{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,26]],"date-time":"2025-11-26T16:12:58Z","timestamp":1764173578549,"version":"3.37.0"},"reference-count":31,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,8,26]],"date-time":"2009-08-26T00:00:00Z","timestamp":1251244800000},"content-version":"vor","delay-in-days":4495,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[1997,5,6]]},"abstract":"<jats:p><jats:bold>Summary\u2014<\/jats:bold>We previously reported that chronic inhibition of NO synthase (NOS) in dogs leads to an upregulation of the cyclooxygenase (COX) pathway in the endothelium of the coronary artery after stimulation by bradykinin (BK) in vitro. The present experiments were designed to identify the nature of the COX isoform involved in this phenomenon. Rings of circumflex (LCX) and left anterior descending (LAD) coronary arteries were isolated from six control dogs and six dogs treated with the NOS\u2010inhibitor, N\u03c9\u2010nitro\u2010L\u2010arginine (L\u2010NNA, 30 mg\/kg\/d, iv, during 7 days). Concentration\u2010response curves to BK in U46619\u2010contracted rings from LCX coronary arteries were constructed in the presence and absence of another NOS inhibitor (N<jats:sup>G<\/jats:sup>\u2010monomethyl\u2010L\u2010arginine, L\u2010NMMA), of selective inhibitors of the inducible isoform of COX (NS\u2010398 and L\u2010745,337) and of a non selective inhibitor of the inducible and constitutive isoforms of COX (indomethacin). Finally, measurements of 6\u2010keto\u2010prostaglandin Fl\u03b1, the stable metabolite of prostacyclin, were performed in the incubation medium by enzymo\u2010immuno\u2010assay on rings of isolated LAD coronary arteries in the presence and absence of the same inhibitors of COX, before and after stimulation by BK. In rings taken from control dogs, BK evoked a concentration\u2010dependent relaxation (Emax: 115 \u00b1 10%; EC<jats:sub>50<\/jats:sub>: 8 \u00b1 4 nM). In the presence of L\u2010NMMA, the concentration\u2010relaxation curve to BK was significantly shifted to the right (Emax: 77 \u00b1 8%; EC50; 43 \u00b1 22 nM,<jats:italic>P<\/jats:italic>&lt; 0.05). Addition of NS\u2010398, L\u2010745,337 and indomethacin to L\u2010NMMA did not further modify the concentration\u2010relaxation curve to BK. After chronic inhibition of NOS, the concentration\u2010relaxation curve to BK was similar to that observed in rings taken from control dogs in the presence of L\u2010NMMA (Emax; 75 \u00b1 5%; EC<jats:sub>50<\/jats:sub>: 69 \u00b1 36 nM). Addition of L\u2010NMMA, alone or in combination with NS\u2010398 or L\u2010745,337 did not significantly modify this concentration\u2010relaxation curve to BK. In contrast, the L\u2010NMMA\u2010indomethacin combination blunted the BK\u2010induced relaxation of the coronary artery (Emax: 28 \u00b1 10%,<jats:italic>P<\/jats:italic>&lt; 0.01). Basal release of prostacyclin was not different in rings taken from control and L\u2010NNA treated dogs (56 \u00b1 16 vs 58 \u00b1 15 pg\u03bc\u2010mm<jats:sup>2<\/jats:sup>). BK significantly increased this release but the increment was twofold greater in rings taken from L\u2010NNA treated dogs than in rings taken from control dogs (<jats:italic>P<\/jats:italic>&lt; 0.05). In rings taken from control and L\u2010NNA treated dogs, the BK\u2010stimulated production of prostacyclin observed in the presence of the solvent was not significantly modified by L\u2010NMMA or the L\u2010NMMA\u2010L\u2010745,337 combination. In contrast, the L\u2010NMMA\u2010indomethacin combination as well as endothelium removal completely suppressed the BK\u2010stimulated production of prostacyclin. These findings demonstrate that in dogs submitted to chronic inhibition of NO synthesis (1) the residual relaxation to BK of canine isolated coronary arteries is mainly due to production of prostacyclin of endothelial origin, and (2) the enhancement of prostacyclin production by these vessels is mainly due to an upregulation of the endothelial constitutive isoform of COX.<\/jats:p>","DOI":"10.1111\/j.1472-8206.1997.tb00193.x","type":"journal-article","created":{"date-parts":[[2009,8,26]],"date-time":"2009-08-26T18:28:04Z","timestamp":1251311284000},"page":"252-259","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Chronic inhibition of NO synthase enhances the production of prostacyclin in coronary arteries through upregulation of the cyclooxygenase type 1 isoform"],"prefix":"10.1111","volume":"11","author":[{"given":"F.","family":"Beverelli","sequence":"first","affiliation":[]},{"given":"ML","family":"B\u00e9a","sequence":"additional","affiliation":[]},{"given":"L.","family":"Puybasset","sequence":"additional","affiliation":[]},{"given":"JF","family":"Giudicelli","sequence":"additional","affiliation":[]},{"given":"A.","family":"Berdeaux","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2009,8,26]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.70.6.1091"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115906"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(92)81292-T"},{"key":"e_1_2_1_5_1","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1016\/S0022-3565(25)10713-1","article-title":"Pharmacology of a selective cyclooxygenase\u20102 inhibitor, L\u2010735,337: a novel nonsteroidal antiinflammatory agent (NSAID) with an ulcerogenic sparing effect in rat and nonhuman primate stomach","volume":"274","author":"Chan CC","year":"1995","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_1_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(88)90687-5"},{"key":"e_1_2_1_7_1","first-page":"6","volume-title":"Proceedings of the 9th International Conference on Prostaglandins and Related Compounds","author":"Engelhardt G.","year":"1994"},{"key":"e_1_2_1_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1988.tb10306.x"},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.3883488"},{"key":"e_1_2_1_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/0090-6980(94)90074-4"},{"key":"e_1_2_1_11_1","first-page":"55","article-title":"Risks of upper gastrointestinal bleeding and perforation associated with individual nonsteroidal anti\u2010inflammatory drugs","volume":"47","author":"Rodriguez Garcia LA","year":"1994","journal-title":"Lancet"},{"key":"e_1_2_1_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-2999(95)00302-2"},{"key":"e_1_2_1_13_1","first-page":"H828","article-title":"Vasoconstriction and increased flow: two principal mechanisms of shear stress\u2010dependent endothelial autacoid release","volume":"265","author":"Hecker M.","year":"1993","journal-title":"Am J Physiol"},{"key":"e_1_2_1_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.92.9.2636"},{"key":"e_1_2_1_15_1","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1016\/S0022-3565(25)23861-7","article-title":"Differential inhibition of human prostaglandin endoperoxide H synthases\u20101 and \u20102 by non\u2010steroidal anti\u2010inflammatory drugs","volume":"271","author":"Laneuville O.","year":"1994","journal-title":"J Pharmacol Exp Ther"},{"key":"e_1_2_1_16_1","doi-asserted-by":"crossref","first-page":"6610","DOI":"10.1016\/S0021-9258(18)53294-4","article-title":"Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non\u2010steroidal and anti\u2010inflammatory drugs","volume":"268","author":"Meade EA","year":"1993","journal-title":"J Biol Chem"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.90.24.11693"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.71.1.137"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1996.tb15206.x"},{"key":"e_1_2_1_20_1","first-page":"109","article-title":"Biosynthesis and endogenous roles of nitric oxide","volume":"43","author":"Moncada S.","year":"1991","journal-title":"Pharmacol. 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