The median preoptic nucleus (MnPO) receives dense reciprocal inputs from both the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), the circumventricular organs known to be important as central neural sensors of circulating angiotensin II (ANG II). This thesis proposes to establish the role of the MnPO in chronic regulation of blood pressure based on the central hypothesis that the MnPO is a crucial component of the central sympathoexcitatory circuitry necessary for chronic blood pressure control following ANG II activation of the SFO and OVLT. Throughout the studies, cardiovascular responses to either pharmacological or physiological changes of circulating ANG II activity were compared between MnPO lesioned rats and sham lesioned controls.
The first specific aim was designed to test the hypothesis that the intact MnPO is necessary for the full hypertensive response to chronic intravenous ANG II administration. In this specific aim, rats with electrolytic lesion of the MnPO displayed significantly attenuated hypertensive responses by day 7 through day 10 of ANG II infusion compared to sham lesioned rats. Therefore, we concluded that the MnPO is a crucial component of the central neuronal circuitry mediating chronic ANG II-induced hypertension.
Sub-aim 1A was designed to determine the specific role of the MnPO neurons versus fibers of passage in the attenuated hypertensive responses to ANG II observed in the MnPO lesioned rats. In line with the findings of specific aim 1, rats with ibotenic acid lesion of the MnPO demonstrated attenuated responses to the hypertensive effect of chronic ANG II administration. However, the attenuated responses were less extensive relative to those seen in the electrolytic lesioned rats. Therefore, it was concluded that neuronal cell bodies in the MnPO are necessary for the full hypertensive response to chronic ANG II administration; however, damage of the fibers of passage partly contributes to the attenuated hypertensive responses observed in the electrolytic lesioned rats.
The second specific aim was to determine the role of the MnPO in mediating the chronic hypotensive effect of the AT1 receptor antagonist, losartan. In this specific aim, rats with ibotenic acid lesion of the MnPO showed exaggerated hypotensive responses to chronic losartan administration. These findings were accompanied with a greater decline in total peripheral resistance in the MnPO lesioned rats. Therefore, we concluded that MnPO neurons do not mediate the chronic hypotensive effect of losartan and that the MnPO is not necessary for basal blood pressure control by endogenous ANG II. However, the findings suggested that the MnPO neurons likely participate in baroreflex mechanisms buffering against losartan-induced hypotension.
The last specific aim was to establish the role of the MnPO in normal blood pressure control during chronic high dietary salt intake. Although plasma sodium concentration and osmolality were raised significantly in rats with electrolytic lesion of the MnPO during high salt intake, their mean arterial pressure and heart rate were comparable with those of sham lesioned rats throughout the study. Therefore, we concluded that the MnPO is not necessary to maintain normal blood pressure during high dietary salt intake. However, MnPO lesioned rats displayed less renal sodium retention during high salt intake compared to sham lesioned rats suggesting the role of the MnPO in the central neurohumoral control of sympathetic outflow, in particular, renal sympathetic activity, during chronic high salt intake.
In conclusion, overall, the findings in this dissertation provide important insights into the role of the MnPO in the chronic hypertension induced by ANG II. Furthermore, they provide additional evidence of the integrative role of the MnPO in chronic normal blood pressure control by circulating ANG II, plasma osmolality, and the baroreflex.
University of Minnesota Ph.D. dissertation. December 2008. Major: Molecular Veterinary Biosciences. Advisor: John P. Collister, D.V.M., Ph.D. 1 computer file (PDF); xii, 215 pages.
Role of the median preoptic nucleus in chronic blood pressure regulation by angiotensin II.
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