Mechanisms for central cannabinoid receptor 1 evoked sympathoexcitation/pressor response in conscious rats / by Badr Mostafa Sadek Ibrahim.
| Author/creator | Ibrahim, Badr Mostafa Sadek |
| Other author | Abdel-Rahman, Abdel A. |
| Other author | East Carolina University. Department of Pharmacology and Toxicology. |
| Format | Theses and dissertations |
| Publication Info | [Greenville, N.C.] : East Carolina University, 2010. |
| Description | 232 pages : illustrations (some color), digital, PDF file. |
| Supplemental Content | Access via ScholarShip |
| Subjects |
| Series | ECU Brody School of Medicine thesis ECU Brody School of Medicine thesis. ^A964744 |
| Summary | The main goal of the current study was to elucidate the molecular mechanisms implicated in central cannabinoid receptor 1 (CBıR)-evoked sympathoexcitation/pressor response. In pursuit of this goal, the candidate first characterized the centrally elicited hemodynamic effects of CBıR activation (WIN55,212-2) in a conscious rat model. The results showed that the pressor response elicited by central CBıR stimulation was associated with enhanced neuronal activity of presympathetic neurons in the rostral ventrolateral medulla (RVLM). The findings of multiple In vivo and in vitro studies have suggested a functional crosstalk between central CBıR and orexins. Therefore, the candidate hypothesized that orexin-A/orexin receptor 1 (OXıR) signaling in the RVLM is essential for the central CBıR-mediated pressor response. In support of this hypothesis, central CBıR activation elevated orexin-A level in the RVLM and inhibition of orexin-A/OXıR signaling abrogated the CBıR-evoked pressor effect. On the other hand, central orexin-A/OXıR-evoked pressor response was not affected by prior blockade of central CBıR. Colocalization studies have unraveled close proximity of orexin-A/OXıR to CBıR immuno-reactive neurons and punctate structures in the RVLM, which support the pharmacological findings. Furthermore, the present study delineated a novel role for PI3K/Akt/ERK1/2 signaling in RVLM and nucleus tractus solitarii (NTS) in the sympathoexcitation elicited by central CBıR activation in conscious rats. The latter findings inferred a causal role for a down-regulated PI3K/Akt signaling in the RVLM and NTS in the central CBıR-evoked pressor response. This conclusion is supported by the exacerbation of WIN55,212-2 evoked pressor response following PI3K/Akt inhibition (wortmannin). By contrast, ERK1/2 phosphorylation was enhanced in the same neuronal pools and the pharmacological and molecular studies suggest that this effect, which is mediated, at least partly, via the reduction in PI3K/Akt signaling, contributes to the central CBıR-evoked pressor response. Finally, the findings demonstrated that direct CBıR activation in the RVLM enhanced the activity of two distinct neuronal pools (catecholaminergic and nitroxidergic), which are essential for the central regulation of cardiovascular function. These latter neuronal responses may be linked to the modulation of brainstem GABAergic neurotransmission (GABAAR) and subsequently to the central CBıR-evoked sympathoexcitatory and pressor response. The findings yield new insight into a functional crosstalk between CBıR and OXıR signaling in the RVLM, a neuronal pool that is heavily implicated in blood pressure control and in hypertension. |
| General note | Presented to the faculty of the Department of Pharmacology. |
| General note | Advisor: Abdel A. Abdel-Rahman. |
| General note | Title from PDF t.p. (viewed February 24, 2011). |
| Dissertation note | Ph.D. East Carolina University 2010. |
| Bibliography note | Includes bibliographical references. |
| Technical details | System requirements: Adobe Reader. |
| Technical details | Mode of access: World Wide Web. |
Availability
| Library | Location | Call Number | Status | Item Actions |
|---|---|---|---|---|
| Electronic Resources | Access Content Online | ✔ Available |