GABA is a mediator of brain AT1 and AT2 receptor-mediated blood pressure responses.

The nucleus tractus solitarius (NTS), paraventricular nucleus (PVN), and rostral ventrolateral medulla (RVLM) are the most targeted regions of central blood pressure control studies. Glutamate and gamma-aminobutyric acid (GABA) interact within these brain regions to modulate blood pressure. The brain renin-angiotensin system also participates in central blood pressure control. Angiotensin II increases blood pressure through the stimulation of angiotensin II type 1 (AT1) receptors within the PVN and RVLM and attenuates baroreceptor sensitivity, resulting in elevated blood pressure within the NTS. Angiotensin II type 2 (AT2) receptors in cardiovascular control centers in the brain also appear to be involved in blood pressure control and counteract AT1 receptor-mediated effects. The current review is focused on the interaction of GABA with AT1 and AT2 receptors in the control of blood pressure within the RVLM, PVN and NTS. Within the NTS, GABA is released from local GABAergic interneurons that are stimulated by local AT1 receptors and mediates a hypertensive response. In contrast, the local increase in GABA levels observed after AT2 receptor stimulation within the RVLM, likely from GABAergic nerve endings originating in the caudal ventrolateral medulla, is important in the mediation of the hypotensive response. Preliminary results suggest that the hypertensive response to AT1 receptor stimulation within the RVLM is associated with a reduction in GABA release. The current experimental evidence therefore indicates that GABA is an important mediator of brainstem responses to AT1 and AT2 receptor stimulation and that increased GABA release may play a role in hypertensive and hypotensive responses, depending on the site of action.

Investigation of the Role of AT2 Receptors in the Nucleus Tractus Solitarii of Normotensive Rats in Blood Pressure Control.

AIM: The nucleus tractus solitarii (NTS) densely expresses angiotensin II type 2 receptors (AT2R), which are mainly located on inhibitory gamma-aminobutyric acid (GABA) neurons. Central AT2R stimulation reduces blood pressure, and AT2R stimulation in the rostral ventrolateral medulla (RVLM), mediates a hypotensive response through a GABAergic mechanism. We aimed to test the hypothesis that an AT2R mediated inhibition of the GABA release within the NTS might be involved in this hypotensive response, by assessing possible alterations in blood pressure and heart rate, as well as in GABA levels in normotensive Wistar rats. METHODS: In vivo microdialysis was used for measurement of extracellular GABA levels and for perfusion of the selective AT2R agonist, Compound 21, within the NTS. Our set-up allowed to determine simultaneously the excitatory glutamate dialysate levels. The mean arterial pressure and heart rate responses were monitored with a pressure transducer. RESULTS: Local perfusion of Compound 21 into the NTS did not modify blood pressure and heart rate, nor glutamate and GABA levels compared to baseline concentrations. A putative effect was also not unmasked by concomitant angiotensin II type 1 receptor blockade with candesartan. Positive control experiments confirmed that the experimental set up had enough sensitivity to detect a reduction in GABA dialysate levels and blood pressure. CONCLUSION: The results did not provide evidence for a role of the AT2R within the NTS in the control of blood pressure, nor for an interaction with local GABAergic signaling in normotensive rats.

AT1 Receptor Mediated Hypertensive Response to Ang II in the Nucleus Tractus Solitarii of Normotensive Rats Involves NO Dependent Local GABA Release.

AIM: It is well-established that angiotensin II exerts a dampening effect on the baroreflex within the nucleus tractus solitarii (NTS), the principal brainstem site for termination of baroreceptor afferents and which is densely populated with gamma-aminobutyric acid (GABA)ergic neurons and nerve terminals. The present study was designed to investigate whether local release of GABA is involved in the effects mediated by local angiotensin II within the NTS. METHODS: In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for infusion of angiotensin II within the NTS of conscious normotensive Wistar rats. The mean arterial pressure (MAP) and heart rate response to local infusion of angiotensin II were subsequently monitored with a pressure transducer under anesthesia. The angiotensin II type 1 receptor (AT1R) antagonist, candesartan, was used to assess whether responses were AT1R dependent and the nitric oxide (NO) synthase inhibitor, N(ω)-nitro-L-arginine methyl ester (L-NAME), was used to assess the involvement of NO in the evoked responses by infusion of angiotensin II. The MAP and heart rate responses were monitored with a pressure transducer. RESULTS: Local infusion into the NTS of angiotensin II induced a significant to ninefold significantly increase in extracellular GABA levels; as well as MAP was increased by 15 mmHg. These responses were both abolished by co-infusion of either, the angiotensin II type 1 receptor antagonist, candesartan, or the NO synthase inhibitor, L-NAME, demonstrating that the effect is not only AT1R dependent but also NO dependent. The pressor response to angiotensin II was reversed by co-infusion with the GABAA receptor antagonist, bicuculline. Local blockade of NO synthase decreased both, GABA and glutamate concentrations. CONCLUSION: Our results suggest that the AT1R mediated hypertensive response to angiotensin II within the NTS in normotensive rats is GABA and NO dependent. Nitric oxide produced within the NTS tonically potentiates local GABA and glutamate release.

Clinical Decision Support Systems for Drug Allergy Checking: Systematic Review.

BACKGROUND: Worldwide, the burden of allergies-in particular, drug allergies-is growing. In the process of prescribing, dispensing, or administering a drug, a medication error may occur and can have adverse consequences; for example, a drug may be given to a patient with a documented allergy to that particular drug. Computerized physician order entry (CPOE) systems with built-in clinical decision support systems (CDSS) have the potential to prevent such medication errors and adverse events. OBJECTIVE: The aim of this review is to provide a comprehensive overview regarding all aspects of CDSS for drug allergy, including documenting, coding, rule bases, alerts and alert fatigue, and outcome evaluation. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed as much as possible and searches were conducted in 5 databases using CPOE, CDSS, alerts, and allergic or allergy as keywords. Bias could not be evaluated according to PRISMA guidelines due to the heterogeneity of study types included in the review. RESULTS: Of the 3160 articles considered, 60 met the inclusion criteria. A further 9 articles were added based on expert opinion, resulting in a total of 69 articles. An interrater agreement of 90.9% with a reliability Κ=.787 (95% CI 0.686-0.888) was reached. Large heterogeneity across study objectives, study designs, study populations, and reported results was found. Several key findings were identified. Evidence of the usefulness of clinical decision support for drug allergies has been documented. Nevertheless, there are some important problems associated with their use. Accurate and structured documenting of information on drug allergies in electronic health records (EHRs) is difficult, as it is often not clear to healthcare providers how and where to document drug allergies. Besides the underreporting of drug allergies, outdated or inaccurate drug allergy information in EHRs poses an important problem. Research on the use of coding terminologies for documenting drug allergies is sparse. There is no generally accepted standard terminology for structured documentation of allergy information. The final key finding is the consistently reported low specificity of drug allergy alerts. Current systems have high alert override rates of up to 90%, leading to alert fatigue. Important challenges remain for increasing the specificity of drug allergy alerts. We found only one study specifically reporting outcomes related to CDSS for drug allergies. It showed that adverse drug events resulting from overridden drug allergy alerts do not occur frequently. CONCLUSIONS: Accurate and comprehensive recording of drug allergies is required for good use of CDSS for drug allergy screening. We found considerable variation in the way drug allergy are recorded in EHRs. It remains difficult to reduce drug allergy alert overload while maintaining patient safety as the highest priority. Future research should focus on improving alert specificity, thereby reducing override rates and alert fatigue. Also, the effect on patient outcomes and cost-effectiveness should be evaluated.

Hypotensive Response to Angiotensin II Type 2 Receptor Stimulation in the Rostral Ventrolateral Medulla Requires Functional GABA-A Receptors.

Objectives: Angiotensin II, glutamate and gamma-aminobutyric acid (GABA) interact within the rostral ventrolateral medulla (RVLM) and the paraventricular nucleus (PVN) modulating the central regulation of blood pressure and sympathetic tone. Our aim was to assess the effects of local angiotensin II type 2 receptor stimulation within the RVLM and the PVN on neurotransmitter concentrations and mean arterial pressure (MAP). Methods:In vivo microdialysis was used for measurement of extracellular glutamate and GABA levels and for local infusion of the angiotensin II type 2 receptor agonist Compound 21 in the RVLM and the PVN of conscious normotensive Wistar rats. The MAP response to local Compound 21 was monitored with a pressure transducer under anaesthesia. Angiotensin II type 2 receptor selectivity was assessed using the angiotensin II type 2 receptor antagonist PD123319; the GABA-A receptor antagonist bicuculline was used to assess the involvement of GABA-A receptors. Results: Infusion of Compound 21 (0.05 µg/µl/h) in the RVLM significantly increased GABA levels and lowered blood pressure. These effects were abolished by co-infusion with PD123319. No changes in neurotransmitter levels or effects on blood pressure were seen with PD123319 infusion alone. Co-infusion of bicuculline abolished the Compound 21 evoked decrease in MAP. Infusion of Compound 21 within the PVN did not change extracellular neurotransmitter levels nor MAP. Conclusion: Selective stimulation of angiotensin II type 2 receptor within the RVLM by local Compound 21 infusion reduces blood pressure and increases local GABA levels in normotensive rats. This hypotensive response requires functional GABA-A receptors, suggesting that GABAergic neurons are involved in the sympatho-inhibitory action underlying this hypotensive response.