Increased sympathetic activity in normotensive offspring of malignant hypertensive parents compared to offspring of normotensive parents

Malignant hypertension seems to be the consequence of very high blood pressure. Furthermore, an increase in sympathetic and renin-angiotensin system activity is considered to be the main mechanisms producing malignant hypertension. In the present study, 10 offspring of malignant hypertensive (OMH) parents (age 28 ± 5 years, 7 males, 3 females, 2 white and 8 non-white) and 10 offspring of normotensive (ONT) parents (age 28 ± 6 years, 2 males, 8 females, 3 white and 7 non-white) were evaluated. The OMH group had significantly higher (P < 0.05) casual blood pressure (125 ± 10/81 ± 5 mmHg) compared with ONT (99 ± 13/67 ± 5 mmHg). The increase in blood pressure was greater in OMH (Δ SBP = 17 ± 2 vs Δ SBP = 9 ± 1 mmHg in ONT) during cold pressor testing, but they had a lower increase in heart rate (Δ HR = 13 ± 2 vs Δ HR = 20 ± 3 bpm in ONT) during isometric exercise (handgrip test). Sympathetic activity, measured by microneurography, was significantly higher (P < 0.05) before exercise in OMH (17 ± 6 vs 11 ± 4 burst/min in ONT) and exhibited a greater increase (Δ = 18 ± 10 vs Δ = 8 ± 3 burst/min in ONT) during isometric exercise. This study showed increased sympathetic activity in OMH before exercise and a greater response during isometric exercise, suggesting an autonomic abnormality before exercise and a greater sympathetic response to physical stress in OMH compared to ONT.

Dental mineralization and salivary activity are reduced in offspring of spontaneously hypertensive rats (SHR)

Several pathologies have been diagnosed in children of hypertensive mothers; however, some studies that evaluated the alterations in their oral health are not conclusive. This study analyzed the salivary gland activity and dental mineralization of offsprings of spontaneously hypertensive rats (SHR). Thirty-day-old SHR males and Wistar rats were studied. The salivary flow was evaluated by injection of pilocarpine, the protein concentration and salivary amylase activity, by the Lowry method and kinetic method at 405 nm, respectively. Enamel and dentin mineralization of the mandibular incisors was quantified with aid of the microhardness meter. The results were analyzed by the ANOVA or Student's t test (p<0.05). It was noticed that the salivary flow rate (0.026 mL/min/100 g ± 0.002) and salivary protein concentration (2.26 mg/mL ± 0.14) of SHR offspring were reduced compared to Wistar normotensive offspring (0.036 mL/min/100 g ± 0.003 and 2.91 mg/mL ± 0.27, respectively), yet there was no alteration in amylase activity (SHR: 242.4 U/mL ± 36.9; Wistar: 163.8 U/mL ± 14.1). Microhardness was lower both in enamel (255.8 KHN ± 2.6) and dentin (59.9 KHN ± 0.8) for the SHR teeth compared to the Wistar teeth (enamel: 328.7 KHN ± 3.3 and dentin: 67.1 KHN ± 1.0). These results suggest that the SHR offspring are more susceptible to development of pathologies impairing oral health, once they presented lesser flow and salivary protein concentration and lower dental mineralization.

Mental disorders in offspring of parents with bipolar and major depressive disorders.

OBJECTIVES: There is limited information on the specificity of associations between parental bipolar disorder (BPD) and major depressive disorder (MDD) and the risk of psychopathology in offspring. The chief aim of the present study was to investigate the association between mood disorder subtypes in the two parents and mental disorders in the offspring. METHODS: A total of 376 offspring (aged 6.0-17.9 years; mean=11.5years) of 72 patients with BPD (139 offspring), 56 patients with MDD (110 offspring), and 66 controls (127 offspring) participated in a family study conducted in two university hospital centers in Switzerland. Probands, offspring, and biological co-parents were interviewed by psychologists blind to proband diagnoses, using a semi-structured diagnostic interview. RESULTS: Rates of mood and anxiety disorders were elevated among offspring of BPD probands (34.5% any mood; 42.5% any anxiety) and MDD probands (25.5% any mood; 44.6% any anxiety) as compared to those of controls (12.6% any mood; 22.8% any anxiety). Moreover, recurrent MDD was more frequent among offspring of BPD probands (7.9%) than those of controls (1.6%). Parental concordance for bipolar spectrum disorders was associated with a further elevation in the rates of mood disorders in offspring (64.3% both parents versus 27.2% one parent). CONCLUSIONS:   These findings provide unique information on the broad manifestations of parental mood disorders in their offspring. The earlier onset and increased risk of recurrent MDD in the offspring of parents with BPD compared to those of controls suggests that the episodicity characterizing BPD may emerge in childhood and adolescence.

The specificity of the familial aggregation of early-onset bipolar disorder: A controlled 10-year follow-up study of offspring of parents with mood disorders.

BACKGROUND: Two major sources of heterogeneity of mood disorders that have been demonstrated in clinical, family and genetic studies are the mood disorder subtype (i.e. bipolar (BPD) and major depressive disorder (MDD)) and age of onset of mood episodes. Using a prospective high-risk study design, our aims were to test the specificity of the parent-child transmission of BPD and MDD and to establish the risk of psychopathology in offspring in function of the age of onset of the parental disorder. METHODS: Clinical information was collected on 208 probands (n=81 with BPD, n=64 with MDD, n=63 medical controls) as well as their 202 spouses and 372 children aged 6-17 years at study entry. Parents and children were directly interviewed every 3 years (mean duration of follow-up=10.6 years). Parental age of onset was dichotomized at age 21. RESULTS: Offspring of parents with early onset BPD entailed a higher risk of BPD HR=7.9(1.8-34.6) and substance use disorders HR=5.0(1.1-21.9) than those with later onset and controls. Depressive disorders were not significantly increased in offspring regardless of parental mood disorder subtype or age of onset. LIMITATIONS: Limited sample size, age of onset in probands was obtained retrospectively, age of onset in co-parents was not adequately documented, and a quarter of the children had no direct interview. CONCLUSIONS: Our results provide support for the independence of familial aggregation of BPD from MDD and the heterogeneity of BPD based on patterns of onset. Future studies should further investigate correlates of early versus later onset BPD.

Autonomic abnormalities demonstrable in young normotensive subjects who are children of hypertensive parents

Although a slightly elevated office blood pressure (BP) has been reported in several studies, little is known about the prolonged resting blood pressure, heart rate (HR) and baroreflex sensitivity (BRS) of prehypertensive subjects with a family history of hypertension. Office blood pressure, prolonged resting (1 h) BP and HR were measured in 25 young normotensives with a positive family history of hypertension (FH+) and 25 young normotensives with a negative family history of hypertension (FH-), matched for age, sex, and body mass index. After BP and HR measurements, blood samples were collected for the determination of norepinephrine, plasma renin activity and aldosterone levels, and baroreflex sensitivity was then tested. Casual BP, prolonged resting BP and heart rate were significantly higher in the FH+ group (119.9 ± 11.7/78.5 ± 8.6 mmHg, 137.3 ± 12.3/74.4 ± 7.9 mmHg, 68.5 ± 8.4 bpm) compared to the FH- group (112.9 ± 11.4/71.2 ± 8.3 mmHg, 128.0 ± 11.8/66.5 ± 7.4 mmHg, 62.1 ± 6.0 bpm). Plasma norepinephrine level was significantly higher in the FH+ group (220.1 ± 104.5 pg/ml) than in the FH- group (169.1 ± 63.3 pg/ml). Baroreflex sensitivity to tachycardia (0.7 ± 0.3 vs 1.0 ± 0.5 bpm/mmHg) was depressed in the FH+ group (P<0.05). The FH+ group exhibited higher casual blood pressure, prolonged resting blood pressure, heart rate and plasma norepinephrine levels than the FH- group (P<0.05), suggesting an increased sympathetic tone in these subjects. The reflex tachycardia was depressed in the FH+ group.

Hypotrophy of conduit artery walls of the offspring of nitric oxide-defective rats

The objective of the present study was to investigate the structure of the arterial walls of the offspring stemming from nitric oxide (NO)-defective hypertensive parents. The parents were treated with N G-nitro-L-arginine methyl ester (40 mg kg-1 day-1) for 5 weeks. Blood pressure was measured noninvasively in six 30-day-old rats and nine age-matched controls. The cardiovascular system was perfused with glutaraldehyde at 120 mmHg. The thoracic aorta and carotid artery were processed for electron microscopy, and geometry was determined by light microscopy. Endothelial cells, smooth muscle cells (SMC) and extracellular matrix (ECM) were determined by the point counting method in electron micrographs of the carotid artery. The blood pressure of experimental offspring was 150.0 ± 2.3 vs 104.6 ± 2.1 mmHg (P < 0.01) for the controls and their heart/body weight ratio of 3.9 ± 0.1 vs 4.4 ± 0.2 (P < 0.05) for the controls indicated cardiac hypotrophy. The wall thickness (tunica intima and media) of the thoracic aorta and carotid artery of experimental offspring was decreased to 78.9% (P < 0.01) and 83.8% (P < 0.01), respectively, compared to controls, as confirmed by a respective cross-sectional area of 85.3% (P < 0.01) and 84.1% (P < 0.01). The wall thickness/inner diameter ratio was reduced to 75% (P < 0.01) in the thoracic artery and to 81.5% (P < 0.01) in the carotid artery. No change in endothelial cell volume density or ECM was observed in the tunica intima of the carotid artery, and SMC volume density was lower in the tunica media (37.6 ± 0.9 vs 44.7 ± 1.1% for controls, P < 0.01), indicating compromised SMC development. Interference with arginine metabolism, a decrease in NO, and other factors are possible mechanisms underlying the structural alterations of the cardiovascular system of offspring from NO-defective hypertensive rats.

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

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

Stimulant medication and psychotic symptoms in offspring of parents with mental illness

BACKGROUND: Stimulants, such as methylphenidate, are among the most commonly used medications in children and adolescents. Psychotic symptoms have been reported as rare adverse reactions to stimulants but have not been systematically inquired about in most previous studies. Family history of mental illness may increase the vulnerability to drug-induced psychotic symptoms. We examined the association between stimulant use and psychotic symptoms in sons and daughters of parents with major mood and psychotic disorders. METHODS: We assessed psychotic symptoms, psychotic-like experiences, and basic symptoms in 141 children and youth (mean ± SD age: 11.8 ± 4.0 years; range: 6–21 years), who had 1 or both parents with major depressive disorder, bipolar disorder, or schizophrenia, and of whom 24 (17.0%) had taken stimulant medication. RESULTS: Psychotic symptoms were present in 62.5% of youth who had taken stimulants compared with 27.4% of participants who had never taken stimulants. The association between stimulant use and psychotic experiences remained significant after adjustment for potential confounders (odds ratio: 4.41; 95% confidence interval: 1.82–10.69; P = .001) and was driven by hallucinations occurring during the use of stimulant medication. A temporal relationship between use of stimulants and psychotic symptoms was supported by an association between current stimulant use and current psychotic symptoms and co-occurrence in cases that were assessed on and off stimulants. CONCLUSIONS: Psychotic symptoms should be monitored during the use of stimulants in children and adolescents. Family history of mood and psychotic disorders may need to be taken into account when considering the prescription of stimulants.

NMR studies of muscle glycogen synthesis in insulin-resistant offspring of parents with non-insulin-dependent diabetes mellitus immediately after glycogen-depleting exercise.

To examine the impact of insulin resistance on the insulin-dependent and insulin-independent portions of muscle glycogen synthesis during recovery from exercise, we studied eight young, lean, normoglycemic insulin-resistant (IR) offspring of individuals with non-insulin-dependent diabetes mellitus and eight age-weight matched control (CON) subjects after plantar flexion exercise that lowered muscle glycogen to approximately 25% of resting concentration. After approximately 20 min of exercise, intramuscular glucose 6-phosphate and glycogen were simultaneously monitored with 31P and 13C NMR spectroscopies. The postexercise rate of glycogen resynthesis was nonlinear. Glycogen synthesis rates during the initial insulin independent portion (0-1 hr of recovery) were similar in the two groups (IR, 15.5 +/- 1.3 mM/hr and CON, 15.8 +/- 1.7 mM/hr); however, over the next 4 hr, insulin-dependent glycogen synthesis was significantly reduced in the IR group [IR, 0.1 +/- 0.5 mM/hr and CON, 2.9 +/- 0.2 mM/hr; (P < or = 0.001)]. After exercise there was an initial rise in glucose 6-phosphate concentrations that returned to baseline after the first hour of recovery in both groups. In summary, we found that following muscle glycogen-depleting exercise, IR offspring of parents with non-insulin-dependent diabetes mellitus had (i) normal rates of muscle glycogen synthesis during the insulin-independent phase of recovery from exercise and (ii) severely diminished rates of muscle glycogen synthesis during the subsequent recovery period (2-5 hr), which has previously been shown to be insulin-dependent in normal CON subjects. These data provide evidence that exercise and insulin stimulate muscle glycogen synthesis in humans by different mechanisms and that in the IR subjects the early response to stimulation by exercise is normal.

Effects of parental larval diet on egg size and offspring traits in Drosophila.

If a mother's nutritional status predicts the nutritional environment of the offspring, it would be adaptive for mothers experiencing nutritional stress to prime their offspring for a better tolerance to poor nutrition. We report that in Drosophila melanogaster, parents raised on poor larval food laid 3-6% heavier eggs than parents raised on standard food, despite being 30 per cent smaller. Their offspring developed 14 h (4%) faster on the poor food than offspring of well-fed parents. However, they were slightly smaller as adults. Thus, the effects of parental diet on offspring performance under malnutrition apparently involve both adaptive plasticity and maladaptive effects of parental stress.

Pathologic ventricular hypertrophy in the offspring of diabetic mothers: a retrospective study.

AIMS: Diabetes in pregnant women is increasing and with that the complications in their offspring. We studied our population of diabetic mothers (2003-2005) for pathologic ventricular hypertrophy (PVH). METHODS AND RESULTS: In our retrospective study of all 87 diabetic pregnancies (92 neonates), 16 were type 1, 17 were type 2, and 54 were gestational diabetes (GD). Haemoglobin glycated (HbA1c) median was 5.8% (5.3-6.5): 17 with HbA1c above normal 2 with congenital heart disease (CHD) and six with PVH. A total of 75 neonates were normal, five had CHD, and 12 had PVH (1/12 died post-natally, 1/12 stillborn, 2/12 required premature delivery, 8/12 normal). The 16 type 1 pregnancies resulted in three neonates with CHD and in 50% PVH, including one death, one premature Cesarean section because of PVH. The 17 neonates of type 2 pregnancies showed in one CHD and in 25% PVH. Of the 54 GD pregnancies, one had CHD and one had PVH. CONCLUSION: Pregnancies of both type 1 and 2 diabetes carry an increased risk for foetal development of PVH compared with those with GD. The insufficient effect of preventive glycaemia controls leads to conclude that although no definite predictive parameters for malignant outcome can be presented, close monitoring of these pregnancies may prevent perinatal catastrophes.

Behavioral characteristics of the offspring of adolescent rats

The aim of this study was to test the hypothesis that, during adulthood, the offspring of adolescent rats differ in emotionality, learning and memory from the offspring of adult rats. The behavior of the offspring of adolescent (age, 50-55 days) and adult rats (age, 90-95 days) was tested in the open field, activity cage, and passive and active avoidance apparatus. The latencies during training and testing in the passive avoidance apparatus of the offspring of adolescent parents were shorter than the latencies of control offspring (P<0.001 on both training and testing days). Offspring of adolescent parents showed shorter latency time in acquisition trials during active avoidance testing compared to control offspring (P<0.001). They also showed a higher number of active avoidance responses in the last four blocks of acquisition (P<0.001) and first two blocks of extinction trials (P<0.05 and P<0.001, respectively). The offspring of adolescent parents showed higher latency on the first day of testing in the open field (P<0.01) and a lower latency on the third day of testing (P<0.01). They also showed higher activity during all three days of testing (1st and 2nd day: P<0.01; 3rd day: P<0.05). The spontaneous activity of the offspring of adolescent parents in the activity cage was higher in the last three intervals of testing (P<0.001). In summary, the offspring of adolescent parents were less anxious and tended to be more active. The results of two learning and memory tests were opposite, but could be explained by a higher exploratory drive of the offspring of adolescent parents. This was probably due to chronic malnutrition stress and the disturbed mother-infant relationship in the litters of adolescent mothers.

Increased Expression Of Hes5 Protein In Notch Signaling Pathway In The Hippocampus Of Mice Offspring Of Dams Fed A High-fat Diet During Pregnancy And Suckling.

Maternal high-fat diet (HFD) impairs hippocampal development of offspring promoting decreased proliferation of neural progenitors, in neuronal differentiation, in dendritic spine density and synaptic plasticity reducing neurogenic capacity. Notch signaling pathway participates in molecular mechanisms of the neurogenesis. The activation of Notch signaling leads to the upregulation of Hes5, which inhibits the proliferation and differentiation of neural progenitors. This study aimed to investigate the Notch/Hes pathway activation in the hippocampus of the offspring of dams fed an HFD. Female Swiss mice were fed a control diet (CD) and an HFD from pre-mating until suckling. The bodyweight and mass of adipose tissue in the mothers and pups were also measured. The mRNA and protein expression of Notch1, Hes5, Mash1, and Delta1 in the hippocampus was assessed by RT-PCR and western blotting, respectively. Dams fed the HFD and their pups had an increased bodyweight and amount of adipose tissue. Furthermore, the offspring of mothers fed the HFD exhibited an increased Hes5 expression in the hippocampus compared with CD offspring. In addition, HFD offspring also expressed increased amounts of Notch1 and Hes5 mRNA, whereas Mash1 expression was decreased. However, the expression of Delta1 did not change significantly. We propose that the overexpression of Hes5, a Notch effector, downregulates the expression of the proneural gene Mash1 in the offspring of obese mothers, delaying cellular differentiation. These results provide further evidence that an offspring's hippocampus is molecularly susceptible to maternal HFD and suggest that Notch1 signaling in this brain region is important for neuronal differentiation.

Time course of training-induced microcirculatory changes and of vegf expression in skeletal muscles of spontaneously hypertensive female rats

Exercise-induced vessel changes modulate arterial pressure (AP) in male spontaneously hypertensive rats (SHR). Vascular endothelial growth factor (VEGF) is important for angiogenesis of skeletal muscle. The present study evaluated the time course of VEGF and angiogenesis after short- and long-term exercise training of female SHR and Wistar Kyoto (WKY) rats, 8-9 weeks (200-250 g). Rats were allocated to daily training or remained sedentary for 3 days (N = 23) or 13 weeks (N = 23). After training, the carotid artery was catheterized for AP measurements. Locomotor (tibialis anterior and gracilis) and non-locomotor skeletal muscles (temporalis) were harvested and prepared for histologic and protein expression analyses. Training increased treadmill performance by all groups (SHR = 28%, WKY = 64%, 3 days) and (SHR = 141%, WKY = 122%, 13 weeks). SHR had higher values of AP than WKY (174 ± 4 vs 111 ± 2 mmHg) that were not altered by training. Three days of running increased VEGF expression (SHR = 28%, WKY = 36%) simultaneously with an increase in capillary-to-fiber ratio in gracilis muscle (SHR = 19%, WKY = 15%). In contrast, 13 weeks of training increased gracilis capillary-to-fiber ratio (SHR = 18%, WKY = 19%), without simultaneous changes in VEGF expression. Training did not change VEGF expression and capillarity of temporalis muscle. We conclude that training stimulates time- and tissue-dependent VEGF protein expression, independent of pressure levels. VEGF triggers angiogenesis in locomotor skeletal muscle shortly after the exercise starts, but is not involved in the maintenance of capillarity after long-term exercise in female rats.