European Journal of Pharmacology, 251 (1994) 103-106 103 Elsevier Science B.V. EJP 21406 Short communication Role of angiotensin AT 1 receptor in the cardiovascular response to footshock Maria Cierco and Anita Israel * School of Pharmacy, Universidad Central de Venezuela and School of Medicine, Universidad Francisco de Miranda, Caracas, Venezuela Received 5 October 1993, accepted 5 November1993 This study assessed the effect of non-peptide angiotensin II receptor subtype antagonists on the cardiovascular response to footshock. Effects of electric stimulation (1, 2 or 5 Hz) on mean arterial pressure (MAP) and heart rate (HR) were determined. Peripheral or central administration of losartan, an angiotensin AT 1 receptor antagonist (1 or 10 mg/kg s.c., or at 10, 30 or 100 /~g/5 Izl i.c.v.), inhibited the mean arterial pressure response but not the heart rate response to footshock. In contrast, the MAP response to exogenous administration of norepinephrine was not inhibited by subcutaneous administration of losartan (10 mg/kg). Given at 100/~g/5/el i.c.v., the angiotensin ATe-selective receptor antagonist, PD 123319, did not reduce hemodynamic responses to electric stimulation. These results suggest that, in acute stress, endogenous angiotensin II facilitation of noradrener- gic transmission is mediated through the angiotensin AT 1 receptor. Angiotensin receptor subtype; Losartan; PD 123319; Footshock 1. Introduction Angiotensin II enhances sympathetic nervous system action. This excitatory influence is multifarious and can be exerted both peripherally and centrally. Peripher- ally, angiotensin II has been shown to stimulate adrenal medulla and sympathetic ganglia (Reit, 1972; Wong et al., 1990). At postganglionic endings angiotensin poten- tiates transmitter biosynthesis (Roth, 1972) and release (Zimmerman et al., 1972) through the activation of prejunctional angiotensin II receptors, inhibition of norepinephrine reuptake and increasing vascular re- sponsiveness to norepinephrine (Story and Ziogas, 1987). Angiotensin II also enhances adrenergic tone by central activation and facilitation of sympathetic trans- mission (Antonaccio and Kerwin, 1981) and increases catecholamine turnover in sympathetic brain nuclei (Sumners and Phillips, 1983). Specific binding sites for angiotensin II have been shown to exist in multiple sites in the sympathetic nervous system, in brain (Saavedra et al., 1986), in adrenal medulla (Israel et al., 1985) and in the sympathetic stellate and superior cervical ganglia (Castr6n et al., 1987). Recent availability of new non-peptidic angiotensin II antagonists has led to the identification of two * Corresponding author. Apartado Postal 50176, Sabana Grande 1050, Caracas, Venezuela. Fax (582) 662.6027 or (582) 979.1336. receptor subtypes, AT 1 and AT e (Chiu et al., 1989). The angiotensin AT 1 receptor is sensitive to losartan while the AT z receptor is sensitive to PD 123319 and CGP 42112A. Brain areas related to sympathetic activ- ity regulation have been shown to contain mainly an- giotensin AT 1 receptors (Tsutsumi and Saavedra, 1991). Angiotensin AT 1 receptors are also located in adrenal medulla (Chiu et al., 1989) and in superior cervical ganglia (Str6mberg et al., 1991). There is evidence suggesting that endogenous angiotensin II enhances renal adrenergic function and facilitates norepineph- rine release from sympathetic nerve terminals in the vasculature of pithed rats at the prejunctional site through the activation of angiotensin AT 1 receptors (Wong et al., 1992). In the present study we examined the effect of peripheral administration of losartan or central block- ade of either AT~ or AT 2 receptors on the cardiovascu- lar response to footshock, an experimental model which causes sympathoadrenal activation (Lee et al., 1989). 2. Material and methods Male Sprague-Dawley rats (160-190 g) were housed under controlled conditions of temperature and pho- toperiod (light on from 06:00 to 18:00 h) and were provided with free access to laboratory chow and wa- ter. A group of rats were implanted with a cannula in SSDI 0014-2999(93)E0812-7