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dc.contributor.advisorStallone, John N.
dc.creatorOsborn, Pamela
dc.date.accessioned2015-01-09T19:58:11Z
dc.date.available2016-05-01T05:30:55Z
dc.date.created2014-05
dc.date.issued2014-01-17
dc.date.submittedMay 2014
dc.identifier.urihttp://hdl.handle.net/1969.1/152520
dc.description.abstractThe relative contributions of cyclooxygenase-1 (COX-1) versus COX-2 to vascular biosynthesis of prostacyclin (PGI_(2)) and thromboxane (TxA_(2)) and the role of estrogen in the regulation of COX function were studied in the thoracic aorta of age-matched 14-16 week old female (F) and male (M) Sprague Dawley rats. We hypothesized that COX-1 and COX-2 contribute differentially to the synthesis of PGI_(2) and TxA_(2) in the presence of estrogen. Ovary intact (Int-F), ovariectomized (OvX-F) and OvX+estrogen-replaced (OvX+ER-F) rats were studied. Rats were sacrificed 14 days post-op, and 3mm aortic rings were incubated in Krebs-Henseleit-bicarbonate buffer (KHB), containing either vehicle (basal), vasopressin (VP, 10^(-6) M), VP+SC-560 (SC, selective COX-1 inhibitor, 10^(-7) M), or VP+NS-398 (NS, selective COX-2 inhibitor, 10^(-5) M). The KHB was analyzed by specific radioimmunoassays (RIA) for 6-keto-PGF_(1α) (stable metabolite of PGI_(2) and TxB_(2) (stable metabolite of TxA2). Basal PGI_(2) was similar in M and all F groups (P=0.19). VP-stimulated PGI_(2) in M (4,528 ± 745) and OvX-F (4,785 ± 773) was reduced similarly by SC and NS (P>0.05). Also, VP-stimulated PGI_(2) in Int-F (15,352 ± 2,209) and OvX-ER-F (13,053 ± 3,086) was reduced significantly by SC and NS (P<0.05). Basal TxA_(2) was similar in all groups (P>0.05). VP-stimulated TxA_(2) in M (30 ± 4) and OvX-F (31 ± 7) was reduced similarly by SC and NS (P>0.05). VP-stimulated TxA_(2) in OvX-ER-F (71 ± 7) was reduced markedly more by NS than by SC (P<0.05). In conclusion, these data suggest that: 1) in the absence of estrogen in OvX-F and M, both PGI_(2) and TxA_(2) are derived equally from COX-1 and COX-2; and 2) in Int-F and OvX-ER-F, estrogen markedly enhances PGI_(2) and TxA_(2) production, primarily by upregulating COX-2 function. Furthermore, the mechanism by which TxA_(2) inhibits PGI_(2) synthesis was investigated in M rats. It was hypothesized that TxA_(2) inhibits PGI_(2) through a PKC-mediated nitrosylation on PGI synthase. Aortic rings were prepared and incubated in KHB, containing either vehicle (VP, 10^(-6) M), Calphostin C (CAL; PKC inhibitor, 10^(-6)M), or Furegrelate (FUR; TP receptor antagonist; 50µM), Ridogrel (RID; combined TP receptor antagonist and TxS inhibitor; 10^(-5)M), or Dazoxiben (DAZ; 50µM). The KHB was analyzed by specific RIA for 6-keto-PGF_(1α) and TxB_(2). TxA_(2) release was significantly attenuated by DAZ, RID, and FUR but was markedly enhanced by CAL 228% (0.001<P<0.05). Despite Ridogrel and Furegrelate significantly decreasing TxA_(2) release, neither of these inhibitors significantly attenuated PGI_(2) release in the aorta (P>0.05). However, PGI_(2) release was enhanced 158% in the presence of DAZ (0.001<P<0.05). It is possible that Calphostin may inhibit a PKC-mediated homologous desensitization loop to increase TxA_(2) release. DAZ effects clearly show that TxS inhibitors increase PGI_(2) release, however, it is puzzling that Ridogrel did not have the same effect. While TxA_(2) does seem to have a depressing effect of PGI_(2), it is clear that PKC-mediated nitrosylation of PGI synthase is not the mechanism by which TxA_(2) inhibits PGI_(2) release.en
dc.format.mimetypeapplication/pdf
dc.language.isoen
dc.subjectprostacyclinen
dc.subjectthromboxaneen
dc.subjectCOX-1en
dc.subjectCOX-2en
dc.titleThe Relative Contributions of COX-1 and COX-2 to Vascular Biosynthesis of Prostacyclin and Thromboxaneen
dc.typeThesisen
thesis.degree.departmentVeterinary Physiology and Pharmacologyen
thesis.degree.disciplineBiomedical Sciencesen
thesis.degree.grantorTexas A & M Universityen
thesis.degree.nameMaster of Scienceen
thesis.degree.levelMastersen
dc.contributor.committeeMemberStewart, Randolph H.
dc.contributor.committeeMemberSohrabji, Farida
dc.contributor.committeeMemberWashburn, Shannon
dc.type.materialtexten
dc.date.updated2015-01-09T19:58:11Z
local.embargo.terms2016-05-01


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