Elevated corticosterone in the dorsal hindbrain increases plasma norepinephrine and neuropeptide Y, and recruits a vasopressin response to stress.

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.

Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats.

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-ß-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.

Nitric oxide impairs baroreflex gain during acute psychological stress.

Psychological stress can suppress baroreflex function, but the mechanism has not been fully elucidated. Nitric oxide in the brain and in the adrenal cortex, as well as plasma glucocorticoids, increases during stress and has been shown to suppress reflex gain in unstressed animals. Therefore, the purpose of this study was to test the hypothesis that stress, caused by exposure to a novel environment, decreases baroreflex gain in rabbits through the actions of nitric oxide to increase corticosterone release. Baroreflex control of heart rate and plasma corticosterone levels was quantified before and after blockade of nitric oxide synthase (NOS) with N(omega)-nitro-L-arginine (L-NNA; 20 mg/kg iv) in conscious rabbits exposed to a novel environment and in the same rabbits once they had been conditioned to the environment. Stress significantly reduced baroreflex gain from -23.4 +/- 2 to -12.2 +/- 1.6 beats x min(-1) x mmHg(-1) (P < 0.05) and increased plasma corticosterone levels from 5.4 +/- 0.7 to 15.5 +/- 5.0 ng/ml (P < 0.05). NOS blockade increased gain in stressed animals (to -27.2 +/- 5.4 beats x min(-1) x mmHg(-1), P < 0.05) but did not alter gain in unstressed rabbits (-26.8 +/- 4.9 beats x min(-1) x mmHg(-1)) such that gain was equalized between the two states. NOS blockade increased plasma corticosterone levels in unstressed animals (to 14.3 +/- 2.1 ng/ml, P < 0.05) but failed to significantly alter levels in stressed rabbits (14.0 +/- 3.9 ng/ml). In conclusion, psychological stress may act via nitric oxide, independently of increases in corticosterone, to decrease baroreflex gain.

Insulin resistance and impaired baroreflex gain during pregnancy.

Pregnancy decreases baroreflex gain, but the underlying mechanism is unclear. Insulin resistance, which has been associated with reduced transport of insulin into the brain, is a consistent feature of many conditions exhibiting impaired baroreflex gain, including pregnancy. Therefore, using conscious pregnant and nonpregnant rabbits, we tested the novel hypothesis that the pregnancy-induced impairment in baroreflex gain is due to insulin resistance and reduced brain insulin. Baroreflex gain was determined by quantifying changes in heart rate in response to stepwise steady-state changes in arterial pressure, secondary to infusion of nitroprusside and phenylephrine. We found that insulin sensitivity and baroreflex gain were strongly correlated in nonpregnant and term pregnant rabbits (r2 = 0.59). The decrease in insulin sensitivity and in baroreflex gain exhibited similar time courses throughout pregnancy, reaching significantly lower levels at 3 wk of gestation and remaining reduced at 4 wk (term is 31 days). Treatment of rabbits with the insulin-sensitizing drug rosiglitazone during pregnancy almost completely normalized baroreflex gain. Finally, pregnancy significantly lowered cerebrospinal fluid insulin concentrations. These data identify insulin resistance as a mechanism underlying pregnancy-induced baroreflex impairment and suggest, for the first time in any condition, that decreased brain insulin concentrations may be the link between reductions in peripheral insulin sensitivity and baroreflex gain.

Roles of nitric oxide and angiotensin II in the impaired baroreflex gain of pregnancy.

The present study tested the hypothesis that nitric oxide (NO) contributes to impaired baroreflex gain of pregnancy and that this action is enhanced by angiotensin II. To test these hypotheses, we quantified baroreflex control of heart rate in nonpregnant and pregnant conscious rabbits before and after: 1) blockade of NO synthase (NOS) with Nomega-nitro-L-arginine (20 mg/kg iv); 2) blockade of the angiotensin II AT1 receptor with L-158,809 (5 microg x kg(-1) x min(-1) iv); 3) infusion of angiotensin II (1 ng x kg(-1) x min(-1) nonpregnant, 1.6-4 ng x kg(-1) x min(-1) pregnant iv); 4) combined blockade of angiotensin II AT(1) receptors and NOS; and 5) combined infusion of angiotensin II and blockade of NOS. To determine the potential role of brain neuronal NOS (nNOS), mRNA and protein levels were measured in the paraventricular nucleus, nucleus of the solitary tract, caudal ventrolateral medulla, and rostral ventrolateral medulla in pregnant and nonpregnant rabbits. The decrease in baroreflex gain observed in pregnant rabbits (from 23.3 +/- 3.6 to 7.1 +/- 0.9 beats x min(-1) x mmHg(-1), P < 0.05) was not reversed by NOS blockade (to 8.3 +/- 2.5 beats x min(-1) x mmHg(-1)), angiotensin II blockade (to 5.0 +/- 1.1 beats x min(-1) x mmHg(-1)), or combined blockade (to 12.3 +/- 4.8 beats x min(-1) x mmHg(-1)). Angiotensin II infusion with (to 5.7 +/- 1.0 beats x min(-1) x mmHg(-1)) or without (to 8.4 +/- 2.4 beats x min(-1) x mmHg(-1)) NOS blockade also failed to improve baroreflex gain in pregnant or nonpregnant rabbits. In addition, nNOS mRNA and protein levels in cardiovascular brain regions were not different between nonpregnant and pregnant rabbits. Therefore, we conclude that NO, either alone or via an interaction with angiotensin II, is not responsible for decrease in baroreflex gain during pregnancy.