title: Disruption of elastic lamellae in aorta and dysfunction of vaso-regulation by rofecoxib in rats.
abstract: We assessed the effects of rofecoxib on cross-linkage formation in elastin and vaso-regulatory function in rats. After administration of rofecoxib at a dose of 10 mg/kg for 7 weeks to young rats and for 7 and 10 weeks to adult rats, thoracic aortas were isolated. The elastic lamellae in the aortas were disrupted histopathologically in all the treated groups. However, the content of cross-linkages in elastin, i.e. desmosine and isodesmosine, which give elasticity to the aortic wall, was not significantly different between the rofecoxib treated and control groups. On the other hand, although the baseline blood pressure was not changed during the treatment period in both young and adult rats, after several weeks of treatment with rofecoxib the change between systolic blood pressure before and after sympathetic stimulation by L-epinephrine was 2 to 3-fold larger than that in the control group. Similar results were obtained using angiotensin II instead of L-epinephrine. The exposure to rofecoxib (area under the plasma concentration-time curve) of rats after single administration was a few times higher than that of humans in clinical use. These findings indicate that rofecoxib did not directly inhibit formation of cross-linkages in elastin of the aorta in rats. However, the treatment with rofecoxib for several weeks disrupted elastic lamellae and caused depression of vaso-regulatory function in rats, which could bring on an increased risk of cardiovascular events in human.
authors.affiliation: Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Tokyo University of Science.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyajima
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okamoto
authors.forename: Takafumi
authors.initials: T
authors.lastname: Muto
authors.forename: Takashi
authors.initials: T
authors.lastname: Hirota
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology*; D062186:Arterial Pressure / Q000187:drug effects*; D002318:Cardiovascular Diseases / Q000139:chemically induced; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D003895:Desmosine / Q000378:metabolism; D004547:Elastic Tissue / Q000187:drug effects* / Q000378:metabolism; D004548:Elasticity / Q000187:drug effects*; D004549:Elastin / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D007524:Isodesmosine / Q000378:metabolism; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood
chemical_list: D000596:Amino Acids; D052246:Cyclooxygenase 2 Inhibitors; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D003895:Desmosine; C015484:pyridinoline; D004549:Elastin; D007524:Isodesmosine