc1 and OsCyc2, encoding putative diterpene cyclases from ultraviolet (UV)-irradiated rice leaves (cv. Nipponbare). The production of phytoalexins in rice leaves is known to be highly induced by UV treatment. Using a bacterial expression system, we demonstrated that OsCyc1 encodes syn-CDP synthase and that OsCyc2 and OsCPS1 encode ent-CDP synthase. The level of expression of the OsCyc1 and OsCyc2 transcripts in rice leaves increased drastically in response to UV treatment, whereas expression of the OsCPS1 transcript was not induced by UV light. These results suggest that OsCyc1, OsCyc2 and OsCPS1 are responsible for the biosynthesis of momilactones A and B and oryzalexin S, oryzalexins A-F and phytocassanes A-E, and GAs, respectively. Our results strongly suggest the presence of two ent-CDP synthase isoforms in rice, one that participates in the biosynthesis of GAs and a second that is involved in the biosynthesis of phytoalexins.
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