Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: Implications for sudden infant death syndrome

Maternal cigarette smoking has a high correlation with Sudden Infant Death Syndrome, a condition in which cardiorespiratory failure occurs during an hypoxic episode, as in sleep apnea. Pregnant rats were given nicotine infusions of 2 or 6 mg/kg/day throughout gestation, regimens that produce plasma nicotine levels spanning the range in smokers. The day after birth, animals in the high dose group displayed excessive mortality during hypoxic challenge. These animals were found to be deficient in an essential response component, namely adrenomedullary catecholamine release that is required to maintain neonatal cardiac rhythm during hypoxia; the defect was in adrenal cell function rather than in altered innervation or nicotinic receptor desensitization. We also examined brainstem and forebrain noradrenergic mechanisms that are involved in neonatal respiratory control. The nicotine group showed suppressed spontaneous neuronal activity, but were hyperresponsive to hypoxia. As these projections are inhibitory for respiration, the nicotine-induced sensitization would be expected to contribute to respiratory arrest during hypoxia. Prenatal nicotine exposure may thus provide a useful animal model with which to study the physiological mechanisms that underlie Sudden Infant Death Syndrome, while at the same time providing a biological explanation for the association of the syndrome with smoking.     

Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study.

BACKGROUND: Although several antidepressants are now available, all have limited efficacy and a delayed onset of action. The current study was undertaken as a proof of the concept that combining norepinephrine and serotonin reuptake inhibition would be more effective and act more rapidly than either drug alone. METHODS: Inpatients with nonpsychotic unipolar major depression and a Hamilton Depression Rating Scale (HAMD) score of at least 18 after 1 week of hospitalization without antidepressant medication were randomized to 6 weeks of treatment with fluoxetine (FLX) 20 mg/day, desipramine (DMI) adjusted to an adequate plasma level, or the combination of FLX 20 mg/day and DMI, given under double-blind conditions. Twenty-four-hour DMI levels were used to rapidly adjust DMI dose to achieve a therapeutic level and to anticipate the enzyme-inhibiting effects of FLX. Treatment-resistant patients were stratified. Patients were rated with the HAMD and the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: Thirty-nine patients began treatment. One patient withdrew consent. The DMI-FLX combination was significantly more likely to result in remission on the MADRS than either FLX or DMI alone [53.8% vs. 7.1% and 0%, respectively; chi(2)(2) = 13.49, p =.001]. The advantage for combined treatment was not explained by history of treatment resistance or by drug plasma concentrations. Rapid response, at 1 or 2 weeks, was neither statistically nor meaningfully greater with combined treatment. CONCLUSIONS: This study supports the hypothesis that the combination of a noradrenergic and serotonergic agent is more likely to result in remission than either selective agent alone during a 6-week treatment period.     

Cortical Catecholamine Secretion Following Intravenous Nitroprusside Infusion: A Voltammetric Study

Intravenous administration of sodium nitroprusside (NP) decreases blood pressure and activates noradrenergic neurons in the locus coeruleus (LC). Microdialysis studies have shown that NP infusion is accompanied by increased extracellular concentrations of norepinephrine (NE) in the medial prefrontal cortex. The present study used in vivo voltammetry to obtain a finer temporal analysis of the NP-induced changes in the extracellular concentrations of catecholamine-like compounds in the LC terminal fields in the rat medial prefrontal cortex. Intravenous infusion of rats with NP caused a rapid decrease in blood pressure that lasted for the duration of the infusion but rapidly reversed when the infusion was terminated. After a delay of between about 2 and 8 min (mean 5 min), there was an increase in extracellular concentrations of a NE-like substance. Presumed cortical release of NE lasted for several minutes but had almost returned to baseline by the time the NP infusion was terminated at 15 min. In many cases, the first peak was followed by a second one, usually of smaller amplitude but more prolonged than the first one. There was no clear response to the cessation of infusion of NP. The time course of the initial response is comparable to the previously reported electrophysiological response of LC-NE neurons to NP. In rats treated with DSP-4 to deplete cortical NE, blood pressure was reduced as in untreated rats, but no voltammetric response to NP infusion was observed. These results suggest that activation of the NE-LC neurons by NP results in a delayed synaptic release of NE in the cerebral cortex which attenuates within several minutes.     

Sympathetic innervation of lymph nodes in mice

Noradrenergic innervation of popliteal and mesenteric lymph nodes in mice was examined with fluorescence histochemistry. Dense varicose plexuses entered the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region. Fine, delicate varicosities and small vascular plexuses continued into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes. A subcapsular plexus contributed fibers into the cortical and paracortical regions. Chemical measurements revealed the presence of norepinephrine in lymph nodes that was depletable with 6-hydroxydopamine. Depletion of norepinephrine from lymph nodes with this agent resulted in a diminished primary immune response in draining lymph nodes following subcutaneous injection of an antigen in two mouse strains, but had no effect in two other strains. These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs.     

Odor detection performance of rats followingd-amphetamine treatment: a signal detection analysis

The effects ofd-amphetamine sulfate (0.2, 0.4, 0.8, and 1.6 mg/kg SC) on the odor detection performance of 16 adult male Long Evans rats was assessed using high precision olfactometry and a go/no-go operant signal detection task. The drug or saline was administered every 3rd day in a counterbalanced order, with the injections occurring 5 min before each 260-trial test session. Relative to saline, enhanced detection performance to the target stimulus (ethyl acetate), as measured by a non-parametric signal detection index (SI), was observed following administration of 0.2 mg/kg of the drug, whereas decreased detection performance was observed following administration of 1.6 mg/kg of the drug. Significant increases in the responsivity index (RI) occurred at the higher drug dosages for the lower odorant concentrations. In addition, small but statistically significant increases in the latency to respond in the presence of the odor (i.e., S+ response latency) were present at the higher drug dosages. Overall, these data suggest that (a) odor detection performance is enhanced by low doses of amphetamine, (b) odor detection performance is depressed by moderate doses of amphetamine, and (c) drug-related alterations in response criteria occur following the administration of moderate doses of amphetamine.     

Neonatal 6-Hydroxydopamine Treatment and the Development of Renal Hypertension in the Rat

The onset and development of 2 kidney-2 clip renal hypertension was studied in chronically sympathectomized rats treated with 6-hydroxy-dopamine (6-OHDA) immediately after birth and with adrenal demedullation performed at the time of clipping. Blood pressure (BP) was lower in 6-OHDA treated animals than in untreated controls and the rate of hypertension development was similar in both groups. Urinary excretion of norepinephrine (NE) was significantly decreased during the 15th week and normal by the end of the 20th week. The cardiac NE content reached negligible levels while the mesenteric arteries retained 50% of its content. In the central nervous system (CNS) the 6-OHDA treatment induced a significant increase in NE concentration in the brain stem and medulla oblongata and a significant decrease in cerebellum. Hypertension produced a significant decrease in NE content in the brain stem while 6-OHDA treatment in hypertensive rats resulted in a generalized NE depletion in all the CNS areas. Results have shown that 6-OHDA treatment does not produce a complete and generally distributed sympathectomy; treatment reduces the level of BP but does not change the slope in BP increase.     

Acute and Chronic Effects of Losartan (Dup 753) on Blood Pressure and Vascular Reactivity in Normotensive Rats

The effects of in vivo treatment with the nonpeptide subtype 1 angiotensin II receptor antagonist, losartan, on blood pressure and vascular reactivity in normotensi male Sprague-Dawley rats were studied. Initial acute experiments demonstrated that blood pressure was significantly decreased six hours following a single injection of losartan (10 mg/kg, sc), but returned to control levels by 24 hours post-injection. Pressor responses to angiotensin II (0.1 ug/kg, iv) in these rats were significantly attenuated 2 and 24 hours following losartan injection. For chronic studies, rats were injected once daily for 21 days with either the same dose of losartan or saline vehicle. Blood pressure and pressor responses to angiotensin II were assessed at the end of the 21 day treatment period. A significant decrease in blood pressure was observed in chronic losartan treated rats 6 hours after the last injection on day 21; however, as in the acute studies, blood pressure had returned to control values by 24 hours post-injection. Although blood pressure had returned to normal, pressor responses to angiotensin II were significantly attenuated in chronic losartan treated rats 24 hours after the last injection. Following the in vivo studies, aortae and tail arteries were removed for experiments on vascular reactivity. Acute and chronic losartan treatment had no effect on KCl and norepinephrine reactivity. Endothelial-dependent and independent relaxation responses were also unaltered. A significant decrease in the maximal contractile response to angiotensin II was observed in aorta from acute and chronic losartan treated rats. Electrical stimulation-induced responses were unaltered in tail arteries from rats acutely treated with losartan but were potentiated in rats chronically treated with losartan. Exogenously applied angiotensin II, in concentrations which did not elicit contractile responses, potentiated electrical stimulation-induced responses of tail arteries from control rats but did not influence responses in arteries from acute and chronic losartan treated rats. These results demonstrate that.     

去甲肾上腺素和多巴胺在非体外循环冠状动脉旁路移植术中维持血流动力学的比较

目的 比较去甲肾上腺素与多巴胺在非体外循环冠状动脉旁路移植术(OPCAB)中对血流动力学的影响.方法 冠心病多支病变患者30例,采用Swan-Ganz导管监测血流动力学.分为多巴胺组[3～5 μg/(kg·min),DA组]和去甲肾上腺素组[0.01～0.1 μg/(kg· min),NE组].分别在麻醉诱导后(T1)、吻合前降支时(T2)、吻合右冠状动脉或后降支时(T3)、吻合回旋支或钝缘支时(T4)、吻合近端时(T5)、手术结束后(T6)记录各项血流动力学参数.T2～T4为使用固定器后血流动力学相对稳定时的数据.术中搬动、探查心脏血压下降明显时,单次静脉注射去甲肾上腺素4～8 μg,记录T1～T6各组去甲肾上腺素的总用量和静注次数.分别记录术前、术后1d、术后1周血肌酐(Cr)和尿素氮(BUN).记录每组患者的术后机械通气时间,ICU停留时间和住院时间.结果 两组患者一般情况和手术一般资料、围术期情况差异均无统计学意义.术前、术后1d、术后1周两组患者肾功能指标组间和组内比较差异无统计学意义.两组患者血流动力学各时相的比较中,T3的中心静脉压(CVP)和肺小动脉楔入压(PAWP),DA组高于NE组.两组T6时心指数(CI)都较基础值增高,每搏量(SV)无明显变化.NE组的外周血管阻力(SVR)基本维持不变,DA组有明显的下降.NE组在吻合血管过程中去甲肾上腺素的总用量[(40±5) vs.(60±25)μg,P＜0.05]和静注次数[(7±2)vs.(13±5)次,P＜0.05]小于DA组.结论 非体外循环冠状动脉旁路移植术中,持续泵注去甲肾上腺素较持续泵注多巴胺加间断单次给予去甲肾上腺素更有利于维持术中循环稳定,可能与维持稳定的SVR有关.     

Effects of methamphetamine on the noradrenergic activity biomarker salivary alpha-amylase

Background

Methamphetamine (METH) potently activates the sympathetic nervous system (SNS) by increasing central and peripheral norepinephrine (NE). Salivary α-amylase (sAA) is a biomarker of SNS activation that correlates with plasma NE levels. The purpose of this study was to determine the impact of METH on sAA activity and whether changes in sAA activity were correlated with subjective effects ratings.

Methods

Non-treatment seeking METH-dependent volunteers (N = 8) participated in this within-subjects laboratory-based study. Volunteers received randomly administered intravenous METH (0 mg, 30 mg) and sAA activity, cardiovascular measures and subjective ratings were assessed at baseline (−15 min) and five post-METH time points (10, 20, 30, 45, and 60 min).

Results

METH (30 mg) increased sAA activity over time. sAA activity significantly correlated with diastolic blood pressure following 0 mg METH and systolic blood pressure following 30 mg METH. Subjective ratings (ANY EFFECT, HIGH, GOOD, STIMULATED, LIKE, WLLING TO PAY) highly correlated with sAA over five post-METH time points (N = 40; r's = 0.543–0.684, p's < 0.001). Age, body mass index and METH amount received on a mg/kg basis were significantly associated with sAA activity. Multiple linear regression analysis indicated sAA activity remained a significant predictor of subjective ratings following METH after controlling for these factors.

Conclusions

The NE peripheral biomarker sAA activity is associated with METH's subjective effects.