The AT-1 Angiotensin Receptor is Involved in the Autonomic and Neuroendocrine Responses to Acute Restraint Stress in Male Rats.

The renin-angiotensin system (RAS) is involved in cardiovascular and hydroelectrolytic control, being associated with the development of hypertension. The restraint stress (RS) model is an aversive situation, which promotes a sustained increase in blood pressure and heart rate, and stimulation of the hypothalamic-pituitary-adrenal axis. Stress leads to an increase of angiotensin-II contents both in the circulation and the central nervous system (CNS), as well as an increased expression of AT-1 receptors in CNS structures related to stress. Stressful stimuli are associated with the modulation of autonomic nervous system, as well as baroreflex; changes in this adjustment mechanism are related to cardiovascular diseases. We hypothesized that RAS is involved in the modulation of autonomic, neuroendocrine, and functional RS-caused alterations. The intravenous (i.v) pretreatment of rats with lisinopril, an angiotensin-converting-enzyme inhibitor, reduced the RS-evoked pressor response. The doses of 0.1 and 0.3 mg/kg also reduced the RS-evoked tachycardia, while in the dose of 1 mg/kg of lisinopril potentiated the tachycardic one. Additionally, i.v. pretreatment with losartan, a selective AT-1 receptor antagonist, reduced the pressor and the tachycardic responses caused by RS. Pretreatment with lisinopril 0.3 mg/kg increased the power of the low frequency (LF) band of the systolic BP spectrum after the treatment without affecting this parameter during RS. The pretreatment with losartan 1 mg/kg increased the power of the high frequency (HF) band and reduced the LF (n.u.) and the LF/HF ratio of the pulse interval spectrum in the first hour of RS. Concerning baroreflex sensitiveness (SBR), pretreatments with losartan or lisinopril did not affect the gain of the baroreflex sequences. However, the pretreatment with losartan reduced the baroreflex effectiveness index of the total sequences in the third hour of the RS. These results indicate that Ang-II, via the AT-1 receptor, plays a facilitating influence on the cardiovascular response caused by RS; facilitates sympathetic activation and reduces parasympathetic activity related to RS; facilitates the baroreflex activation during RS and favors corticosterone release under this stress model. The impairment of Ang-II synthesis, as well as the blockade of AT-1 receptors, may constitute an important pharmacological strategy to treat cardiovascular consequences caused by stress.

The Dorsomedial Hypothalamus Is Involved in the Mediation of Autonomic and Neuroendocrine Responses to Restraint Stress.

We hypothesized that dorsomedial hypothalamus (DMH) modulates autonomic and neuroendocrine responses in rats at rest and when subjected to restraint stress (RS). Male Wistar rats were used, and guide cannulas were bilaterally implanted in the DMH for microinjection of vehicle or the nonspecific synaptic blocker CoCl2 (1 mM/100 nl). A polyethylene catheter was inserted into the femoral artery for the recording of arterial pressure and heart rate (HR). Tail temperature was measured using a thermal camera. The session of RS started 10 min after DMH treatment with vehicle or CoCl2. Under home-cage condition, the pretreatment of DMH with CoCl2 increased baseline blood pressure (BP), and heart rate (HR) without affecting the tail temperature. In addition, it decreased plasma vasopressin levels without affecting plasma corticosterone and oxytocin contents. When rats pretreated with CoCl2 were exposed to RS, the RS-evoked cardiovascular were similar to those observed in vehicle-treated animals; however, because cobalt pretreatment of the DMH increased baseline BP and HR values, and the RS-evoked cardiovascular responses did not exceed those observed in vehicle-treated animals, suggesting a possible celling limit, the possibility that DMH is involved in the modulation of RS-evoked cardiovascular responses cannot be certainly excluded. Nonetheless, the pretreatment of DMH with CoCl2 blocked the reduction in tail temperature caused by RS. The DMH pretreatment with CoCl2 did not modify the RS-evoked increase in plasma corticosterone and oxytocin contents. In conclusion, the present data suggest the involvement of DMH in the maintenance of BP, HR, and vasopressin release under the rest conditions at the home-cage. Furthermore, indicate that DMH is an important thermoregulatory center during exposure to RS, regulating tail artery vasoconstriction.

AT1 and AT2 Receptors in the Prelimbic Cortex Modulate the Cardiovascular Response Evoked by Acute Exposure to Restraint Stress in Rats.

The prelimbic cortex (PL) is an important structure in the neural pathway integrating stress responses. Brain angiotensin is involved in cardiovascular control and modulation of stress responses. Blockade of angiotensin receptors has been reported to reduce stress responses. Acute restraint stress (ARS) is a stress model, which evokes sustained blood pressure increase, tachycardia, and reduction in tail temperature. We therefore hypothesized that PL locally generated angiotensin and angiotensin receptors modulate stress autonomic responses. To test this hypothesis, we microinjected an angiotensin-converting enzyme (ACE) inhibitor or angiotensin antagonists into the PL, prior to ARS. Male Wistar rats were used; guide cannulas were bilaterally implanted in the PL for microinjection of vehicle or drugs. A polyethylene catheter was introduced into the femoral artery to record cardiovascular parameters. Tail temperature was measured using a thermal camera. ARS was started 10 min after PL treatment with drugs. Pretreatment with ACE inhibitor lisinopril (0.5 nmol/100 nL) reduced the pressor response, but did not affect ARS-evoked tachycardia. At a dose of 1 nmol/100 nL, it reduced both ARS pressor and tachycardic responses. Pretreatment with candesartan, AT1 receptor antagonist reduced ARS-evoked pressor response, but not tachycardia. Pretreatment with PD123177, AT2 receptor antagonist, reduced tachycardia, but did not affect ARS pressor response. No treatment affected ARS fall in tail temperature. Results suggest involvement of PL angiotensin in the mediation of ARS cardiovascular responses, with participation of both AT1 and AT2 receptors. In conclusion, results indicate that PL AT1-receptors modulate the ARS-evoked pressor response, while AT2-receptors modulate the tachycardic component of the autonomic response.