Sustained Activation of the Central Baroreceptor Pathway in Angiotensin Hypertension

Abstract

Abstract-Recent studies indicate that renal sympathetic nerve activity is chronically suppressed in angiotensin (Ang II) hypertension and that baroreflexes play a critical role in mediating this response. To support these findings, we determined whether the hypertension associated with chronic infusion of Ang II at 4.8 pmol/kg per minute (5ng/kg per minute) produces sustained activation of medullary neurons that participate in the central baroreceptor reflex pathway. We used Fos-like (Fos-Li) protein immunohistochemical methods to determine activation of neurons in the nucleus tractus solitarius (NTS), caudal ventrolateral medulla (CVLM), and rostral ventrolateral medulla (RVLM). Results were compared in three groups of chronically instrumented dogs subjected to infusion of: 1) saline (control); 2) Ang II-2 hours (acute); and 3) Ang II-5 days (chronic here has been a long-standing interest in the mechanisms that contribute to the hypertension induced by pathophysiological levels of angiotensin (Ang II) in the circulation. Although circulating Ang II has sustained actions on the kidneys, vasculature, and adrenal glands that promote chronic hypertension, acute studies have also demonstrated that circulating Ang II can act in the central nervous system to increase sympathetic activity and arterial pressure. 1 However, the relevance of these acute studies to the pathophysiological role of Ang II in hypertension has not been settled. In large part, this is because of technical limitations that prevent determination of both the long-term changes in sympathetic activity and the sustained influence of the sympathetic nervous system on renal excretory function.It is well established that the kidneys play a critical role in the long-term regulation of arterial pressure. 2 The few studies that have determined the temporal changes in renal sympathetic nerve activity and the resultant neurally-induced renal excretory responses during chronic Ang II infusion strongly indicate interactions between the renin-angiotensin and sympathetic nervous systems in the genesis of the hypertension. [3][4][5][6][7] In direct opposition to the notion that the sympathetic nervous system contributes to Ang II hypertension, these studies indicate that suppression of renal sympathetic nerve activity and attendant increases in sodium excretion are sustained responses in Ang II hypertension. 3-7 These findings therefore suggest that the sympathetic nervous system actually attenuates rather than contributes to the severity of Ang II hypertension. Furthermore, based on a recent study in chronically instrumented dogs, it seems that chronic renal sympathoinhibition in Ang II hypertension is mediated by baroreflexes. 6 As it is well established that baroreceptors undergo rapid adaptation and resetting, 8 this recent study is rather surprising. In fact, the implication of this study is that the baroreflex does not completely reset in chronic hypertension and, therefore, may play a role in the chronic regulation of arterial pressure. The primary object...

Central neural distribution of immunoreactive Fos and CRH in relation to plasma ACTH and corticosterone during sepsis in the rat

“…Furthermore, intravenous doses of endotoxin Zhang, et al, 2003) or interleukin-1 (Ericsson, et al, 1994) increase central Fos for about 6 h with a peak at 2 to 3 h. Improved detection of Fos through the use of optimized fixation and antibodies as in the present study may reveal responses of longer duration, but their intensity frequently declines from the initial peak. Sustained expression of Fos in the NTS and ventrolateral medulla does occur in some experimental models of chronic hypertension (Lohmeier et al, 2002;Lohmeier et al, 2003); and, in contrast to the present findings, CRH neurons in the PVH show a sustained increase in Fos mRNA during chronic insulin-induced hypoglycemia (Brown and Sawchenko, 1997). The areas showing sustained expression of Fos after CLP may reflect unique features in the course of sepsis such as the recruitment of new incoming pathways.…”

Increased dietary sodium alters neural control of blood pressure during intravenous ANG II infusion

“…Data for 0. the neural component of the pressor response increases over longer-term (hours to days) infusions until the hypertension is predominantly due to increased SNS drive (6,25,48). Finally, in addition to sympathoexcitation, which tends to increase arterial blood pressure, long-term intravenous administration of pressor concentrations of ANG II stimulates central centers resulting in sympathoinhibition associated with baroreflex activation (28).…”

“…It has been shown that long-term (in hours) intravenous infusion of pressor concentrations of ANG II activates central sites mediating sympathoinhibition and SNS withdrawal (28). Furthermore, increased dietary sodium enhances depressor responses to chemical stimulation of the nucleus tractus solitarius (19) and electrical stimulation of the aortic depressor nerve (39), and increases bradycardia to aortic depressor nerve stimulation (39).…”

Renal Denervation Does Not Abolish Sustained Baroreflex-Mediated Reductions in Arterial Pressure

“…[1][2][3][4][5][6][7][8][9][10] These studies, conducted over several weeks, indicate that baroreflex resetting is incomplete in experimental models of hypertension. They also indicate that during chronic increases in arterial pressure, there is sustained baroreflex-mediated suppression of renal sympathetic nerve activity and attendant increments in renal excretory function, responses expected to attenuate the severity of hypertension.…”