Earlier studies indicate that G₁ mediates enhanced renovascular responses to Ang II in SHR. The potentiation of Ang II by the G₁ pathway is blocked by pretreatment with pertussis toxin, an inhibitor of G₁. The G₁ pathway is also activated by receptors for PP-fold peptides; NPY, PYY, and PYY₃₋₃₆. Therefore, we hypothesize that in genetically predisposed models of hypertension PP-fold peptides augment renovascular responses to endogenous Ang II. Our study shows that LPNPY, an analogue of NPY selective for the Y₁ receptor, potentiates Ang II responses in SHR, but not WKY, kidneys in vitro. LPNPY'fs ability to potentiate Ang II renovascular responses is dependent on the Y₁ receptor and an intact G₁ pathway. The renal expression of Y₁ receptors is similar in SHR versus WKY. Our study also demonstrates that PYY₃₋₃₆, selective for the Y₂ receptor, potentiates renovascular responses to Ang II in SHR, but not WKY, in vitro. PYY₃₋₃₆ is dependent on an intact Y₂-G₁ pathway, and the Y₂ receptor is similarly expressed in the kidney of both strains. In comparing the PP-fold peptides, PYY is the most efficacious at potentiating Ang II-induced renovascular responses. Lower levels of these peptides have little effect on renal vasculature. Yet, these peptides are released with other G₁ coupled agonists, namely NE that acts on ∀₂-adrenoceptors. We observe a significant enhancement of Ang II-induced renal vasoconstriction with low level combinations of UK 14,304, an ∀₂-adrenoceptor agonist, and PYY/NPY. We demonstrate, in SHR, that nerve stimulation potentiates renal vasoconstrictive responses to Ang II. This interaction is dependent on an intact Y₁-G₁ pathway suggesting that NPY plays a predominate role in increasing renal vascular responses. PYY is a more potent agonist at augmenting renal vascular responses than is PYY₃₋₃₆. Blockade of the conversion of PYY to PYY₃₋₃₆ via a DPPIV inhibitor, P32/98, results in an increase in MABP in SHR. We also demonstrate that this effect is dependent on the Y₁ receptor pathway. This project demonstrates that PP-fold peptides may play a role in the etiology of genetic hypertension. This project is significant because it suggests a link between a high fat diet, sympathetic activation, and hypertension in a genetically susceptible animal.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08232006-153035 |
| Date | 28 August 2006 |
| Creators | Dubinion, John Harvey |
| Contributors | Peter Friedman, Edwin K. Jackson, Aaron Barchowsky, Thomas Kleyman, Chet De Groat |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-08232006-153035/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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