Age-related Hypertension Research Articles

Up‐regulation of Adrenal Leptin Receptor Expression and Tyrosine Hydroxylase Activation in Age‐related Hypertension

Blood pressure (BP) and sympathetic activation have been shown to increase with age. The aim of the present study was to examine whether increased adrenal OB‐Rb expression and tyrosine hydroxylase (TH) activation mediated age‐related hypertension.Method4‐6 mth (young) and 20‐24 mth (old) male F344/BN rats (n=4‐6 rats/age) were implanted with telemetry for 24‐hrs arterial pressure (MAP) monitoring and were housed in individual metabolic cages. Adrenal leptin receptors (OB‐Ra & OB‐Rb) and TH protein expressions were determined by Western Blot.ResultsOld rats exhibited a significant increase in MAP (107±1 vs 98±1mmHg), body weight (556±11 vs 332±5g) and serum leptin (24±5 vs 5.1±0.7ng/ml) compared with young rats (p<0.05). The increased MAP was positively correlated with serum leptin (r2=0.7, p<0.0001). Western Blot analysis revealed a higher OB‐Rb expression (54%) than OB‐Ra in young adrenal. Although OB‐Ra expression did not change with age, OB‐Rb protein expression was markedly up‐regulated by 211±13% in old compared with young rats. TH activation (as measured by phosphorylated TH/total TH) in adrenal was also elevated by 185±10% in old compared with young rats.ConclusionResults of the present study suggest that the increased BP with age may, at least in part, be mediated by the elevated circulating leptin levels, up‐regulated adrenal OB‐Rb protein expression and TH activation.

Possible Links of Age Related Hypertension and Evolution Imposed Features of Heart and Aorta

The left ventricle thickness is a limiting factor of optimal heart size and strength. Due to disappearance of all the features compromising left ventricular compliance, mammalian heart has decreased vascular density and coronary vessel diameter and it requires sufficient diastolic aortic pressure for the left ventricle perfusion. Atrial muscle and the right ventricle are perfused during the entire heart cycle. The systolic pressure in the left ventricle forces blood vessels in the muscle wall to collapse, particularly in the subendocardial muscle layer. This makes the most active part of the heart prone to hypoxia. Optimal perfusion of the left ventricle wall requires sufficient aortic pressure during diastole, making individuals with higher diastolic pressures advantageous, in situations requiring combination of increased heart rate and output. Described mechanisms might have contributed to the hereditary quality of age-related hypertension in humans.

Aging-associated insulin resistance predisposes to hypertension and its reversal by exercise: the role of vascular vasorelaxation to insulin

Aging is an independent risk factor for hypertension, and hypertension and insulin resistance commonly coexist in the elderly. This study was designed to examine the effects of aging-related insulin resistance on blood pressure (BP) and its underlying mechanisms, with specific focus on the role of exercise in reversing hypertensive response. Adult (6-month-old) and aging (24-month-old) male Sprague-Dawley rats were subjected to a 10 weeks free-of-loading swim training (60 min/day, 5 days/week). Arterial vasorelaxation, cardiac contraction, eNOS activation, and iNOS and gp91(phox) expression were determined. Under aging-related insulin resistance conditions, insulin infusion significantly elevated BP (P < 0.05). Aging caused significant endothelial dysfunction (P < 0.05 - 0.01), which was responsible for decreased arterial vasorelaxation to insulin. Aging attenuated myocardial contractile response to insulin, decreased eNOS expression and its phosphorylation by insulin, and increased iNOS and gp91(phox) expression in aging arteries (P < 0.01). Exercise improved insulin sensitivity, potentiated insulin's positive inotropic effects, facilitated arterial vasorelaxation to insulin, increased arterial eNOS activation in adult and aging rats, and thus attenuated insulin resistance-related hypertensive response to insulin. Moreover, exercise markedly reversed increased iNOS and gp91(phox) expression in aging arteries. Inhibition of eNOS with Cavtratin or L-NAME significantly blocked exercise-facilitated arterial vasorelaxation to insulin and exercise-lowered BP response to insulin. In conclusion, these results demonstrate that endothelial dysfunction in response to insulin, but not insulin's positive inotropic effects, plays an important role in the development of aging-related hypertension. The reversal of hypertensive response to insulin by exercise is most likely associated with improved insulin sensitivity in an eNOS-dependent manner and reduced oxidative and nitrative stresses.

Age-dependent Decrease in 11 -Hydroxysteroid Dehydrogenase Type 2 (11 -HSD2) Activity in Hypertensive Patients

The prevalence of arterial hypertension lacking a defined underlying cause increases with age. Age-related arterial hypertension is insufficiently understood, yet known characteristics suggest an aldosterone-independent activation of the mineralocorticoid receptor. Therefore, we hypothesized that 11beta-HSD2 activity is age-dependently impaired, resulting in a compromised intracellular inactivation of cortisol (F) with F-mediated mineralocorticoid hypertension. Steroid hormone metabolites in 24-h urine samples of 165 consecutive hypertensive patients were analyzed for F and cortisone (E), and their TH-metabolites tetrahydro-F (THF), 5alphaTHF, TH-deoxycortisol (THS), and THE by gas chromatography-mass spectroscopy. Apparent 11beta-HSD2 and 11beta-hydroxylase activity and excretion of F metabolites were assessed. In 72 female and 93 male patients aged 18-84 years, age correlated positively with the ratios of (THF + 5alphaTHF)/THE (P = 0.065) and F/E (P < 0.002) suggesting an age-dependent reduction in the apparent 11beta-HSD2 activity, which persisted (F/E; P = 0.020) after excluding impaired renal function. Excretion of F metabolites remained age-independent most likely as a consequence of an age-dependent diminished apparent 11beta-hydroxylase activity (P = 0.038). Reduced 11beta-HSD2 activity emerges as a previously unrecognized risk factor contributing to the rising prevalence of arterial hypertension in elderly. This opens new perspectives for targeted treatment of age-related hypertension.

Impairment of the Natriuretic Peptide System in Follitropin Receptor Knockout Mice and Reversal by Estradiol: Implications for Obesity-Associated Hypertension in Menopause

Estrogen is considered a major regulator of adipose tissue in females. Estrogen increases circulating levels of atrial natriuretic peptide (ANP), a hormone with renal and cardiovascular effects. The aim of this study was to determine the status of the natriuretic peptide system in female follitropin-receptor knockout (FORKO) mice that could be associated with obesity and hypertension observed in these mutants. Furthermore, estradiol treatment was used to reverse alterations observed. FORKO and wild-type (WT) mice received daily injections of estradiol for 4 d. On the fifth day, blood was collected for determination of plasma ANP levels, and selected tissues were collected for determination of ANP, natriuretic peptide receptor type-A (NPR-A) and type-C (NPR-C) gene expression by RT-PCR and binding of [(125)I]ANP by autoradiography. At 5 months of age, FORKO mice were heavier and had more adipose tissue than WT mice. FORKO mice had lower plasma ANP levels and atrial ANP gene expression and higher renal and adipocyte NPR-C gene expression than WT mice. Estradiol treatment reduced weight gain and increased atrial ANP synthesis as well as decreased ANP clearance NPR-C receptors, resulting in elevation of circulating ANP level. In conclusion, this study shows that FORKO females have an impaired natriuretic peptide system, which may contribute to the susceptibility of FORKO mice to developing age-related hypertension previously shown in these animals. This study establishes a relation between estrogen, adipose tissue, and ANP, which may have important implications in menopausal women.

Intravitreous bevacizumab and blood pressure: does ‘safe’ mean ‘safe enough’?

e read with great interest thecommunication of Kernt et al.(2007) describing their investigationinto the behaviour of intraocular pres-sure (IOP) and blood pressure (BP)following intravitreal bevacizumabinjection. Although we very muchappreciate the special care taken inthe safety assessment of this off-labeltreatment, we can not relate to the gen-eral statements because of the meth-odological limitations of the study.Measuring BP is not as easy as eyespecialists might suggest and judgingwhether or not BP is ‘sufficiently’ con-trolled is not a trivial decision. Thus,we want to raise some questions, moreto be sure of making the right treat-ment decisions in our own hyperten-sive patients than to aggrandize bysophisticated criticism.(1) The authors mention the highcomorbidity of age-related maculardegeneration and hypertension, bothof which show higher incidences, andeven exponentially increase, with age.We totally agree that control of BP isof the utmost relevance. The seventhreport of the Joint National Commit-tee (JNC 7) on Prevention, Detection,Evaluation and Treatment of HighBlood Pressure issued new guidelinesfor the definition and management ofhypertension (Chobanian et al. 2003).According to this report: ‘The relation-ship between BP and risk of cardio-vascular disease events is continuous,consistent, and independent of otherrisk factors. The higher the BP, thegreater the chance of myocardialinfarction, heart failure, stroke andkidney disease.’ Given this close anddirect relationship, we wonder whetherour colleagues made any concreterecommendations to their patients.How many individual patients showedBP values – whether affected or not bythe injection and the drug bevacizumab– which signalled a need to intensifyantihypertensive medication?From our point of view, it mightnot be wise to look for a significantchange in BP over the time)course ofthe study period only, and to leavesome patients with insufficiently con-trolled BP. Boxplots and medianspoint out that many patients may suf-fer from insufficient pharmacotherapy(the target level for uncomplicatedhypertension is 140⁄90 mmHg, and130⁄80 mmHg in cases of diabetes ornephropathy). Despite several obsta-cles in the real world, we would liketo encourage all ophthalmologists tothink in terms of risk-based manage-ment in hypertension and to makefurther efforts while trying to main-tain an interdisciplinary approach(Scheltens et al. 2007).(2) Blood pressure shows highinter- and intraindividual variabilityas well as diurnal oscillation (Ceyhanet al. 2003). Unfortunately, the paperdoes not contain any specification ofthe statistical tests applied to copewith this variance. Was the sample of45 patients sufficient in number toshow normal distribution (especiallygiven the outliers at the 6-hour meas-urement)? Was the intraindividualinformation evaluated by usingmatched-pair analysis? Were the injec-tions (and the measurements) per-formed at particular times of day?We understand that Kernt et al.(2007) did not want to overlook earlychanges in BP after the injection. How-ever, given the potential white-coateffect, would ambulatory monitoringnot be superior to single measurementstaken at 1, 3 and 6 hours? Clinicalsphygmomanometric measurement ofBP is known to show low short- andlongterm reproducibility (Fotherby &Potter 1993). Waiting for 6 hours orreturning several times to the outpa-tient clinic might aggravate the artifi-cial monitoring situation and thereforelimits further conclusions for otherpatients, who may be discharged fromthe clinic and go on to pursue otheractivities after the injection.(3) Because of the decline in dia-stolic BP, Kernt et al. (2007) hypothes-ize a relevant influence of conceivable‘surgery-related stress’ on preoperativeBP, which they refer to as ‘baseline’.The exact time interval between themeasurement ‘before’ and the injectionis not given in the text. Previous workshave shown that the stress-inducedincrease in sympathicotonus can vary alot between individuals. In a subgroupof patients, the assumed stable BP (nosignificant change in time)course)could therefore mean simply a persist-ently increased BP compared with thereal, stress-free situation before theinjection. If the first measurements, towhich all the statistics were related,were not reliable, the conclusion wouldappear to be quite adventurous. Byclaiming that emotional factors aredependent on the procedure, theauthors admit that their baseline doesnot constitute a consistent reference.Assessing the risk profile of anti-VEGF (vascular endothelial growthfactor) drugs may be very important.Already a slight increase in BP impliesa direct and relevant rise in cardiovas-cular events and mortality. We knowthat large, industry-driven safety stud-ies, previously performed and takeninto account during the approval pro-cess, were also restricted to incidentaland clinical measurements. However,the designs of such studies may havebeen influenced by the financial inter-ests of the manufacturer and weretherefore often not in accordance withclinical guidelines.From our point of view, increasedawareness will be necessary for atleast as long as clinical data indicate atendency towards a dose-dependentrisk of stroke after treatment with theclosely related drug, ranibizumab(Rosenfeld et al. 2006).

Influence of age and sex on high-fat diet-induced increase in blood pressure.

We are studying to elucidate the reason for increase in age-related hypertension and the mechanism thereof using rats. We would like to introduce model animals and the results obtained from these animal experiments. Based on a study regarding whether the elevation of blood pressure caused by dietary fat is due to excessive calorie intake and resulting body-weight gain or else fat itself--if so which type of fat is responsible for elevating blood pressure, it was suggested that elevated blood pressure was due to some effects specific to animal fat. According to a study if insulin resistance involves elevated blood pressure, it became apparent that the build-up of visceral fat caused by high-fat diet together with worsening of insulin sensitivity were responsible for elevating blood pressure. Next, we studied if there are sexual differences in dietary-fat induced hypertension and influence of male hormone. It became clear that the mechanism of elevated blood pressure caused by high-fat diet involved a condition of insulin resistance due to high-fat diet and furthermore, only when testosterone was present, the blood pressure was elevated. In addition, we studied aging effects on hypertension due to dietary fat. As a result, it became clear that the older the person gets, more likely he/she suffers from visceral obesity and conditions of insulin resistance, making blood pressure proneto rise. In summary, even without having excessively high calorie diet and without body weight gain, intake of excessive animal fat will cause visceral obesity and so do hypertension. Also, when taking high-fat diet, males tend to suffer from hypertension more often than females, suggesting testosterone is involved as the cause. Further, it was shown that the older the persons are, the greater the dietary effects result in, causing their blood pressures likely to increase.

Functional characterization of brain mitochondrial nitric oxide synthase during hypertension and aging

Nitric oxide (NO*) plays an important role in various physiological processes. The aim of the present study was to investigate if brain mitochondrial nitric oxide synthase (mtNOS) is active and functional during hypertension. L-citrulline production, an indicator of nitric oxide synthesis, was concentration-dependent on L-arginine in all strains and all ages tested, and was inhibited by 7-Nitroindazole (7-NI). Brain mitochondria of 1 month-old (prehypertensive) spontaneously hypertensive rats (SHR) exhibited a significantly (p < 0.05) low basal L-citrulline content as compared to age-matched Wistar (W) and Wistar-Kyoto (WKY) rats. L-citrulline synthesis in SHR rats showed a significant (p < 0.01) low response to L-arginine in 3 and 7 months-old rats. Respiratory rates in states 3 and 4 increased with low L-arginine concentration in all strains and all ages. The results suggest that in rat brain mitochondria, L-citrulline synthesis is constant once age-related hypertension is installed and NO* does not regulate oxidative phosphorylation.

Age-Related Reduction in Estrogen Receptor–Mediated Mechanisms of Vascular Relaxation in Female Spontaneously Hypertensive Rats

Hypertension increases with aging, and changes in vascular estrogen receptors (ERs) may play a role in age-related hypertension in women. We tested whether age-related increases in blood pressure in female spontaneously hypertensive rats (SHRs) are associated with reduction in amount and/or vascular relaxation effects of estrogen and ER. Arterial pressure and plasma estradiol were measured in adult (12 weeks) and aging (16 months) female SHRs, and thoracic aorta was isolated for measurement of active stress, 45Ca2+ influx, and ERs. Arterial pressure was greater and plasma estradiol was less in aging females than in adult females. In aorta of adult females, Western blots revealed alpha- and beta-ERs that were slightly reduced in aging rats. In endothelium-intact vascular strips, phenylephrine (Phe; 10(-5) mol/L) caused greater active stress in aging rats (9.3+/-0.2) than in adult rats (6.2+/-0.3x10(4) N/m2). 17beta-estradiol (E2) caused relaxation of Phe contraction and stimulation of vascular nitrite/nitrate production, which was reduced in aging rats. In endothelium-denuded strips, E2 still caused relaxation of Phe contraction, which was smaller in aging rats than adult rats. KCl (51 mmol/L), which stimulates Ca2+ influx, produced greater active stress in aging rats (9.1+/-0.3) than in adult rats (5.9+/-0.2x10(4) N/m2). E2 caused relaxation of KCl contraction and inhibition of Phe- and KCl-induced 45Ca2+ influx, which were reduced in aging rats. Thus, aging in female SHR is associated with reduction in ER-mediated NO production from endothelial cells and decrease in inhibitory effects of estrogen on Ca2+ entry mechanisms of smooth muscle contraction. The age-related decrease in ER-mediated vascular relaxation may explain the increased vascular contraction and arterial pressure associated with aging in females.

Priorities in perioperative geriatrics.

T he aging of the baby-boom population and the decreases in adult mortality seen in the last few decades will dramatically increase the age of Americans between 2010 and 2030. During that time, the population older than age 65 yr is expected to grow by 75%, whereas between 1995 and 2050, the cumulative growth of the population older than 85 yr is expected to exceed 400% (1). Furthermore, it has been reported that the increased demand for surgery in this population may exceed the rate of population growth (2). The implications of an aging population for the practice of anesthesiology are profound. Age-related changes in physiology and pharmacology can affect every aspect of perioperative care. The changes in surgical demographics will compel the anesthesiologist to become familiar with the physiology and clinical care of the aged. This review will serve as an introduction. First, some of the physiologic changes that occur with aging will be presented. Second, the preoperative assessment of the older surgical patient will be discussed. Third, some of the research related to intraoperative management of the geriatric surgical patient will be described. In the fourth section, we will discuss some geriatric-specific issues related to postoperative management.

Oral reduced B-nicotinamide adenine dinucleotide (NADH) affects blood pressure, lipid peroxidation, and lipid profile in hypertensive rats (SHR).

A gradual increase in blood pressure (BP), often attaining hypertensive levels, is common during aging--"age-related hypertension." Therefore, means to prevent or ameliorate this elevated BP safely are important. Although oral B-nicotinamide adenine dinucleotide (NADH), a natural coenzyme, is used principally to treat various neurologic disorders, we wished to investigate whether this agent had the same potential to lower BP and benefit the cardiovascular system as does coenzyme Q10, a similar-type agent. As a first approximation, spontaneously hypertensive rats (SHR) were used to determine effects of oral NADH. In a blinded, placebo-controlled study, ten rats received placebo; and ten, NADH for ten weeks. Systolic BP was measured by tail plethysmography. Blood was collected terminally, and chemistries were performed by routine methodologies. Thiobarbituric acid reactive species (TBARS) (an estimate of lipid peroxidation/free radical formation) was measured in renal and hepatic tissues. The following was noted: water and food intake were comparable, and the steady weight gain of young SHR were similar in the placebo and NADH groups. Although systolic BP did not differ between the two groups over the first month, it decreased and stayed markedly lower for the remainder of study in SHR receiving oral NADH. At the end of 60 days, SBP in NADH-treated SHR was 184 mm Hg +/- 2.8 (SEM) compared to 201 mm Hg +/- 2.1 (SEM) in control SHR (p < 0.001). No significant differences were seen in blood levels of glucose, insulin, triglyceride, and HDL levels but NADH intake lowered total cholesterol (p < 0.002) and LDL (p < 0.02). Renal TBARS were also significantly lower in SHR receiving NADH (P < 0.001). Accordingly, supplementation with the natural coenzyme NADH theoretically could prove to be useful in preventing age-related increases in BP and, thus, various cardiovascular maladies.

K11 At what point will limiting food intake no longer be effective in preventing age-related hypertension and kidney disease in the obese zucker rat?

K11 At what point will limiting food intake no longer be effective in preventing age-related hypertension and kidney disease in the obese zucker rat?

Ageing induces left ventricular concentric remodelling in normotensive subjects

To assess whether age affects left ventricular anatomy independently of age-related hypertension or concomitant heart diseases. In 430 consecutive normotensive and clinically healthy subjects aged 16-85 years we obtained echocardiographic measurements of left ventricular posterior wall thickness, internal diameter, relative wall thickness, Penn mass index and systemic haemodynamics. The pulse pressure : stroke volume ratio was calculated as an estimate of systemic arterial stiffness. The subjects were divided into three age groups: < or = 40 (group 1, n = 137), 41-64 (group 2, n = 261) and > or = 65 years (group 3, n = 32). Systolic blood pressure increased from group 1 to group 3, as did the pulse pressure : stroke volume ratio and posterior wall thickness, whereas the left ventricular internal diameter was less in group 3 than in groups 1 and 2. The relative wall thickness increased from group 1 to groups 2 and 3, whereas the left ventricular mass index did not differ among age groups. Age was related positively to the systolic blood pressure, pulse pressure : stroke volume ratio, posterior wall thickness index and relative wall thickness, and negatively to the left ventricular internal diameter but not to the left ventricular mass index. In healthy adults, relative wall thickness increases with age whereas left ventricular mass does not change. The concentric remodelling of left ventricular geometry parallels age-related stiffening of the arterial tree, elevation of systolic blood pressure and decrease in left ventricular volume. Thus partition values of relative wall thickness should be adjusted for age.

Sugar-induced hypertension in Fischer 344 and F1-hybrid rats (F344/BN) at different ages

Epidemiological evidence suggests that some nutrients, like sodium and potassium, participate in age-related hypertension. A role for refined carbohydrates (CHO), principally sugar, in blood pressure regulation is not generally recognized. This may be unfortunate, since modern lifestyle is associated with large amounts of dietary refined CHO. We examined the effect of a high sugar diet on systolic blood pressure (SBP) in Fischer 344 rats (F344) and the F1-hybrid of this strain (F344/BN). These genotypes have been used to develop experimental models for studies on different aspects of aging. Age-dependent hypertension has not been reported in either strain. In fact, insensitivity to salt-induced hypertension has been found in F344 rats. Upon arrival at our laboratory, the mean difference in SBP between the youngest (4 months) and oldest (18 months) F344 and F1-hybrid rats was 10 mm Hg, the highest mean SBP was 123 mm Hg. These values remained relatively constant over the next month when both strains consumed a low sugar diet. Differently, a steady increase in SBP occurred in both strains when rats of all ages were fed a diet high in sucrose content, mean SBP increasing to over 170 mm Hg at termination of study. Older rats proved more sensitive initially to sugar-induced SBP elevations. Associated with rising SBP was evidence of Na retention. We conclude that a diet containing excess sugar can create a gradual elevation of SBP into a hypertensive range with aging of F344 and F1-hybrid rats. This contrasts with previous findings.