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A substantial literature details the relationship between age-related changes to the hypothalamic-pituitary-adrenal axis and deterioration of mnemonic functions that depend on the hippocampus. The relationship between adrenocortical status and other forms of memory that depend on the prefrontal cortex is less well understood in the context of advanced age. Here, we characterized performance of young adult and aged F344 rats on a prefrontal cortex-dependent working memory task and subsequently measured corticosterone (CORT) levels over the diurnal cycle and during exposure to an acute stressor. Our analyses revealed that aged rats with better working memory mounted a greater CORT response during acute stress exposure than either young adults or age-matched rats with impaired working memory. We also observed that age-related elevation of basal CORT levels is not associated with working memory performance. Jointly, these data reveal that the hypothalamic-pituitary-adrenal axis-mediated response to acute stress is positively associated with working memory in aging., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Angiotensin-II acts at its type-1 receptor (AT1R) in the brain to regulate body fluid homeostasis, sympathetic outflow and blood pressure. However, the role of the angiotensin type-2 receptor (AT2R) in the neural control of these processes has received far less attention, largely because of limited ability to effectively localize these receptors at a cellular level in the brain. The present studies combine the use of a bacterial artificial chromosome transgenic AT2R-enhanced green fluorescent protein (eGFP) reporter mouse with recent advances in in situ hybridization (ISH) to circumvent this obstacle. Dual immunohistochemistry (IHC)/ISH studies conducted in AT2R-eGFP reporter mice found that eGFP and AT2R mRNA were highly co-localized within the brain. Qualitative analysis of eGFP immunoreactivity in the brain then revealed localization to neurons within nuclei that regulate blood pressure, metabolism, and fluid balance (e.g., NTS and median preoptic nucleus [MnPO]), as well as limbic and cortical areas known to impact stress responding and mood. Subsequently, dual IHC/ISH studies uncovered the phenotype of specific populations of AT2R-eGFP cells. For example, within the NTS, AT2R-eGFP neurons primarily express glutamic acid decarboxylase-1 (80.3 ± 2.8 %), while a smaller subset express vesicular glutamate transporter-2 (18.2 ± 2.9 %) or AT1R (8.7 ± 1.0 %). No co-localization was observed with tyrosine hydroxylase in the NTS. Although AT2R-eGFP neurons were not observed within the paraventricular nucleus (PVN) of the hypothalamus, eGFP immunoreactivity is localized to efferents terminating in the PVN and within GABAergic neurons surrounding this nucleus. These studies demonstrate that central AT2R are positioned to regulate blood pressure, metabolism, and stress responses.

Macrophage migration inhibitory factor (MIF) counteracts pressor effects of angiotensin II (ANG II) in the paraventricular nucleus of the hypothalamus (PVN) in normotensive rats, but this mechanism is absent in spontaneously hypertensive rats (SHRs) due to a lack of MIF in PVN neurons. Since endogenous ANG II in the PVN modulates stress reactivity, we tested the hypothesis that replacement of MIF in PVN neurons would reduce baseline blood pressure and inhibit stress-induced increases in blood pressure and plasma corticosterone in adult male SHRs. Radiotelemetry transmitters were implanted to measure blood pressure, and then an adeno-associated viral vector expressing either enhanced green fluorescent protein (GFP) or MIF was injected bilaterally into the PVN. Cardiovascular responses to a 15-min water stress (1-cm deep, 25°C) and a 60-min restraint stress were evaluated 3-4 wk later. MIF treatment in the PVN attenuated average restraint-induced increases in blood pressure (37.4 ± 2.0 and 27.6 ± 3.5 mmHg in GFP and MIF groups, respectively, P < 0.05) and corticosterone (42 ± 2 and 36 ± 3 μg/dl in GFP and MIF groups, respectively, P < 0.05). MIF treatment in the PVN also reduced stress-induced elevations in the number of c-Fos-positive cells in the rostral ventrolateral medulla (71 ± 5 in GFP and 47 ± 5 in MIF SHRs, P < 0.01) and corticotropin-releasing factor mRNA expression in the PVN. However, MIF had no significant effects on the cardiovascular responses to water stress in SHRs or to either stress in Sprague-Dawley rats. Therefore, viral vector-mediated restoration of MIF in PVN neurons of SHRs attenuates blood pressure and hypothalamic pituitary adrenal axis responses to stress., (Copyright © 2015 the American Physiological Society.)

Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) in response to hypertensive stimuli including stress and hyperosmolarity. However, it is unclear whether BDNF in the PVN contributes to increases in blood pressure (BP). We tested the hypothesis that increased BDNF levels within the PVN would elevate baseline BP and heart rate (HR) and cardiovascular stress responses by altering central angiotensin signaling. BP was recorded using radiotelemetry in male Sprague-Dawley rats after bilateral PVN injections of adeno-associated viral vectors expressing green fluorescent protein (GFP) or myc epitope-tagged BDNF fusion protein. Cardiovascular responses to acute stress were evaluated 3 to 4 wk after injections. Additional GFP and BDNF-treated animals were equipped with osmotic pumps for intracerebroventricular infusion of saline or the angiotensin type-1 receptor (AT1R) inhibitor losartan (15 μg·0.5 μl(-1)·h(-1)). BDNF treatment significantly increased baseline BP (121 ± 3 mmHg vs. 99 ± 2 mmHg in GFP), HR (394 ± 9 beats/min vs. 314 ± 4 beats/min in GFP), and sympathetic tone indicated by HR- and BP-variability analysis and adrenomedullary tyrosine hydroxylase protein expression. In contrast, body weight and BP elevations to acute stressors decreased. BDNF upregulated AT1R mRNA by ∼80% and downregulated Mas receptor mRNA by ∼50% in the PVN, and losartan infusion partially inhibited weight loss and increases in BP and HR in BDNF-treated animals without any effect in GFP rats. Our results demonstrate that BDNF overexpression in the PVN results in sympathoexcitation, BP and HR elevations, and weight loss that are mediated, at least in part, by modulating angiotensin signaling in the PVN., (Copyright © 2015 the American Physiological Society.)

Repeated stress and chronically elevated glucocorticoids cause exaggerated cardiovascular responses to novel stress, elevations in baseline blood pressure, and increased risk for cardiovascular disease. We hypothesized that elevated corticosterone (Cort) within the dorsal hindbrain (DHB) would: 1) enhance arterial pressure and neuroendocrine responses to novel and repeated restraint stress, 2) increase c-Fos expression in regions of the brain involved in sympathetic stimulation during stress, and 3) recruit a vasopressin-mediated blood pressure response to acute stress. Small pellets made of 10% Cort were implanted on the surface of the DHB in male Sprague-Dawley rats. Blood pressure was measured by radiotelemetry. Cort concentration was increased in the DHB in Cort-treated compared with Sham-treated rats (60 ± 15 vs. 14 ± 2 ng Cort/g of tissue, P < 0.05). DHB Cort significantly increased the integrated arterial pressure response to 60 min of restraint stress on days 6, 13, and 14 following pellet implantation (e.g., 731 ± 170 vs. 1,204 ± 68 mmHg/60 min in Sham- vs. Cort-treated rats, day 6, P < 0.05). Cort also increased baseline blood pressure by day 15 (99 ± 2 vs. 108 ± 3 mmHg for Sham- vs. Cort-treated rats, P < 0.05) and elevated baseline plasma norepinephrine and neuropeptide Y concentrations. Cort significantly enhanced stress-induced c-Fos expression in vasopressin-expressing neurons in the paraventricular nucleus of the hypothalamus, and blockade of peripheral vasopressin V1 receptors attenuated the effect of DHB Cort to enhance the blood pressure response to restraint. These data indicate that glucocorticoids act within the DHB to produce some of the adverse cardiovascular consequences of chronic stress, in part, by a peripheral vasopressin-dependent mechanism., (Copyright © 2014 the American Physiological Society.)

Catecholaminergic neurons within the central nervous system are an integral part of stress-related neurocircuitry, and the nucleus of the solitary tract (NTS) plays a critical role in cardiovascular regulation. We tested the hypothesis that NTS catecholaminergic neurons attenuate psychological stress-induced increases in blood pressure and promote neuroendocrine activation in response to psychological stress.Anti-dopamine-β-hydroxylase antibody conjugated to the neurotoxin saporin (DSAP) or saline vehicle was microinjected into the NTS to lesion catecholaminergic neurons in male Sprague-Dawley rats, and 17 days later the rats were subjected to 60 min of restraint stress for five consecutive days. DSAP treatment significantly enhanced the integrated increase in mean arterial pressure during restraint on the first (800 ± 128 and 1115 ± 116 mmHg (min) for saline- and DSAP-treated rats) and fifth days (655 ± 116 and 1035 ± 113 mmHg (min) for saline- and DSAP-treated rats; P<0.01 for overall effect of DSAP treatment) of restraint. In contrast, after 60 min of restraint plasma corticosterone concentration was significantly lower in DSAP-treated compared with saline-treated rats (25.9 ± 7 compared with 46.8 ± 7 μg dl(-1) for DSAP- and saline-treated rats; P <0.05). DSAP treatment also significantly reduced baseline plasma adrenaline concentration (403 ± 69 compared with 73 ± 29 pg ml(-1) for saline- and DSAP-treated rats), but did not alter the magnitude of the adrenaline response to restraint. The data suggest that NTS catecholaminergic neurons normally inhibit the arterial pressure response, but help maintain the corticosterone response to restraint stress.

Chronic stress causes elevations in glucocorticoid secretion and also increases the incidence of hypertension and other manifestations of cardiovascular disease. The extent to which the elevated glucocorticoids mediate the stress-associated increase in cardiovascular disease risk is unknown. Chronically elevated glucocorticoids can cause hypertension by acting in the periphery, but their effects within the brain on blood pressure regulation remain largely unexplored. We developed a method to produce selective chronic increases in the endogenous glucocorticoid corticosterone or the glucocorticoid receptor antagonist mifepristone within the hindbrain region, which includes a key cardiovascular regulatory area, the nucleus of the solitary tract (NTS). Experiments were performed in male Sprague-Dawley, Wistar-Kyoto (WKY) and borderline hypertensive rats (BHR). The results indicate that elevated exogenous corticosterone can act within the hindbrain to enhance the arterial pressure response to novel restraint stress and to reduce the gain and increase the mid-point of the arterial baroreflex. Basal levels of endogenous corticosterone have no effect on the arterial pressure response to stress in normotensive rats but enhance this response in BHR. Chronic stress-induced increases in baseline corticosterone enhance the arterial pressure response to stress in BHR but attenuate the adaptation of the response in WKY rats. Furthermore, an elevated corticosterone concentration within the hindbrain is necessary but not sufficient to cause glucocorticoid-induced hypertension. The effects of corticosterone within the hindbrain on blood pressure regulation are mediated in part by the glucocortiocid receptor, but are also likely to involve mineralocorticoid receptor-mediated effects and NTS catecholaminergic neurons. These data support the hypothesis that elevated glucocorticoids acting within the brain probably contribute to the adverse effects of stress on cardiovascular health in susceptible people.

Exogenous glucocorticoids act within the hindbrain to enhance the arterial pressure response to acute novel stress. Here we tested the hypothesis that endogenous glucocorticoids act at hindbrain glucocorticoid receptors (GR) to augment cardiovascular responses to restraint stress in a model of stress hyperreactivity, the borderline hypertensive rat (BHR). A 3- to 4-mg pellet of the GR antagonist mifepristone (Mif) was implanted over the dorsal hindbrain (DHB) in Wistar-Kyoto (WKY) and BHRs. Control pellets consisted of either sham DHB or subcutaneous Mif pellets. Rats were either subjected to repeated restraint stress (chronic stress) or only handled (acute stress) for 3-4 wk, then all rats were stressed on the final day of the experiment. BHR showed limited adaptation of the arterial pressure response to restraint, and DHB Mif significantly (P

Macrophage migration inhibitory factor (MIF) expression is increased by angiotensin II (Ang II) within paraventricular nucleus (PVN) neurons of normotensive rats and acts via its intrinsic thiol protein oxidoreductase (TPOR) to counterregulate the central nervous system-mediated pressor action of Ang II. Considering that the PVN-mediated actions of Ang II are enhanced in spontaneously hypertensive rats (SHRs) and contribute to the development of hypertension in these animals, we investigated this MIF regulatory mechanism in SHRs. Here, we have demonstrated that Ang II failed to increase MIF protein expression in the PVN of SHRs. Furthermore, although basal levels of MIF protein and mRNA were similar in the PVN of SHRs and normotensive rats, immunostaining revealed that MIF was either absent from or diminished in PVN neurons of SHRs. AAV2-mediated increases in MIF expression within PVN neurons of young (8 wk old) SHRs produced a chronic attenuation of hypertension and cardiac hypertrophy. However, similar AAV2-mediated transduction of [C60S]-MIF, which lacks TPOR activity, did not alter the development of hypertension or cardiac hypertrophy in SHRs. Collectively, these findings suggest that a lack of MIF expression within PVN neurons contributes to the development of hypertension and cardiac hypertrophy in SHRs.

An adverse intrauterine environment can increase the incidence of hypertension and other cardiovascular disease risk factors. However, in clinical and experimental studies the magnitude of the effect is variable. Possibly, the relative influence of the prenatal environment on cardiovascular disease is determined in part by genetic factors that predispose individuals to the development of environmentally induced hypertension. We tested this hypothesis by comparing the effects of prenatal dexamethasone treatment (Dex, 300 microg kg(-1) i.p. on days 15 and 16 of gestation) in borderline hypertensive rats (BHR) and control Wistar-Kyoto (WKY) rats. Blood pressure, heart rate and plasma corticosterone values were measured at rest during the middle of the day, and during 1 h of restraint stress in the adult offspring using indwelling arterial catheters implanted at least 4 days prior to data collection. Compared with the saline (vehicle) control treatment, prenatal dexamethasone significantly (P < 0.05) increased baseline mean arterial pressure in male (123 +/- 2 versus 131 +/- 3 mmHg, saline versus Dex) and female (121 +/- 2 versus 130 +/- 2 mmHg, saline versus Dex) BHR, but not in male (108 +/- 3 versus 113 +/- 2 mmHg, saline versus Dex) or female (112 +/- 2 versus 110 +/- 2 mmHg, saline versus Dex) WKY rats. Relative to saline treatment, prenatal Dex also significantly increased baseline heart rate (328 +/- 6 versus 356 +/- 5 beats min(-1), saline versus Dex) and plasma corticosterone (5 +/- 2 versus 24 +/- 4 microg dl(-1), saline versus Dex), and prolonged the corticosterone response to acute stress, selectively in female BHR. However, prenatal Dex significantly enhanced the arterial pressure response to acute stress only in female WKY, while Dex augmented the elevation in heart rate during stress only in male rats. We conclude that prenatal dexamethasone increased baseline arterial pressure selectively in BHR, and plasma corticosterone only in female BHR. In contrast, prenatal Dex enhanced cardiovascular reactivity to stress in both BHR and WKY rats.

Augmented cardiovascular responses to acute stress can predict cardiovascular disease in humans. Chronic systemic increases in glucocorticoids produce enhanced cardiovascular responses to psychological stress; however, the site of action is unknown. Recent evidence indicates that glucocorticoids can act within the dorsal hindbrain to modulate cardiovascular function. Therefore, we tested the hypothesis that the endogenous glucocorticoid corticosterone can act in the dorsal hindbrain to enhance cardiovascular responses to restraint stress in conscious rats. Adrenal-intact animals with indwelling arterial catheters were treated for 4 or 6 days with 3- to 4-mg pellets of corticosterone or silastic (sham pellets) implanted on the dorsal hindbrain surface. Corticosterone pellets were also implanted either on the surface of the dura or subcutaneously to control for the systemic effects of corticosterone (systemic corticosterone). The integrated increase in arterial pressure during 1 hour of restraint stress was significantly (P<0.05) greater in dorsal hindbrain corticosterone (912+/-98 mm Hg per 60 minutes) relative to dorsal hindbrain sham (589+/-57 mm Hg per 60 minutes) or systemic corticosterone (592+/-122 mm Hg per 60 minutes) rats. The plasma glucose response after 10 minutes of stress was also significantly higher in dorsal hindbrain corticosterone-treated rats relative to both other groups. There were no significant between-group differences in the heart rate or corticosterone responses to stress. There were no differences in baseline values for any measured parameters. We conclude that corticosterone can act selectively in the dorsal hindbrain in rats with normal plasma corticosterone levels to augment the arterial pressure response to restraint stress.

Systemic corticosterone (Cort) modulates arterial baroreflex control of both heart rate and renal sympathetic nerve activity. Because baroreceptor afferents terminate in the dorsal hindbrain (DHB), an area with dense corticosteroid receptor expression, we tested the hypothesis that prolonged activation of DHB Cort receptors increases the midpoint and reduces the gain of arterial baroreflex control of heart rate in conscious rats. Small (3-4 mg) pellets of Cort (DHB Cort) or Silastic (DHB Sham) were placed on the surface of the DHB, or Cort was administered systemically by placing a Cort pellet on the surface of the dura (Dura Cort). Baroreflex control of heart rate was determined in conscious male Sprague Dawley rats on each of 4 days after initiation of treatment. Plots of arterial pressure vs. heart rate were analyzed using a four-parameter logistic function. After 3 days of treatment, the arterial pressure midpoint for baroreflex control of heart rate was increased in DHB Cort rats (123 +/- 2 mmHg) relative to both DHB Sham (108 +/- 3 mmHg) and Dura Cort rats (109 +/- 2 mmHg, P < 0.05). On day 4, baseline arterial pressure was greater in DHB Cort (112 +/- 2 mmHg) compared with DHB Sham (105 +/- 2 mmHg) and Dura Cort animals (106 +/- 2 mmHg, P < 0.05), and the arterial pressure midpoint was significantly greater than mean arterial pressure in the DHB Cort group only. Also on day 4, maximum baroreflex gain was reduced in DHB Cort (2.72 +/- 0.12 beats x min(-1) x mmHg(-1)) relative to DHB Sham and Dura Cort rats (3.51 +/- 0.28 and 3.37 +/- 0.27 beats x min(-1) x mmHg(-1), P < 0.05). We conclude that Cort acts in the DHB to increase the midpoint and reduce the gain of the heart rate baroreflex function.

Glucocorticoid receptors (GRs) are present at a high density in the nucleus of the solitary tract (NTS), an area of the dorsal hindbrain (DHB) that is critical for blood pressure regulation. However, whether these receptors play any role in the regulation of blood pressure is unknown. We tested the hypothesis that glucocorticoids act in the DHB to increase arterial pressure using two experimental strategies. In one approach, we implanted pellets of corticosterone (Cort) or sham pellets onto the DHB over the NTS. Compared with rats with sham pellets, rats with DHB Cort pellets had an increased (P < 0.05) mean arterial pressure (111 +/- 2 vs. 104 +/- 1 mmHg) and heart rate (355 +/- 9 vs. 326 +/- 5 beats/min) after 4 days. In the second approach, we implanted subcutaneous Cort pellets to increase the systemic Cort concentration and then subsequently implanted pellets of the GR antagonist mifepristone (Mif; previously RU-38486) or sham pellets onto the DHB. Two days of DHB Mif treatment reduced (P < 0.05) mean arterial pressure in those rats with elevated plasma Cort levels (118 +/- 2 vs. 108 +/- 1 mmHg for sham vs. Mif DHB pellets). Cort and Mif pellets placed on the dura had no effects on arterial pressure or heart rate, ruling out systemic cardiovascular effects of the steroids. DHB Cort treatment had no effects on plasma Cort concentration or adrenal weight, indicating that the contents of the DHB Cort pellet did not diffuse into the systemic circulation or into the forebrain areas that regulate plasma Cort concentration in concentrations sufficient to produce physiological effects. Immunohistochemistry for the occupied GRs demonstrated that the Cort and Mif from the DHB pellets were delivered to the DHB with minimal diffusion to the ventral hindbrain or forebrain. We conclude that glucocorticoids act in the DHB to increase arterial pressure.

We tested the hypothesis that glucocorticoids attenuate changes in arterial pressure and renal sympathetic nerve activity (RSNA) in response to activation and blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors within the nucleus of the solitary tract (NTS). Experiments were performed in Inactin-anesthetized male Sprague-Dawley rats treated for 7 +/- 1 days with a subcutaneous corticosterone (Cort) pellet or in control rats. Baseline mean arterial pressure (MAP) was significantly higher in Cort-treated rats (109 +/- 2 mmHg, n = 39) than in control rats (101 +/- 1 mmHg, n = 48, P < 0.05). In control rats, microinjection of AMPA (0.03, 0.1, and 0.3 pmol/100 nl) into the NTS significantly decreased MAP at all doses and decreased RSNA at 0.1 and 0.3 pmol/100 nl. Responses to AMPA in Cort-treated rats were attenuated at all doses of AMPA (P < 0.05). Responses to the AMPA-kainate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) were also significantly reduced in Cort-treated rats relative to control rats. Blockade of glucocorticoid type II receptors with mifepristone significantly enhanced responses to CNQX in both control and Cort rats. We conclude that glucocorticoids attenuate MAP and RSNA responses to activation and blockade of AMPA receptors in the NTS.

The amygdala plays an important role in the regulation of motivational states, especially those associated with addiction. The amygdala also expresses high levels of brain-derived neurotrophic factor (BDNF), an activity-dependent neurotrophin that can influence the reinforcing and locomotor activating properties of psychostimulants. In the present study, we examined the effects of acute and repeated amphetamine administration on the expression and production of this factor in the forebrain of rats. Animals given a single, acute injection (5 mg/kg, i.p.) of D-amphetamine developed hyperactivity followed by stereotypical behavior but showed no change in the basal expression of BDNF mRNA or its immunocytochemical profile in any region except the piriform cortex. Repeated injections (5 days) of 5 mg/kg amphetamine were accompanied by an enhanced onset of stereotypical behavior and elevated BDNF mRNA in the basolateral amygdala, rostral piriform cortex and paraventricular nucleus of the hypothalamus. Repeated treatment also increased BDNF immunoreactivity in perikarya of these same regions. In addition, increased BDNF immunoreactivity was found in fibers of many projection targets of the basolateral amygdala--the central extended amygdala, olfactory tubercle, medial nucleus accumbens, and in small zones resembling striosomes in the dorsal medial striatum. These results suggest that the upregulation of BDNF expression and protein in the basolateral nucleus of the amygdala and its targets could be an important part of the neuroadaptive response to psychostimulants., (Copyright 2002 Elsevier Science B.V.)

The effect of glucocorticoids on arterial baroreceptor reflex control of heart rate (HR) was determined in conscious rats. Corticosterone (Cort) treatment for 4-6 days doubled plasma Cort in Cort-treated relative to control rats. Cort had no significant effect on mean arterial pressure (MAP) or HR. Ramped changes in MAP were produced using infusions of phenylephrine and nitroprusside. Baroreflex control of HR was analyzed using a four-parameter logistic function. The midpoint of the baseline baroreflex function curve was significantly increased in Cort-treated (n = 14) relative to control (n = 14) rats (112 +/- 2 vs. 98 +/- 2 mmHg, n = 14), and the slope was significantly decreased (0.065 +/- 0.002 vs. 0.091 +/- 0.007). Three hours after the glucocorticoid type II receptor antagonist mifepristone (Mif) was administered to Cort-treated rats (n = 8), the midpoint of the baroreflex function was significantly reduced from 113 +/- 4 to 99 +/- 2 mmHg, and the slope was significantly increased from 0.061 +/- 0.004 to 0.083 +/- 0.005. Mif decreased HR in Cort-treated rats from 355 +/- 17 to 330 +/- 14 beats/min (P = 0.04) but did not alter MAP (111 +/- 2 to 107 +/- 3 mmHg, P = 0.14). Mif had no significant effects on baroreflex function in control rats. Therefore, a moderate elevation in Cort for several days causes pressure-independent modulation of baroreflex control of HR.

Experiments were performed to determine if glucocorticoids potentiate central hypertensive actions of ANG II. Male Sprague-Dawley rats were treated for 3 days to 3 wk with corticosterone (Cort). Experiments were performed in conscious rats that had previously been instrumented with arterial and venous catheters and an intracerebroventricular guide cannula in a lateral ventricle. Baseline arterial pressure (AP) was greater in Cort-treated rats than in control rats (119 +/- 2 vs. 107 +/- 1 mmHg, P < 0.01). Microinjection of ANG II intracerebroventricularly produced a significantly larger increase in AP in Cort-treated rats than in control rats. For example, at 30 ng ANG II, AP increased by 23 +/- 1 and 16 +/- 2 mmHg in Cort-treated and control rats, respectively (P < 0.01). Microinjection of an angiotensin type 1 receptor antagonist significantly decreased AP (-6 +/- 2 mmHg) and heart rate (-26 +/- 7 beats/min) in Cort-treated but not control rats. Increases in AP produced by intravenous administration of ANG II were not different between control and Cort-treated rats. Intravenous injections of ANG II antagonist had no significant effects on mean AP or heart rate in control or Cort-treated rats. Therefore, a sustained increase in plasma Cort augments the central pressor effects of ANG II without altering the pressor response to peripheral administration of the hormone.

Experiments were performed to determine the effects of glucocorticoids on arterial baroreceptor reflex control of renal sympathetic nerve activity (RSNA). Intravenous infusions of phenylephrine and nitroprusside were used to produce graded changes in arterial pressure (AP) in Inactin-anesthetized male Sprague-Dawley rats. Baroreflex control of RSNA was determined during a baseline period and 2 and 3 h after administration of the glucocorticoid type II receptor antagonist Mifepristone (30 mg/kg sc) or vehicle (oil). Corticosterone (cort) treatment (100 mg cort pellet sc for 2-3 wk) increased baseline AP from 115 +/- 2 to 128 +/- 1 mmHg. Cort treatment also decreased the gain coefficient and increased the midpoint of the baroreflex curve. Treatment of cort rats with Mifepristone decreased AP within 2 h and increased the gain coefficient and decreased the midpoint of the baroreflex function curve back toward values measured in control rats. Mifepristone altered the baroreflex function curve even when AP was maintained at baseline levels. Therefore, these data demonstrate for the first time that glucocorticoids can modulate baroreflex control of RSNA by a mechanism that is, in part, independent of changes in AP.

Chronic stress in humans has been correlated with increased risk for ischemic heart disease. Thus experiments were conducted to determine if repeated intermittent restraint stress increased infarct size in a rat model of myocardial ischemia-reperfusion injury. Male Sprague-Dawley rats were subjected to no stress (control) or to daily restraint stress for 1-1.5 h for 8-14 days (stress protocol A) or for 2 h daily for 11 or 12 days (stress protocol B). Myocardial ischemia-reperfusion (30-min ischemia, 3-h reperfusion) was performed in anesthetized rats. Average baseline arterial pressures were 111 +/- 4, 120 +/- 10, and 125 +/- 7 mmHg in the control, stress protocol A, and stress protocol B groups, respectively. Infarct size (%area at risk) was significantly larger in both groups of stressed rats compared with control rats (58 +/- 5, 78 +/- 2, and 79 +/- 3% in the control, stress protocol A, and stress protocol B groups, respectively). During ischemia or early reperfusion, zero of eight control, two of six protocol A stress, and two of five protocol B stress rats had at least one period of severe arrhythmia. Therefore, these results provide experimental evidence corroborating correlative studies in humans that link chronic stress with increased morbidity and mortality from ischemic heart disease.

Experiments were conducted to determine the effect of chronic elevations in corticosterone on myocardial infarct size. Male Sprague-Dawley rats were treated for 7-22 days with corticosterone. Plasma corticosterone concentrations averaged 0.8 +/- 0.3 in control and 14.9 +/- 1.2 micrograms/dl in corticosterone-treated conscious rats. Experiments were performed in anesthetized rats. After a 30-min control period, myocardial ischemia (30 min)-reperfusion (3 h) was performed in control and corticosterone-treated rats. Mean arterial pressure (+/-SE) in control rats during control, ischemia, and reperfusion periods averaged 111 +/- 4, 100 +/- 5, and 94 +/- 4 mmHg (n = 6), respectively. Chronic treatment with corticosterone increased mean arterial pressure in all three periods 128 +/- 6, 117 +/- 7, and 109 +/- 7 mmHg; n = 8; P < 0.05). Infarct size (as % area at risk) was significantly larger in rats with chronic elevations in corticosterone compared with control rats (77 +/- 2 vs. 51 +/- 5%, P < 0.05). Acute (2 h) blockade of the glucocorticoid type II receptors with mifepristone antagonized the increases in arterial pressure and infarct size produced by chronic administration of corticosterone. Neither mifepristone nor acutely administered corticosterone affected arterial pressure or infarct size in rats without chronic corticosterone treatment. The effect of chronic elevations in plasma corticosterone concentration to increase infarct size could contribute to the increased risk of cardiovascular disease in clinical conditions associated with elevated glucocorticoid levels.

1. Temporal processing of heterogenous afferent signals by nucleus of the solitary tract (NTS) neurons has been previously characterized. Experiments were performed in 26 pentobarbital-sodium-anesthetized male Sprague-Dawley rats to characterize the temporal processing of evoked activity in NTS neurons with the use of the aortic nerve, which contains exclusively arterial baroreceptor afferent fibers. 2. Extracellular single-cell activity was examined in the NTS during electrical stimulation of the aortic nerve with the use of a conditioning-test paradigm. 3. Results were obtained from 49 neurons, 22 of which were characterized as receiving monosynaptic input from aortic nerve afferents. The average number of evoked potentials per aortic nerve stimulation was 1.1 +/- 0.1 (SE) for the monosynaptic neurons and 1.2 +/- 0.2 for the polysynaptic neurons. Spontaneous activity averaged 3.7 +/- 0.7 Hz. No neuron exhibited an obvious pulse-rhythmic discharge. The average peak onset latency for monosynaptic cells of 17 +/- 2 ms (range 3-31 ms) was significantly (P < 0.05) shorter than the average of 26 +/- 1 ms (range 13-38 ms) for the polysynaptic cells. The average onset latency variability was also less in monosynaptic compared with polysynaptic cells (4 +/- 1 ms vs. 8 +/- 1 ms; P < 0.05). 4. Neurons characterized as receiving a monosynaptic input from the aortic afferents generally did not exhibit time-dependent inhibition. Significant inhibition was observed only at a conditioning-test interval of 50 ms, when the average test response was 79 +/- 8% of control. In contrast, the average response following a 50-ms conditioning-test interval for neurons receiving polysynaptic input from the aortic nerve was only 32 +/- 8% of control. Significant inhibition was observed at conditioning-test intervals of up to 200 ms. 5. At a conditioning-test interval of 50 ms, only 5 of 22 monosynaptic neurons were inhibited by > 50%. Mean arterial pressure during the conditioning-test procedure was significantly lower for these neurons than for the 17 cells that were inhibited by < 50%. This suggests that the level of activity in convergent afferent input might influence the magnitude of time-dependent inhibition. 6. There was an essentially linear recovery from time-dependent inhibition evident in polysynaptic neurons that were tested at all conditioning-test intervals, suggesting a single mechanism of variable duration. Results reported here are consistent with current theory that time-dependent inhibition is mediated by disfacilitation. 7. The results demonstrate that NTS neurons receiving monosynaptic input from the aortic depressor nerve infrequently exhibit time-dependent inhibition. This could allow for the original, unmodified afferent information to be dispersed to subsequent neurons. In contrast, neurons receiving polysynaptic input undergo time-dependent inhibition similar to that which has been reported for other afferent inputs. This could allow for differential degrees of fidelity in the transfer of the afferent information to specific efferent pathways. Therefore the temporal pattern of firing in individual baroreceptor afferents could play a critical role in the function of the arterial baroreflex and therefore in the regulation of blood pressure.

Arginine vasopressin (AVP) has been shown to increase the inhibitory influence of the baroreflex on sympathetic nerve activity by a mechanism involving receptors located in the area postrema. The purpose of these experiments was to study the functional effect of this action of AVP by testing the hypothesis that AVP can buffer its own vasoconstrictor effect by facilitating baroreflex-mediated withdrawal of sympathetic nerve activity. Specifically, we determined 1) if AVP can attenuate increases in hindquarter vascular resistance during the infusion of another vasoconstrictor, phenylephrine, and 2) whether the effects of AVP on vascular resistance are associated with appropriate corresponding changes in lumbar sympathetic nerve activity (LSNA). In pentobarbital-anesthetized New Zealand White rabbits the baroreflex was stimulated by phenylephrine-induced elevations in arterial pressure. Baroreflex-mediated changes in heart rate (HR), calculated hindquarter vascular resistance index (R), and LSNA were determined during the simultaneous intravertebral infusion of AVP (0, 0.5, or 1.0 ng.kg-1, min-1). Intravertebral infusion of AVP alone had no effect on resting mean arterial pressure (MAP) but reduced baseline values for LSNA and HR. Intravenous infusion of phenylephrine alone produced dose-dependent increases in MAP and R and decreases in LSNA and HR. The simultaneous infusion of AVP (0.5 or 1.0 ng.kg-1 min-1) and phenylephrine (1.25, 2.5, 5.0, 7.5, and 10.0 micrograms.kg-1.min-1) had no effect on the increase in MAP but attenuated the increases in R and facilitated the reductions in LSNA at all doses of phenylephrine. The higher dose of AVP also enhanced the phenylephrine-induced reductions in HR. In contrast, the intravenous infusion of AVP (1.0 ng.kg-1.min-1) did not alter baroreflex-mediated changes in R, LSNA, or HR. Therefore, we conclude that the action of AVP to increase baroreflex-mediated sympathoinhibition results in an attenuated rise in hindquarter vascular resistance during the infusion of another vasoconstrictor, phenylephrine.

Angiotensin (ANG) can produce a biphasic arterial pressure response, i.e., an increase followed by a decrease. Because ANG type 1 (AT1) receptors mediate the pressor response to ANG, we hypothesized that the opposing depressor action is mediated by the ANG type 2 (AT2) receptors. In thiobutabarbital (Inactin)-anesthetized rats bolus injections of angiotensin III (ANG III; 100, 300, and 1,000 ng/kg iv) produced peak increases in MAP at 20 s of 13.4 +/- 1.4, 20.1 +/- 2, and 27.5 +/- 2.8 mmHg and maximum decreases in pressure at 120 s of -6.3 +/- 1.5, -6.8 +/- 2.2, and -11.4 +/- 4.9 mmHg. During blockade of the AT1 receptors with DuP 753 (losartan, 10 mg/kg) the increases in MAP were eliminated (P < 0.01), whereas the depressor responses (-24.7 +/- 8, -32.8 +/- 9.3, and -42.0 +/- 10.0 mmHg) were significantly (P < 0.05) larger. In separate groups of rats, combined blockade of both AT1 and AT2 receptors eliminated all changes in MAP in response to ANG III, whereas blockade of AT2 receptors alone enhanced the pressor response to ANG III. During AT1 receptor blockade angiotensin II also caused consistent decreases in pressure, which were inhibited during combined blockade of AT1 and AT2 receptors. Therefore, we have demonstrated that the AT2 receptors mediate a depressor response to ANG.

A technique was developed to produce acute, reversible cardiac nerve blockade (CNB) in the conscious dog by infusion of 2% procaine into the pericardial (PC) space. During CNB, reflex changes in heart rate (HR) in response to intravenous bolus injections of phenylephrine (100 micrograms) and nitroglycerin (300 micrograms) and the reflex tachycardia and hypotension after a 50-micrograms bolus injection of veratridine into the left atrium were abolished. In response to CNB, HR increased from 79 +/- 10 to 142 +/- 10 beats/min and mean arterial pressure (MAP) increased from 101 +/- 5 to 117 +/- 6 mmHg. Baseline values for plasma arginine vasopressin (AVP), plasma renin activity (PRA), and plasma norepinephrine (NE) were unchanged by CNB, but there was a small increase in plasma cortisol levels (1.4 +/- 0.3 to 2.3 +/- 0.3 micrograms/dl) during CNB. There was no significant change in the baseline levels of any of these hormones during PC infusion of 0.9% saline. To control for the possibility that procaine leaked into the systemic circulation, identical amounts of procaine were infused intravenously. Systemic administration of procaine caused a rise in MAP but had no effect on HR and did not alter plasma levels of AVP, PRA, NE, or cortisol. The relationship between plasma osmolality and plasma AVP, as well as the drinking response to a 60-min infusion of hypertonic NaCl, was unaltered by CNB. We conclude that PC procaine infusion is an effective technique for producing acute, reversible blockade of the cardiac nerves in the conscious dog.

We have reported that infusion of atrial natriuretic factor (ANF) inhibited the rise in plasma renin activity (PRA) in response to constriction of the abdominal aorta to cause a reduction in renal perfusion pressure (RPP). To evaluate the effect of ANF on neural control of renin release, acute thoracic inferior vena caval constriction (TIVCC) was performed in conscious dogs to reduce arterial pressure by 25% of control and stimulate PRA by a reflex increase in renal nerve activity and a reduction in RPP. Propranolol was used to block neural stimulation of renin release. TIVCC caused significant increases in PRA, plasma aldosterone, arginine vasopressin (AVP), and adrenocorticotropic hormone (ACTH) concentrations. The increase in PRA was significantly reduced by the infusion of either ANF at 20 ng.kg-1.min-1 or propranolol. The combined infusion of ANF and propranolol produced an additive and complete inhibition of the renin response to TIVCC; therefore the effect of ANF is independent of neural stimulation of renin release. ANF at 20 ng.kg-1.min-1 also inhibited increases in aldosterone, AVP, and ACTH, but ANF at 5 ng.kg-1.min-1 only affected the aldosterone response to TIVCC. Therefore ANF inhibits angiotensin II-stimulated aldosterone synthesis and/or secretion at very low doses and at higher doses attenuates reflex increases in AVP and ACTH caused by hypotension.

We have reported that the renin response to systemic hypotension is inhibited in the presence of elevated atrial pressure and that elevations in atrial pressure of similar or larger magnitude cause graded increases in plasma atrial natriuretic peptide (ANP). Therefore we tested the hypothesis that comparable increments in plasma ANP can inhibit renal hypotension-induced increases in plasma renin activity (PRA) in conscious dogs. Renal perfusion pressure was controlled using cuffs implanted around the abdominal aorta just above the renal arteries. Reducing renal perfusion pressure by 10 or 30% of control caused graded increases in PRA (P less than 0.01). Infusion of 1-28 rat ANP (5 ng X kg-1 X min-1), which increased plasma ANP by 34.8 +/- 7.5 (SE) pg/ml, eliminated increases in PRA in response to a 10% reduction in renal perfusion pressure and markedly inhibited the response to a 30% pressure reduction (P less than 0.01). These results indicate that increments in plasma ANP which reproduce endogenous release inhibit renal hypotension-induced stimulation of PRA. Furthermore, the results provide an explanation for the inhibition of the renin response to renal hypotension during elevated atrial pressure.

We have reported that the renin response to systemic hypotension during a simultaneous increase in left atrial pressure (LAP) depends, in part, on intact renal nerves. Because efferent neural control of renin release is mediated by renal sympathetic nerves, we tested the hypothesis that withdrawal of renal sympathetic tone is an essential component of the inhibitory mechanism. In conscious dogs, the ascending aorta was partially constricted to produce a simultaneous decrease, of up to 30%, in renal perfusion pressure (RPP) and a rise in LAP. Sympathetic neural control of renin release was reversibly blocked with propranolol. Propranolol infusion did not affect the increases in LAP or atrial natriuretic factor (ANF) during ascending aortic constriction. There was no increase in renin (P greater than 0.1) during ascending aortic constriction, with or without propranolol infusion. Identical reductions in RPP during constriction of the abdominal aorta caused renin to rise (P less than 0.03). Therefore acute withdrawal of renal sympathetic tone is not necessary for the inhibition of the renin response to systemic hypotension by elevated LAP.