Environmental Factors Influence Language Development in Children with Autism Spectrum Disorders

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The contributions of muscarinic receptors and changes in plasma aldosterone levels to the anti-hypertensive effect of Tulbaghia violacea

Background: Tulbaghia violacea Harv. (Alliaceae) is used to treat various ailments, including hypertension (HTN) in South Africa. This study aims to evaluate the contributions of muscarinic receptors and changes in plasma aldosterone levels to its anti-hypertensive effect. Methods: In the acute experiments, methanol leaf extracts (MLE) of T. violacea (30–120 mg/kg), muscarine (0.16 -10 μg/kg), and atropine (0.02 - 20.48 mg/kg), and/or the vehicle (dimethylsulfoxide (DMSO) and normal saline (NS)) were respectively and randomly administered intravenously in a group of spontaneously hypertensive (SHR) weighing 300 to 350 g and aged less than 5 months. Subsequently, T. violacea (60 mg/kg) or muscarine (2.5 μg/kg) was infused into eight SHRs, 20 min after atropine (5.12 mg/kg) pre-treatment. In the chronic (21 days) experiments, the SHRs were randomly divided into three groups, and given the vehicle (0.2 ml/day of DMSO and NS), T. violacea (60 mg/kg/day) and captopril (10 mg/kg/day) respectively into the peritoneum, to investigate their effects on blood pressure (BP), heart rate (HR), and plasma aldosterone levels. Systolic BP and HR were measured using tail-cuff plethysmography during the intervention. BP and HR were measured via a pressure transducer connecting the femoral artery and the Powerlab at the end of each intervention in the acute experiment; and on day 22 in the chronic experiment. Results: In the acute experiments, T. violacea, muscarine, and atropine significantly (p < 0.05) reduced BP dose-dependently. T. violacea and muscarine produced dose-dependent decreases in HR, while the effect of atropine on HR varied. After atropine pre-treatment, dose-dependent increases in BP and HR were observed with T. violacea; while the BP and HR effects of muscarine were nullified. In the chronic experiments, the T. violaceatreated and captropril-treated groups had signicantly lower levels of aldosterone in plasma when compared to vehicle-treated group. Compared to the vehicle-treated group, significant reduction in BP was only seen in the captopril-treated group; while no difference in HR was observed among the groups. Conclusion: The results obtained in this study suggest that stimulation of the muscarinic receptors and a reduction in plasma aldosterone levels contribute to the anti-hypertesive effect of T. violacea.IS

Genetic ablation of angiotensinogen in the subfornical organ of the brain prevents the central angiotensinergic pressor response

The subfornical organ (SFO) of the brain has long been considered a critical integrating center for the cardiovascular actions of the renin-angiotensin system (RAS). Early reports of angiotensin II (Ang II) immunoreactivity in the SFO and its neural projections to downstream cardiovascular nuclei raised the possibility that Ang II is produced locally and functions as a putative neurotransmitter in these circuits. However, evidence of functionally significant de novo synthesis of Ang II in the SFO has been lacking. Here, implementing spatiotemporally restricted gene ablation by way of the Cre recombinase/loxP system, we provide the first direct evidence that the local RAS in the SFO has a critical role in blood pressure regulation. Using a transgenic mouse harboring an angiotensinogen (AGT) gene modified for Cre-mediated deletion (hAGTflox), in combination with gene transfer of an adenovirus encoding Cre targeted to the SFO, we show that deletion of the Ang II substrate in this brain region nearly abolishes the pressor and bradycardic effects of renin infused in the CNS. Immunohistochemical analyses verified intense and restricted expression of Cre in the SFO, which paralleled the decrease in AGT expression selectively in this site. Further physiological studies confirmed the integrity of central angiotensinergic and nonangiotensinergic cardiovascular response systems in the Cre-treated mice. In addition to establishing that AGT expression in the SFO and its local conversion to Ang II has a profound effect on blood pressure, this study provides proof-of-principle of the utility of this approach for dissecting the brain RAS and other complex systems in CNS cardiovascular circuits

Enhanced water and salt intake in transgenic mice with brain-restricted overexpression of angiotensin (AT1) receptors

To address the relative contribution of central and peripheral angiotensin II (ANG II) type 1A receptors (AT1A) to blood pressure and volume homeostasis, we generated a transgenic mouse model [neuron-specific enolase (NSE)-AT1A] with brain-restricted overexpression of AT1A receptors. These mice are normotensive at baseline but have dramatically enhanced pressor and bradycardic responses to intracerebroventricular ANG II or activation of endogenous ANG II production. Here our goal was to examine the water and sodium intake in this model under basal conditions and in response to increased ANG II levels. Baseline water and NaCl (0.3 M) intakes were significantly elevated in NSE-AT1A compared with nontransgenic littermates, and bolus intracerebroventricular injections of ANG II (200 ng in 200 nl) caused further enhanced water intake in NSE-AT1A. Activation of endogenous ANG II production by sodium depletion (10 days low-sodium diet followed by furosemide, 1 mg sc) enhanced NaCl intake in NSE-AT1A mice compared with wild types. Fos immunohistochemistry, used to assess neuronal activation, demonstrated sodium depletion-enhanced activity in the anteroventral third ventricle region of the brain in NSE-AT1A mice compared with control animals. The results show that brain-selective overexpression of AT1A receptors results in enhanced salt appetite and altered water intake. This model provides a new tool for studying the mechanisms of brain AT1A-dependent water and salt consumption