Blood-borne interleukin-1ß acts on the subfornical organ to upregulate the sympathoexcitatory milieu of the hypothalamic paraventricular nucleus.

We previously reported that microinjection of the proinflammatory cytokine interleukin-1ß (IL-1ß) into the subfornical organ (SFO) elicits a pressor response accompanied by increases in inflammation and renin-angiotensin system (RAS) activity in the SFO and hypothalamic paraventricular nucleus (PVN). The present study sought to determine whether blood-borne IL-1ß induces similar neurochemical changes in the SFO and PVN and, if so, whether increased inflammation and RAS activity at the SFO level orchestrate the sympathoexcitatory response to circulating IL-1ß. In urethane-anesthetized male Sprague-Dawley rats, intravenous injection of IL-1ß (500 ng) increased blood pressure, heart rate, renal sympathetic nerve activity, and mRNA for angiotensin-converting enzyme, angiotensin II type 1a receptor, cyclooxygenase-2, tumor necrosis factor-α, and IL-1ß, as well as the tumor necrosis factor-α p55 receptor and the IL-1 receptor, in the SFO and PVN. Pretreatment with SFO microinjections of the angiotensin II type 1a receptor blocker losartan (1 µg), the angiotensin-converting enzyme inhibitor captopril (1 µg), or the cyclooxygenase-2 inhibitor NS-398 (2 µg) attenuated expression of these excitatory mediators in the SFO and downstream in the PVN and the IL-1ß-induced pressor responses. An SFO lesion minimized the IL-1ß-induced expression of inflammatory and RAS components as well as c-Fos, an indicator of neuronal excitation, in the PVN. These studies demonstrate that circulating IL-1ß, which increases in cardiovascular disorders such as hypertension and heart failure, acts on the SFO to increase inflammation and RAS activity in the SFO and PVN and that intervening in these neurochemical processes in the SFO can significantly reduce the sympathetic response.

Role of the subfornical organ in the chronic hypotensive response to losartan in normal rats.

Angiotensin II is known to act at a unique set of brain regions known as the circumventricular organs. These structures lack the normal blood-brain barrier and are therefore thought to participate in the central nervous system processing of neuroendocrine signals. We have reported that chronic treatment with the angiotensin type 1 (AT1) receptor antagonist, losartan, decreases arterial pressure in normotensive rats. Furthermore, this hypotension is attenuated in area postrema-lesioned rats, suggesting a role of endogenous angiotensin II at this circumventricular organ. Another circumventricular organ, the subfornical organ (SFO), has also been shown to mediate actions of angiotensin II. The present study tested the hypothesis that the SFO is a central site of action of endogenous angiotensin II at AT1 receptors. Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic apparatus, and the SFO was sham or electrolytically lesioned. One week later, rats were instrumented with venous catheters and radiotelemetry pressure transducers for continuous infusion and monitoring of mean arterial pressure, respectively. After 3 days of control, losartan was administered intravenously (10 mg x kg(-1) x d(-1)) for 10 days in both SFO-lesioned and sham rats. By day 4 of losartan administration, mean arterial pressure had decreased to 75+/-2 mm Hg in sham rats (n=9) but had only fallen to 83+/-2 mm Hg in lesioned rats (n=10). This attenuated hypotensive response in SFO-lesioned rats continued through day 10 of losartan treatment. These results support the hypothesis that the SFO mediates part of the hypotensive effects of chronic AT1 receptor blockade in the normotensive rat.

Influence of the subfornical organ on meal-associated drinking in rats.

A lesion of the subfornical organ (SFO) may disrupt drinking after a meal of dry chow as it does drinking after intragastric administration of hypertonic saline. Food and water intakes of SFO-lesioned (SFOX) and sham-lesioned rats were measured during 90-min tests following various lengths of food deprivation. During the tests, all rats began eating before they began drinking. After 20-24 h of food deprivation, latency to begin drinking after eating had started was longer for SFOX than for sham-lesioned rats. Plasma osmolality was elevated by 2-3% in both lesion groups at 12 min, the latency for sham-lesioned rats to drink, but SFOX rats nevertheless continued eating and delayed drinking. Eating after shorter 4-h food deprivations and ad libitum feeding produced more variable drinking latencies and less consistent effects of SFO lesion. During 24 h of water deprivation, SFO lesion had no effect on the suppression of food intake and did not affect food or water intakes during the first 2 h of subsequent rehydration. These findings indicate that the SFO is involved in initiating water intake during eating and in determining drinking patterns and the amount of water ingested during a meal.

Role of the subfornical organ in the relaxin-induced prolongation of gestation in the rat.

The role of the subfornical organ in the timing of birth in the rat was investigated. Animals with radiofrequency lesions of the subfornical organ made on day 12 of pregnancy gave birth significantly earlier (P < 0.05) than intact and control-lesioned rats. Animals with lesions made on day 19 of pregnancy gave birth within control times. In addition, the natural fall in plasma relaxin observed at the end of gestation in rats was prevented by i.v. infusion of porcine relaxin (4.2 micrograms/h for 5 days from day 19 of gestation), which maintained plasma relaxin levels at approximately 100 ng/ml. This rate of infusion was selected because the resultant circulating levels of relaxin reflect plasma concentrations observed on day 20 of pregnancy in rats. The effect of lesion of the subfornical organ was then studied on the timing of birth in relaxin-infused rats. Intact animals and rats with control lesions receiving an infusion of relaxin had significantly (P < 0.05) prolonged pregnancies compared with intact saline-infused controls. However, the timing of birth of rats with lesions of the subfornical organ receiving an infusion of relaxin was not significantly (P > 0.05) different from that in intact saline-infused controls. The results support the hypothesis that the subfornical organ appears to mediate the central effects of relaxin and may have a natural role in the events that lead to delivery in the rat.