Angiotensin II-induced contractions in human internal mammary artery: effects of cyclooxygenase and lipoxygenase inhibition.
OBJECTIVE
This study investigated, in isolated human internal mammary artery, the involvement of the cyclooxygenase and the lipoxygenase pathways of arachidonic acid metabolism in the contraction induced by angiotensin II.


METHODS
Rings of human internal mammary arteries were suspended in organ baths for recording of isometric tension. In addition, the release of eicosanoids in response to angiotensin II (0.3 microM) was measured by enzyme immunoassay.


RESULTS
In human arterial rings without endothelial dependent relaxation in response to substance P or acetylcholine, the angiotensin II-induced contractions were significantly (P<0.05) reduced by 27% in the presence of GR32191 0.3 microM (thromboxane A(2) (TXA(2)) receptor antagonist) but remained unchanged in the presence of dazoxiben 100 microM (thromboxane synthase inhibitor). In addition, angiotensin II failed to modify TXB(2) and 6-keto-PGF(1alpha) production. These results suggest the contribution of a TXA(2)/PGH(2) agonist other than TXA(2) in angiotensin II-induced contractions. However, indomethacin increased (P<0.05) angiotensin II-mediated contractile response and cysteinyl leukotriene production, suggesting a redirection of arachidonic acid metabolism from the cyclooxygenase pathway to the lipoxygenase pathway. Indeed, the contractions induced by angiotensin II were inhibited (P<0.05) by phenidone 100 microM (cyclooxygenase and lipoxygenase inhibitor), baicalein 100 microM (5-, 12- and 15-lipoxygenases inhibitor), AA861 10 microM (5-lipoxygenase inhibitor) and MK571 1 microM (CysLT(1) receptor antagonist). Cysteinyl leukotrienes were released in response to angiotensin II (pg/mg dry weight tissue: 32+/-9 (basal, n=6) vs. 49+/-9 (angiotensin II 0.3 microM, n=6), P<0.05). LTD(4), and at a lesser degree LTC(4), induced contractions of internal mammary artery and MK571 1 microM abolished the contraction to LTD(4).


CONCLUSIONS
This study suggests that the in vitro vasoconstrictor effects of angiotensin II in human internal mammary artery are enhanced at least in part by eicosanoids produced by the cyclooxygenase pathway, probably PGH(2), acting on TXA(2)/PGH(2) receptors, and by lipoxygenase-derived products, particularly cysteinyl leukotrienes acting on CysLT(1) receptors.
Stanke-Labesque
F
F
Laboratory of Pharmacology, University of Medicine, LSCPA EA2937, La Tronche, France. francoise.stanke@ujf-grenoble.fr
Devillier
P
P
Bedouch
P
P
Cracowski
J L
JL
Chavanon
O
O
Bessard
G
G
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044950:Flavanones; D005419:Flavonoids / Q000494:pharmacology; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D015289:Leukotrienes / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008323:Mammary Arteries / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013373:Substance P / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects*
D016227:Benzoquinones; D001713:Biphenyl Compounds; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D044950:Flavanones; D005419:Flavonoids; D006538:Heptanoic Acids; D007093:Imidazoles; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011720:Pyrazoles; D011804:Quinolines; D017482:Receptors, Thromboxane; C029166:dazoxiben; D000804:Angiotensin II; D013373:Substance P; C006680:baicalein; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C059141:verlukast; C036837:2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone; D013930:Thromboxane-A Synthase; C015429:phenidone; C060013:vapiprost; D000109:Acetylcholine; D007213:Indomethacin