Research reportOral administration of an AT1 receptor antagonist prevents the central effects of angiotensin II in spontaneously hypertensive rats
Introduction
Angiotensin II (Ang II), the acting principal of the renin–angiotensin system, (RAS) is a circulating and local hormone and paracrine factor that regulates blood pressure and fluid metabolism [15], [47]. The physiologically active receptors mediating the peripheral actions of Angiotensin belong to the AT1 type [47]. Peripheral AT2 receptors are not well characterized [12], perhaps mediating angiotensin formation and release of catecholamines in the adrenal gland [26], [32], and contributing to protect the kidney from ischemia [5].
Circulating Ang II, however, also affects the brain through stimulation of receptors located outside the blood–brain barrier [38], [40]. In addition, there is a brain Ang II system that contributes to the regulation of hormone release, central sympathetic activity, central response to stress, and many other brain functions [40]. Brain Ang II contributes to the development and maintenance of genetic hypertension, even in models where the circulating RAS is not stimulated, such as spontaneously hypertensive rats (SHRs) [40]. Whereas brain AT1 receptors mediate most of the central effects of Ang II, the role of brain AT2 receptors is not well understood, and they are probably involved in brain development and the regulation of sensory and motor systems [12], [41]. In addition, the brain AT2 receptors have been recently proposed to regulate blood pressure and drinking response to centrally administered Ang II [31].
We have demonstrated that peripheral administration of selective Ang II AT1 receptor antagonist blocks not only peripheral receptors but also central AT1 receptors [36]. Such a treatment prevents the central and peripheral components of the hormonal and sympathoadrenal response to stress [2] and protects the brain against ischemia [25], [37]. These results indicated that administration of AT1 antagonists could not only control systemic blood pressure but also exert central effects of additional therapeutic value.
We wished to clarify whether long-term oral administration of an AT1 receptor antagonist inhibiting both peripheral and brain receptors could selectively affect specific central actions of Ang II. We selected the AT1 antagonist, candesartan, an insurmountable antagonist [44] which, when administered peripherally, readily crosses the blood–brain barrier and significantly inhibits brain AT1 receptors [36]. To further establish the possibility that blockade of brain AT1 receptors could be considered therapeutically useful, we studied the effect of AT1 receptor blockade after the central administration of Ang II to SHRs, an animal model with increased activation of the brain sympathetic and Ang II systems, and with increased susceptibility to stress [22], [40]. In this study, we did not submit the SHRs to specific stress protocols; we focused on the effects of brain AT1 receptor blockade with or without intracerebroventricular (i.c.v.) administration of Ang II.
Section snippets
Animals and surgical preparation
The Animal Care and Use Committee of the National Institute of Mental Health, National Institutes of Health approved all experimental procedures. We studied male SHRs, 200–250 g weight, 8 weeks old, housed three to five per cage at a room temperature of 20 °C, with food and water available ad libitum, under a 12-h light/dark cycle. Animals were randomly divided into groups of eight animals each, and were treated with oral candesartan-celexetil (TCV 116; ASTRA, Mölndal, Sweden), 10 mg/kg/day,
Systolic blood pressure, plasma catechols, and plasma hormones after treatment of SHRs with the AT1 receptor antagonist
Systolic arterial blood pressure was high in SHRs treated with vehicle and decreased to normal levels in animals treated with the AT1 receptor antagonist (Fig. 1A). This treatment parallels the normalization of the increased blood pressure in SHRs, as described earlier, from 180 to 240 mm Hg before the treatment to values about 100–110 mm Hg after treatment [25], [37]. Levels of plasma catecholamines, as measured here in SHRs treated with vehicle, were consistent to, and in the same range of,
Discussion
Long-term oral administration of the AT1 receptor antagonist, candesartan, normalizes the increased blood pressure in SHRs [25], [37] and inhibits binding to brain AT1 receptors in addition to peripheral AT1 sites in a manner similar to that of subcutaneously injected candesartan in normotensive rats [36]. Candesartan, an insurmountable AT1 receptor antagonist [44], was administered until the day of the experiment, and inhibition of binding as detected in vitro was probably due, at least in
Acknowledgements
A.S. is a member of the Argentinean National Research Council (CONICET).
References (54)
- et al.
Losartan potassium, a nonpeptide antagonist of angiotensin II, chronically administered p.o. does not readily cross the blood–brain barrier
Eur. J. Pharmacol.
(1992) - et al.
The AT2 receptor: fact, fancy and fantasy
Regul. Pept.
(1999) - et al.
Source and physiological significance of plasma 3,4-dihydroxyphenylglycol and 3-methoxy-4-hydroxyphenylglycol
J. Auton. Nerv. Syst.
(1988) - et al.
Characterization and distribution of angiotensin II receptor subtypes in the mouse brain
Eur. J. Pharmacol.
(1998) - et al.
Quantitative autoradiography of Angiotensin II AT2 receptors with [125I]CGP 42112
Brain Res.
(1995) - et al.
The role of angiotensin, AT1 and AT2 receptors in the pressor, drinking and vasopressin responses to central angiotensin
Brain Res.
(1992) - et al.
Chemical lesion of the inferior olive reduces [125I]Sarcosine1–Angiotensin II binding to AT2 receptors in the cerebellar cortex of young rats
Brain Res.
(1998) - et al.
Biochemical mapping of noradrenergic nerves arising from the rat locus coeruleus
Brain Res.
(1974) - et al.
The use of 14C-labeled tissue paste standards for the calibration of 125I-labeled ligands in quantitative autoradiography
Neurosci. Lett.
(1987) - et al.
Chronic peripheral administration of the angiotensin II AT1 receptor antagonist candesartan blocks brain AT1 receptors
Brain Res.
(2000)