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.

Erdos B, Clifton RR, Liu M, Li H, McCowan ML, Sumners C, Scheuer DA. Novel mechanism within the paraventricular nucleus reduces both blood pressure and hypothalamic pituitary-adrenal axis responses to acute stress. Am J Physiol Heart Circ Physiol 309: H634-H645, 2015. First published June 12, 2015 doi:10.1152/ajpheart.00207.2015.-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 stressinduced 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 restraintinduced increases in blood pressure (37.4 Ϯ 2.0 and 27.6 Ϯ 3.5 mmHg in GFP and MIF groups, respectively, P Ͻ 0.05) and corticosterone (42 Ϯ 2 and 36 Ϯ 3 g/dl in GFP and MIF groups, respectively, P Ͻ 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 Ϯ 5 in GFP and 47 Ϯ 5 in MIF SHRs, P Ͻ 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. psychological stress; blood pressure; brain; angiotensin ii; hypertension NEW & NOTEWORTHY Exaggerated activation of the sympathetic nervous system and/or the hypothalamic-pituitary-adrenal (HPA) axis increases cardiovascular disease risk. The present study demonstrates that macrophage migration inhibitory factor (MIF) in paraventricular nucleus (PVN) neurons is a novel mechanism mediating attenuation of both the sympathetic and HPA axis responses to acute stress.SEVERAL LINES OF EVIDENCE suggest that the amplitude of blood pressure increases in response to psychological or physical stressors in young and middle-aged normotensive adults elevates the risk of developing hypertension and other cardiovascular diseases such as coronary artery disease, myocardial ischemia, and stroke later in their life (8,20,39,41,42,44,50,60). Larger variations in blood pressure in response to repeated everyday stressors may lead to accelerated damage of the kidneys and vasculature. Altered central mechanisms that mediate augmented...

We previously reported that chronic increases in corticosterone within the dorsal hindbrain, including the Nuclues of the Solitary Tract (NTS), augment the arterial pressure response to restraint stress. This study tested the hypothesis that diminishing actions of corticosterone selectively within NTS catecholaminergic neurons would attenuate the cardiovascular responses to novel and repeated restraint stress. AAV2-based viral vectors were constructed to express either GFP or 11-beta-hydroxysteroid dehydrogenase 2 (HSD2) selectively in catecholaminergic neurons using the PRSx8 promoter. HSD2 degrades corticosterone to an inactive metabolite. Adult male Sprague-Dawley rats were instrumented with telemetry mitters to measure arterial pressure and heart rate. At least 3 weeks later AAV2-PRSx8-HSD2 (n=7) or AAV2-PRSx8-eGFP (n=8) was microinjected bilaterally into the NTS (125 nl/side). After another 3 weeks rats underwent daily restraint stress (60 min per day) for 15 days. Baseline mean arterial pressure was not significantly different in GFP- versus HSD2-transduced rats prior to stress 1 (98±2 and 99±3 mmHg respectively) or stress 15 (96±3 and 100±2 mmHg respectively). During the first restraint stress, the average increase in arterial pressure in response to restraint was significantly (P<0.05) greater in the GFP- compared with the HSD2-transduced rats during the final 10 min of stress (13±1 and 5±2 mmHg respectively). During the last restraint stress the average increase in arterial pressure in response to stress was significantly (P<0.05) greater in the GFP- compared with the HSD2- transduced rats throughout the stress (11±2 and 4±1 mmHg respectively). Baseline heart rate was significantly higher in GFP- versus HSD2- transduced rats prior to stress 1 (340±6 and 317±7 bpm respectively) but not prior to stress 15 (308±6 and 309±9 bpm respectively). HSD2 transduction had no significant effect on the heart rate response to the first stress, but significantly reduced the average heart rate response to the last restraint stress (63±13 and 30±7 bpm for GFP vs HSD2). We conclude that over-expression of HSD2 in NTS catecholaminergic neurons lowers baseline heart rate and attenuates the cardiovascular responses to restraint stress.

MIF acts within PVN neurons to attenuate the excitatory actions of the neuropeptide angiotensin II, but is absent in PVN neurons of Spontaneously Hypertensive rats (SHR). Since angiotensin II in the PVN activates the hypothalamic pituitary adrenal axis resulting in corticosterone (Cort) secretion from the adrenal, we tested the hypothesis that restoration of MIF within SHR PVN neurons will attenuate the Cort response to stress. AAV2‐based viral vectors were microinjected into the PVN to express either GFP (n=6) or MIF (n=7) in adult male 11 week old SHR. Three weeks later a femoral arterial catheter was implanted under isoflurane anesthesia. At least 3 days later, rats were subjected to 60 min of restraint stress. Prior to stress, baseline plasma Cort was not significantly different between GFP‐ and MIF‐treated rats (6±1 and 4±1 μg/dl). However, during stress, plasma Cort was significantly (P<0.05) lower in MIF‐ compared with GFP‐treated rats at 15 min (36±2 vs 43±2 μg/dl) and 45 min (48±3 vs 58±2 μg/dl), and tended to be lower (P=0.057) at 60 min (48±2 vs 59±5 μg/dl). Thus, the integrated average increase in Cort during stress was significantly lower in MIF‐ compared with GFP‐treated rats (39±2 vs 44±1 μg/dl/min). We conclude that MIF acts in the PVN to attenuate the Cort response to restraint stress. Supported by HL093186 (MPI Sumners and Scheuer)