Role of the Subfornical Organ in the Chronic Hypotensive Response to Losartan in Normal Rats

Abstract

Abstract-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 (AT 1 ) 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 AT 1 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 ⅐ kg Ϫ1 ⅐ d Ϫ1 ) for 10 days in both SFO-lesioned and sham rats. By day 4 of losartan administration, mean arterial pressure had decreased to 75Ϯ2 mm Hg in sham rats (nϭ9) but had only fallen to 83Ϯ2 mm Hg in lesioned rats (nϭ10). 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 AT 1 receptor blockade in the normotensive rat. Key Words: antagonists, angiotensin Ⅲ autonomic nervous system Ⅲ blood pressure Ⅲ brain Ⅲ receptors, angiotensin II Ⅲ renin-angiotensin system Ⅲ circumventricular organ T he role of the renin-angiotensin system (RAS) in chronic blood pressure regulation is still not fully understood and continues to be studied. Much of our current understanding of this system is based on the response of arterial pressure to drugs that block the RAS, including ACE inhibitors and angiotensin type 1 (AT 1 ) receptor antagonists. We have demonstrated a profound chronic hypotensive response to the AT 1 receptor antagonist losartan in normotensive, salt-replete rats. 1 After 10 days of losartan treatment, rats consuming a normal-salt diet demonstrated a progressive hypotensive response of Ϸ35 mm Hg. This clearly shows an important role of this hormone in the maintenance of arterial pressure in normal animals, and yet, we do not fully understand the mechanism of this response.The mechanism by which blockade of the endogenous RAS lowers arterial pressure chronically is difficult to determine because of the numerous actions of angiotensin (Ang) II, which include vasoconstriction, 2 renal retention of sodium and water, 3-5 sympathoexcitation, 6 and vascular hypertrophy. 7 It has been reported that chronic low-dose Ang II hypertension is not solely caused by...

Simultaneous administration of Ang(1-7) or A-779 does not affect the chronic hypertensive effects of angiotensin II in normal rats

“…21,22 After surgery, all rats were given appropriate antibiotics and analgesics as previously described. 21,22 The rats were started on a continuous intravenous infusion of sterile 0.9% saline (7 ml/24 h) and housed individually in metabolic cages. A 0.4% NaCl diet (Research Diets) and distilled water were provided ad libitum.…”

The role of Ang (1-7) in mediating the chronic hypotensive effects of losartan in normal rats

“…In rats with lesions of either the area postrema or subfornical organ, the chronic hypotensive steady-state response to losartan was attenuated by nearly 40%. 2,5 Much recent research has focused on the angiotensin metabolite, Ang (1-7), an active peptide of the renin-angiotensin system (RAS) which is formed from either angiotensin I (Ang I) or Ang II. [6][7][8] This peptide has been shown to possess vasodilatory properties 9,10 and is thought to act at a non-AT 1 /AT 2 -receptor, due to the fact that its actions can be blocked by a specific antagonist (A779) which affects neither AT 1 -nor AT 2 -receptors.…”

Sodium balance, arterial pressure, and the role of the subfornical organ during chronic changes in dietary salt

“…Rats were then positioned in a stereotaxic apparatus. SFO lesions were completed as previously reported (6). Briefly, a dorsal midline incision was made through the skin of the skull.…”

“…The animals were then instrumented with radio-telemetric pressure transducers (model TA11PA-C40, Data Sciences International) for the purpose of continuous 24-h sampling of MAP and HR. The rats were anesthetized as described above, and transmitters were implanted as previously described (6). At the end of surgery, each rat received antibiotic and analgesic injections as described above.…”