Fos-Related Antigen Immunoreactivity After Acute and Chronic Angiotensin II–Induced Hypertension in the Rabbit Brain

Abstract

Abstract-Several brain regions are proposed as contributing to chronic sympatho-excitatory effects of elevated circulating angiotensin II. However, earlier c-Fos studies have been limited to acute angiotensin II exposure. This study aims to determine brain regions responding with chronic elevated angiotensin II. Rabbits were administered angiotensin II (50 ng/kg per minute) or saline for 3 hours, 3 days, or 14 days. Basal mean arterial pressure was 71Ϯ2 mm Hg and increased 23Ϯ2 mm Hg, 32Ϯ4 mm Hg, and 22Ϯ2 mm Hg for 3 hours, 3 days, and 14 days, respectively, with angiotensin II infusion. Neuronal activation was detected using Fos-related antigens, which recognizes all of the known members of the Fos family. Neurons located in the amygdala and area postrema were activated transiently after acute infusion of angiotensin II but were not responsive by days 3 or 14. Neurons located in the nucleus of the solitary tract, caudal ventrolateral medulla, and lateral parabrachial nucleus were activated for Յ3 days after infusion of angiotensin II but were not responsive by day 14, which is consistent with their role in response to baroreceptor pathways that reset with sustained hypertension. The vascular organ of the lamina terminalis and subfornical organ showed sustained but diminishing activation over the 14-day period. However, the downstream hypothalamic nuclei that receive inputs from these nuclei, the paraventricular, supraoptic, and arcuate nuclei, showed marked sustained activation. These findings suggest that there is desensitization of circumventricular organs but sensitization of neurons in hypothalamic regions to long-term angiotensin II infusion. Key Words: angiotensin II Ⅲ chronic hypertension Ⅲ Fos-related antigen Ⅲ immunohistochemistry Ⅲ rabbit brain A lthough renal hypertension is thought to be largely volume dependent, there is growing evidence to suggest that sympathetic nerve activity in hypertensive animals and also in human forms of the disease is likely to be increased. 1 A greater depressor response to ganglion blockade has been observed in angiotensin II (Ang II)-infused hypertensive rats 2 and renal wrap hypertensive rabbits. 3 In renovascular hypertensive patients, noradrenaline spillover is elevated. 4 Thus, it has been suggested that there are 2 distinct phases of Ang II-induced hypertension, an initial hypertension because of Ang II-mediated vasoconstriction that is replaced by a longer-term, neurogenic component. 2,3,5 Even so, the expected greater sympathetic activity in renovascular hypertension has been surprisingly difficult to confirm because of the use of indirect measures, which have yielded conflicting findings. 6,7 Moreover, recent studies have suggested that baroreceptor mechanisms inhibit sympathetic activity not only acutely but over several days, preventing sympathetic activation. 8,9 This hypothesis questions whether baroreceptors reset completely and suggests that, if they do not, then they may contribute to blood pressure regulation in the long term. These studies are limited ...

Pregnancy and the endocrine regulation of the baroreceptor reflex

“…2). Consistent with this hypothesis, chronic infusion of ANG II has been shown to cause activation of PVN neurons (49).…”

The hypothalamic arcuate nucleus: a new site of cardiovascular action of angiotensin-(1–12) and angiotensin II

“…Cardiovascular responses to microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the ARCN. The ARCN (ϳ2 mm long in the rostrocaudal direction) was arbitrarily divided into the following three equal segments (the coordinates mentioned for each segment indicate the level caudal to the bregma): the rostral segment (2.1-2.9 mm), middle segment (2.9 -3.7 mm), and caudal segment (3.7-4.5 mm).…”

“…Bilateral microinjections of ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) into the NTS have been reported to elicit transient depressor responses and an attenuation of baroreflex sensitivity (1). Chronic immunoneutralization of endogenous brain ANG- (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12) by intracerebroventricular injections of anti-ANG-(1-12) IgG in hypertensive rats have been reported to elicit antihypertensive effects (21). Several components of the renin-ANG system (RAS) have been identified in the ARCN.…”

Relaxin increases sympathetic nerve activity and activates spinally projecting neurons in the paraventricular nucleus of nonpregnant, but not pregnant, rats

“…The decrease in plasma osmolality and osmotic threshold for AVP secretion normally seen in the first half of pregnancy occurs simultaneous to increased plasma RLX (52), and a decrease in osmolality does not occur in ovariectomized or RLX-immunoneutralized P rats (38). Immunoneutralization of RLX (icv) in the second half of rat pregnancy (days [12][13][14][15][16][17][18][19][20][21][22] blocks the increase in water consumption that is normally mediated by an effect of RLX in the forebrain at this time (58).…”

“…However, a limitation of the c-Fos technique is that expression is maximal within 90 min, after which time, it becomes progressively downregulated and thus does not allow for direct comparisons of the baseline level of neuronal activation in P vs. NP rats. To assess whether endogenously secreted RLX chronically activates neurons in the SFO and PVN of P rats and to evaluate the time course of neuronal activation during gestation, future experiments could evaluate rats at different stages of gestation using an antibody that detects multiple members of the Fos family (some with induction times over weeks) (12). In addition, future experiments, in which RLX receptors are blocked or downregulated throughout pregnancy, would provide functional data on the potential role of endogenous RLX in elevated SNA in P rats.…”