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Prenatal hypoxia increases blood pressure in male rat offspring and affects their response to artificial light at night
Abstract
Prenatal hypoxia (PH) has negative consequences on the cardiovascular system in adulthood and can affect the responses to additional insults later in life. We explored the effects of PH imposed during embryonic day 20 (10.5% O 2 for 12 h) on circadian rhythms of systolic blood pressure (BP) and heart rate (HR) in mature male rat offspring measured by telemetry. We evaluated: (1) stability of BP and HR changes after PH; (2) circadian variability of BP and HR after 2 and 5 weeks of exposure to artificial light at night (ALAN; 1–2 lx); and (3) response of BP and HR to norepinephrine. PH increased BP in the dark (134 ± 2 mmHg vs. control 127 ± 2 mmHg; p = 0.05) and marginally in the light (125 ± 1 mmHg vs. control 120 ± 2 mmHg) phase of the day but not HR. The effect of PH was highly repeatable between 21- and 27-week-old PH male offspring. Two weeks of ALAN decreased the circadian variability of HR ( p < 0.05) and BP more in control than PH rats. After 5 weeks of ALAN, the circadian variability of HR and BP were damped compared to LD and did not differ between control and PH rats ( p < 0.05). Responses of BP and HR to norepinephrine did not differ between control and PH rats. Hypoxia at the end of the embryonic period increases BP and affects the functioning of the cardiovascular system in mature male offspring. ALAN in adulthood decreased the circadian variability of cardiovascular parameters, more in control than PH rats.
... Moreover, a study associated with intrauterine growth restriction induced by intermittent hypoxia from ED 14 to ED 18 showed no changes in dP/dt max on ED 22 and postnatally; however, these rats had an increased inotropic response [50]. On the other hand, in rats exposed to 12 h of hypoxia on ED 20, no differences in heart rate and blood pressure response to noradrenaline compared with the control rats were observed [132], thus, it seems that changes are prenatal hypoxia duration dependent. ...
... Exposure of rats to intermittent 4 h periods of hypoxia on ED 19 and ED 20 during the daytime (passive phase for rats) increased the blood pressure in adult male offspring but did not affect the circadian rhythms of blood pressure and heart rate [14]. Similarly, prenatal hypoxia (12 h, ED 20) during the light phase did not change the circadian rhythms of blood pressure and heart rate in male offspring, as well as the response of the cardiovascular system to vasoconstriction drugs [30,132]; however, these animals had an altered response to artificial light at night [132], which is considered as a risk factor for the disruption of circadian control and the development of cardiovascular diseases [225]. ...
... Exposure of rats to intermittent 4 h periods of hypoxia on ED 19 and ED 20 during the daytime (passive phase for rats) increased the blood pressure in adult male offspring but did not affect the circadian rhythms of blood pressure and heart rate [14]. Similarly, prenatal hypoxia (12 h, ED 20) during the light phase did not change the circadian rhythms of blood pressure and heart rate in male offspring, as well as the response of the cardiovascular system to vasoconstriction drugs [30,132]; however, these animals had an altered response to artificial light at night [132], which is considered as a risk factor for the disruption of circadian control and the development of cardiovascular diseases [225]. ...
Prenatal hypoxia during the prenatal period can interfere with the developmental trajectory and lead to developing hypertension in adulthood. Prenatal hypoxia is often associated with intrauterine growth restriction that interferes with metabolism and can lead to multilevel changes. Therefore, we analysed the effects of prenatal hypoxia predominantly not associated with intrauterine growth restriction using publications up to September 2021. We focused on: (1) The response of cardiovascular regulatory mechanisms, such as the chemoreflex, adenosine, nitric oxide, and angiotensin II on prenatal hypoxia. (2) The role of the placenta in causing and attenuating the effects of hypoxia. (3) Environmental conditions and the mother’s health contribution to the development of prenatal hypoxia. (4) The sex-dependent effects of prenatal hypoxia on cardiovascular regulatory mechanisms and the connection between hypoxia-inducible factors and circadian variability. We identified that the possible relationship between the effects of prenatal hypoxia on the cardiovascular regulatory mechanism may vary depending on circadian variability and phase of the days. In summary, even short-term prenatal hypoxia significantly affects cardiovascular regulatory mechanisms and programs hypertension in adulthood, while prenatal programming effects are not only dependent on the critical period, and sensitivity can change within circadian oscillations.
... In addition to phase shifts, constant dim light of 5 lx (Witte et al., 1998a) and artificial light at night (ALAN) of 2 lx also significantly reduce circadian rhythms of the heart rate in normotensive Wistar rats within a few days Sutovska et al., 2020). ...
... ALAN exposure is a phenomenon of modern society and affects blood pressure and heart rate in humans (Obayashi et al., 2014(Obayashi et al., , 2019 and rats, probably through the sympathetic nervous system Rumanova et al., 2019;Sutovska et al., 2020). The sympathetic nervous system accelerates heart rate, heart contractility and heart relaxation (lusitropy), which is mediated by SERCA2. ...
... Therefore, we hypothesize that ALAN can also be related to a decrease in ryanodine receptor 2 expression. Decreased expression of ryanodine receptor 2 is responsible for reduced calcium release from the sarcoplasmic reticulum to the cytosol, probably due to reduced adrenergic stimulation of the heart after ALAN ( Figure 6) Sutovska et al., 2020). Therefore, we propose a longterm decrease in calcium release that can adaptively decrease SERCA2 expression (Oh et al., 2010;Sallinen et al., 2007). ...
New findings:
What is the central question of this study? Artificial light at night decreases blood pressure and heart rate in rats. Are mentioned changes in heart rate accompanied by changes in protein expression in the heart's left ventricle? What is the main finding and its importance? For the first time, we reported that five weeks of artificial light at night affected protein expression in the heart's left ventricle in normotensive and hypertensive rats. Artificial light at night decreased expression of the sarco/endoplasmic reticulum Ca2+ -ATPase, angiotensin II receptor type 1, and endothelin-1.
Abstract:
Artificial light at night (ALAN) affects the circadian rhythm of the heart rate in normotensive Wistar (WT) and spontaneously hypertensive rats (SHR) through the autonomic nervous system, which regulates the heart's activity through calcium handling, an important regulator in heart contractility. We analysed the expression of the sarco/endoplasmic reticulum Ca2+ -ATPase (SERCA2) and other selected regulatory proteins involved in the regulation of heart contractility, angiotensin II receptor type 1 (AT1 R), endothelin-1 (ET-1) and tyrosine hydroxylase (TH) in the left ventricle of the heart in WT and SHR after two and five weeks of ALAN with intensity 1-2 lx. Expression of SERCA2 was decreased in WT (control: 0.53 ± 0.07; ALAN: 0.46 ± 0.10) and SHR (control: 0.72 ± 0.18; ALAN: 0.56 ± 0.21) after five weeks of ALAN (p = 0.067). Expression of AT1 R was significantly decreased in WT (control: 0.51 ± 0.27; ALAN: 0.34 ± 0.20) and SHR (control: 0.38 ± 0.07; ALAN: 0.23 ± 0.09) after two weeks of ALAN (p = 0.028) and in SHR after five weeks of ALAN. Expression of ET-1 was decreased in WT (control: 0.51 ± 0.27; ALAN: 0.28 ± 0.12) and SHR (control: 0.54 ± 0.10; ALAN: 0.35 ± 0.23) after five weeks of ALAN (p = 0.015). ALAN did not affect the expression of TH in WT or SHR. In conclusion, ALAN suppressed the expression of SERCA2, AT1 R and ET-1, which are important for the regulation of heart contractility, in a strain-dependent pattern in both WT and SHR. This article is protected by copyright. All rights reserved.
... [3][4][5] It is reported that offspring of pregnant rats exposed to hypoxic environment show elevated blood pressure and blood glucose compared to those exposed to normal oxygen level. 6,7 In addition, some animal models of mid-to-late-pregnancy hypoxia have shown that ICH leads to lung and nerve damage, reduction in ovarian primordial follicle count, telomere length shortening, and accelerated aging in offspring of rodents. [8][9][10][11] ICH caused by various factors will induce fetal blood flow to be preferentially supplied to the heart and brain and other vital organs, possibly at the expense of others, 12 thus affecting fetal development. ...
Background:
Intrauterine chronic hypoxia (ICH) can lead to pancreatic dysmetabolism in offspring. This study aimed to determine the changes in islet function of offspring through a rat ICH model and detect the factors affecting islet function.
Methods:
Twenty couples of healthy Sprague - Dawley adult rats were randomly mated, and the pregnant rats were randomly allocated to ICH and normal control (NC) groups. Pregnant rats in the ICH group were placed in a hypoxic chamber with 13% oxygen concentration for hypoxia treatment twice a day for 4 h until delivery at 21 days. NC group is inlet with normal air from beginning to end. After delivery, blood was taken from the heart of pregnant rats for blood gas analysis. The weight of the offspring rats was measured at 12 h after birth and 16 weeks after birth. At 16 weeks, the immunohistochemical results of β-cell total, islet area, insulin (INS), and glucose transporter 2 (GLUT2) proteins were obtained from the islets. The mRNA data of INS and pancreatic and duodenal homeobox 1 (PDX-1) genes were obtained from pancreas.
Results:
We found the β-cell total, islet area, and the positive cell area of INS and GLUT2 of offspring rats in ICH group were lower than those of NC group, while the levels of INS and PDX-1 genes were higher in ICH group than in NC group.
Conclusions:
ICH can lead to islet hypoplasia in adult male offspring rats. However, this is within the compensatory range.
Prenatal, perinatal, and adulthood exposure to chronic intermittent hypoxia (IH) increases blood pressure in rodents. Males exposed to chronic IH have higher blood pressure vs females. However, it is unknown if this same sex difference exists with acute perinatal IH. We tested the hypothesis that acute perinatal IH increases baseline blood pressure and enhances sensitivity to angiotensin II-induced hypertension in male Sprague Dawley rats. Male and female pups were randomized to control (room air) or IH (10 minutes of ~10% O2 three times/day) for the first 8 days of life. IH decreased oxygen saturation, confirmed via pulse oximeter. Pups were weaned at postnatal day 21. Blood pressure was measured via telemetry beginning at 14 weeks of age and analyzed separated into light and dark phase to assess circadian rhythm. Osmotic mini-pumps to deliver angiotensin II were implanted at 15 weeks of age. Perinatal IH exposure did not alter baseline blood pressure. One week of Ang II treatment increased blood pressure in the light and dark periods in males exposed to IH vs control; there was no effect in females. Blood pressure among groups was comparable following 2 weeks of angiotensin II infusion. Perinatal IH did not change circadian rhythm. Following angiotensin II treatment, indices of renal injury were measured. Perinatal IH did not alter kidney size, structure, nephron number or creatinine clearance. These data indicate that acute perinatal IH enhances early angiotensin II-induced hypertension in males, independent of nephron loss or decreases in body weight or kidney function.
The hypotensive effects of melatonin are based on a negative correlation between melatonin levels and blood pressure in humans. However, there is a positive correlation in nocturnal animals that are often used as experimental models in cardiovascular research, and the hypotensive effects and mechanism of melatonin action are often investigated in rats and mice. In rats, the hypotensive effects of melatonin have been studied in normotensive and spontaneously or experimentally induced hypertensive strains. In experimental animals, blood pressure is often measured indirectly during the light (passive) phase of the day by tail-cuff plethysmography, which has limitations regarding data quality and animal well-being compared to telemetry. Melatonin is administered to rats in drinking water, subcutaneously, intraperitoneally, or microinjected into specific brain areas at different times. Experimental data show that the hypotensive effects of melatonin depend on the experimental animal model, blood pressure measurement technique, and the route, time and duration of melatonin administration. The hypotensive effects of melatonin may be mediated through specific membrane G-coupled receptors located in the heart and arteries. Due to melatonin’s lipophilic nature, its potential hypotensive effects can interfere with various regulatory mechanisms, such as nitric oxide and reactive oxygen species production and activation of the autonomic nervous and circadian systems. Based on the research conducted on rats, the cardiovascular effects of melatonin are modulatory, delayed, and indirect. Does melatonin have blood pressure-lowering effects, and are nocturnal animals suitable for testing the hypotensive effects of melatonin? The hypotensive effects of melatonin depend on the experimental animal model, blood pressure measurement method, route, time and duration of melatonin administration.
Cardiovascular (CV) health is often expressed by changes in heart rate and blood pressure, the physiological record of which may be affected by moving, anaesthesia, handling, time of day and many other factors in rodents. Telemetry measurement minimises these modulations and enables more accurate physiological recording of heart rate and blood pressure than non-invasive methods. Measurement of arterial blood pressure by telemetry requires implanting a catheter tip into the artery. Telemetry enables us to sample physiological parameters with a high frequency continuously for several months. By measuring the pressure in the artery using telemetry, we can visualize pressure changes over a heart cycle as the pressure wave. From the pressure wave, we can subtract systolic, diastolic, mean and pulse pressure. From the beat-to-beat interval (pressure wave) and the RR' interval (electrocardiogram), we can derive the heart rate. From beat-to-beat variability, we can evaluate the autonomic nervous system's activity and spontaneous baroreflex sensitivity and their impact on CV activity. On a long-term scale, circadian variability of CV parameters is evident. Circadian variability is the result of the circadian system's activity, which synchronises and organises many activities in the body, such as autonomic and reflex modulation of the CV system and its response to load over the day. In the presented review, we aimed to discuss telemetry devices, their types, implantation, set-up, limitations, short-term and long-term variability of heart rate and blood pressure in CV research. Data collection by telemetry should be, despite some limitations, standard in modern experimental CV research.
Aim:
We sought to explore whether fetal hypoxia exposure, an insult of placental insufficiency, is associated with left ventricular dysfunction and increased aortic stiffness at early postnatal ages.
Methods:
Pregnant Sprague Dawley rats were exposed to hypoxic conditions (11.5% FiO2 ) from embryonic day E15-21 or normoxic conditions (controls). After delivery, left ventricular function and aortic pulse wave velocity (measure of aortic stiffness) were assessed longitudinally by echocardiography from day 1 through week 8. A mixed ANOVA with repeated measures was performed to compare findings between groups across time. Myocardial hematoxylin and eosin and picro-sirius staining were performed to evaluate myocyte nuclear shape and collagen fiber characteristics, respectively.
Results:
Systolic function parameters transiently increased following hypoxia exposure primarily at week 2 (p < .008). In contrast, diastolic dysfunction progressed following fetal hypoxia exposure beginning weeks 1-2 with lower early inflow Doppler velocities, and less of an increase in early to late inflow velocity ratios and annular and septal E'/A' tissue velocities compared to controls (p < .008). As further evidence of altered diastolic function, isovolumetric relaxation time was significantly shorter relative to the cardiac cycle following hypoxia exposure from week 1 onward (p < .008). Aortic stiffness was greater following hypoxia from day 1 through week 8 (p < .008, except week 4). Hypoxia exposure was also associated with altered nuclear shape at week 2 and increased collagen fiber thickness at week 4.
Conclusion:
Chronic fetal hypoxia is associated with progressive LV diastolic dysfunction, which corresponds with changes in nuclear shape and collagen fiber thickness, and increased aortic stiffness from early postnatal stages.
The molecular mechanism of antenatal hypoxia impacting on fetal heart development and elevated risk of heart disease of adult offspring is poorly understood. We present a dataset integrating DNA methylome and transcriptome analyses of antenatal hypoxia affecting rat fetal and adult offspring hearts to understand hypoxia-mediated epigenomic reprogramming of the heart development. We showed that antenatal hypoxia not only induced DNA methylomic and transcriptomic changes in the fetal hearts, but also had a delayed and lasting effect on the adult offspring hearts. Of interest, antenatal hypoxia induced opposite changes in DNA methylation patterns in fetal and adult hearts, with a hypermethylation in the fetus and a hypomethylation in the adult. An extensive preprocessing, quality assessment, and downstream data analyses were performed on the genomic dataset so that the research community may take advantage of the public resource. These dataset could be exploited as a comprehensive resource for understanding fetal hypoxia-mediated epigenetic reprogramming in the heart development and further developmental programming of heart vulnerability to disease later in life.
Figshare doi: https://doi.org/10.6084/m9.figshare.9948572
Autonomic innervation of the pulmonary vasculature triggers vasomotor contractility predominately through activation of alpha-adrenergic receptors (α-ARs) in the fetal circulation. Long-term hypoxia (LTH) modulates pulmonary vasoconstriction potentially through upregulation of α1-AR in the vasculature. Our study aimed to elucidate the role of α-AR in phenylephrine (PE)-induced pulmonary vascular contractility, comparing the effects of LTH in the fetal and adult periods on α-AR subtypes and PE-mediated Ca2+ responses and contractions. To address this, we performed wire myography, Ca2+ imaging, and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α2-AR activation contracted fetal vessels; however, this was suppressed by LTH. α1A- and α1B-AR subtypes contributed to arterial contractions in all groups. The α1D-AR was also important to contractility in fetal normoxic vessels and LTH mitigated its function. Postnatal maturity increased the number of myocytes with PE-triggered Ca2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca2+. The results illustrate that α-adrenergic signaling and vascular function change during development and that LTH modifies adrenergic signaling. These changes may represent components in the etiology of pulmonary vascular disease and foretell the therapeutic potential of adrenergic receptor antagonists in the treatment of pulmonary hypertension.
Cardiac arrhythmias are a leading cause of cardiovascular death. It has long been accepted that life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation and sudden cardiac death) are more likely to occur in the morning after waking. It is perhaps less well recognised that there is a circadian rhythm in cardiac pacemaking and other electrophysiological properties of the heart. In addition, there is a circadian rhythm in other arrhythmias, for example bradyarrhythmias and supraventricular arrhythmias. Two mechanisms may underlie this: (1) a central circadian clock in the suprachiasmatic nucleus in the hypothalamus may directly affect the electrophysiology of the heart and arrhythmogenesis via various neurohumoral factors, particularly the autonomic nervous system; or (2) a local circadian clock in the heart itself (albeit under the control of the central clock) may drive a circadian rhythm in the expression of ion channels in the heart, which in turn varies arrhythmic substrate. This review summarises the current understanding of the circadian rhythm in cardiac electrophysiology, arrhythmogenesis and the underlying molecular mechanisms.
Preterm infants frequently suffer cardiovascular compromise, with hypotension and/or low systemic blood flow, leading to tissue hypoxia-ischemia (HI). Many preterm infants respond inadequately to inotropic treatments using adrenergic agonists such as dobutamine or dopamine. This may be due to altered cardiac adrenoceptor expression due to tissue HI, or prolonged exposure to adrenergic agonists. We assessed the effects of severe HI with and without dobutamine/dopamine treatment on cardiac adrenoceptor expression in preterm fetal sheep. Fetal sheep (93-95d) exposed to sham surgery or severe HI induced by umbilical cord occlusion, received intravenous dobutamine (DB) or saline for 74 hrs (HI+DB, HI, Sham+DB, Sham). The HI groups were also compared with fetal sheep exposed to HI and dopamine (HI+DA). Fetal hearts were collected to determine β-adrenoceptor numbers using [125I]-cyanopindolol binding, and mRNA expression of β1-, β2-, α1A-, α2A- or α2B-adrenoceptors. The HI group had increased β-adrenoceptor numbers compared to all other groups in all 4 heart chambers (p<0.05). This increase in β-adrenoceptor numbers in the HI group was significantly reduced by dobutamine infusion in all 4 heart chambers, but dopamine infusion in the HI group only reduced β-adrenoceptor numbers in the left atria and ventricle. Dobutamine alone did not affect β-adrenoceptor numbers in the sham animals. Changes in β1-adrenoceptor mRNA levels trended to parallel the binding results. We conclude that HI upregulates preterm fetal cardiac β-adrenoceptors, but prolonged exposure to adrenergic agonists downregulates adrenoceptors in the preterm heart exposed to HI, and may underpin the frequent failure of inotropic therapy in preterm infants.
Prenatal hypoxia is associated with growth restriction and adverse cardiovascular outcomes. Here, we describe renal and cardiovascular outcomes in ageing mouse offspring prenatally exposed to hypoxia (12% O2) from embryonic day 14.5 until birth. At 12 months of age, both male and female offspring exposed to prenatal hypoxia had elevated mean arterial pressure. Glomerular number was reduced by 25% in hypoxia-exposed male, but not female, offspring and this was associated with increased urinary albumin excretion, glomerular hypertrophy and renal fibrosis. Hypoxia-exposed offspring of both sexes were more susceptible to salt-induced cardiac fibrosis, however, renal fibrosis was exacerbated by high salt in males only. In male but not female hypoxia-exposed offspring, renal renin mRNA was increased at weaning. By 12 months, renal renin mRNA expression and concentrations were elevated in both sexes. mRNA expression of At 1a R was also elevated in male hypoxia-exposed offspring at 12 months. These results demonstrate that prenatal hypoxia programs elevated blood pressure and exacerbates salt-induced cardiovascular and renal pathology in a sex specific manner. Given sex differences observed in RAS expression and nephron number, future studies may consider RAS blockade as a therapeutic target in this model.
Adult-onset chronic non-communicable diseases (NCDs) can originate from early life through so-called the “developmental origins of health and disease” (DOHaD) or “developmental programming”. The DOHaD concept offers the “reprogramming” strategy to shift the treatment from adulthood to early life, before clinical disease is apparent. Melatonin, an endogenous indoleamine produced by the pineal gland, has pleiotropic bioactivities those are beneficial in a variety of human diseases. Emerging evidence support that melatonin is closely inter-related to other proposed mechanisms contributing to the developmental programming of a variety of chronic NCDs. Recent animal studies have begun to unravel the multifunctional roles of melatonin in many experimental models of developmental programming. Even though some progress has been made in research on melatonin as a reprogramming strategy to prevent DOHaD-related NCDs, future human studies should aim at filling the translational gap between animal models and clinical trials. Here, we review several key themes on the reprogramming effects of melatonin in DOHaD research. We have particularly focused on the following areas: mechanisms of developmental programming; the interrelationship between melatonin and mechanisms underlying developmental programming; pathophysiological roles of melatonin in pregnancy and fetal development; and insight provided by animal models to support melatonin as a reprogramming therapy. Rates of NCDs are increasing faster than anticipated all over the world. Hence, there is an urgent need to understand reprogramming mechanisms of melatonin and to translate experimental research into clinical practice for halting a growing list of DOHaD-related NCDs.
Disturbed circadian activity of the sympathetic system may be involved in negative consequences of chronodisruption on the cardiovascular system. We studied daily changes in pressure response to adrenergic stimulation in rats exposed to repeated phase advance shifts (PAS) of light/dark (LD) regimen. Blood pressure (BP), heart rate (HR) and locomotor activity was measured by radiotelemetry in normotensive Wistar rats exposed to repeated PAS (three 8-h shifts per week) lasting for 12 weeks. Norepinephrine was administered subcutaneously in the middle of L and D during week 12 of PAS exposure. In the control LD cycle, cardiovascular parameters exhibited significant daily rhythms with expected higher values during D than L phase. Rats exposed to PAS showed disturbed rhythms without a BP and HR increase. Administration of norepinephrine to control rats revealed daily variability in the cardiovascular response with higher stimulation of BP during L than D. This daily pattern of BP response to norepinephrine was diminished in the PAS group. The damped daily variability in pressure response to norepinephrine and augmented response during the light phase of the day suggest that the increased and desynchronised activity of the sympathetic system may worsen responses of the cardiovascular system to load in individuals exposed to irregular LD conditions.
Circadian misalignment between internal and environmental rhythms dysregulates blood pressure (BP) variability because of disruption of the biological clock, resulting in increased nighttime BP. Although exposure to light-at-night is associated with the circadian misalignment, it remains unclear whether exposure to light-at-night in home settings is associated with nighttime BP. In this cross-sectional analysis of 528 elderly individuals (mean age: 72.8 years), we measured bedroom light intensity at 1-min intervals on two consecutive nights along with ambulatory BP, overnight urinary melatonin excretion and actigraphy. With regard to adjusted mean comparisons using analysis of covariance, the light-at-night group (average: ≥5 lux; n = 109) showed significantly higher nighttime systolic BP (SBP; adjusted mean: 120.8 vs. 116.5 mmHg, p = 0.01) and diastolic BP (70.1 vs. 67.1 mmHg, p < 0.01) compared with the Darker group (average: <5 lux; n = 419) independently of potential confounding factors including overnight urinary melatonin excretion and actigraphic sleep quality. We observed consistent associations between light-at-night and nighttime BP in different cutoff values for light-at-night intensity (i.e. 3 and 10 lux). In conclusion, exposure to light-at-night in home settings is significantly associated with increased nighttime BP in elderly individuals independently of overnight urinary melatonin excretion. A 4.3 mmHg increase in nighttime SBP is associated with a 6.1% increase in total mortality, which corresponds to approximately 10 000 annual excess deaths in Japanese elderly population.
It is now recognized that the quality of the fetal environment during early development is important in programming cardiovascular health and disease in later life. Fetal hypoxia is one of the most common consequences of complicated pregnancies worldwide. However, in contrast to the extensive research effort on pregnancy affected by maternal nutrition or maternal stress, the contribution of pregnancy affected by fetal chronic hypoxia to developmental programming is only recently becoming delineated and established. This review discusses the increasing body of evidence supporting the programming of cardiac susceptibility to ischaemia and reperfusion (I/R) injury, of endothelial dysfunction in peripheral resistance circulations, and of indices of the metabolic syndrome in adult offspring of hypoxic pregnancy. An additional focus of the review is the identification of plausible mechanisms and the implementation of maternal and early life interventions to protect against adverse programming.
The risk of developing cardiovascular diseases is known to begin before birth and the impact of the intrauterine environment on subsequent adult health is currently being investigated from many quarters. Following our studies demonstrating the impact of hypoxia in utero and consequent intrauterine growth restriction (IUGR) on the rat cardiovascular system, we hypothesized that changes extend throughout the vasculature and alter function of the renal artery. In addition, we hypothesized that hypoxia induces renal senescence as a potential mediator of altered vascular function. We demonstrated that IUGR females had decreased responses to the adrenergic agonist phenylephrine (PE; pEC50 6.50 ± 0.05 control v. 6.17 ± 0.09 IUGR, P < 0.05) and the endothelium-dependent vasodilator methylcholine (MCh; E
max 89.8 ± 7.0% control v. 41.0 ± 6.5% IUGR, P < 0.001). In IUGR females, this was characterised by increased basal nitric oxide (NO) modulation of vasoconstriction (PE pEC50 6.17 ± 0.09 IUGR v. 6.42 ± 0.08 in the presence of the NO synthase inhibitor N-nitro-l-arginine methyl ester hydrochloride (l-NAME; P < 0.01) but decreased activated NO modulation (no change in MCh responses in the presence of l-NAME), respectively. In contrast, IUGR males had no changes in PE or MCh responses but demonstrated increased basal NO (PE pEC50 6.29 ± 0.06 IUGR v. 6.42 ± 0.12 plus l-NAME, P < 0.01) and activated NO (E
max 37.8 ± 9.4% control v. −0.8 ± 13.0% plus l-NAME, P < 0.05) modulation. No significant changes were found in gross kidney morphology, proteinuria or markers of cellular senescence in either sex. In summary, renal vascular function was altered by hypoxia in utero in a sex-dependent manner but was unlikely to be mediated by premature renal senescence.
Fetal hypoxia is a common complication of pregnancy. It has been shown to programme cardiac and endothelial dysfunction in the offspring in adult life. However, the mechanisms via which this occurs remain elusive, precluding the identification of potential therapy. Using an integrative approach at the isolated organ, cellular and molecular levels, we tested the hypothesis that oxidative stress in the fetal heart and vasculature underlies the molecular basis via which prenatal hypoxia programmes cardiovascular dysfunction in later life. In a longitudinal study, the effects of maternal treatment of hypoxic (13% O(2)) pregnancy with an antioxidant on the cardiovascular system of the offspring at the end of gestation and at adulthood were studied. On day 6 of pregnancy, rats (n = 20 per group) were exposed to normoxia or hypoxia ± vitamin C. At gestational day 20, tissues were collected from 1 male fetus per litter per group (n = 10). The remaining 10 litters per group were allowed to deliver. At 4 months, tissues from 1 male adult offspring per litter per group were either perfusion fixed, frozen, or dissected for isolated organ preparations. In the fetus, hypoxic pregnancy promoted aortic thickening with enhanced nitrotyrosine staining and an increase in cardiac HSP70 expression. By adulthood, offspring of hypoxic pregnancy had markedly impaired NO-dependent relaxation in femoral resistance arteries, and increased myocardial contractility with sympathetic dominance. Maternal vitamin C prevented these effects in fetal and adult offspring of hypoxic pregnancy. The data offer insight to mechanism and thereby possible targets for intervention against developmental origins of cardiac and peripheral vascular dysfunction in offspring of risky pregnancy.
Prenatal hypoxia in mammals causes fetal growth restriction and catecholaminergic overstimulation that, in turn, alter signaling pathways associated with adrenergic receptors. Beta-adrenoceptors (beta-ARs) are essential for fetal cardiac development and regulation of cardiac contractility. We studied the effects of chronic prenatal hypoxia on cardiac beta-AR signaling and the incidence of alterations in the juvenile beta-AR system due to the embryonic treatment. We measured functional beta-AR density (B(max)) through binding with [(3)H]CGP-12177 and the effect of agonists on beta-AR-dependent contractility (pEC(50)) through concentration-response curves to epinephrine. Eggs from broiler chickens were incubated in normoxia (N, 21% O(2)) or chronic hypoxia (H, 14% O(2)). Cardiac tissue from embryos and juveniles was used (15 and 19 day of embryonic development and 14 and 35 days posthatching, E19, E15, P14, and P35, respectively). Relative cardiac enlargement was found in the hypoxic groups at E15, E19, and P14, but not P35. B(max) significantly decreased in E19H. B(max) more than doubled posthatching but decreased from P14 to P35. The sensitivity to epinephrine was lower in E19N compared with E15N, but hypoxia increased the sensitivity to agonist in both E15H and E19H. Despite maintained receptor density, the P35H juvenile displayed a decreased sensitivity to beta-AR agonist, something that was not seen in P14H. The postnatal decrease in beta-AR sensitivity as an effect of chronic prenatal hypoxia, without a concomitant change in beta-AR density, leads us to conclude that the embryonic hypoxic challenge alters the future progression of beta-AR signaling and may have important implications for cardiovascular function in the adult.
Emerging evidence demonstrates a link between preterm birth (PTB) and later life cardiovascular disease (CVD). We conducted a systematic review and meta-analysis to compare conventional CVD risk factors between those born preterm and at term. PubMed, CINAHL, SCOPUS, and EMBASE databases were searched. The review protocol is registered in PROSPERO (CRD42018095005). CVD risk factors including systolic blood pressure (SBP), diastolic blood pressure (DBP), body mass index, lipid profile, blood glucose, and fasting insulin among those born preterm (<37 weeks' gestation) were compared with those born at term (≥37 weeks' gestation). Subgroup analyses based on gender, age, gestational at birth (<32 weeks' gestation and <28 weeks' gestation), and PTB associated with small for gestational age or average for gestational age were also performed. Fifty-six studies provided data on 308,987 individuals. Being born preterm was associated with 3.26 mmHg (95% confidence interval [CI] 2.08 to 4.44) higher mean SBP and 1.32 mmHg (95% CI: 0.61 to 2.04) higher mean DBP compared to being born at term. Subgroup analyses demonstrated that SBP was higher among (a) preterm compared to term groups from early adolescence until adulthood; (b) females born preterm but not among males born preterm compared to term controls; and (c) those born at <32 weeks or <28 weeks compared to term. Our meta-analyses demonstrate higher SBP and DBP among those born preterm compared to term. The difference in SBP is evident from early adolescence until adulthood.
The circadian system, that is ubiquitous across species, generates ∼24 h rhythms in virtually all biological processes, and allows them to anticipate and adapt to the 24 h day/night cycle, thus ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular (CV) events, and controlled laboratory studies demonstrate a circadian influence on key markers of CV function and risk. Furthermore, circadian misalignment, that is typically experienced by shift workers as well as by individuals who experience late eating, (social) jet lag, or circadian rhythm sleep-wake disturbances, increases CV risk factors. Therefore, understanding the mechanisms by which the circadian system regulates CV function, and which of these are affected by circadian disruption, may help to develop intervention strategies to mitigate CV risk.
Sympathetic overactivation contributes to the pathogenesis of both experimental and human hypertension. We have previously reported that oxidative stress in sympathetic premotor neurons leads to arterial baroreflex dysfunction and increased sympathetic drive to the kidneys in an experimental model of neurogenic hypertension. In this study, we hypothesized that melatonin, a potent antioxidant, may be protective in the brainstem regions involved in the tonic and reflex control of blood pressure (BP) in renovascular hypertensive rats. Neurogenic hypertension was induced by placing a silver clip (gap of 0.2 mm) around the left renal artery, and after 5 weeks of renal clip placement, the rats were treated orally with melatonin (30 mg/kg/day) by gavage for 15 days. At the end of melatonin treatment, we evaluated baseline mean arterial pressure (MAP), renal sympathetic nerve activity (rSNA), and the baroreflex control of heart rate (HR) and rSNA. Reactive oxygen species (ROS) were detected within the brainstem regions by dihydroethidium staining. Melatonin treatment effectively reduced baseline MAP and sympathoexcitation to the ischemic kidney in renovascular hypertensive rats. The baroreflex control of HR and rSNA were improved after melatonin treatment in the hypertensive group. Moreover, there was a preferential decrease in ROS within the rostral ventrolateral medulla (RVLM) and the nucleus of the solitary tract (NTS). Therefore, our study indicates that melatonin is effective in reducing renal sympathetic overactivity associated with decreased ROS in brainstem regions that regulate BP in an experimental model of neurogenic hypertension.
Circadian rhythms are an inherent property of physiological processes and can be disturbed by irregular environmental cycles, including artificial light at night (ALAN). Circadian disruption may contribute to many pathologies, such as hypertension, obesity, and type 2 diabetes, but the underlying mechanisms are not understood. Our study investigated the consequences of ALAN on cardiovascular and metabolic parameters in spontaneously hypertensive rats, which represent an animal model of essential hypertension and insulin resistance. Adult males were exposed to a 12 h light - 12 h dark cycle and the ALAN group experienced dim light at night (1-2 lx), either for 2 or 5 weeks. Rats on ALAN showed a loss of light-dark variability for systolic blood pressure, but not for heart rate. Moreover, a gradual increase of systolic blood pressure was recorded over 5 weeks of ALAN. Exposure to ALAN increased plasma insulin and hepatic triglyceride levels. An increased expression of metabolic transcription factors, Pparα and Pparγ, in the epididymal fat and a decreased expression of Glut4 in the heart was found in the ALAN group. Our results demonstrate that low-intensity ALAN can disturb blood pressure control and augment insulin resistance in spontaneously hypertensive rats, and may represent a serious risk factor for cardiometabolic diseases.
Aims:
Cardiovascular parameters exhibit significant 24-h variability, which is coordinated by the suprachiasmatic nucleus (SCN), and light/dark cycles control SCN activity. We aimed to study the effects of light at night (ALAN; 1-2 lx) on cardiovascular system control in normotensive rats.
Main methods:
Heart rate (HR) and blood pressure (BP) were measured by telemetry during five weeks of ALAN exposure. From beat-to-beat telemetry data, we evaluated spontaneous baroreflex sensitivity (sBRS). After 2 (A2) and 5 (A5) weeks of ALAN, plasma melatonin concentrations and the response of BP and HR to norepinephrine administration were measured. The expression of endothelial nitric oxide synthase (eNOS) and endothelin-1 was determined in the aorta. Spontaneous exploratory behaviour was evaluated in an open-field test.
Key findings:
ALAN significantly suppressed the 24-h variability in the HR, BP, and sBRS after A2, although the parameters were partially restored after A5. The daily variability in the BP response to norepinephrine was reduced after A2 and restored after A5. ALAN increased the BP response to norepinephrine compared to the control after A5. Increased eNOS expression was found in arteries after A2 but not A5. Endothelin-1 expression was not affected by ALAN. Plasma melatonin levels were suppressed after A2 and A5. Spontaneous exploratory behaviour was reduced.
Significance:
ALAN decreased plasma melatonin and the 24-h variability in the haemodynamic parameters and increased the BP response to norepinephrine. A low intensity ALAN can suppress circadian control of the cardiovascular system with negative consequences on the anticipation of a load.
Background:
Numerous clinical studies have evaluated valsartan and found more efficacious control of blood pressure (BP) variability when administered before sleep. The treatment leads to improved outcomes when compared to administration upon awakening. The mechanism underlying this etiology is not fully understood. The present study investigates the safety and efficacy of asleep administration of valsartan in spontaneously hypertensive rats (SHR) with a non-dipping blood pressure pattern compared to SHRs receiving administration during awake time.
Materials and methods:
84 Male SHRs and 28 male Wistar-Kyoto rats (WKY) were kept under a strict alternating 12-h light/dark cycle. WKYs were utilized as a non-disease control. Meanwhile, SHRs were randomly divided into three groups: untreated, Valsartan asleep administration (VSA) and Valsartan awake administration (VWA) respectively. The VSA group was treated with valsartan (30 mg/kg/d) after the light onset, while the VWA group was treated with valsartan (30 mg/kg/d) after light offset. Both groups were treated for 6 weeks. Tail artery blood pressure was measured every 4 h via a noninvasive tail cuff blood pressure measurement method. HE and Masson staining were used to evaluate any damage within the target organs. ELISA was used to determine the 24-h plasma renin-angiotensin system (RAS) concentration at 4-h intervals.
Results:
Based on our findings, VSA significantly reduced 24-h and evening mean BP and restored the abnormal circadian rhythm compared to VWA, which attenuated injuries in the majority of target organs except for the kidneys. Furthermore, VSA was found to activate RAS during the light cycle and inhibit it during the dark cycle. Conversely, VWA was found to deactivate RAS throughout the day which may be related to the circadian BP rhythm.
Conclusion:
VSA may be more efficacious than VWA in controlling BP, circadian BP rhythm and blood RAS rhythm. Recent cardiovascular outcome investigations substantiate that chronotherapy treatment might be a novel therapeutic strategy for hypertension therapy.
Abbreviations:
Angiotensin-converting enzyme (ACE); Angiotensin converting enzyme inhibitors (ACEIs); Angiotensin II (ANG II); Analysis of variance (ANOVA); Angiotensin receptor blockers (ARBs); Blood Pressure (BP); Calcium Antagonists Calcium Channel Blockers (CCB); Chronic kidney diseases (CKD); Sodium carboxyl methyl cellulose (CMC-Na); Cardiac mass index (CMI); Cardiovascular diseases (CVD); Diastolic blood pressure (DBP); Enzyme-linked immunosorbent assay (ELISA); Hematoxylin-eosin (H&E); Kidney mass index (KMI); Liver mass index (LMI); Mean arterial blood pressure (MAP); Plasma renin concentration (PRC); Renin-angiotensin system (RAS); Rennin (REN); Systolic blood pressure (SBP); Student-Newman-Keuls q test (SNK-q test); Spontaneous hypertension rats (SHR); Valsartan asleep Administration (VSA); Valsartan awake Administration (VWA); Wistar-Kyoto (WKY); Mesor (M); Amplitude (A); Phase (φ).
Prenatal hypoxia can affect vascular functions in young offspring. However, there is limited knowledge regarding whether and how prenatal hypoxia influences vascular functions in aged offspring. This study compared the effects of prenatal hypoxia on the mesenteric arteries (MA) between a young adult and aged offspring and investigated the underlying mechanisms. Pregnant rats were randomly divided into the control and prenatal hypoxia groups. The vascular functions and molecular levels were assessed in 5-month-old (5 M) or 20-month-old (20 M) offspring. Prenatal hypoxia decreased acetylcholine-mediated vascular relaxations in 20-M but not 5-M offspring. Sodium nitroprusside-mediated relaxation curves were not altered by prenatal hypoxia in 5- and 20-M offspring. Prenatal hypoxia enhanced the contractile responses caused by phenylephrine, phorbol 12,13-dibutyrate, and 5-hydroxytryptamine only in 5-M offspring. The endothelial NO synthase (eNOS) activities were decreased along with downregulated eNOS mRNA expression and phosphorylated eNOS/total eNOS protein expression in 20-M offspring with prenatal hypoxia. The NADPH oxidase (NOX) inhibitor apocynin and superoxide dismutase (SOD) mimetic tempol restored the acetylcholine-mediated weaker relaxations in 20-M offspring with prenatal hypoxia. Enzyme-linked immunosorbent and dihydroethidium assay showed that prenatal hypoxia enhanced oxidative stress in 20-M offspring. Transmission electron microscopy showed that prenatal hypoxia damaged mitochondrial structures in the MA endothelial cells of 20-M offspring. Increased NOX2 protein expression and decreased SOD3 expression were found in 20-M offspring. The results demonstrated that endothelial dysfunction induced by intrauterine hypoxia occurred with aging via enhanced oxidative stress and decreased nitric oxide activities in aged offspring.
Suboptimal conditions during prenatal and early postnatal development can increase risk of hypertension later in life. We studied consequences of a changed perinatal environment by initiating the cross-fostering of homozygous Ren-2 transgenic rat (TGR) offspring to normotensive, transgene-negative control mothers, and vice versa. We hypothesized that cross-fostering to a normotensive female can attenuate the development of malignant hypertension in TGR offspring (TGRx) and change their salt-sensitive response. Blood pressure (BP) was monitored by the telemetry system under normal salt intake, and BP responses to increased salt intake in the phase of established hypertension. Under normal salt conditions, BP was not markedly different in cross-fostered animals compared with controls. However, BP responses to 2% salt intake led to a stronger BP response in TGRx during the active phase when compared with the control TGR group. The TGRx also exhibited increased albuminuria, lower sodium excretion, and creatinine clearance under higher salt intake compared with control salt intake. Higher salt intake resulted in a significant increase of aldosterone concentrations only in the TGRx group; moreover, TGRx rats exhibited more pronounced renal injury compared with controls. In conclusion, our data indicate that cross-fostering in TGR not only did not attenuate the development of hypertension but, on the contrary, led to the deterioration of BP regulation, particularly due to exaggerated salt sensitivity and sodium retention in TGRx. Results underline the important role of the mother during lactation in postnatal development of the offspring, since these changes reflected different ion content in milk of a particular strain of rats.
All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.
Objective:
Hypertensive disorders during pregnancy increase cardiovascular risk later in life by 2 to 9-fold. Endothelial activation is one of the underlying mechanisms of cardiovascular risk. Therefore, we decided to investigate endothelial activation in primiparous women, 2.5 years after a hypertensive pregnancy disorder.
Study design:
Plasma samples were taken from women 2.5 years after gestational hypertension (GH) or late onset preeclampsia (cases) and from women 2.5 years after a normotensive pregnancy (controls). We studied the effects of patient plasma on the endothelial barrier function of primary human umbilical vein endothelial cells (HUVECs) using Electric Cell-Substrate Impedance Sensing (ECIS) and we measured levels of endothelial activation markers soluble intercellular adhesion molecule 1 (sICAM-1) and soluble endothelial selectin (sE-selectin) in the plasma samples of patients.
Results:
Plasma from primiparous women with a history of late onset preeclampsia disrupted the endothelial barrier more than plasma from women with a history of GH. Endothelial resistance was reduced by 22% in samples taken after preeclampsia, 16% after normotensive pregnancy and 3% after GH (p ≤ 0.0001 GH versus preeclampsia and p = 0.0003 versus normotensive pregnancy). We did not find differences in the levels of soluble endothelial activation markers (sICAM-1 p = 0.326 and sE-selectin p = 0.978). However, the BMI ≥25 showed a strong correlation with increased levels of sICAM-1 (p = 0.046) and sE-selectin (p = 0.002).
Conclusion:
Our results indicate that GH and late onset preeclampsia are distinct disease entities with a different pathogenic mechanism underlying their cardiovascular risk. Furthermore, this study supports the hypothesis that these two diseases are early manifestations of cardiovascular vulnerability due to an unfavorable risk profile, and that obesity plays a main role. Our results suggest that this high-risk female population would be eligible for preventive care.
Cardiovascular diseases (CVDs) are the leading cause of mortality and hypertension contributes substantially to the incidence of stroke, coronary artery disease, heart failure, atrial fibrillation and peripheral vascular disease. The origin of hypertension is clearly multifactorial, and a complex and multifaceted approach is necessary to decrease its incidence. The most recognizable factors involved in reducing the incidence of hypertension are prevention, early diagnosis and treatment; however, the importance of the foetal environment and early postnatal development has recently been considered. In clinical practice, these factors are still frequently overlooked, probably because of a lack of knowledge about the underlying mechanisms and effective treatment or prevention. Pathophysiological mechanisms underlying the prenatal programming of CVDs were investigated in the study by Shah et al. published recently in Clinical Science (2017) 131(17), 2303-2317. The study explored cardiac susceptibility of adult male and female rat offspring to ischaemic myocardial injury due to prenatal exposure to hypoxia. The results demonstrated significant changes in global cardiac function and left ventricular dilatation following myocardial infarction in rat offspring prenatally exposed to hypoxia. The effects were gender specific and occurred only in males, whereas females were protected. These findings are important from several perspectives. First, they point to the fact that an inadequate foetal environment can increase susceptibility to death from myocardial infarction. Second, during their reproductive life, females are better protected from cardiovascular insult than males, but it is not known if they lose this advantage after menopause, and can be equally at risk as males.
Intrauterine growth restriction following prenatal hypoxia exposure leads to a higher risk of developing cardiovascular disease in later life. Our aim was to evaluate cardiac susceptibility and its pathophysiological mechanisms following acute myocardial infarction (MI) in adult rat offspring exposed to prenatal hypoxia. Male and female rat offspring which experienced normoxia (21% O2) or hypoxia (11% O2) in utero underwent sham or MI surgery at 12 weeks of age. Echocardiographic data revealed that both sexes had systolic dysfunction following MI surgery, independent of prenatal hypoxia. Male offspring exposed to prenatal hypoxia, however, had left ventricular dilatation, global dysfunction and signs of diastolic dysfunction following MI surgery as evidenced by increased left ventricular internal diameter during diastole (MI effect, P < 0.01, Tei index (MI effect, P < 0.001) and E/E' ratio (prenatal hypoxia or MI effect, P < 0.01). In contrast, diastolic dysfunction in female offspring was not as evident. Cardiac superoxide levels were increased only in prenatal hypoxia-exposed male offspring. Cardiac sarcoendoplasmic reticulum Ca(2+)-ATPase2a levels, a marker of cardiac injury and dysfunction, were decreased in both male and female MI groups independent of prenatal hypoxia. Prenatal hypoxia increased cardiac ryanodine receptor 2 (RYR2) protein levels, while MI reduced RYR2 in only male offspring. In conclusion, male offspring exposed to prenatal hypoxia had an increased susceptibility to ischemic myocardial injury involving cardiac phenotypes similar to heart failure involving diastolic dysfunction in adult life compared to both offspring from healthy pregnancies and their female counterparts.
Accumulating research shows that prenatal exposure to maternal stress increases the risk for behavioral and mental health problems later in life. This review systematically analyzes the available human studies to identify harmful stressors, vulnerable periods during pregnancy, specificities in the outcome and biological correlates of the relation between maternal stress and offspring outcome. Effects of maternal stress on offspring neurodevelopment, cognitive development, negative affectivity, difficult temperament and psychiatric disorders are shown in numerous epidemiological and case-control studies. Offspring of both sexes are susceptible to prenatal stress but effects differ. There is not any specific vulnerable period of gestation; prenatal stress effects vary for different gestational ages possibly depending on the developmental stage of specific brain areas and circuits, stress system and immune system. Biological correlates in the prenatally stressed offspring are aberrations in neurodevelopment, neurocognitive function, cerebral processing, functional and structural brain connectivity involving amygdalae and (pre)frontal cortex, changes in hypothalamo-pituitary-adrenal (HPA)-axis and autonomous nervous system.
In most persons, blood pressure (BP) rises slowly during late sleep; increases rapidly upon morning awakening and commencement of diurnal activity; exhibits two -- morning and afternoon/early evening -- daytime peaks; minor midday nadir, and decline during nighttime sleep by 10 to 20% in systolic BP and somewhat lesser amount in diastolic BP relative to wake-time means. Nyctohemeral cycles of ambient temperature, light, noise and behaviorally driven food, liquid, salt, and stimulant consumption, mental/emotional stress, posture, and physical activity intensity plus circadian rhythms of wake/sleep, pineal gland melatonin synthesis, autonomic and central nervous, hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, renin-angiotensinaldosterone, renal hemodynamic, endothelial, vasoactive peptide, and opioid systems constitute the key regulators and determinants of the BP 24h profile. Environmental and behavioral cycles are believed to be far more influential than circadian ones. However, the facts that the: i) BP 24h pattern of secondary hypertension, e.g., diabetes and renal disease, is characterized by absence of BP fall during sleep, and ii) scheduling of conventional long-acting medications at bedtime, rather than morning, results in much better hypertension control and vascular risk reduction, presumably because highest drug concentration coincides closely with the peak of most key circadian determinants of the BP 24h profile, indicates endogenous rhythmic influences are of greater importance than previously appreciated.
Decreased oxygenation during pregnancy and early periods of ontogeny can affect normal body development and result in diseases in adulthood. The aim of this study was to use the model of prenatal intermittent hypoxia (PIH) and evaluate the effects of short-term hypoxia at the end of gestation on blood pressure (BP) control in adulthood. Wistar rats were exposed daily to PIH for 4 h during gestational day 19 and 20. In adult male rats, heart rate (HR), systolic BP and pulse pressure (PP) were acquired by radiotelemetry during 1 week. On the basis of HR variability and BP variability, sympathovagal balance (LF/HF) and spontaneous baroreflex sensitivity (sBRS) were evaluated. Systolic BP and PP were significantly elevated in PIH rats in comparison with control rats during the light and dark phase of the day, while LF/HF increased only during the light phase of the day. In contrast, sBRS tended to decrease only during the dark phase in PIH rats. In all measured and calculated parameters, significant circadian rhythms were present and were not affected by PIH. In conclusion, our data suggest that short intermittent hypoxia at the end of gestation can increase BP and PP via significant changes in LF/HF, which occur especially during the passive phase of the day. Results suggest that minor changes in the autonomous nervous system activity induced by environmental conditions during the perinatal period may contribute to development of hypertension in adulthood.Hypertension Research advance online publication, 25 February 2016; doi:10.1038/hr.2016.21.
We previously reported that gestational intermittent hypoxia (GIH) causes anxiety-like behavior in neonatal rats. Here, we showed that the anxiogenic effect was correlated with upregulation of corticotropin-releasing hormone receptor 1 (CRHR1) in the hypothalamic paraventricular nuclei (PVN) by GIH, and was selective to male offspring. The anxiety-like behavior was assessed by both the open field (OF) and elevated plus maze (EPM) tests. We demonstrated that GIH triggered anxiety-like behavior in male offspring, but not in female offspring or in the postpartum dams. Microinjection of antalarmin, a CRHR1-selective antagonist, into the PVN of the male offspring significantly increased the distance travelled and time spent in the central portion of the OF, and the time spent in the open arms in the EPM compared with controls. However, microinjection of the CRHR2 agonist, urocortin III, into the PVN did not affect anxiogenic behavior in the male offspring. These findings clearly demonstrate a gender-selective effect of GIH to increase anxiety-like behavior and this anxiogenic effect might be linked to embryogenically-driven upregulation of PVN CRHR1.
Blood and tissue O2 levels are major determinants of short-term autoregulatory adjustments in vascular smooth muscle cell (SMC) tension and may effect long-term alterations in SMC catecholamine responsiveness. We examined the hypothesis that prolonged hypoxia altered gene expression of alpha 1-adrenoceptors. After exposure of cultured aortic (in vitro) SMC to 3% O2 for 8 h, alpha 1B mRNA increased to 523% (P = 0.02) of control cells (21% O2) and to 205% (P = 0.04) in in situ organ-cultured aortic SMC. In vivo hypoxic hypoxia (10% inspired O2) similarly increased aortic SMC alpha 1B mRNA 180% (P = 0.02). In contrast, alpha 1D, alpha-actin and beta-actin mRNA levels were not changed in aortic SMC by low O2 in the in vitro, in situ, or in vivo models. Unlike aortic SMC, vena caval SMC alpha 1B mRNA expression did not change with low-O2 exposure in vitro or in vivo, nor did alpha 1D, alpha-actin or beta-actin mRNA. Aortic SMC alpha 1B transcription rate increased 360% (P = 0.02), whereas alpha 1D, alpha-actin, and beta-actin transcription was unchanged. Neither alpha 1B nor alpha 1D mRNA stability was altered by low-O2 exposure. Total alpha 1-adrenoceptor density ([3H]prazosin binding) increased 12% (P = 0.04) after 24 h of 3% O2. This was associated with a 200% increase (P < 0.01) in the chloroethylclonidine (CEC)-sensitive alpha 1-adrenoceptor population and no change in CEC-insensitive alpha 1-adrenoceptor density. Exposure of aortic SMC to 24 h of 3% O2 increased the maximum response of norepinephrine-evoked elevations in intracellular Ca2+ as measured using fura 2. Low O2 did not change responses to another G protein-coupled receptor, angiotensin II. These data suggest that reduced O2, during prolonged hypoxemia or tissue ischemia, may selectively increase expression of functionally coupled alpha 1B-adrenoceptors in arterial blood vessels.
The paraventricular nucleus of the hypothalamus has efferent connections to autonomic nuclei known to ultimately regulate cardiovascular function. Studies have revealed projections to the sympathetic preganglionic neurons of the spinal cord and presympathetic motor neurons of the rostral ventrolateral medulla. This study set out to establish whether the same neurons in the paraventricular nucleus innervate both these regions. In rats the fluorescent neuroanatomical tracers FluoroGold, Fast Blue or Dextran tetramethyl rhodamine were injected into either the rostral ventrolateral medulla or T2 region of the spinal cord. After a suitable survival period (five to seven days) three populations of neurons could be identified in the paraventricular nucleus, double-labelled neurons and single-labelled neurons resulting from the injections into the spinal cord or injections into the rostral ventrolateral medulla. The neurons were of similar size regardless of the dye content. Most neurons were found in the parvocellular subdivision of the mid rostral paraventricular nucleus. The number of labelled neurons decreased in the caudal sections.
It is now well accepted that the sympathetic nervous system responds to specific afferent stimuli in a unique non-uniform fashion. The means by which the brain transforms the signals from a single type of receptor into an appropriate differential sympathetic output is discussed in this brief review. The detection of and response to venous filling are used for illustration. An expansion of blood volume has been shown in a number of species to increase heart rate reflexly via sympathetic nerves and this effect is primarily an action of volume receptors at the venous-atrial junctions of the heart. Stimulation of these volume receptors also leads to an inhibition of renal sympathetic nerve activity. Thus the reflex response to an increase in plasma volume consists of a distinctive unique pattern of sympathetic activity to maintain fluid balance. This reflex is dependent on neurones in the paraventricular nucleus (PVN). Neurones in the PVN show early gene activation on stimulation of atrial receptors, and a similar differential pattern of cardiac sympathetic excitation and renal inhibition can be evoked by activating PVN neurones. Cardiac atrial afferents selectively cause a PVN GABA neurone-induced inhibition within the PVN of PVN spinally projecting vasopressin-containing neurones that project to renal sympathetic neurones. A lesion of these spinally projecting neurones abolishes the reflex. With regard to the cardiac sympathetics, there is a population of PVN spinally projecting neurones that selectively increase heart rate by the release of oxytocin, a peptide pathway that has no action on renal sympathetic outflow. In heart failure the atrial reflex becomes blunted, and evidence is emerging that there is a downregulation of nitric oxide synthesis and reduced GABA activity in the PVN. How this might give rise to increased sympathetic activity associated with heart failure is briefly discussed.
Although it is well-recognized that catecholamines are generally unable to penetrate the developed blood-brain barrier (BBB) to gain entry into brain, except at circumventricular sites where the BBB is absent or deficient, ontogenetic development of this barrier seems to have escaped systematic study. To explore BBB development, several approaches were used. In the first study rats were treated once on a specific day of postnatal ontogeny, as early as the day of birth, with the neurotoxin 6-hydroxydopamine (6-OHDA; 60 mg/kg), and then terminated in adulthood for regional analysis of endogenous norepinephrine (NE) content of brain. In another study, rats were treated once, on a specific day of postnatal ontogeny, with the BBB-permeable neurotoxin 6-hydroxydopa (6-OHDOPA; 60 mg/kg) following pretreatment with the BBB-impermeable amino acid decarboxylase inhibitor carbidopa (100 mg/kg IP), then terminated in adulthood for regional analysis of endogenous NE content of brain. In the third study rats were treated once, on a specific day of postnatal ontogeny, with the analog [3H]metaraminol, and terminated 1 hour later for determination of regional distribution of tritium in brain. On the basis of [3H]metaraminol distribution and NE depletions after neurotoxin treatments, it is evident that the BBB in neocortex, striatum, cerebellum and other brain regions forms in stages over a period of at least 2 weeks from birth. Moreover, because the BBB consists of several element (physical-, ion-restrictive-, and enzymatic-barrier), the method employed will derive data mainly applicable to the targeted aspect of the barrier, which may or may not necessarily coincide with elements of the barrier that have a different rate of ontogenetic development. Accordingly, it is evident that some aspects of physical- and ion-restrictive elements of the BBB form within approximately the first week after birth in rat neocortex and striatum, while enzymatic elements of the BBB form more than than 2 weeks later. Regardless, the BBB forms at earlier times in forebrain vs hindbrain regions.
Stressful events before or just after parturition alter the subsequent phenotypical response to stress in a general process termed programming. Hypoxia during the period before and during parturition, and in the postnatal period, is one of the most common causes of perinatal distress, morbidity, and mortality. We have found that perinatal hypoxia (prenatal day 19 to postnatal day 14) augmented the corticosterone response to stress and increased basal corticotrophin-releasing hormone (CRH) mRNA levels in the parvocellular portion of the paraventricular nucleus (PVN) in 6-month-old rats. There was no effect on the levels of hypothalamic parvocellular PVN vasopressin mRNA, anterior pituitary pro-opiomelanocortin or CRH receptor-1 mRNA, or hippocampus glucocorticoid receptor mRNA. We conclude that hypoxia spanning the period just before and for several weeks after parturition programmes the hypothalamic-pituitary-adrenal axis to hyper-respond to acute stress in adulthood, probably as a result of drive from the parvocellular CRH neurones.
Prenatal developmental origins of behavior and mental health: the influence of maternal stress in pregnancy
- Van Den Bergh
- Br
- M I Van Den Heuvel
- M Lahti
Chronos-Fit 1.06. Chronos-Fit
- P Zuther
- S Gorbey
- B Lemmer