bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypotensive Effect of Low-Fat, High-Carbohydrate Diet Can Be Independent of Changes in Plasma Insulin Concentrations
Authors: Straznicky Nora E. , O’Callaghan Christopher J. , Barrington Vicki E. , Louis William J.
Published: June 2012

Abstract
—To examine the relationship between diet, blood pressure, and plasma insulin concentrations, we studied 14 healthy males who were prescribed low-fat and high-fat diets. The low-fat diet contained 25% (of energy intake) fat and 54% carbohydrate; the high-fat diet was 45% fat (predominantly saturated fat) and 36% carbohydrate. The diets were consumed over consecutive 2-week periods in random sequence, separated by a 2-week washout period. Resting supine systolic and diastolic blood pressures decreased significantly by 7 and 3 mm Hg, respectively, and plasma total cholesterol, LDL cholesterol, and HDL cholesterol concentrations all fell (by 21.6%, 25.7%, and 18.0%, respectively; all
P
<0.001) on the low-fat compared with the high-fat diet. Fasting glucose and the glucose area under the curve during the frequently sampled intravenous glucose tolerance test (300 mg/kg glucose load with blood sampling for 180 minutes) were significantly lower, and the glucose disappearance rate tended to be faster after the low-fat diet. In contrast, fasting insulin concentrations and the insulin response (insulin area under the curve) to glucose challenge were unchanged. Insulin sensitivity (defined as the rate of glucose disappearance per unit of insulin increase during the period 0 to 40 minutes after the glucose load) was significantly higher on the low-fat diet. These results suggest that the hypotensive effects of a low-fat, high-carbohydrate diet, although associated with an improvement in insulin sensitivity, are not mediated by changes in plasma insulin concentration.
Congenic Substitution Mapping Excludes
Sa
as a Candidate Gene Locus for a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1
Authors: Hübner Norbert , Lee Young-Ae , Lindpaintner Klaus , Ganten Detlev , Kreutz Reinhold
Published: June 2012

Abstract
—Previously, linkage analysis in several experimental crosses between hypertensive rat strains and their contrasting reference strains have identified a major quantitative trait locus (QTL) for blood pressure on rat chromosome 1 (Chr 1) spanning the
Sa
gene locus. In this study, we report the further dissection of this Chr 1 blood pressure QTL with congenic substitution mapping. To address whether the
Sa
gene represents a candidate gene for the Chr 1 blood pressure QTL, congenic strains were developed by introgressing high blood pressure QTL alleles from the stroke-prone spontaneously hypertensive rat (SHRSP) into the normotensive Wistar-Kyoto (WKY-1) reference strain. Congenic animals carrying a chromosomal segment from stroke-prone spontaneously hypertensive rats between genetic markers
Mt1pa
and
D1Rat200
(including the
Sa
gene locus) show a significant increase in basal systolic and diastolic blood pressure compared with their normotensive Wistar-Kyoto progenitors (
P
<0.001, respectively), whereas congenic animals carrying a subfragment of this Chr 1 region defined by markers
Mt1pa
and
D1Rat57
(also spanning the
Sa
gene) do not show elevated basal blood pressure levels (
P
=0.83 and
P
=0.9, respectively). Similar results were obtained for NaCl-induced blood pressure values. Thus, the blood pressure QTL on Chr 1 is located centromeric to the
Sa
gene locus in a region that is syntenic to human chromosome 11p15.4-p15.3. This region excludes the
Sa
as a blood pressure–elevating candidate gene locus on the basis of congenic substitution mapping approaches.
Increased Availability of Nitric Oxide Leads to Enhanced Nitric Oxide Dependency of Tubuloglomerular Feedback in the Contralateral Kidney of Rats With 2-Kidney, 1-Clip Goldblatt Hypertension
Authors: Turkstra Erika , Boer Peter , Braam Branko , Koomans Hein A.
Published: June 2012

Abstract
—The contralateral kidney of 2-kidney, 1-clip hypertensive (2K1C) rats is unable to escape the renal vasoconstrictive and sodium-retaining effects of increased circulating angiotensin II levels. Evidence is accumulating that renal function is relatively preserved by enhanced influence of NO in the contralateral kidney. In this study, we investigated (1) whether the high NO dependency of renal hemodynamics in the contralateral kidney is due to increased availability of NO or increased sensitivity to NO and (2) whether elevated NO activity dampens the actions of angiotensin II to enhance tubuloglomerular feedback (TGF) responses in the nonclipped kidney of 2K1C rats. To estimate whether the available NO is increased, the NO clamp technique was applied in rats that underwent sham operation (n=6) and in the contralateral kidney of 2K1C Sprague-Dawley rats (3 weeks old; 0.25-mm silver clip; n=6). During systemic infusion of nitro-
l
-arginine (
l
-NNA; 50 μg/kg · min
−1
), sodium nitroprusside (SNP) was infused in the renal artery and the rate was adjusted so that renal vascular resistance (RVR) was restored to baseline levels. In sham rats, RVR increased during
l
-NNA treatment from 17.2±2.0 to 33.0±3.6 U (
P
<0.01) and was restored to baseline values during SNP infusion (17.1±2.3 U); 9.2±1.8 nmol/min of SNP was needed to restore RVR to baseline values. In 2K1C rats, RVR increased during
l
-NNA treatment from 16.7±1.1 to 53.4±3.5 U (
P
<0.01). This increase of RVR was significantly larger than in sham rats. RVR was restored to baseline values during SNP infusion (17.4±0.9 U); 26.0±4.3 nmol/min of SNP was needed to restore RVR to baseline values (
P
<0.05 versus sham). Furthermore, maximum TGF responses were assessed before and during late proximal tubular infusion of
l
-NNA in the kidneys of sham rats and the nonclipped kidneys of 2K1C rats. Control maximum TGF responses were 4.7±0.7 and 5.1±0.4 mm Hg in sham and 2K1C rats, respectively. During intraluminal
l
-NNA infusion, maximum TGF responses were 15.4±0.9 mm Hg in sham rats and 22.2±2.5 mm Hg in 2K1C rats (
P
<0.05 versus sham). Finally, urinary NO
2
+NO
3
excretion in the nonclipped kidney was significantly higher than in the clipped kidney (
P
<0.05). In conclusion, (1) as assessed using the NO clamp, ambient intrarenal NO levels are increased in the contralateral kidney of 2K1C rats and (2) the NO dependency of the TGF system is enhanced. These experiments indicate that adaptations in NO activity lead to relatively low TGF responsiveness, which will offset the simultaneous sodium-retaining actions of angiotensin II on proximal tubular reabsorption and TGF responsiveness.
Ambulatory Physical Activity as a Determinant of Diurnal Blood Pressure Variation
Authors: Kario Kazuomi , Schwartz Joseph E. , Pickering Thomas G.
Published: June 2012

Abstract
—There are reports that indicate that diurnal blood pressure (BP) variation, in addition to high BP per se, is related to target organ damage and the incidence of cardiovascular events. However, the determinants of diurnal BP variation are not adequately understood. We used actigraphy and ambulatory BP monitoring to study the diurnal variation of BP and physical activity in 160 adults. Within individuals, activity was more strongly related to pulse rate than to BP. The correlation between BP and activity was stronger during sleep than when awake, but the correlation between activity and pulse rate was higher during the awake period than during sleep. Between individuals, the sleep/awake ratio of systolic BP (SBP) was correlated with mean sleep activity (
r
=.17,
P
<0.05), mean awake activity (
r
=−0.16,
P
<0.05), and, especially, the ratio of sleep/awake activity (
r
=.24,
P
<0.01). Awake BP variability (SD of awake SBP) was positively correlated with awake activity (
r
=.16,
P
<0.05). In regard to the effect of position, the standing-supine SBP difference was negatively correlated with the sleep/awake SBP ratio (
r
=−0.39,
P
<0.01) and positively correlated with awake SBP variability (
r
=.33,
P
<0.01). When we divided the subjects into 3 groups, 19 extreme dippers (with a sleep SBP decrease of ≥20% of awake SBP), 102 dippers (with decreases of ≥10% to <20%), and 39 nondippers (with decreases of <10%), no significant differences existed in awake activity among the groups. However, the nondippers exhibited greater sleep activity than extreme dippers (
P
<0.05) and an increased sleep/awake activity ratio compared with extreme dippers and dippers (
P
<0.01). Extreme dipping may also be associated with increased BP variability (
P
=0.08). Individual SBP responses to activity (the within-person slope of awake SBP regressed on activity) did not differ significantly among the 3 subgroups. In conclusion, physical activity is one of the determinants of ambulatory BP and its diurnal variation. We hypothesize that the association of sleep activity to sleep BP and dipping reflects differences in sleep quality.
l-
Arginine Restores the Effect of Ouabain on Baroreceptor Activity and Prevents Hypertension
Authors: Abreu Glaucia R. , Futuro-Neto Henrique A. , Cabral Antonio M. , Vasquez Elisardo C.
Published: June 2012

Abstract
—In spontaneously hypertensive rats, ouabain exerts an excitatory effect on baroreceptor nerve activity (BNA). The aim of this study was to determine the effects of ouabain on BNA in other experimental models of hypertension and its interaction with nitric oxide. Rats were made hypertensive using the procedures for
N
ω
-nitro-
l-
arginine methyl ester (L-NAME), deoxycorticosterone acetate (DOCA) salt, and 2-kidney, 1 clip (2K1C) hypertension models. In these groups, systolic arterial pressure was 195±7, 149±6, and 148±4 mm Hg, respectively, compared with 110±4 mm Hg in normotensive rats. Acute ouabain administration had an excitatory effect on BNA in normotensive rats (37±4%), an inhibitory effect in L-NAME hypertensive rats (−60±7%), and no effect in DOCA-salt and 2K1C hypertensive rats. The effects of ouabain were not related to arterial pressure levels, and no excitatory effect on BNA was observed in prehypertensive DOCA-salt rats. Long-term administration of
l
-arginine (3 g · kg
−1
· day
−1
) prevented DOCA-salt (121±8 mm Hg) and 2K1C (104±4 mm Hg) hypertension, markedly attenuated L-NAME (130±9 mm Hg) hypertension, and restored the excitatory effect of ouabain on BNA in these groups to levels similar to the normotensive rats and their respective control groups. We conclude that ouabain has a diverse effect on BNA in experimental models of hypertension, and it can be normalized by
l-
arginine. The data also indicate that nitric oxide may play a pivotal role in mediating the excitatory effect of ouabain on BNA, and we speculate that a therapeutic combination of ouabain and
l-
arginine may be beneficial in secondary hypertension.
Nitric Oxide–Dependent Guanylyl Cyclase Participates in the Glutamatergic Neurotransmission Within the Rostral Ventrolateral Medulla of Awake Rats
Authors: Martins-Pinge Marli C. , Araújo Gessi C. , Lopes Oswaldo U.
Published: June 2012

Abstract
—A well-known action of nitric oxide (NO) is to stimulate the soluble form of guanylyl cyclase, evoking an accumulation of cyclic GMP in target cells. The aim of the present study was to examine the effects of inhibition of guanylyl cyclase dependent on NO during cardiovascular responses induced by
l
-glutamate and
S
-nitrosoglutathione (SNOG) microinjected into the rostral ventrolateral medulla (RVLM) of awake rats. Three days before the experiments, adult male Wistar rats (280 to 320 g) were anesthetized for implantation of guide cannulas to the desired stereotaxic position (AP=−2.5 mm, L=1.8 mm) in relation to lambda. The cannulas were fixed to the skull with acrylic cement. Twenty-four hours before the experiments, a femoral artery and vein were cannulated for recording arterial pressure (AP) and heart rate (HR) and injection of anesthetic. Unilateral microinjections (100 nL) of
l
-glutamate (5 nmol/L) and SNOG (2.5 nmol/L) were made into the histologically confirmed RVLM. The cardiovascular responses to these drugs were evaluated before and after microinjection (3 nmol/L, 200 nL) of either methylene blue or oxodiazoloquinoxaline (ODQ). The hypertensive effect of
l
-glutamate was attenuated by 74% after methylene blue (ΔAP=49±8 to 13±4 mm Hg) and by 80.5% after ODQ (ΔAP=30±2 to 6±2 mm Hg). The increase in AP produced by SNOG was fully blocked by ODQ (ΔAP=39±8 to 1±2 mm Hg). These data indicate that cyclic GMP mechanisms have a key role in glutamatergic neurotransmission in the RVLM of awake rats, and it is most probable that NO participates in this response.
Context-Dependent Associations of the ACE I/D Polymorphism With Blood Pressure
Authors: Turner Stephen T. , Boerwinkle Eric , Sing Charles F.
Published: June 2012

Abstract
—The objective of the present study was to assess whether the influences of gender, age, or measures of body size on blood pressure are homogeneous among genotypes of the insertion/deletion (I/D) polymorphism of the gene that codes for angiotensin-converting enzyme (ACE). We studied a sample of 1875 non-Hispanic white individuals (988 female and 887 male subjects) between 5 and 90 years of age from the general population of Rochester, Minn. When statistical interactions between effects associated with the I/D polymorphism and age, height, and weight were not considered, there was no evidence of a significant relationship between variation in blood pressure level or diagnostic category (hypertension versus normotension) and variation in ACE genotype in either gender. However, in females 5 to 29.9 years of age, the linear regression relationships of systolic blood pressure level with age and weight and of diastolic blood pressure level with age were significantly heterogeneous among ACE genotypes. For these concomitant traits, the rank order of expected blood pressure levels associated with each genotype reversed from low values of the concomitant, in which blood pressure was lower for I/D heterozygotes than for II or DD homozygous, to high levels of the concomitant, in which blood pressure was higher for I/D heterozygotes than for II or DD homozygotes. In male subjects 50 to 90 years of age, the logistic regression relationship of the probability of having hypertension with height was also heterogeneous among ACE genotypes; it was statistically significant in II homozygotes but not statistically significant in either I/D heterozygotes or DD homozygotes. Findings of this study are consistent with the conclusion that the influence of variation in the ACE gene on interindividual variation in blood pressure is dependent on contexts that are indexed by gender, age, and measures of body size.
In Vivo Renal Vascular and Tubular Function in Experimental Hypercholesterolemia
Authors: Feldstein Ariel , Krier James D. , Sarafov Mirit Hershman , Lerman Amir , Best Patricia J. M. , Wilson Stephanie H. , Lerman Lilach O.
Published: June 2012

Abstract
—Hypercholesterolemia (HC) is often associated with impaired peripheral and coronary vascular responses to endothelium-dependent vasodilators, which are probably due to low bioavailability of nitric oxide. To examine the effect of HC on renal vascular and tubular function, 22 domestic pigs were studied after being fed a 12-week normal (n=11) or HC (n=11) diet. Renal regional perfusion and intratubular contrast media concentration in each nephron segment (representing fluid reabsorption) were quantified in vivo with electron-beam computed tomography before and after a suprarenal infusion of either acetylcholine (6 pigs of each diet) or sodium nitroprusside (SNP; 5 pigs of each diet). An increase in cortical perfusion, observed in normal pigs with acetylcholine (+35±6%,
P
=0.002) and SNP (+12±4%,
P
=0.005), was blunted in the HC group (+8.8±4.0,
P
=0.01, and −4.6±4.0%,
P
=0.1, respectively,
P
=0.003 and
P
=0.005 compared with normal) as was an increase in medullary perfusion (+58±21 in normal versus +24±11% in HC,
P
=0.04). A decrease in the intratubular contrast media concentration in the distal tubule and collecting duct of normal pigs was observed in all tubular segments (and was significantly enhanced in the proximal tubule and Henle’s loop) in the HC group, which was associated with increased sodium excretion. The tubular and renal excretory responses to SNP were similar between the groups. In conclusion, early experimental HC in the pig attenuates renal perfusion response to both endothelium-dependent and -independent vasodilators possibly because of decreased bioavailability or decreased vascular responsiveness to nitric oxide. This vascular impairment may play a role in maladjusted renovascular responses and contribute to renal damage in later stages of atherosclerosis.
Enhanced Vascular Reactivity and Ca
2+
Entry With Low-Salt Diet
Authors: Khalil Raouf A. , Crews Janice K. , Carroll Joan F. , Hall John E.
Published: June 2012

Abstract
—Salt moderation is often recommended as a nonpharmacological therapy for hypertension, particularly in overweight individuals; however, the effects of low dietary salt on the Ca
2+
-dependent mechanisms of vasoconstriction are unclear. The purpose of this study was to investigate the effect of low salt diet on vascular reactivity and Ca
2+
mobilization mechanisms and the modulation of these effects with obesity. Active stress and
45
Ca
2+
influx were measured in deendothelialized aortic strips isolated from lean (3.74 kg) and obese (5.51 kg) female rabbits on a normal (0.75%) or low (0.23%) salt (sodium chloride) diet for 18 weeks. Both phenylephrine (Phe, 10
−5
mol/L) and membrane depolarization by 96 mmol/L KCl caused extracellular Ca
2+
–dependent increases in active stress and
45
Ca
2+
influx. In lean rabbits, the Phe- and KCl-induced stress and Ca
2+
influx were significantly greater with the low-salt versus the normal-salt diet. The Phe-induced Ca
2+
influx–stress relationship was significantly greater than that induced by KCl with low-salt diet. In obese rabbits on a normal-salt diet, the Phe- and KCl-induced stress and Ca
2+
influx were significantly less than that in lean rabbits but the Ca
2+
influx-stress relationship was not significantly altered. Feeding the obese rabbits a low-salt diet was associated not only with significant increases in Phe- and KCl-induced active stress and Ca
2+
influx but also with significant enhancement in the Ca
2+
influx-stress relationship. In Ca
2+
-free (2 mmol/L EGTA) Krebs solution, stimulation of intracellular Ca
2+
release by Phe or caffeine (25 mmol/L) caused a transient contraction that was not significantly different in all groups of rabbits. Thus, with normal salt intake, obesity is associated with a reduction in Ca
2+
entry and vascular reactivity. Low-salt diet is associated with an increase in Ca
2+
entry and vascular reactivity in both obese and lean rabbits. The enhancement of the Ca
2+
influx-stress relationship with low-salt diet, particularly in the obese rabbits, suggests activation of other contractile mechanisms in addition to Ca
2+
entry.
Development of Nitric Oxide and Prostaglandin Mediation of Shear Stress–Induced Arteriolar Dilation With Aging and Hypertension
Authors: Koller Akos , Huang An
Published: June 2012

Abstract
—We hypothesized that during hypertension, the impairment of mediation of shear stress–induced dilation by nitric oxide (NO) is due to the prevailing hemodynamic forces, and that mediation of this response by NO should still be present in young spontaneously hypertensive rats (SHR). Thus, responses to increases in perfusate flow eliciting increases in wall shear stress were investigated in pressurized (80 mm Hg), isolated arterioles (≈70 to 100 μm) of the left or right gracilis muscle obtained from the same WKY and SHR at 4 and 12 weeks of age. Flow-induced dilations were similar in WKY and SHR at 4 weeks (maximum, 26.5±1.8 and 24.2±2.0 μm, respectively). Also, the middle of the upward portion of the shear stress–diameter curves was similar in arterioles of the 2 strains. Inhibition of NO synthase with
N
ω
-nitro-
l
-arginine (L-NNA) or inhibition of synthesis of prostaglandins (PGs) with indomethacin elicited an ≈50% reduction in flow-dependent dilation, whereas their combined administration eliminated the responses in both groups. In arterioles of 12-week-old WKY, flow-induced dilation became significantly greater (maximum, 46.1±2.3 μm) than responses of arterioles of 4-week-old WKY and 12-week-old SHR (maximum, 18.3±5.9 μm), which shifted only the shear stress–diameter curve of the 12-week-old WKY significantly to the left. Also, at 12 weeks of age, flow-dependent dilation of arterioles from SHR is mediated solely by PGs. Thus, shear stress–induced arteriolar dilation is mediated by NO and PGs in 4-week-old WKY and SHR. With aging, the release of NO and PGs increases in normotensive rats, whereas the contribution of NO to the regulation of shear stress disappears in 12-week-old SHR, which suggests that this change is probably caused by the increase in intraluminal pressure as hypertension develops.
Elevated Skeletal Muscle Blood Flow in Noncomplicated Type 1 Diabetes Mellitus
Authors: Vervoort Gerald , Wetzels Jack F. , Lutterman Jos A. , van Doorn Laurus G. , Berden Jo H. , Smits Paul
Published: June 2012

Abstract
—Capillary hyperperfusion precedes and contributes to the occurrence of diabetic microangiopathy. Vascular tone is regulated by the balance of vasodilating and vasoconstricting factors, of which nitric oxide (NO; an endothelium dependent vasodilator) and norepinephrine (NE; a potent vasoconstrictor), respectively, are of primary importance. To investigate the role of these factors in hyperperfusion, we measured forearm blood flow (FBF) in 50 patients with noncomplicated type 1 diabetes (DP) and 50 healthy control subjects (CS) under baseline conditions and during intrabrachial infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA), an endothelium-dependent vasoconstrictor, and acetylcholine (ACh), an endothelium-dependent vasodilator. Furthermore, we determined arterial plasma NE concentration at baseline and then determined α-adrenergic receptor sensitivity by measuring FBF response to intra-arterially infused NE. We found that basal FBF was increased in DP (2.9±0.1 versus 2.0±0.1 mL · min
−1
· dL
−1
in CS;
P
<0.01). L-NMMA caused a similar vasoconstriction in both groups (28.5±1.7% in DP versus 31.2±2.2% in CS;
P
=NS). Maximum blood flow during infusion of ACh was not different (23.3±1.9 mL · min
−1
· dL
−1
in DP versus 20.1±1.6 in CS). Arterial plasma NE concentrations were significantly decreased in DP (0.57±0.03 versus 0.81±0.05 nmol/L in CS;
P
<0.01). The vasoconstrictive effect of NE was increased in DP (slope log dose-response curve, 31.3±1.5 versus 24.3±1.8 in CS;
P
<0.01). We conclude that basal FBF is increased in noncomplicated type 1 diabetes. We found no evidence of a disturbance of basal or stimulated NO production. Arterial plasma NE concentrations are decreased in noncomplicated type 1 diabetes. This may explain the vasodilatation at baseline and the increased vascular response to intra-arterially NE.
Blood Pressure Increase With Impaired Glucose Tolerance in Young Adult American Blacks
Authors: Falkner Bonita , Sherif Katherine , Sumner Anne E. , Kushner Harvey
Published: June 2012

Abstract
—Hypertension and non–insulin-dependent diabetes mellitus are more prevalent in blacks than whites. The convergence of these 2 disorders augments the expression and severity of cardiovascular disease. The purpose of this study was to determine whether alterations in glucose metabolism are related to an increase in blood pressure (BP). This study was conducted on 304 nondiabetic blacks (mean age=32 years). Measurements in all subjects included BP, anthropometric measures, oral glucose tolerance test, insulin clamp to measure insulin sensitivity, and plasma lipids. The sample was stratified according to plasma glucose on oral glucose tolerance test to normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and diabetes mellitus (DM). A 2-way ANOVA was performed to determine differences between the metabolic groups. With the use of American Diabetic Association criteria, 20.4% of the samples were classified as IGT and 5.9% were diabetic. A significant increase in BP existed from NGT to IGT to DM, which was stronger in women than men (systolic blood pressure in women: NGT=122, IGT=127, and DM=140 mm Hg,
P
<0.001) with a significant linear trend (
P
<0.001). With the use of body mass index as a covariate, the group difference in BP remained significant (
P
=0.006). Measures of insulin sensitivity demonstrated significant metabolic group differences (
P
<0.001) with a linear trend (
P
<0.001) of decreasing insulin sensitivity from NGT to DM. These results indicate that early alterations in glucose metabolism effects an upward shift in BP. The higher BP in IGT and DM may be due to vascular endothelial cell resistance to insulin action.
Role of Renal Nerves in the Stimulation of the Renin System by Reduced Renal Arterial Pressure
Authors: Wagner Charlotte , Hinder Markus , Krämer Bernhard K. , Kurtz Armin
Published: June 2012

Abstract
—The aim of this study was to determine the role of renal innervation in the prolonged stimulation of renin secretion and renin synthesis accompanying renal artery stenosis. Male Sprague-Dawley rats, in which the left kidney had been denervated or sham denervated 4 days earlier, received a left renal artery clip (ID 0.2 mm). Plasma renin activity and renin mRNA were assayed 1, 2, or 4 days after clipping. The stimulation of both plasma renin activity and renin mRNA was blunted markedly in the rats with the denervated clipped kidney. The typical suppression of renin mRNA in the intact right kidney, however, was not different between rats with sham-denervated or denervated left kidneys, nor was the increase of blood pressure in response to renal artery clipping different between the experimental groups. To test whether the suppression of renin mRNA in the contralateral kidney was related to the increase of blood pressure, another group of rats with denervated clipped left kidneys was treated additionally with the T-type calcium channel blocker mibefradil (15 mg · kg
−1
· d
−1
). Despite blood pressure normalization by mibefradil, plasma renin activities and renin mRNA levels in the clipped denervated kidneys and in the intact right kidneys remained unchanged. These findings suggest that renal nerves are responsible for marked background stimulation of both renin secretion and renin mRNA expression, which is normally masked by the inhibitory effect of renal perfusion pressure on the renin system. Renal nerve activity is therefore an important determinant of the gain of renin stimulation during reduced renal arterial pressure.
Impaired Renal Adaptation to Stress in the Elderly With Isolated Systolic Hypertension
Authors: Castellani Sergio , Ungar Andrea , Cantini Claudia , La Cava Giuseppe , Di Serio Claudia , Vallotti Barbara , Altobelli Anna , Masotti Giulio
Published: June 2012

Abstract
—The aim of this study was to evaluate the renal response in the elderly with isolated systolic hypertension (ISH) when an adrenergic activation, as induced by mental stress, is applied. Renal hemodynamics and kidney neurohumoral response to mental stress were studied in 8 elderly patients with ISH (aged 63 to 82 years) along with 8 elderly normotensive subjects. The study encompassed four 30-minute experimental periods (baseline, mental stress, and recovery I and II). In these patients, the mental stress–induced blood pressure rise was associated with a significant increase in both effective renal plasma flow (
131
I-labeled hippurate clearance) and glomerular filtration rate (
125
I-labeled iothalamate clearance) (+42% and +29%, respectively;
P
<0.01 for both), without variations in filtration fraction, while elderly normotensives reacted to adrenergic stimulation with renal vasoconstriction but with the glomerular filtration rate constant. Variations in renal vasoactive substances, which paralleled hemodynamics of the kidney, differed in the 2 groups. In normotensives, excretion (radioimmunoassay) of endothelin-1, prostaglandin E
2
, and cGMP increased during the stimulus (+50%, +54%, and +59%, respectively;
P
<0.05). In ISH patients the release of these autacoids did not vary in any of the experimental periods. In conclusion, in patients with ISH the renal adaptive capacity to sympathetic activation is impaired, and the data may suggest that the glomerulus passively suffers the blood pressure increase, probably because of the insufficiency of the neurohumoral response, particularly in regard to the increase of endothelin-1. This hemodynamic pattern may predispose ISH patients to a higher risk of renal injury.
AT
2
Receptor Stimulation Enhances Antihypertensive Effect of AT
1
Receptor Antagonist in Hypertensive Rats
Authors: Barber Melissa N. , Sampey Donella B. , Widdop Robert E.
Published: June 2012

Abstract
—In the present study, we investigated the role of the angiotensin type 2 (AT
2
) receptor in the regulation of blood pressure in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We tested the hypothesis that AT
2
receptor activation may contribute to the antihypertensive effects of angiotensin type 1 (AT
1
) receptor antagonists. Mean arterial pressure (MAP) and heart rate were measured over a 4-day protocol in various groups of rats that received the following drug combinations: the AT
1
receptor antagonist candesartan (0.01 or 0.1 mg/kg IV) alone, the AT
2
receptor agonist
CGP42112
(1 μg/kg per minute) alone, and candesartan plus
CGP42112
. In both SHR and WKY, 4-hour infusions of saline and
CGP42112
alone did not alter MAP. In WKY, both doses of candesartan alone caused small decreases in MAP, which were similar when combined with
CGP42112
. In SHR, candesartan (0.1 mg/kg) caused an immediate, marked decrease in MAP, which was unaffected when combined with
CGP42112
. By contrast, in separate SHR, a 10-fold lower dose of candesartan (0.01 mg/kg) caused a slower-onset depressor response, which was enhanced when combined with
CGP42112
. The involvement of AT
2
receptors was confirmed in another group of SHR, since this facilitation of the antihypertensive effect of candesartan by
CGP42112
was abolished by the coinfusion of the AT
2
receptor antagonist
PD123319
(50 μg/kg per minute) with the candesartan/CGP42112 combination. Collectively, these data suggest that in SHR, AT
2
receptor activation can facilitate the initial depressor response caused by an AT
1
receptor antagonist.
Impeded Alveolar-Capillary Gas Transfer With Saline Infusion in Heart Failure
Authors: Guazzi Marco , Agostoni Piergiuseppe , Bussotti Maurizio , Guazzi Maurizio D.
Published: June 2012

Abstract
—The microvascular pulmonary endothelium barrier is critical in preventing interstitial fluid overflow and deterioration in gas diffusion. The role of endothelium in transporting small solutes in pathological conditions, such as congestive heart failure (CHF), has not been studied. Monitoring of pulmonary gas transfer during saline infusion in CHF was used to probe this issue. Carbon monoxide diffusion (DL
CO
), its membrane diffusion (D
M
) and capillary blood volume (V
C
) subcomponents, and mean right atrial (
rap
) and mean pulmonary wedge (
wpp
) pressures after saline or 5%
d
-glucose solution infusions were compared with baseline in 26 moderate CHF patients. Saline was also tested in 13 healthy controls. In patients, 750 mL of saline lowered DL
CO
(−8%,
P
<0.01 versus baseline), D
M
(−10%,
P
<0.01 versus baseline), aldosterone (−29%,
P
<0.01 versus baseline), renin (−52%,
P
<0.01 versus baseline), and hematocrit (−6%,
P
<0.05 versus baseline) and increased V
C
(20%,
P
<0.01 versus baseline), without changing
rap
and
wpp
. Saline at 150 mL produced qualitatively similar results regarding DL
CO
(−5%,
P
<0.01 versus baseline), D
M
(−7%,
P
<0.01 versus baseline), V
C
(9%,
P
<0.01 versus baseline),
rap
,
wpp
, aldosterone (−9%,
P
<0.05 versus baseline), and renin (−14%,
P
<0.05 versus baseline). Glucose solution (750 mL), on the contrary, increased DL
CO
(5%,
P
<0.01 versus 750 mL of saline) and D
M
(11%,
P
<0.01 versus 750 mL of saline) and decreased V
C
(−9,
P
<0.01 versus 750 mL of saline); aldosterone (−40%), renin (−41%), hematocrit (−3%),
rap
, and
wpp
behaved as they did after saline infusion. In controls, responses to both saline amounts were similar to responses in CHF patients regarding aldosterone, renin, hematocrit,
rap
, and
wpp
, whereas DL
CO
, D
M
, and V
C
values tended to rise. Hindrance to gas transfer (reduced DL
CO
and D
M
) with salt infusion in CHF, despite an increase in V
C
and no variations in pulmonary hydrostatic forces, indicates an upregulation in sodium transport from blood to interstitium with interstitial edema. Redistribution of blood from the lungs, facilitating interstitial fluid reabsorption, or sodium uptake from the alveolar lumen by the sodium-glucose cotransport system might underlie the improved alveolar-capillary conductance with glucose.
Insulin and Diastolic Dysfunction in Lean and Obese Hypertensives
Authors: Grandi Anna M. , Zanzi Paolo , Fachinetti Anna , Gaudio Giovanni , Ceriani Luca , Bertolini Andrea , Guasti Luigina , Venco Achille
Published: June 2012

Abstract
—We investigated the influence of genetic predisposition to hypertension by studying the relation between insulin sensitivity and left ventricular (LV) mass and function in untreated lean and obese hypertensives. We selected 50 lean hypertensives with normotensive parents (negative family history of hypertension [F−]), 64 lean hypertensives with 1 or both parents hypertensive (positive family history of hypertension [F+]), 40 obese F− hypertensives, and 43 obese F+ hypertensives. The 4 groups were comparable regarding age, gender, 24-hour blood pressure profile, and known duration of hypertension. We measured glucose, insulin, and C-peptide during fasting and during an oral glucose tolerance test; LV morphology and function were assessed by digitized M-mode echocardiography. Glucose (fasting and test) levels were normal in all and similar among the 4 groups. Insulin and C-peptide (fasting and stimulated) levels were higher in obese hypertensives than in lean hypertensives; at similar body mass index, insulin and C-peptide levels were higher in F+ than in F− groups. Compared with lean hypertensives, obese hypertensives had greater LV mass index; LV systolic function was normal in all and similar among the groups. The indices of LV diastolic function were significantly lower in F+ than in F− groups. LV mass index did not correlate with metabolic parameters; the indices of LV diastolic function were inversely correlated with insulin area during test in only the 2 F+ groups. In conclusion, genetic predisposition to hypertension is associated with a reduced insulin sensitivity and affects the response of the myocardium to increased insulin levels, inducing a greater impairment of diastolic function. Insulin sensitivity and genetic predisposition to hypertension seem to have no influence on LV mass.
Thiol Protein Defect in Sodium-Lithium Countertransport in Subset of Essential Hypertension
Authors: Mead Paul , Wilkinson Robert , Thomas Trevor H.
Published: June 2012

Abstract
—There is probably a heterogeneous etiology for essential hypertension (EHT), and abnormal erythrocyte sodium-lithium countertransport (Na/Li CT) is common in a subgroup of patients with a strong family history of hypertension and cardiovascular disease (EHT-FH patients). The aim of this study was to test the hypothesis that altering a membrane thiol protein could mimic the abnormal Na/Li CT observed in the patients and that a more refined understanding of the mechanism of abnormal Na/Li CT would facilitate a clearer identification of a subgroup of patients with a homogeneous biochemical abnormality. Na/Li CT kinetics were determined in untreated erythrocytes and after thiol group alkylation with
N
-ethylmaleimide (NEM). Compared with normal control erythrocytes, untreated erythrocytes from EHT-FH patients had a low
K
m
of Na/Li CT, with a high ratio of maximum velocity to
K
m
. This kinetic pattern was reproduced in normal erythrocytes by treatment with NEM in sodium-free medium. The same treatment in EHT-FH erythrocytes caused a markedly abnormal effect with an increase in maximum velocity, indicating an increase in transporter turnover in contrast to the increase in sodium affinity seen in normal control erythrocytes. Frequency distributions of these kinetic changes showed a subgroup of ≈75% of EHT-FH patients with abnormal kinetic changes with NEM. Therefore, the key Na/Li CT thiol group that is very reactive to NEM and causes the abnormal Na/Li CT in a subgroup of hypertensive patients may be a useful intermediate phenotype for a disease group within the syndrome of EHT. The single flux assay of Na/Li CT at 140 mmol/L sodium poorly discriminates this group. Identification of the thiol protein involved may lead to a molecular explanation of the altered membrane function in this subgroup of patients.
Effect of the HMG-CoA Reductase Inhibitors on Blood Pressure in Patients With Essential Hypertension and Primary Hypercholesterolemia
Authors: Glorioso Nicola , Troffa Chiara , Filigheddu Fabiana , Dettori Francesco , Soro Aldo , Parpaglia Paolo Pinna , Collatina Stefano , Pahor Marco
Published: June 2012

Abstract
—Certain hydroxymethylglutaryl coenzyme A reductase inhibitors, ie, statins, may cause vasodilation by restoring the endothelial dysfunction that frequently accompanies hypertension and hypercholesterolemia. Several studies have found that a blood pressure reduction is associated with the use of statins, but conclusive evidence from controlled trials is lacking. After an 8-week placebo and diet run-in period, 30 persons with moderate hypercholesterolemia and untreated hypertension (total cholesterol 6.29±0.52 mmol/L, systolic and diastolic blood pressure 149±6 and 97±2 mm Hg) were randomized in a double-blind manner to placebo or pravastatin (20 to 40 mg/d) in a crossover design. In 25 participants who completed the 32-week trial, pravastatin decreased total and LDL cholesterol (both −1.09 mmol/L,
P
=0.001), systolic and diastolic blood pressure (−8 and −5 mm Hg, both
P
=0.001), and pulse pressure (−3 mm Hg,
P
=0.011) and blunted the blood pressure increase caused by the cold pressor test (−4 mm Hg,
P
=0.005) compared with placebo. It also reduced the level of circulating endothelin-1 (
P
=0.001). The blood pressure results were virtually unchanged in stratified analyses according to gender and age and in intention-to-treat analyses that included the 5 patients who dropped out of the study. When the participants were taking either placebo or pravastatin, blood pressure was not significantly correlated with total or LDL cholesterol or with circulating endothelin-1. Pravastatin decreases systolic, diastolic, and pulse pressures in persons with moderate hypercholesterolemia and hypertension. This antihypertensive effect may contribute to the documented health benefits of certain statins.
Step-Down of Enalapril Treatment for Arterial Hypertension
Authors: González-Juanatey José Ramón , Reino Antonio Pose , García-Acuña José María , González-Juanatey Carlos , Valdes Luis , Cabezas-Cerrato José
Published: June 2012

Abstract
—Enalapril treatment (20 mg every 12 hours) of 24 patients with essential hypertension and left ventricular (LV) hypertrophy established normal blood pressures after 8 weeks, and after 5 years, it had reduced LV mass index by 39% (from 148±34 to 90±16 g/m
2
) and had normalized LV structure and function and QT dispersion. Stepwise reduction of the enalapril dosage from 40 to 30, 20, 10, and 5 mg/d during the eighth year caused no significant change in blood pressure, LV structure, LV systolic function, or QT dispersion, which all likewise remained unaltered during an additional 2-year period of the 5-mg/d regimen. We conclude that for hypertensive patients in whom prolonged treatment with high doses of enalapril has normalized blood pressure, LV structure, LV function, and QT dispersion, the dose may be reduced as much as 8-fold without detriment to cardiovascular control. The use of smaller doses is evidently advantageous from the point of view of health costs.
AT
1
Receptors Mediate Excitatory Inputs to Rostral Ventrolateral Medulla Pressor Neurons From Hypothalamus
Authors: Tagawa Tatsuya , Dampney Roger A. L.
Published: June 2012

Abstract
—Angiotensin II type 1 (AT
1
) receptors are located on pressor neurons in the rostral ventrolateral medulla, and their activation results in an increase in arterial pressure. However, the normal role of these AT
1
receptors in cardiovascular regulation is unknown. In this study, we tested the hypothesis that these receptors mediate synaptic excitation of rostral ventrolateral medullary pressor neurons in response to activation of the hypothalamic paraventricular nucleus. In anesthetized rats, microinjections of the γ-aminobutyric acid receptor antagonist bicuculline were made into the paraventricular nucleus; this injection causes activation of the nucleus as a consequence of disinhibition. The pressor and sympathoexcitatory responses evoked by paraventricular nucleus activation were significantly reduced (by ≈40% to 50%) after microinjection of the specific AT
1
receptor antagonists losartan or L-158,809 into the rostral ventrolateral medulla on the ipsilateral, but not contralateral, side. These responses were reduced to a similar degree after microinjections of the neuroinhibitory compound muscimol into the ipsilateral, but not contralateral, rostral ventrolateral medulla. However, bilateral microinjections of the glutamate receptor antagonist kynurenic acid into the rostral ventrolateral medulla had no effect on the responses evoked from the paraventricular nucleus. Conversely, bilateral microinjections of kynurenic acid into the rostral ventrolateral medulla virtually abolished the somatosympathoexcitatory reflex, whereas bilateral microinjections of losartan or L-158,809 had no effect on this reflex. The results indicate that excitatory synaptic inputs to pressor neurons in the rostral ventrolateral medulla arising from activation of the paraventricular nucleus are mediated predominantly by AT
1
receptors.
Tyrosine Phosphorylation of Human Platelet Plasma Membrane Ca
2+
-ATPase in Hypertension
Authors: Blankenship K. A. , Dawson C. B. , Aronoff G. R. , Dean W. L.
Published: June 2012

Abstract
—Intracellular Ca
2+
is increased in the platelets of hypertensive individuals. Previously, we demonstrated that platelet plasma membrane Ca
2+
-ATPase (PMCA) activity inversely correlates with diastolic blood pressure and that inhibition of this Ca
2+
pump could explain the elevation of cytosolic Ca
2+
in hypertension. More recently, we discovered that PMCA is phosphorylated on tyrosine residues during thrombin-stimulated platelet aggregation and that this phosphorylation causes inhibition of PMCA activity. In the present work, we tested the hypothesis that tyrosine phosphorylation of PMCA in hypertensive patients could account for the observed inhibition of the Ca
2+
pump. Platelets were obtained from untreated hypertensive and normotensive volunteers. PMCA was immunoprecipitated from solubilized platelets, and tyrosine phosphorylation was quantified by chemiluminescence of immunoblots treated with anti-phosphotyrosine. PMCA content was measured on the same immunoblots by stripping and reprobing with anti-PMCA. Phosphorylation was reported as normalized phosphotyrosine chemiluminescence per nanogram PMCA (mean±SE). The average PMCA tyrosine phosphorylation for 15 normotensive subjects was 0.53±0.09, whereas the average for 8 hypertensive individuals was 1.82±0.25 (
P
<0.0005, Mann-Whitney
U
test). Age, gender, and systolic blood pressure did not correlate with PMCA phosphorylation. These results suggest that PMCA in platelets of hypertensive individuals is inhibited because of tyrosine phosphorylation, resulting in increased platelet intracellular Ca
2+
, hyperactive platelets, and increased risk of heart attack and stroke.
Reproducibility of the Hyperbaric Index as a Measure of Blood Pressure Excess
Authors: Hermida Ramón C. , Fernández José R. , Mojón Artemio , Ayala Diana E.
Published: June 2012

Abstract
—The approach of establishing a time-specified tolerance limit reflecting the circadian variability in blood pressure and then determining the hyperbaric index, the area of blood pressure excess above the upper limit of the tolerance interval, has been proposed for diagnosing hypertension as well as for evaluating the patient’s response to treatment. The retrospective evaluation of this test provided high sensitivity and specificity in the diagnosis of hypertension, with a threshold value for the hyperbaric index of 15 mm Hg · h. To evaluate the stability and reproducibility of this tolerance-hyperbaric test, we studied 332 previously untreated subjects (218 men) who underwent sequential 48-hour ambulatory blood pressure monitoring for 2 years, providing a total of 1337 blood pressure profiles. Diagnosis of hypertension was established for each subject on the restricted basis of presenting at least 1 blood pressure profile with a hyperbaric index above the previously defined threshold. Sensitivity of this tolerance-hyperbaric test was 98.6%, with a negative predictive value of 99.7%. For the same subjects, the blood pressure load (percentage of values >140/110/90 mm Hg for systolic/mean arterial/diastolic blood pressure during activity or >120/95/80 mm Hg during resting hours) had a sensitivity of 49% and specificity of 25%. The 24-hour mean, still the most common approach for diagnosing hypertension on the basis of ambulatory monitoring, had sensitivities of 40% and 31% for systolic and diastolic blood pressure, respectively. Despite the limitations of ambulatory blood pressure monitoring, the tolerance-hyperbaric test represents a reproducible, noninvasive, and high-sensitivity test for the identification of subjects in need of prophylactic or therapeutic intervention.
Effect of Obesity on Electrocardiographic Left Ventricular Hypertrophy in Hypertensive Patients
Authors: Okin Peter M. , Jern Sverker , Devereux Richard B. , Kjeldsen Sverre E. , Dahlöf Björn , Group for the LIFE Study
Published: June 2012

Abstract
—Obesity may limit sensitivity of ECG voltage criteria for left ventricular hypertrophy (LVH) because of the attenuating effects of increased body mass on precordial voltages. However, obesity is associated with an increased prevalence of anatomic LVH, making more accurate ECG criteria in obese patients a clinical priority. ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage criteria was used to select patients for the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study. Clinical and ECG data were available in 8417 patients (54% women; mean age, 67±7 years); 2519 were overweight and 1573 were obese by gender-specific body mass index criteria. Increased body mass index had significant but directionally opposite effects on ECG LVH by these 2 criteria. Compared with normal-weight patients, obese and overweight patients had lower Sokolow-Lyon voltage and a lower prevalence of ECG LVH by Sokolow-Lyon criteria (10.9% versus 16.2% versus 31.4%;
P
<0.001). In contrast, obese and overweight patients had higher mean values of the Cornell product and higher prevalences of ECG LVH by this criterion (75.1% versus 69.9% versus 60.7%;
P
<0.001). After adjustment for age, gender, race, myocardial infarction, and diastolic and pulse pressure with the use of logistic regression analysis, increased body mass remained highly predictive of the presence of ECG LVH. Compared with normal-weight patients, obese patients had a >2-fold higher risk of ECG LVH by the Cornell product but a 4-fold lower risk of ECG LVH by Sokolow-Lyon voltage; overweight status was associated with intermediate risks, with a 151% greater likelihood of ECG LVH by the Cornell product but only 44% of the risk of LVH by Sokolow-Lyon voltage criteria compared with normal-weight individuals. Thus, Sokolow-Lyon voltage criteria underestimate the prevalence of anatomic LVH in the presence of obesity, whereas Cornell product criteria for ECG LVH appear to provide a more accurate measure of LVH in obese and overweight patients.