P2Y1 receptors expressed by C1 neurons determine peripheral chemoreceptor modulation of breathing, sympathetic activity, and blood pressure

Catecholaminergic C1 cells of the rostral ventrolateral medulla (RVLM) are key determinants of the sympathoexcitatory response to peripheral chemoreceptor activation. Overactivation of this reflex is thought to contribute to increased sympathetic activity and hypertension; however, molecular mechanisms linking peripheral chemoreceptor drive to hypertension remain poorly understood. We have recently determined that activation of P2Y1 receptors in the RVLM mimicked effects of peripheral chemoreceptor activation. Therefore, we hypothesize that P2Y1 receptors regulate peripheral chemoreceptor drive in this region. Here, we determine whether P2Y1 receptors are expressed by C1 neurons in the RVLM and contribute to peripheral chemoreceptor control of breathing, sympathetic activity, and blood pressure. We found that injection of a specific P2Y1 receptor agonist (MRS2365) into the RVLM of anesthetized adult rats increased phrenic nerve activity (≈55%), sympathetic nerve activity (38±6%), and blood pressure (23±1 mm Hg), whereas application of a specific P2Y1 receptor antagonist (MRS2179) decreased peripheral chemoreceptor–mediated activation of phrenic nerve activity, sympathetic nerve activity, and blood pressure. To establish that P2Y1 receptors are expressed by C1 cells, we determine in the brain slice preparation using cell-attached recording techniques that cells responsive to MRS2365 are immunoreactive for tyrosine hydroxylase (a marker of C1 cells), and we determine in vivo that C1-lesioned animals do not respond to RVLM injection of MRS2365. These data identify P2Y1 receptors as key determinants of peripheral chemoreceptor regulation of breathing, sympathetic nerve activity, and blood pressure.

Sleep-related changes in blood pressure in hypocretin-deficient narcoleptic mice

Objectives. Blood pressure (BP) physiologically has higher and lower values during the active and rest period, respectively. Subjects failing to show the appropriate BP decrease (10-20%) on passing form diurnal activity to nocturnal rest and sleep have increased risk of target organ damage at the cardiac, vascular and cerebrovascular levels. Hypocretin (HCRT) releasing neurons, mainly located in the lateral hypothalamus, project widely to the central nervous system. Thus HCRT neurons are involved in several autonomic functions, including BP regulation. HCRT neurons also play a key role in wake-sleep cycle regulation, the lack of which becomes evident in HCRT-deficient narcoleptic patients. I investigated whether chronic lack of HCRT signaling alters BP during sleep in mouse models of narcolepsy. Methods. The main study was performed on HCRT-ataxin3 transgenic mice (TG) with selective post-natal ablation of HCRT neurons, HCRT gene knockout mice (KO) with preserved HCRT neurons, and Wild-Type control mice (WT) with identical genetic background. Experiments where replicated on TG and WT mice with hybrid genetic background (hTG and hWT, respectively). Mice were implanted with a telemetric pressure transducer (TA11PA-C10, DSI) and electrodes for discriminating wakefulness (W), rapid-eye-movement sleep (REMS) and non-REMS (NREMS). Signals were recorded for 3 days. Mean BP values were computed in each wake-sleep state and analyzed by ANOVA and t-test with significance at p<0.05. Results. The decrease in BP between either NREMS or REMS and W was significantly blunted in TG and KO with respect to WT as well as in hTG with respect to hWT. Conclusions. Independently from the genetic background, chronic HCRT deficiency leads to a decreased BP difference between W and sleep potentially adverse in narcoleptic subjects. These data suggest that HCRT play an important role in the sleep-dependent cardiovascular control.

Effects of maternal PETN treatment of spontaneously hypertensive rats on blood pressure in the offspring

Pentaerithrityltetranitrat (PETN) ist ein organisches Nitrat und wird in der Klinik zur Behandlung der Angina Pectoris eingesetzt. PETN hat, wenn direkt verabreicht, kaum Wirkung auf den Blutdruck. Diese Arbeit wurde konzipiert, um einen potentiellen „perinatalen Programmierung“-Effekt von PETN in spontan-hypertensiven Ratten (SHR), einem Rattenmodel der genetischen Hypertonie, zu testen. Die F0-Elterntiere wurden mit PETN (50 mg/kg/Tag) während der Schwangerschaft und der Laktation behandelt; die F1-Nachkommen bekamen nach der Ablaktation normales Haltungsfutter. Der Blutdruck wurde an den Nachkommen vom 3. Monat bis zum 8. Monat nach der Geburt gemessen. Maternale PETN-Behandlung hatte kaum Wirkung auf den Blutdruck in den männlichen SHR-Nachkommen. Dagegen zeigten die weiblichen Nachkommen der PETN-Behandlungsgruppe eine persistente Reduktion des Blutdrucks. Der systolische Blutdruck war in den weiblichen Nachkommen in der PETN-Gruppe etwa 13 mmHg niedriger im 4. Monat und etwa 10 mmHg niedriger im 8. Monat als in den Kontrolltieren. Dieser lang-anhaltende Effekt ging mit einer substanziellen Änderung der Genexpression einher, die auch beim 8. Monat noch nachzuweisen war. In den Aorten der weiblichen F1-Nachkommen wurde Veränderungen an Genexpression der α-adrenergen Rezeptoren sowie Endothelin-Rezeptoren festgestellt, die aber funktionell von minimaler Bedeutung für die PETN-Wirkung waren. Hingegen war eine klare Rolle des StickstoffmoNOXid (NO) zu sehen. Maternale PETN-Behandlung führte zur Heraufregulation der endothelialen NO-Synthase (eNOS) und der GTP-Cyclohydrolase I (GCH-1). GCH-1 ist für die Biosynthese des Tetrahydrobiopterins, eines essentiellen eNOS-Kofaktors, entscheidend, und dadurch auch für die eNOS-Funktionalität. Zusätzlich wurden auch anti-oxidative Enzyme wie die mitochondriale Superoxid-Dismutase (SOD2), die Glutathion-Peroxidase 1 (GPx1) und die Hem-Oxygenase 1 (HO-1) heraufreguliert, und die Superoxid-produzierende NADPH-Oxidase NOX1 herunterreguliert. Dies kann zur Verminderung vom oxidativen Stress und Erhöhung der NO-Bioverfügbarkeit führen. Letztlich wurde auch ~ 74 ~ die Sirtuin 1 (SIRT1) durch maternale PETN-Behandlung heraufreguliert, die auch zur Heraufregulation der SOD2, GPx1 und eNOS beitragen kann. Im Organbad-Experiment wurde die Acetylcholin-induzierte, Endothel-abhängige Vasodilatation in der Aorta der weiblichen Nachkommen der PETN-Gruppe verstärkt. Diese verbesserte Endothelfunktion, was vermutlich aus der Genexpressionsänderung resultiert, stellt sehr wahrscheinlich einen Schlüsselmechanismus der Blutdrucksenkung in den Nachkommen der PETN-behandelten F0-Tiere dar.

Should we target blood pressure in sepsis?

To review blood pressure targets and their implementation in sepsis.

The relationship between self-efficacy and resting blood pressure in spousal Alzheimer's caregivers

Objective. To examine whether high levels of self-efficacy for problem-focused coping were significantly related to several resting BP measures in spousal Alzheimer's disease caregivers. Design. Cross-sectional. Methods. Participants included 100 older caregivers (mean age = 73.8 ± 8.14 years) providing in home care for a spouse with Alzheimer's disease. All participants completed a 13-item short form of the Coping Self-Efficacy Scale and underwent an in-home assessment where a visiting nurse took the average of three serial BP readings. Multiple regression was used to examine the relationship between self-efficacy and mean arterial pressure (MAP), systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) after controlling for age, gender, smoking history, body mass index, the care recipient's clinical dementia rating, diabetes, alcohol use, and the use of antihypertensive medications. Results. Overall, high levels of self-efficacy for problem-focused coping were associated with lower MAP, SBP, and PP. Self-efficacy for problem-focused coping was marginally associated with resting DBP, but not significant. In addition, we conducted secondary analyses of the other two self-efficacy scales to explore the relationship between each dimension and MAP. We found that there were no significant relationships found between MAP and self-efficacy for stopping unpleasant thoughts/emotions or self-efficacy for getting social support. Conclusions. The present study adds to the current body of literature by illustrating the possibility that higher self-efficacy can have physiological advantages, perhaps by buffering chronic stress's impact on resting BP. Another contribution of the current study is its attempt to understand the role of each individual component of self-efficacy. These findings invite future research to investigate whether caregivers might experience cardiovascular benefits from interventions aimed at enhancing self-efficacy.

Effects of {beta}-blocker selectivity on blood pressure variability and stroke: A systematic review

β-Blockers increase variability in systolic blood pressure (SBP), which probably explains their lesser effectiveness in preventing stroke vs myocardial infarction compared with other agents. This increase in variability in blood pressure (BP) may be particularly marked on non-cardioselective agents, potentially calling into question the widespread first-line use of propranolol in migraine with aura, elderly patients with essential tremor or anxiety, and other groups at risk of stroke.

Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis

Unexplained differences between classes of antihypertensive drugs in their effectiveness in preventing stroke might be due to class effects on intraindividual variability in blood pressure. We did a systematic review to assess any such effects in randomised controlled trials.

Systolic blood pressure below 110 mmHg is associated with increased mortality in penetrating major trauma patients: Multicentre cohort study

Non-invasive systolic blood pressure (SBP) measurement is a commonly used triaging tool for trauma patients. A SBP of <90mmHg has represented the threshold for hypotension for many years, but recent studies have suggested redefining hypotension at lower levels. We therefore examined the association between SBP and mortality in penetrating trauma patients.

Systolic blood pressure below 110 mm Hg is associated with increased mortality in blunt major trauma patients: multicentre cohort study

Non-invasive systolic blood pressure (SBP) measurement is often used in triaging trauma patients. Traditionally, SBP< 90 mm Hg has represented the threshold for hypotension, but recent studies have suggested redefining hypotension as SBP < 110 mm Hg. This study aims to examine the association of SBP with mortality in blunt trauma patients.