Effects of β-adrenergic receptor agonists on drinking and arterial blood pressure in young and old rats

These experiments examined water-drinking and arterial blood pressure responses to β-adrenergic receptor activation in young (4 mo), "middle-aged" adult (12 mo), and old (29 mo) male rats of the Brown-Norway strain. We used isoproterenol to simultaneously activate β(1)- and β(2)-adrenergic receptors, salbutamol to selectively activate β(2)-adrenergic receptors, and the combination of isoproterenol and the β(2)-adrenergic receptor antagonist ICI 118,551 to stimulate only β(1)-adrenergic receptors. Animals received one of the drug treatments, and water drinking was measured for 90 min. About 1 wk later, animals received the same drug treatment for measurement of arterial blood pressure responses for 90 min. In some rats, levels of renin and aldosterone secretion in response to isoproterenol or salbutamol were measured in additional tests. Old and middle-aged rats drank significantly less after isoproterenol than did young rats and also had greater reductions in arterial blood pressure. Old and middle-aged rats drank significantly less after salbutamol than did young rats, although reductions in arterial blood pressure were equivalent across the ages. The β(2)-adrenergic antagonist ICI 118,551 abolished drinking after isoproterenol and prevented most of the observed hypotension. Renin secretion after isoproterenol and salbutamol was greater in young rats than in middle-aged rats, and wholly absent in old rats. Aldosterone secretion was reduced in old rats compared with young and middle-aged rats after treatment with isoproterenol, but not after treatment with salbutamol. In conclusion, there are age-related differences in β-adrenergic receptor-mediated drinking that can be explained only in part by age-related differences in renin secretion after β-adrenergic receptor stimulation.     

Wnt/β-catenin regulates blood pressure and kidney injury in rats

Activation of the renin-angiotensin system (RAS) plays a pivotal role in mediating hypertension, chronic kidney and cardiovascular diseases. As Wnt/β-catenin regulates multiple RAS genes, we speculated that this developmental signaling pathway might also participate in blood pressure (BP) regulation. To test this, we utilized two rat models of experimental hypertension: chronic angiotensin II infusion and remnant kidney after 5/6 nephrectomy. Inhibition of Wnt/β-catenin by ICG-001 blunted angiotensin II-induced hypertension. Interestingly, angiotensin II was able to induce the expression of multiple Wnt genes in vivo and in vitro, thereby creating a vicious cycle between Wnt/β-catenin and RAS activation. In the remnant kidney model, renal β-catenin was upregulated, and delayed administration of ICG-001 also blunted BP elevation and abolished the induction of angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II type 1 receptor. ICG-001 also reduced albuminuria, serum creatinine and blood urea nitrogen, and inhibited renal expression of fibronectin, collagen I and plasminogen activator inhibitor-1, and suppressed the infiltration of CD3⁺ T cells and CD68⁺ monocytes/macrophages. In vitro, incubation with losartan prevented Wnt/β-catenin-mediated fibronectin, α-smooth muscle actin and Snail1 expression, suggesting that the fibrogenic action of Wnt/β-catenin is dependent on RAS activation. Taken together, these results suggest an intrinsic linkage of Wnt/β-catenin signaling with BP regulation. Our studies also demonstrate that hyperactive Wnt/β-catenin can drive hypertension and kidney damage via RAS activation.     

Association of plasma Aß peptides with blood pressure in the elderly

Background

Aß peptides are often considered as catabolic by-products of the amyloid ß protein precursor (APP), with unknown physiological functions. However, several biological properties have been tentatively attributed to these peptides, including a role in vasomotion.We assess whether plasma Aß peptide levels might be associated with systolic and diastolic blood pressure values (SBP and DBP, respectively).

Methodology/Principal Findings

Plasma Aß_1-40 and Aß_1-42 levels were measured using an xMAP-based assay in 1,972 individuals (none of whom were taking antihypertensive drugs) from 3 independent studies: the French population-based 3C and MONA-LISA (Lille) studies (n = 627 and n = 769, respectively) and the Australian, longitudinal AIBL study (n = 576). In the combined sample, the Aß_1-42/ Aß_1-40 ratio was significantly and inversely associated with SBP (p = 0.03) and a similar trend was observed for DBP (p = 0.06). Using the median age (69) as a cut-off, the Aß_1-42/Aß_1-40 ratio was strongly associated with both SBP and DBP in elderly individuals (p = 0.002 and p = 0.03, respectively). Consistently, a high Aß_1-42/ Aß_1-40 ratio was associated with a lower risk of hypertension in both the combined whole sample (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56-0.90) and (to an even greater extent) in the elderly subjects (OR, 0.53; 95% CI, 0.37–0.75). Lastly, all these associations appeared to be primarily driven by the level of plasma Aß_1-40.

Conclusion

The plasma Aß_1-42/Aß_1-40 ratio is inversely associated with SBP, DBP and the risk of hypertension in elderly subjects, suggesting that Aß peptides affect blood pressure in vivo. These results may be particularly relevant in Alzheimer''s disease, in which a high Aß_1-42/Aß_1-40 plasma ratio is reportedly associated with a decreased risk of incident disease.     

Atropine lowers blood pressure in normotensive rats through blockade of α-adrenergic receptors

Atropine sulfate elicited a dose-dependent decrease in blood pressure in normotensive rats at doses higher than needed to cause muscarinic blockade. This hypotensive effect was not altered by pretreatment with ganglionic or β-adrenergic blockers, but was fully abolished by α-adrenergic blockers. In addition, atropine inhibited the pressor response to α-agonists in a dose-dependent manner. The time course for hypotension and α-blockade were the same (onset < 1 minute; duration < 20 minutes). $\text{In vitro}$, atropine was found to be 200 times more potent in displacing the α₁-adrenergic receptor ligand ([³H] WB-4101) than the α₂-ligand ([³H] clonidine). Thus the observed hypotensive effect is apparently due to α-blockade as demonstrated $\text{in vivo}$ and $\text{in vitro}$.     

Remodeling of atrial ATP-sensitive K⁺ channels in a model of salt-induced elevated blood pressure

Hypertension is associated with the development of atrial fibrillation; however, the electrophysiological consequences of this condition remain poorly understood. ATP-sensitive K(+) (K(ATP)) channels, which contribute to ventricular arrhythmias, are also expressed in the atria. We hypothesized that salt-induced elevated blood pressure (BP) leads to atrial K(ATP) channel activation and increased arrhythmia inducibility. Elevated BP was induced in mice with a high-salt diet (HS) for 4 wk. High-resolution optical mapping was used to measure atrial arrhythmia inducibility, effective refractory period (ERP), and action potential duration at 90% repolarization (APD(90)). Excised patch clamping was performed to quantify K(ATP) channel properties and density. K(ATP) channel protein expression was also evaluated. Atrial arrhythmia inducibility was 22% higher in HS hearts compared with control hearts. ERP and APD(90) were significantly shorter in the right atrial appendage and left atrial appendage of HS hearts compared with control hearts. Perfusion with 1 μM glibenclamide or 300 μM tolbutamide significantly decreased arrhythmia inducibility and prolonged APD(90) in HS hearts compared with untreated HS hearts. K(ATP) channel density was 156% higher in myocytes isolated from HS animals compared with control animals. Sulfonylurea receptor 1 protein expression was increased in the left atrial appendage and right atrial appendage of HS animals (415% and 372% of NS animals, respectively). In conclusion, K(ATP) channel activation provides a mechanistic link between salt-induced elevated BP and increased atrial arrhythmia inducibility. The findings of this study have important implications for the treatment and prevention of atrial arrhythmias in the setting of hypertensive heart disease and may lead to new therapeutic approaches.     

Association of 24 h–systolic blood pressure variability and cardiovascular disease in patients with obstructive sleep apnea

Background

To evaluate association of 24 h–systolic blood pressure (SBP) variability and obstructive sleep apnea (OSA) as defined by the apnea-hypopnea index ≥5/h; and association of 24 h–SBP variability and prevalent cardiovascular disease (CVD) in OSA patients.

Methods

Participants underwent polysomongraphy to evaluate the presence of OSA, and 24 h–ambulatory blood pressure monitoring was applied to evaluate 24 h–SBP variability as indexed by weighted 24 h–standard deviation (SD) of SBP. Between-group differences were evaluated in participants with and without OSA. Participants with OSA were divided into high and low 24 h–SBP variability groups and between-group differences were evaluated.

Results

Mean age of 384 participants was 50 years old and 42.2% had OSA. Mean 24 h–systolic/diastolic BP were 130/78 mmHg, with mean weighted 24 h–SD of systolic/diastolic BP were 12.9/7.3 mmHg. Compared to those without OSA, OSA participants had higher clinic-, 24 h-, daytime- and nighttime-SBP, and weighted 24 h, daytime- and nighttime-SD of SBP. Age, prevalent CVD and OSA, usage of angiotensin converting enzyme inhibitor/angiotensin receptor blocker, calcium channel blocker and diuretic were significantly associated with 24 h–SBP variability. In OSA patients, compared to those with low variability, participants with high variability had higher weighted 24 h, daytime- and nighttime-SD of SBP. After adjusted for covariates including clinic-SBP and 24 h–SBP, per 1-SD increment weighted 24 h–SD of SBP was associated with 21% increased prevalent CVD.

Conclusions

Patients with newly-diagnosed OSA have higher 24 h–SBP variability compared to those without OSA; in OSA patients, increased 24 h–SBP variability is associated with increased prevalence of CVD.

     

Exercise prevents leptin-induced increase in blood pressure in Sprague–Dawley rats

Although leptin has been shown to increase blood pressure (BP), it is however unclear if this increase can be prevented by exercise. This study therefore investigated the effect of leptin treatment with concurrent exercise on blood pressure (BP), sodium output, and endothelin-1 (ET-1) levels in normotensive rats. Male Sprague–Dawley rats weighing 250–270 g were divided into four groups consisting of a control group (n?=?6), leptin-treated (n?=?8), non-leptin-treated exercise group (n?=?8), and a leptin-treated exercise group (n?=?8). Leptin was given subcutaneously daily for 14 days (60 μg/kg/day). Animals were exercised on a treadmill for 30 min at a speed of 0.5 m/s and at 5° incline four times per week. Measurement of systolic blood pressure (SBP) and collection of urine samples for estimation of sodium and creatinine was done once a week. Serum samples were collected at the end of the experiment for determination of sodium, creatinine and ET-1. At day 14, mean SBP and serum ET-1 level in the leptin-treated group was significantly higher than that in the control group whereas mean SBP and serum ET-1 level was significantly lower in the leptin-treated exercise group than those in leptin-treated and control groups. Creatinine clearance, urinary sodium excretion, and urine output were not different between the four groups. Regular treadmill exercise prevents leptin-induced increases in SBP in rats, which might in part result from increased urinary sodium excretion and preventing the leptin-induced increases in serum ET-1 concentration.     

Effects of nandrolone and resistance training on the blood pressure,cardiac electrophysiology,and expression of atrial β-adrenergic receptors

AimsThis study was performed to assess isolated and combined effects of nandrolone and resistance training on the blood pressure, cardiac electrophysiology, and expression of the β₁- and β₂-adrenergic receptors in the heart of rats.Main methodsWistar rats were randomly divided into four groups and submitted to a 6-week treatment with nandrolone and/or resistance training. Cardiac hypertrophy was accessed by the ratio of heart weight to the final body weight. Blood pressure was determined by a computerized tail-cuff system. Electrocardiography analyses were performed. Western blotting was used to access the protein levels of the β₁- and β₂-adrenergic receptors in the right atrium and left ventricle.Key findingsBoth resistance training and nandrolone induced cardiac hypertrophy. Nandrolone increased systolic blood pressure depending on the treatment time. Resistance training decreased systolic, diastolic and mean arterial blood pressure, as well as induced resting bradycardia. Nandrolone prolonged the QTc interval for both trained and non-trained groups when they were compared to their respective vehicle-treated one. Nandrolone increased the expression of β₁- and β₂-adrenergic receptors in the right atrium for both trained and non-trained groups when they were compared to their respective vehicle-treated one.SignificanceThis study indicated that nandrolone, associated or not with resistance training increases blood pressure depending on the treatment time, induces prolongation of the QTc interval, and increases the expression of β₁- and β₂-adrenergic receptors in the cardiac right atrium, but not in the left ventricle.     

The Munich Wistar Fr?mter rat: proteinuria and blood pressure in correlation to the number of superficial glomeruli.

Rats with a high number of superficial nephrons (MWF/Ztm) also show an elevated urinary protein excretion and a high systolic blood pressure. To investigate a possible correlation between the number of superficial glomeruli and these physiological changes, MWF/Ztm rats were crossed and backcrossed to Wistar cryptorchic (WC/Ztm) animals with no superficial nephrons in order to produce genotypes with differing numbers of superficial glomeruli. In the parental strains, the F1 hybrids and the 8 possible backcrosses, the number of superficial glomeruli, the distance of the 10 most superficial glomeruli to the renal surface, and the diameter of Bowman's capsules were determined by morphometric analysis. The excretion of total protein, in detail low molecular weight proteins, albumin, and high molecular weight proteins were measured quantitatively in 5 males of each genotype. Systolic blood pressure was determined by a tail-cuff method in conscious rats. Means of each variate of the 12 available genotypes were linearly correlated and demonstrate a close correlation between the amount of superficial nephrons and the observed physiological changes, i.e. the more superficial the glomeruli the higher the urinary protein excretion, especially albumin, and the higher the systolic blood pressure.     

Do night and around-the-clock firefighters’ shift schedules induce deviation in tau from 24 hours of systolic and diastolic blood pressure circadian rhythms?

Systolic (S) and diastolic (D) blood pressures (BP) [SBP and DBP] are circadian rhythmic with period (τ) in healthy persons assumed to be maintained at 24.0h. We tested this assumption in a sample of 30 healthy career (mean >12 yrs) 30-to-46 yr-old male Caucasian French firefighters (FFs) categorized into three groups according to work schedule and duties: Group A – 12 FFs working 12h day, 12h night, and occasionally 24h shifts and whose primary duties are firefighting plus paramedical and road rescue services; Group B – 9 FFs working mostly 12h day and 12h night shifts and whose duties are answering incoming emergency calls and coordinating service vehicle dispatch from fire stations with Group A personnel; Group C – 9 day shift (09:00–17:00h) FFs charged with administrative tasks. SBP and DBP, both in winter and in summer studies of the same FFs, were sampled by ambulatory BP monitoring every 1h between 06:00–23:00h and every 2h between 23:01–05:59h, respectively, their approximate off-duty wake and sleep spans, for 7 consecutive days. Activity (wrist actigraphy) was also sampled at 1-min intervals. Prominent τ of each variable was derived by a power spectrum program written for unequal-interval time series data, and between-group differences in incidence of τ≠24h of FFs were assessed by chi square test. Circadian rhythm disruption (τ≠24h) of either the SBP or DBP rhythm occurred almost exclusively in night and 24h shift FFs of Group A and B, but almost never in day shift FFs of Group C, and it was not associated with altered τ from 24.0h of the circadian activity rhythm. In summer, occurrence of τ≠24 for FFs of Group A and B differed from that for FFs of Group C in SBP (p=0.042) and DBP (p=0.015); no such differences were found in winter (p>0.10). Overall, manifestation of prominent τ≠24h of SBP or DBP time series was greater in summer than winter, 27.6% versus 16.7%, when workload of Group B FFs, i.e. number of incoming emergency telephone calls, and of Group A FFs, i.e. number of dispatches for provision of emergency services, was, respectively, two and fourfold greater and number of 12h night shifts worked by Group B FFs and number of 24h shifts worked by Group A FFs was, respectively, 92% and 25% greater. FFs of the three groups exhibited no winter-summer difference in τ≠24h of SBP or SDP; however, τ≠24h of DBP in Group B FFs was more frequent in summer than winter (p=0.046). Sleep/wake cycle disruption, sleep deprivation, emotional and physical stress, artificial light-at-night, and altered nutrient timings are hypothesized causes of τ≠24h for BP rhythms of affected Groups A and B FFs, but with unknown future health effects.     

On the effect of sharp rises in blood pressure in the Shah–Humphrey model for intracranial saccular aneurysms

We consider the model originally proposed by Shah and Humphrey (J Biomech 32:593–599, 1999) for a class of intracranial saccular aneurysms and show that for constant pressure the addition of the viscoelastic term corresponding to the presence of cerebral spinal fluid outside the membrane, no matter how small, does ensure convergence to an equilibrium. Our arguments apply to a general equation of this type, and thus also hold for variations of this model such as that proposed by David and Humphrey (J Biomech 36:1143–1150, 2003). On the other hand, it is known that the presence of damping may destabilize periodic orbits of periodically forced systems or even prevent them from existing altogether. We present numerical simulations showing that for some forcing terms the high-frequency oscillations do not die out with time, and a much more complex behaviour may emerge as a discontinuous forcing term is approached. The key point for this situation to occur is related to the derivative of the forcing term, supporting the hypothesis that sharper rises (or falls) in blood pressure may increase the risk of aneurysm rupture.     

Tracking of familial resemblance for resting blood pressure over time in the Québec Family Study

The etiology of familial resemblance for systolic (SBP) and diastolic (DBP) blood pressure, both within a single time point as well as across time points, was assessed to determine how familial etiologies underlying a trait may change across time. SBP and DBP measurements were taken roughly 12 years apart in family members participating in the longitudinal Québec Family Study. A longitudinal (bivariate) familial correlation model yields 3 types of correlations: intraindividual cross-time (e.g., father's BP at time 1 with his own BP at time 2); interindividual within-time (e.g., father time 1 with child time 1); and interindividual cross-time (e.g., father time 1 with child time 2). In addition, the change in BP across time (i.e., time 1-time 2) is examined using a univariate family correlation model. This combined method is useful in assessing the degree to which the same familial factors are operating across time (interindividual cross-time correlations), as well as the degree to which different heritable components are involved across time (change score). Maximal heritabilities for SBP were about 70% at each time point, while for DBP the heritability was larger at time 1 (87%) than time 2 (39%). Both the change scores (48% for SBP and 54% for DBP) and the cross-time comparisons (58% to 72% for SBP and 63% to 65% for DBP) evidenced significant familial resemblance. These results illustrate how simple methodologies can be used to specify how familial etiologies underlying a trait may change across time. For BP, the model includes unique familial factors that are specific to each time measurement, and an additional familial factor which is common to both time points. The factors leading to differences in longitudinal familial resemblance for BP (i.e., the unique factors) may be primarily genetic in origin, while those leading to stability across time may include both genetic and familial environmental effects. Sex and/or age interactions with the genotypes are also suggested.     

The blood pressure responses to an acute and long-term whole-body cryotherapy (−110°C) in men and women

The blood pressure responses to an acute and long-term (three months) whole-body cryotherapy (WBC) were measured in men and women. Acute cold exposure (−10°C, −60°C, −110°C) increased both systolic and diastolic blood pressures temporarily. Neither significant gender differences nor adaptation in blood pressures were found during WBC. The variation of individual responses to the acute and long-term WBC was wide.     

PGC-1α overexpression suppresses blood pressure elevation in DOCA-salt hypertensive mice

Increasing evidences have accumulated that endothelial dysfunction is involved in the pathogenesis of hypertension. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) has been identified as an essential factor that protects against endothelial dysfunction in vascular pathologies. However, the functional role of PGC-1α in hypertension is not well understood. Using an adenovirus infection model, we tested the hypothesis that PGC-1α overexpression retards the progression of hypertension in deoxycorticosterone acetate (DOCA)-salt mice model through preservation of the function of endothelium. We first demonstrated that PGC-1α expression not only in conductance and resistance arteries but also in endothelial cells was decreased after DOCA-salt treatment. In PGC-1α adenovirus-infected mice, the elevation of blood pressure in DOCA-salt mice was attenuated, as determined using tail-cuff measurement. Furthermore, PGC-1α overexpression inhibited the decrease in nitric oxide (NO) generation and the increase in superoxide anion (O₂⁻) production in DOCA-salt-treated mice, in parallel with improved endothelium-dependent relaxation. Rather than affecting endothelial NO synthase (eNOS) total expression and phosphorylation, PGC-1α significantly inhibited eNOS uncoupling, as evidenced by increased eNOS homodimerization, BH4 levels, GTP-cyclohydrolase 1 (GTPCH1) and dihydrofolate reductase (DHFR) expression and heat-shock protein (Hsp)90–eNOS interaction. Our findings demonstrate that PGC-1α overexpression preserves eNOS coupling, enhances NO generation, improves endothelium-dependent relaxation and thus lowers blood pressure, suggesting that up-regulation of PGC-1α may be a novel strategy to prevent and treat hypertension.     

Synergistical effect of 20-HETE and high salt on NKCC2 protein and blood pressure via ubiquitin–proteasome pathway

We previously generated a cytochrome P450 4F2 (CYP4F2) transgenic mouse model and demonstrated that overexpressed CYP4F2 and overproduced 20-HETE in the kidneys contribute to the increase of blood pressure in the CYP4F2 transgenic mice with normal salt intake. We currently expect to elucidate a potential mechanism of salt-related hypertension whereby diverse levels of 20-HETE interact with dietary salt on Na⁺-K⁺-2Cl^? cotransporter, isoform 2 (NKCC2) in the kidneys of the transgenic and wild-type mice with high salt intake. High salt intake reduced about 85 % abundance of renal NKCC2 protein in the transgenic mice and about 24 % in the wild-type mice by Western blot. Furthermore, we first found that NKCC2 was ubiquitinated and interacted with Nedd4-2 by immunoprecipitation in the transgenic mice with high salt intake. In addition, inhibition of 20-HETE synthesis or proteasome activity reversed the reduction of NKCC2 expression induced by 20-HETE and high salt intake. These results suggest that 20-HETE and high salt intake synergistically decrease the expression of NKCC2 protein via Nedd4-2-mediated ubiquitin–proteasome pathway, and thereby modulate natriuresis and blood pressure. We propose that diverse levels of 20-HETE have diverse effects on blood pressure in different salt concentrations.     

Low blood pressure,low mood?

OBJECTIVE--To determine whether a set of physical symptoms is associated with low blood pressure and to investigate the possible role of psychological factors in their occurrence. DESIGN--Analysis of data collected by questionnaire and physical screening from the first phase of the Whitehall II study, a cohort study of an employed population. SETTING--23 civil service departments in London. SUBJECTS--10,314 male and female London based civil servants aged between 35 and 55. MAIN OUTCOME MEASURES--Symptoms of dizziness-giddiness and unexplained tiredness; psychological functioning as measured by the 30 item general health questionnaire in which the response "no more than usual" to an item about disease was scored as indicating chronic illness. RESULTS--Dizziness-giddiness in men and unexplained tiredness in both men and women were significantly related to low systolic blood pressure. There was a highly significant inverse relation between general health questionnaire score and systolic blood pressure for both men and women, which persisted after controlling for potentially confounding variables, including age, body mass index, drug treatment, physical illness, and exercise. This association of low blood pressure with physical symptoms was no longer significant when general health questionnaire score was controlled for. CONCLUSIONS--There seems a strong relation between low systolic blood pressure and minor psychological dysfunction. Associated physical symptoms seem to be secondary to the primary disturbance in mental state.     

Does sodium restriction lower blood pressure?

Data from 13 randomised trials on the effect of sodium restriction on blood pressure were analysed. The hypotensive effect of sodium restriction was found to be small and restricted largely to systolic blood pressure, which fell by an average of 3.6 mm Hg (range 0.5-10.0 mm Hg). The reduction increased with age and in those with higher blood pressure. Sodium restriction therefore seems to be of limited use in those who are most eligible for non-pharmacological treatment of high blood pressure--namely, young patients with mild hypertension.     

Are there mappable genes for family resemblance for the magnitude of intra-individual variation in systolic blood pressure?

Background

The genetic regulation of variation in intra-individual fluctuations in systolic blood pressure over time is poorly understood. Analysis of the magnitude of the average fluctuation of a person's systolic blood pressure around his or her age-adjusted trend line, however, shows moderate, albeit significant, family resemblance in Cohort 1 of the Framingham Heart Study. To determine whether genomic regions affecting this phenotype could be identified, we pursued a "model-free" multipoint quantitative linkage analysis.

Results

Two different linkage methods revealed multiple nominally significant signals, two to four of which are "replicated" in Cohort 2. When both cohorts are assembled into extended pedigrees, three linkage signals remain nominally significant by one or both methods.

Conclusion

Any or all of the genomic regions in the vicinity of D5S1456, D11S2359, and D20S470 may contain elements that regulate systolic blood pressure homeostasis.