The endothelial layer of blood vessels is able to produce a number of vasoactive substances, and these substances can work to either relax or contract the underlying vascular smooth muscle. A hallmark of hypertension is the development of endothelial dysfunction, a shift in the balance of these substances to a state of increased contraction. Hydrogen sulfide (H2S) has recently garnered much interest as a gaseous signaling molecule with the discoveries that is can relax isolated blood vessels and lower blood pressure in young spontaneously hypertensive rats (SHR). Here we investigate whether chronic H2S treatment (56 μmol/kg of the H2S donor sodium hydrosulfide (NaHS), once daily for 5 weeks) can lower the blood pressure of adult aged SHR when compared to normotensive control Wistar Kyoto rats (WKY), and whether there are changes in the endothelium-dependent relaxation and contraction pathways. Invasive hemodynamic measurements including systolic, diastolic, and mean blood pressure, as well as heart rate were measured. Isolated vessel myography was performed on the common carotid artery to determine whether there were changes in the endothelium-dependent and independent relaxation and contraction pathways. This was achieved using a number of dose response curves. Changes in endothelium dependent dilation to ACh, VSM sensitivity to NO and H2S, and NO bioavailability were tested with dose response curves using ACh, SNP (an NO donor), H2S and indomethacin, respectively. TP receptor sensitivity, as well as COX-mediated constriction in quiescent vessels was also examined by using the TP receptor agonist U46619 and L-NAME (eNOS inhibitor), respectively. Biochemical analyses included Western blotting to assess protein levels of CSE (H2S generating enzyme) and eNOS (NO generating enzyme) as well as determining prostacyclin production. Determination of H2S concentration in the blood via a sulfide electrode was also performed to confirm that the H2S treatment was effective. There were no main effects of H2S treatment in any of the hemodynamic measurements taken. ACh dose response revealed a blunting in the recontraction at 10-5 and 10-4.5 log M concentrations (p<0.05) in SHR treated with H2S. No effects were observed, however, in any other myography protocol. Western blot analysis revealed no difference in the protein expression of CSE or eNOS with H2S treatment, and there were no differences in prostacyclin production with H2S treatment. In conclusion, these data suggest that H2S may not be an effective treatment for hypertension in adult SHR, in contrast to previous work finding a similar dosing regimen to be effective at lowering blood pressure in young SHR. Further work must be completed to ascertain the mechanism for the alteration in the ACh dose response curve and to determine at what time point the H2S treatment becomes ineffective.
| Identifer | oai:union.ndltd.org:WATERLOO/oai:uwspace.uwaterloo.ca:10012/7389 |
| Date | January 2013 |
| Creators | Reid, Eric Benjamin |
| Source Sets | University of Waterloo Electronic Theses Repository |
| Language | English |
| Detected Language | English |
| Type | Thesis or Dissertation |
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