An endogenous nitric oxide synthase inhibitor from hind limbs of infrarenal aortic cross-clamped rats.
dc.contributor.author | Jin, Jong-Shiaw | en_US |
dc.contributor.advisor | D'Alecy, Louis G. | en_US |
dc.date.accessioned | 2014-02-24T16:23:47Z | |
dc.date.available | 2014-02-24T16:23:47Z | |
dc.date.issued | 1995 | en_US |
dc.identifier.other | (UMI)AAI9610152 | en_US |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9610152 | en_US |
dc.identifier.uri | https://hdl.handle.net/2027.42/104796 | |
dc.description.abstract | We tested the hypothesis that an endogenous nitric oxide synthase (NOS) inhibitor released from ischemic hind limbs increases the activity of calcium channels in vascular smooth muscle, thus contributing to intraoperative hypertension, cardiac arrhythmias and declamping mortality. Intraoperative hypertension was generated in rats by infrarenal aortic cross-clamping for 5 hours after which plasma was obtained from femoral vein blood. In vitro contractile activity of naive aortic rings incubated for 2 hours in plasma collected from ischemic rats demonstrated reduced relaxation to acetylcholine. The impaired relaxation to acetylcholine in ischemic plasma incubated rings was significantly reversed by L-arginine, but not by prior treating ischemic plasma with heating or superoxide dismutase and catalase. These results suggest a non-protein and non-free radical mediated inhibition of NOS. Incubating naive aortic rings (endothelium intact) in ischemic plasma for 2 hours significantly increased contraction to the calcium channel agonist, Bay K 8644. However, in isolated smooth muscle cells (without endothelium) loaded with fura-2, no difference was noted in Bay K 8644 stimulated (Ca$\sp{2+}$) $\sb{\rm i}$. The increase in responsiveness to Bay K 8644 exhibited a negative correlation with the maximal relaxation to acetylcholine (R = $-$0.99) suggesting that the apparent increase in activity of calcium channels is mediated through inhibition of nitric oxide by an endogenous NOS inhibitor on endothelium. In in vivo studies, hind limb ischemia was generated by infrarenal aortic cross-clamping and tying the left femoral artery for 5 hours in rats with bilateral femoral and sciatic nerves cut. Mean blood pressure significantly increased during the 5 hour ischemic period. However, in ischemic rats infused with L-arginine, the intraoperative hypertension was prevented during the 5 hour period suggesting that the hypertension may be mediated by overcoming the actions of nitric oxide. The rates of mortality and arrhythmias two hours after declamping were 50% in ischemic alone, and 100% in ischemic rats treated 10 minutes before declamping with N$\sp{\omega}$-nitro-L-arginine (nitric oxide inhibitor). In ischemic rats infused with L-arginine, the mortality rate was reduced to zero and arrhythmic rate was inhibited. These findings suggest the impaired vascular smooth muscle relaxation is mediated endogenously through inhibition of the nitric oxide-cyclic GMP pathway. Further we conclude that the profound increase in sensitivity of calcium channels in vascular smooth muscle is mediated through inhibition of NOS in endothelium by an endogenous NOS inhibitor released from the ischemic hind limbs. L-Arginine prevents intraoperative hypertension during cross-clamping and decreases the mortality rate and arrhythmias after declamping by maintaining the synthesis of nitric oxide by mass action. | en_US |
dc.format.extent | 178 p. | en_US |
dc.subject | Biology, Animal Physiology | en_US |
dc.subject | Health Sciences, Medicine and Surgery | en_US |
dc.title | An endogenous nitric oxide synthase inhibitor from hind limbs of infrarenal aortic cross-clamped rats. | en_US |
dc.type | Thesis | en_US |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Physiology | en_US |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | en_US |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/104796/1/9610152.pdf | |
dc.description.filedescription | Description of 9610152.pdf : Restricted to UM users only. | en_US |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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