Angiogenesis is reportedly enhanced by prostaglandins (PGs). In the present study, we investigated whether or not cyclo‐oxygenase (COX)‐2 mediated angiogenesis in chronic and proliferate granuloma. In rat sponge implants, angiogenesis was gradually developed over a 14‐day experimental period as granuloma formed. This angiogenesis was enhanced by topical injections of human recombinant basic fibroblast growth factor (bFGF). In sponge granuloma, mRNA of COX‐1 was constitutively expressed, whereas that of COX‐2 was increased with neovascularization in parallel with that of vascular endothelial growth factor (VEGF). Topical injections of bFGF increased the expression of COX‐2 mRNA. bFGF‐stimulated angiogenesis was inhibited by indomethacin or selective COX‐2 inhibitors, NS‐398, nimesulide, and JTE‐522. The levels of PGE2 and 6‐keto‐PGF1α in the sponge granuloma were increased with bFGF 13 fold and 9 fold, respectively, and these levels were markedly reduced by NS‐398. The expression of VEGF mRNA in the granuloma was also enhanced by bFGF, and was reduced by NS‐398. Topical injections of PGE2 and beraprost sodium, a PGI2 analogue, increased the expression of VEGF mRNA, with angiogenesis enhancement. The enhanced angiogenesis by bFGF was significantly inhibited by topical injections of VEGF anti‐sense oligonucleotide. These results suggested that COX‐2 may enhance bFGF‐induced neovascularization in sponge granuloma by PG‐mediated expression of VEGF, and that a COX‐2 inhibitor would facilitate the management of conditions involving angiogenesis. British Journal of Pharmacology (2000) 130, 641–649; doi:

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The enzyme activities of CYP2D6 and CYP2C19 show a genetic polymorphism, and the frequency of poor metabolizers (PMs) on these enzymes depends on races. In the present study, the frequencies of mutant alleles and PMs in each race were analyzed based on information from published studies, considering the genetic polymorphisms of CYP2D6 and CYP2C19 as the causal factors of racial and inter-individual differences in pharmacokinetics. As a result, it was shown that there were racial differences in the frequencies of each mutant allele and PMs. The frequencies of PMs on CYP2D6 are 1.9% of Asians and 7.7% of Caucasians, and those of PMs on CYP2C19 are 15.8% of Asians and 2.2% of Caucasians. Based on the results, it was suggested that there would be racial differences in the frequencies of PM subjects whose blood concentrations might be higher for drugs metabolized by these enzymes. Additionally, it was suggested that enzyme activities would vary according to the number of functional alleles even in subjects judged to be extensive metabolizers (EMs). In the bridging study, genetic information regarding CYP2D6 and CYP2C19 of the subjects will help extrapolate foreign clinical data to a domestic population.

1 Physiological roles of angiotensin II type 2 receptor (AT 2 ) are not well de®ned. This study was designed to investigate the mechanisms of AT 2 -dependent vascular relaxation by studying vasodilation in pressurized and perfused rat mesenteric arterial segments. 2 Perfusion of angiotensin II in the presence of AT 1 antagonist elicited vascular relaxation, which was completely dependent on AT 2 receptors on endothelium. FR173657 (41 mM), a bradykinin (BK) B 2 -speci®c antagonist, signi®cantly suppressed AT 2 -dependent vasodilation (maximum inhibition: 68.5% at 10 mM). 3 Kininogen-de®cient Brown Norway Katholiek rats showed a signi®cant reduction in AT 2 -mediated vasodilatory response compared with normal wild-type Brown Norway rats. 4 Indomethacin (41 mM), aprotinin (10 mM) and soybean trypsin inhibitor (10 mM) also reduced AT 2 -dependent vasodilation. 5 Our results demonstrated that stimulation of AT 2 receptors caused a signi®cant vasodilation through local production of BK in resistant arteries of rat mesentery in a¯ow-dependent manner. Such vasodilation counterbalances AT 1 -dependent vasoconstriction to regulate the vascular tone.

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