Effect of vinpocetine on embryonic heart rate in vitro.

Vinpocetine is a readily available nutritional supplement claimed to improve memory and weight loss. However, it blocks the Ikr current essential for cardiac action potential repolarisation and Ikr inhibition can cause "torsade de pointes" arrhythmias and sudden death. Moreover, Ikr blockers have exhibited teratogenic effects in reproductive toxicology studies, leading to increased birth defects and embryonic mortality. The FDA advises against vinpocetine use in pregnant and prospective mothers based on animal studies showing dose-dependent fetal mortality in rats and rabbits, and cardiovascular malformations in surviving fetuses. However, the mechanisms responsible for vinpocetine's fetal toxicity remain unclear. The present study used rat embryo culture to evaluate vinpocetine and its major metabolite, apovincaminic acid, on embryonic heart rate, a possible causative factor behind its adverse effects. Both compounds induced embryonic bradycardia in a concentration-dependent manner, with vinpocetine proving more potent. The minimum vinpocentine concentration to induce bradycardia was 100 nM, a level unlikely to be reached in humans following typical doses. Embryonic arrhythmias were also observed at the highest concentrations. These results suggest that the FDA's cautionary statement may generate undue anxiety, although re-evaluation of teratogenicity risk associated with vinpocetine should be revisited if a link to cardiac arrhythmias in adults is established.

Cardiac and vascular health in late preterm infants.

Adults who were born preterm are at increased risk of hypertension and cardiovascular disease in later life. Infants born late preterm are the majority of preterm births; however, the effect of late preterm on risk of cardiovascular disease is unclear. The objective of this study was to assess whether vascular health and cardiac autonomic control differ in a group of late preterm newborn infants compared to a group of term-born infants.A total of 35 healthy late preterm newborn infants, with normal growth (34-36 completed weeks' gestation) and 139 term-born infants (37-42 weeks' gestation) were compared in this study. Aortic wall thickening, assessed as aortic intima-media thickness (IMT) by high-resolution ultrasound, and cardiac autonomic control, assessed by heart rate variability, were measured during the first week of life. Postnatal age of full-term and late preterm infants at the time of the study was 5 days (standard deviation [SD] 5) and 4 days (SD 3), respectively.Infants born late preterm show reduced aortic IMT (574 µm [SD 51] vs. 612 µm [SD 73]) and reduced heart rate variability [log total power 622.3 (606.5) ms2 vs. 1180. 6 (1114.3) ms2], compared to term infants. These associations remained even after adjustment for sex and birth weight.Infants born late preterm show selective differences in markers of cardiovascular risk, with potentially beneficial differences in aortic wall thickness in contrast to potentially detrimental differences in autonomic control, when compared with term-born control infants. These findings provide pathophysiologic evidence to support an increased risk of hypertension and sudden cardiac death in individuals born late preterm.

Ghrelin Signaling Affects Feeding Behavior, Metabolism, and Memory through the Vagus Nerve.

Vagal afferent neuron (VAN) signaling sends information from the gut to the brain and is fundamental in the control of feeding behavior and metabolism [1]. Recent findings reveal that VAN signaling also plays a critical role in cognitive processes, including affective motivational behaviors and hippocampus (HPC)-dependent memory [2-5]. VANs, located in nodose ganglia, express receptors for various gut-derived peptide signals; however, the function of these receptors with regard to feeding behavior, metabolism, and memory control is poorly understood. We hypothesized that VAN-mediated processes are influenced by ghrelin, a stomach-derived orexigenic hormone, via communication to its receptor (GHSR) expressed on gut-innervating VANs. To examine this hypothesis, rats received nodose ganglia injections of an adeno-associated virus (AAV) expressing short hairpin RNAs targeting GHSR (or a control AAV) for RNAi-mediated VAN-specific GHSR knockdown. Results reveal that VAN GHSR knockdown induced various feeding and metabolic disturbances, including increased meal frequency, impaired glucose tolerance, delayed gastric emptying, and increased body weight compared to controls. Additionally, VAN-specific GHSR knockdown impaired HPC-dependent contextual episodic memory and reduced HPC brain-derived neurotrophic factor expression, but did not affect anxiety-like behavior or general activity levels. A functional role for endogenous VAN GHSR signaling was further confirmed by results revealing that VAN signaling is required for the hyperphagic effects of ghrelin administered at dark onset, and that gut-restricted ghrelin-induced increases in VAN firing rate require intact VAN GHSR expression. Collective results reveal that VAN GHSR signaling is required for both normal feeding and metabolic function as well as HPC-dependent memory.

Influence of maternal and placental factors on newborn body composition.

AIM: The objective of this study was to assess whether maternal characteristics, placental size or histological chorioamnionitis was associated with newborn body composition. Furthermore, we sought to determine whether placental weight may mediate the association between maternal pre-pregnancy weight and age with newborn body composition. METHODS: A cross-sectional study was conducted at Royal Prince Alfred Hospital, Sydney, Australia. This study included 136 healthy, singleton, term-born newborns. Recruitment was stratified by newborn body fat percentiles (gender and gestational adjusted). Body fat was assessed by air displacement plethysmography. Placental examination was conducted by an anatomical pathologist. Maternal (chorioamnionitis) and fetal (chorionic and umbilical vasculitis, funisitis) inflammatory responses were classified according to Redline criteria. RESULTS: Maternal pre-pregnancy weight, parity, labour, placental weight and surface area were associated with newborn fat mass and fat-free mass. Gestational diabetes and maternal age were associated with newborn fat mass but not fat-free mass. There was no association between histological chorioamnionitis and newborn body composition; however, spontaneous onset of labour was strongly associated with the presence of histological chorioamnionitis. Only 25-31% of the association of maternal weight and age with newborn fat mass was mediated via the placenta. CONCLUSIONS: Maternal factors associated with newborn fat mass and fat-free mass differed, indicating that different mechanisms control fat mass and fat-free mass. Our mediation analysis suggests that placental weight partly mediates the association of maternal factors with newborn body composition. Histological chorioamnionitis was not associated with newborn body composition.

Autonomic dysfunction in programmed hypertension.

Hypertension is an important modifiable risk factor for cardiovascular diseases. Its high prevalence, combined with the significant morbidity and mortality associated with secondary complications, make it a major public health concern. Despite decades of research, over 95% of all cases of hypertension remain of unknown etiology, necessitating that treatments target the established symptoms and not the cause. One of the important recent advances in hypertension research is an understanding that hypertension often may have a developmental origin. A substantial body of evidence indicates that exposure to an adverse intrauterine environment during critical periods of development may predispose an individual to develop hypertension later in life. A causative mechanism has yet to be identified, but may include epigenetic modifications, and/or alterations in renal, vascular or autonomic cardiovascular functions. This review will present evidence regarding changes in autonomic activity as a possible causative pathophysiological mechanism underlying the development of programmed hypertension. In man, low birth weight is the best-known risk factor for hypertension of developmental origins, although this is a broad surrogate measure for intrauterine adversity. This review will include clinical studies across the lifespan that have investigated autonomic function in individuals with fetal growth restriction and those born preterm. A determination of whether altered autonomic function is seen in these individuals in early life is imperative, as hypertensive disorders that have their origins in utero, and that can be identified early, will open the door to risk stratification, and the development of new strategies that prevent or specifically target these mechanisms.

Body Fatness and Cardiovascular Health in Newborn Infants.

Birth weight is associated with cardiovascular disease, with those at both ends of the spectrum at increased risk. However, birth weight is a crude surrogate of fetal growth. Measures of body composition may more accurately identify high risk infants. We aimed to determine whether aortic wall thickening, cardiac autonomic control, and cardiac structure/function differ in newborns with high or low body fatness compared to those with average body fatness. 189 healthy singleton term born neonates were recruited and stratified by body fat percentiles (sex and gestation-specific). Infants with low body fat had higher aortic intima-media thickness (43 µm (95% confidence interval (CI) 7, 78), p = 0.02), lower heart rate variability (log total power, -0.5 (95% CI -0.8, -0.1), p = 0.008), and thicker ventricular walls (posterior wall thickness, 3.1 mm (95% CI 1.6, 4.6), p < 0.001) compared to infants with average body fatness. Infants with high body fat showed no differences in aortic intima-media thickness (-2 µm (95% CI -37, 33), p = 0.91) or cardiac structure compared to average body fatness, although stroke volume (-0.3 mL/kg (95% CI -0.6, -0.0), p = 0.003) and heart rate variability were lower (log total power, -0.8 (95% CI -1.1, -0.5), p < 0.001). The non-linear association of body fatness with heart rate variability was independent of birth weight. Infants born with low or high body fat have altered markers of cardiovascular health. Assessment of body fatness alongside birth weight may assist in identifying high risk individuals.

Noninvasive assessment of autonomic function in human neonates born at the extremes of fetal growth spectrum.

Birth weight is associated with adult cardiovascular disease, such that those at both ends of the spectrum are at increased risk. This may be driven in part by modification to autonomic control, a mechanistic contributor to hypertension. However, birth weight is a relatively crude surrogate of fetal growth; and newborn body composition may more accurately identify the "at risk" infant. Accordingly, we sought to determine whether newborns with high or low body fat have altered autonomic control of vasomotor function and cardiac contractility. Body fat was assessed by air-displacement plethysmography <24 h postnatal. Measures of spontaneous baroreflex sensitivity (sBRS), blood pressure variability (BPV), and dP/dtmax variability were compared between newborns categorized according to established body fat percentiles: high body fat (HBF, >90th percentile, n = 7), low body fat (LBF, ≤10th percentile, n = 12), and normal body fat (control, >25th to ≤75th percentile, n = 23). BPV was similar across body fat percentiles; similarly, low frequency dP/dtmax variability was similar across body fat percentiles. sBRS was reduced in HBF compared to controls (11.0 ± 6.0 vs. 20.1 ± 9.4 msec/mmHg, P = 0.03), but LBF did not differ (18.4 ± 6.0 msec/mmHg, P = 0.80). Across the entire body fat spectrum (n = 62), there was a nonlinear association between newborn body fat and sBRS (P = 0.03) that was independent of birth weight (P = 0.04). Autonomic modulation of vasomotor function and cardiac contractility in the newborn did not differ by body fat, but newborns born with high body fat show depressed baroreflex sensitivity.

Long-term programming effects on blood pressure following gestational exposure to the IKr blocker Dofetilide.

A slow embryonic heart rate in early-mid gestation is associated with increased risk of embryonic death and malformation, however, the long-term consequences remain unknown. We administered Dofetilide (Dof, 2.5 mg/kg), a drug that produces embryo-specific bradycardia, to pregnant rats from gestational days 11-14. Embryonic heart rate and rhythm were determined using embryo culture. Cardiovascular function was assessed in surviving adult offspring at rest, during acute psychological stress (air jet stress, AJS), and after 7 days of repeated AJS. Dof reduced embryonic HR by 40% for ~8 h on each of the treatment days. On postnatal day 3, Dof offspring were ~10% smaller. Blood pressure was elevated in adult Dof rats (systolic blood pressure, night: 103.8 ± 3.9 vs. 111.2 ± 3.0 mmHg, P = 0.01). While the pressor response to AJS was similar in both groups (control 17.7 ± 3.4; Dof 18.9 ± 0.9 mmHg, P = 0.74), after 7 days repeated AJS, clear habituation was present in control (P = 0.0001) but not Dof offspring (P = 0.48). Only Dof offspring showed a small increase in resting blood pressure after 7 days repeated stress (+3.9 ± 1.7 mmHg, P = 0.05). The results indicate that embryonic bradycardia programs hypertension and impaired stress adaptation, and have implications for the maternal use of cardioactive drugs during pregnancy.

Quantity and Quality of Carbohydrate Intake during Pregnancy, Newborn Body Fatness and Cardiac Autonomic Control: Conferred Cardiovascular Risk?

The fetal environment has an important influence on health and disease over the life course. Maternal nutritional status during pregnancy is potentially a powerful contributor to the intrauterine environment, and may alter offspring physiology and later life cardio-metabolic risk. Putative early life markers of cardio-metabolic risk include newborn body fatness and cardiac autonomic control. We sought to determine whether maternal dietary carbohydrate quantity and/or quality during pregnancy are associated with newborn body composition and cardiac autonomic function. Maternal diet during pregnancy was assessed in 142 mother-infant pairs using a validated food frequency questionnaire. Infant adiposity and body composition were assessed at birth using air-displacement plethysmography. Cardiac autonomic function was assessed as heart rate variability. The quantity of carbohydrates consumed during pregnancy, as a percentage of total energy intake, was not associated with meaningful differences in offspring birth weight, adiposity or heart rate variability (p > 0.05). There was some evidence that maternal carbohydrate quality, specifically higher fibre and lower glycemic index, is associated with higher heart rate variability in the newborn offspring (p = 0.06). This suggests that poor maternal carbohydrate quality may be an important population-level inter-generational risk factor for later cardiac and hemodynamic risk of their offspring.

Early Gestational Hypoxia and Adverse Developmental Outcomes.

Hypoxia is a normal and essential part of embryonic development. However, this state may leave the embryo vulnerable to damage when oxygen supply is disturbed. Embryofetal response to hypoxia is dependent on duration and depth of hypoxia, as well as developmental stage. Early postimplantation rat embryos were resilient to hypoxia, with many surviving up to 1.5 hr of uterine clamping, while most mid-gestation embryos were dead after 1 hour of clamping. Survivors were small and many had a range of defects, principally terminal transverse limb reduction defects. Similar patterns of malformations occurred when embryonic hypoxia was induced by maternal hypoxia, interruption of uteroplacental flow, or perfusion and embryonic bradycardia. There is good evidence that high altitude pregnancies are associated with smaller babies and increased risk of some malformations, but these results are complicated by increased risk of pre-eclampsia. Early onset pre-eclampsia itself is associated with small for dates and increased risk of atrio-ventricular septal defects. Limb defects have clearly been associated with chorionic villus sampling, cocaine, and misoprostol use. Similar defects are also observed with increased frequency among fetuses who are homozygous for thalassemia. Drugs that block the potassium current, whether as the prime site of action or as a side effect, are highly teratogenic in experimental animals. They induce embryonic bradycardia, hypoxia, hemorrhage, and blisters, leading to transverse limb defects as well as craniofacial and cardiovascular defects. While evidence linking these drugs to birth defects in humans is not compelling, the reason may methodological rather than biological. Birth Defects Research 109:1358-1376, 2017.© 2017 Wiley Periodicals, Inc.

The effect of air puff stress on c-Fos expression in rat hypothalamus and brainstem: central circuitry mediating sympathoexcitation and baroreflex resetting.

Psychological stress evokes increases in sympathetic activity and blood pressure, which are due at least in part to an upward resetting of the baroreceptor-sympathetic reflex. In this study we determined whether sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM), which have a critical role in the reflex control of sympathetic activity, are activated during air puff stress, a moderate psychological stressor. Secondly, we identified neurons that are activated by air puff stress and that also project to the nucleus tractus solitarius (NTS), a key site for modulation of the baroreceptor reflex. Air puff stress resulted in increased c-Fos expression in several hypothalamic and brainstem nuclei, including the paraventricular nucleus (PVN), dorsomedial hypothalamus, perifornical area (PeF), periaqueductal gray (PAG), NTS and rostral ventromedial medulla, but not in the RVLM region that contains sympathetic premotor neurons. In contrast, neurons in this RVLM region, including catecholamine-synthesizing neurons, did express c-Fos following induced hypotension, which reflexly activates RVLM sympathetic premotor neurons. The highest proportion of NTS-projecting neurons that were double-labelled with c-Fos after air puff stress was in the ventrolateral PAG (29.3 ± 5.5%), with smaller but still significant proportions of double-labelled NTS-projecting neurons in the PVN and PeF (6.5 ± 1.8 and 6.4 ± 1.7%, respectively). The results suggest that the increased sympathetic activity during psychological stress is not driven primarily by RVLM sympathetic premotor neurons, and that neurons in the PVN, PeF and ventrolateral PAG may contribute to the resetting of the baroreceptor-sympathetic reflex that is associated with psychological stress.

Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro- or chemoreceptor reflex responses.

Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77%; 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.

Relationship of aortic pulse wave velocity and baroreceptor reflex sensitivity to blood pressure control in patients with repaired coarctation of the aorta.

BACKGROUND: Increased aortic stiffness and reduced baroreceptor reflex sensitivity have been described independently after coarctation of the aorta (CoA) repair. This study sought to determine the relationship between these variables and blood pressure control in adolescents after early CoA repair. METHODS: Spontaneous baroreceptor reflex sensitivity (sBRS) and aortic pulse wave velocity (PWV) were measured in 29 adolescents after CoA repair and compared with 20 age-matched controls. Patients treated for hypertension or having residual aortic narrowing were excluded. Ambulatory blood pressure (ABP), heart rate variability, and cardiac output were also recorded. After ABP measurement, CoA subjects were classified as normotensive or hypertensive. RESULTS: Nine patients (31%) were hypertensive according to standard definitions, and this subgroup had higher aortic PWV than the normotensive subgroup (P = .004). There was a significant positive correlation between ABP and PWV seen in the whole CoA group (r(2) = 0.5, P < .01). The normotensive subgroup had increased sBRS compared with controls (P = .02). This difference was not seen between the hypertensive subgroup and controls. There was a significant inverse relationship between sBRS and aortic PWV in the whole CoA group (r(2) = 0.25, P = .01). The normotensive subgroup had a significant reduction in stroke index compared with controls (P = .02), which was not seen in the hypertensive subgroup (P = .96). CONCLUSIONS: Adolescents with hypertension after CoA repair have increased aortic PWV and a relative reduction in sBRS compared with normotensive CoA patients. Thus, failure of the baroreceptor reflex to compensate for increasing arterial stiffness may herald the onset of hypertension in these patients.

Hypertension and coarctation of the aorta: an inevitable consequence of developmental pathophysiology.

Patients with coarctation of the aorta develop early onset hypertension in spite of early effective repair. This is associated with significant morbidity and is arguably the single most important outcome variable in this patient group. We discuss the potential pathophysiological mechanisms involved in the development of hypertension with clinical reference to monozygotic twins, and review potential strategies for therapy and prevention in this setting.

Surgical approach for aortic coarctation influences arterial compliance and blood pressure control.

BACKGROUND: Increased arterial stiffness is linked to hypertension in adults after surgical repair for coarctation of the aorta. We evaluated the influence of surgical approaches, namely, subclavian flap repair (SFR) and end-to-end anastomosis (EEA), on arterial stiffness, blood pressure, cardiac output, and cardiac baroreceptor function in a cohort of young children after coarctation repair to determine if the surgical approach influenced longer term blood pressure control. METHODS: We measured pulse wave velocity in 21 children with a mean age of 5 years, after early (less than 6 months) coarctation repair (SFR, n = 11; EEA, n = 10), and compared these with 18 matched controls. Blood pressure was recorded on three occasions from the right arm. Cardiac output was recorded using a transthoracic bioimpedence technique. We measured spontaneous baroreceptor reflex sensitivity to evaluate whether increased arterial stiffness was associated with reduced aortic baroreflex sensitivity. RESULTS: Right arm systolic blood pressure (108.3 + or - 3.5 mm Hg SFR versus 97.8 + or - 2.9 mm Hg EEA, p = 0.03) and pulse wave velocity (6.0 + or - 0.2 ms(-1) SFR versus 5.2 + or - 0.2 ms(-1) EEA, p = 0.02) were significantly greater in the SFR compared with EEA group. Blood pressure and pulse wave velocity were also higher in the SFR group compared with controls. These differences were not demonstrated when comparing the EEA group with controls. There was no difference in stroke volume, spontaneous baroreceptor reflex sensitivity, or heart rate or blood pressure variability between the groups. CONCLUSIONS: Young children undergoing SFR have higher blood pressure and stiffer upper limb arteries compared with matched children undergoing EEA. Our data suggest that better longer-term cardiovascular outcome is to be expected with the EEA surgical approach.

Shift to an involvement of phosphatidylinositol 3-kinase in angiotensin II actions on nucleus tractus solitarii neurons of the spontaneously hypertensive rat.

RATIONALE: Central angiotensin (Ang) II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood. OBJECTIVE: Our objective in the present study was to characterize the signal transduction mechanism of phosphatidylinositol 3-kinase (PI3K) involvement in Ang II-induced stimulation of central neuronal activity in cultured neurons and Ang II-induced inhibition of baroreflex in spontaneously hypertensive rats (SHR) versus WKY rats. METHODS AND RESULTS: Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Although the Ang II-mediated increase in firing rate was abolished entirely by the protein kinase (PK)C inhibitor GF109230 in the WKY, blockade of both PKC and PI3K activity was necessary in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH oxidase-reactive oxygen species (ROS)-mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3K in the SHR. Inhibition of PI3K resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels, and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart-brainstem preparations, inhibition of PKC activity in the nucleus of the solitary tract in situ abolished the Ang II-mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the nucleus of the solitary tract of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain. CONCLUSIONS: These observations demonstrate that PI3K in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II-mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.

Ramp rate of blood pressure changes does not affect aortic afferent sensitivity in anesthetized rats.

To investigate whether the rate of change in blood pressure affects the sensitivity of the aortic baroreceptor afferent response, the change in aortic nerve activity (ANA) to two different rates of ramp increase in mean blood pressure (MBP), elicited by phenylephrine administration, was determined in the rat under urethane (1.5 g kg(-1)) anesthesia. The sensitivity of the increase in ANA following a rapid (average ramp rate, 9.14+/-0.60 mm Hg s(-1), n=11) or gradual (1.78+/-0.24 mm Hg s(-1), n=11) increase in MBP was 2.03+/-0.14% and 1.81+/-0.20% of baseline mm Hg(-1), respectively. These values were not significantly different from each other (P=0.16). Furthermore, we found no correlation between the rate of ramp increase in MBP and the sensitivity of the increase in ANA (r=0.24, P=0.29, n=22). These results suggest that, at least within the normal physiological range of MBP, the rate of the ramp change in blood pressure does not affect aortic baroreceptor afferent sensitivity in the anesthetized rat.

Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension.

Angiotensin II (AngII) is a major culprit in essential hypertension. Based on a genetic rodent model of hypertension, we review here evidence that AngII may signal across the blood brain barrier to affect neuronal circuits within the nucleus tractus solitarii (NTS) of the brainstem, a pivotal region regulating both the baroreceptor reflex and set point control of arterial pressure. We have termed this form of signalling as vascular-neuronal signalling. We describe that the depressant action of AngII in NTS on the baroreceptor reflex is mediated via activation of endothelial nitric oxide synthase (eNOS) releasing NO that promotes release of the inhibitory transmitter-GABA. This could shunt the incoming excitatory baroreceptor afferent traffic impinging on NTS neurones. Chronic studies recording arterial pressure in conscious unrestrained rats using radio-telemetry have revealed that eNOS in NTS plays an endogenous physiological role in the homeostatic regulation of the gain of the cardiac baroreceptor reflex. However, in the spontaneously hypertensive rat, eNOS mRNA was higher (compared to normotensive rats), and its chronic blockade in NTS restored the abnormally depressed cardiac baroreceptor reflex to levels akin to normotensive rats, improved heart rate variability and lowered arterial pressure. Hence, it seems that excessive eNOS activity in NTS of the SHR contributes to the pathological state of this animal model's cardiovascular autonomic nervous system. We speculate on why eNOS activity may be up regulated in the NTS of the SHR and propose that it is a consequence of high cerebral vascular resistance and inadequate blood perfusion of the brainstem.

Evidence for cardiovascular autonomic dysfunction in neonates with coarctation of the aorta.

BACKGROUND: Coarctation of the aorta (CoA) is associated with hypertension and abnormalities of blood pressure control, which persist after late repair. Assumptions that neonatal repair would prevent development of blood pressure abnormalities have not been supported by recent data. We hypothesized that early pathological adjustment of autonomic cardiovascular function may already be established in the neonate with coarctation. METHODS AND RESULTS: We studied 8 otherwise well neonates with simple CoA and compared measures of spontaneous baroreflex sensitivity, heart rate variability, and blood pressure variability with 13 healthy newborn babies. Spontaneous baroreflex sensitivity was calculated with sequence methodology from an ECG, and noninvasive blood pressure was recorded with a Portapres. Heart rate variability was determined with time- and frequency-domain measures. Blood pressure variability was measured in the frequency domain. In comparison with normal controls, neonates with CoA had raised blood pressure (78.9+/-3.8 versus 67.1+/-2.1 mm Hg), depressed baroreflex sensitivity (8.7+/-1.5 versus 13.8+/-1.1 ms/mm Hg), reduced heart rate variability (total power 16.5+/-3.1 versus 31.5+/-2.2 ms2), and an increase in the high-frequency component of blood pressure variability (3.1+/-0.3 versus 2.2+/-0. 2 mm Hg2). This is not the pattern expected if neonates with CoA simply had subclinical cardiac failure. CONCLUSIONS: These data suggest that infants with CoA already show signs of pathological adjustment of autonomic cardiovascular homeostasis. Further longitudinal studies are required to determine whether these alterations play a role in the increased risk of late hypertension in these patients.