bluuebunny/crossref_metadata_2025 huggingface dataset:
The Renal Medulla and Hypertension
Authors: Cowley Allen W. , Mattson David L. , Lu Shanhong , Roman Richard J.
Published: June 2012

Abstract
We review evidence supporting the conclusion that renal dysfunction underlies the development of all forms of hypertension in humans and experimental animals. Indexes of global renal function are generally normal in the early stages of most genetic forms of hypertension, but renal function is clearly impaired in long-established hypertension. Studies in our laboratory over the past decade summarized below have established that the renal medulla plays an important role in sodium and water homeostasis and in the long-term control of arterial pressure. Development of implanted optical fibers for measurement of cortical and medullary blood flows with laser-Doppler flowmetry and techniques for delivery of vasoactive compounds into the medullary interstitial space enabled us to examine determinants of medullary flow (nitric oxide, atrial natriuretic peptides, kinins, eicosanoids, vasopressin, renal sympathetic nerves, etc). We have shown in spontaneously hypertensive rats that the initial changes of renal function begin as a reduction of medullary blood flow in the absence of changes of cortical flow. Long-term medullary interstitial infusion of captopril, which preferentially increased medullary blood flow, resulted in a lowering of arterial pressure. In normal Sprague-Dawley rats, selective reduction of medullary flow with medullary interstitial or intravenous infusion of small amounts of
N
G
-nitro-
l
-arginine methyl ester resulted in hypertension. These and other studies we review show that although blood flow to the inner renal medulla comprises less than 1% of the total renal blood flow, changes in flow to this region can have a major effect on sodium and water homeostasis and on the long-term control of arterial blood pressure.
Comparison of Effects of Angiotensin I– Converting Enzyme Inhibition and β-Blockade for 2 Years on Function of Small Arteries From Hypertensive Patients
Authors: Schiffrin Ernesto L. , Deng Li-Yuan
Published: June 2012

Abstract
The effect of treatment with two different antihypertensive agents on the function of small arteries from 17 patients with essential hypertension randomly assigned to receive either the angiotensin I–converting enzyme inhibitor cilazapril or the β-blocker atenolol was investigated. Subcutaneous small arteries obtained from gluteal fat biopsies were studied on a wire myograph before treatment and at 1 and 2 years of treatment. Blood pressure was mildly elevated in both groups of patients (mean, 150/100 mm Hg) and was well controlled throughout the 2 years of treatment (mean, 130/85 mm Hg). We previously reported, in arteries from patients treated with cilazapril, an improvement at 1 year of treatment of the vasoconstrictor effect of endothelin-1, which had been significantly attenuated in the untreated hypertensive patients compared with normotensive subjects. After 2 years of treatment, this normalization of endothelin-1 response was still present in small arteries of patients treated with the angiotensin I–converting enzyme inhibitor, whereas in patients treated with atenolol, responses were still unchanged after 2 years of treatment. Endothelial function was tested by examining the response of norepinephrine-precontracted arteries to acetylcholine. Untreated hypertensive patients exhibited a slightly but significantly blunted vasorelaxation in response to 10 μmol/L acetylcholine compared with normotensive subjects. After 1 and 2 years of effective antihypertensive treatment, cilazapril-treated patients exhibited responses to acetylcholine that were not different from those of normotensive subjects, whereas atenolol-treated patients still had impaired responses. Thus, together with the correction of the structure of small arteries that we previously reported occurs after 1 or 2 years of treatment with cilazapril, there is persistent normalization of endothelin-1–mediated vasoconstriction and slight improvement of endothelium-dependent vasorelaxation. This suggests that impaired smooth muscle and endothelial function in small arteries of patients with essential hypertension may be corrected by treatment with angiotensin I–converting enzyme inhibitors but not with β-blockers.
Endothelin Receptor Subtypes in Small Arteries
Authors: Takase Hiroyuki , Moreau Pierre , Lüscher Thomas F.
Published: June 2012

Abstract
We studied the effects of the selective endothelin A receptor antagonist FR139317 and the combined endothelin A/endothelin B receptor antagonist bosentan in rat mesenteric arteries by using a video dimension analyzer. In endothelium-denuded arteries, increasing concentrations of endothelin-1 evoked a biphasic vasoconstriction. The first phase was observed at low concentrations (10
−16
to 10
−11
mol/L) of endothelin-1 and was relatively weak. However, the contractions characterizing the second phase, which occurred at higher concentrations (10
−10
to 3×10
−8
mol/L) of endothelin-1, were much stronger. FR139317 concentration-dependently shifted the second phase of the endothelin-1–induced contraction curve to the right without affecting the first phase. In contrast, bosentan inhibited both the first and the second phase. Even after the blockade of endothelin A receptor, increasing concentrations of the endothelin B receptor agonists endothelin-3 and sarafotoxin S6c still induced small contractions. Maximal contractions induced by single-bolus extraluminal application of endothelin-3 (10
−9
mol/L) or sarafotoxin S6c (3×10
−8
mol/L) were markedly more pronounced than responses induced by cumulative concentrations, suggesting endothelin B receptor downregulation upon repeated and sustained activation. The response induced by a single bolus of endothelin-3 (10
−9
mol/L) was antagonized by bosentan but not by FR139317, confirming that endothelin B receptors were involved. In endothelium-intact arteries half-maximally precontracted with norepinephrine, bosentan but not FR139317 inhibited the relaxations induced by intraluminally applied endothelin-3. Thus, selective endothelin A receptor antagonist preserves relaxations to endothelins, and combined endothelin A/endothelin B receptor antagonist is more efficacious in inhibiting contractions in resistance arteries.
Renal Sympathetic Nerve Activity Is Increased in Obese Zucker Rats
Authors: Morgan Donald A. , Anderson Erling A. , Mark Allyn L.
Published: June 2012

Abstract
A low level of sympathetic nerve activity (SNA) to brown adipose tissue has been found in genetically obese Zucker rats and may promote obesity through decreased thermogenesis. In contrast, acquired obesity is reportedly associated with increased SNA. To determine whether low SNA levels in obese Zucker rats extend to the kidney, we compared baseline levels of renal SNA in obese and lean conscious unrestrained Zucker rats fed for 2 weeks on low salt (0.4% NaCl) and high salt (8.0% NaCl) diets. Baseline renal SNA was calculated from multifiber recordings obtained before death under conscious, resting conditions and after death. Body weight averaged 490±12 g (mean±SEM) in obese rats (n=17) and 339±7 g in lean rats (n=19). Mean arterial pressure did not differ in obese and lean Zucker rats fed the low salt diet. However, on the high salt diet, mean arterial pressure was significantly higher in obese rats (n=8) than in lean rats (n=9) (113±3 and 101±3 mm Hg, respectively;
P
<.05). Baseline renal SNA was approximately 2 to 2.5 times higher (
P
<.05) in obese rats than in lean rats in all groups. These studies suggest that obese Zucker rats have heightened levels of SNA to the kidney in contrast to reduced SNA to brown adipose tissue.
Effects of
l
-Arginine Infusion on Renal Hemodynamics in Patients With Mild Essential Hypertension
Authors: Higashi Yukihito , Oshima Tetsuya , Ozono Ryoji , Watanabe Mitsuaki , Matsuura Hideo , Kajiyama Goro
Published: June 2012

Abstract
Previous studies have shown that endothelium-derived relaxing factor/nitric oxide plays an important role in the regulation of systemic and renal hemodynamics. The purpose of the present study was to determine whether endothelium-dependent renovascular relaxation was impaired in patients with mild essential hypertension who had normal renal plasma flow and glomerular filtration rate. We evaluated the effects of intravenous administration of
l
-arginine on blood pressure and renal hemodynamics in 13 patients with mild essential hypertension and 15 normotensive control subjects.
l
-Arginine infusion (500 mg/kg over 30 minutes) reduced mean blood pressure (from 82.5±2.5 to 76.3±2.6 mm Hg in hypertensive patients and from 106.1±3.0 to 97.5±2.9 mm Hg in control subjects;
P
<.001) and renovascular resistance (from 0.084±0.009 to 0.067±0.009 mm Hg · mL
−1
· min
−1
· [1.48 m
2
]
−1
and from 0.105±0.010 to 0.093±0.011 mm Hg · mL
−1
· min
−1
· [1.48 m
2
]
−1
, respectively;
P
<.001).
l
-Arginine infusion increased renal plasma flow (from 602±36 to 698±40 mL · min
−1
· [1.48 m
2
]
−1
,
P
<.05) in normotensive subjects but not in hypertensive subjects, and glomerular filtration rate was unaffected in both groups. Although the
l
-arginine–induced reduction in mean blood pressure was similar in both groups, the decline in renovascular resistance was smaller in hypertensive subjects. The response of renal plasma flow was also smaller in hypertensive subjects. These findings suggest that dysfunction of the
l
-arginine–nitric oxide pathway exists in the renal circulation even in mild essential hypertension with normal renal plasma flow and glomerular filtration rate. Thus, changes in renal endothelial function could be a cause rather than a consequence of hypertension.
Role of Bradykinin in Insulin Sensitivity and Blood Pressure Regulation During Hyperinsulinemia
Authors: Kohlman Osvaldo , de Assis Rocha Neves Francisco , Ginoza Milton , Tavares Agostinho , Cezaretti Mario Luiz , Zanella Maria Tereza , Ribeiro Artur Beltrame , Gavras Irene , Gavras Haralambos
Published: June 2012

Abstract
The purpose of these experiments was to determine in normotensive rats the role of endogenous bradykinin, prostaglandins, and nitric oxide in glucose metabolism and blood pressure response to hyperinsulinemia. Normotensive Wistar rats were treated with two different bradykinin antagonists, indomethacin or
N
ω
-nitro-
l
-arginine methyl ester, concurrently with a euglycemic clamp with insulin infusion rates of 3 or 6 mU/kg per minute. Glucose uptake, steady-state plasma insulin levels, and insulin sensitivity index were determined over 2 hours. Bradykinin inhibition dramatically reduced glucose uptake and insulin sensitivity index during both the lower and higher insulin infusion rates to 30% and 32%, respectively, of values observed in control rats. Inhibition of prostaglandins or nitric oxide did not alter glucose metabolism in these rats. Blood pressure remained unchanged in the control group throughout the clamp but increased significantly in rats submitted to inhibition of bradykinin, prostaglandins, or nitric oxide, suggesting that these vasodilator systems tend to counteract the hypertensive effect of hyperinsulinemia. The counterregulatory component attributable to bradykinin was about twice as great as that attributable to nitric oxide. These findings suggest that insulin infusion in normotensive Wistar rats fails to raise blood pressure because its effects are offset by mobilization of vasodilator mechanisms, such as bradykinin, prostaglandins, and nitric oxide. Bradykinin seems to play the most important homeostatic role under these conditions, because its inhibition significantly reduces insulin sensitivity and allows blood pressure to rise.
Renal Interstitial Fluid Angiotensin
Authors: Siragy Helmy M. , Howell Nancy L. , Ragsdale N. Virginia , Carey Robert M.
Published: June 2012

Abstract
Using a microdialysis technique, we monitored changes in right and left renal interstitial fluid angiotensins in anesthetized and conscious dogs (both n=5) in response to right renal interstitial epinephrine (0.2 mg/kg per minute) administration. Renal interstitial and plasma angiotensin levels also were monitored in conscious dogs (n=4) in response to dietary sodium deprivation (10 mmol/d) for 5 consecutive days. Changes in renal interstitial and plasma angiotensins in response to interstitial administration of a specific renin inhibitor, ACRIP (0.5 μg/kg per minute for 20 minutes), were monitored on day 5 of sodium depletion. At basal levels, there were no significant differences between the right and left renal interstitial immunoreactive angiotensin levels in anesthetized dogs. Renal interstitial epinephrine administration caused a significant increase in renal interstitial immunoreactive angiotensin concentrations in both anesthetized and conscious dogs (
P
<.01). However, anesthetized dogs had significantly higher renal interstitial immunoreactive angiotensin levels basally and in response to epinephrine than conscious dogs (
P
<.05). Renal interstitial immunoreactive angiotensin concentrations increased significantly and progressively during exposure to a low sodium diet from 3.9±1 nmol on day 1 to 740±332 nmol on day 5 (
P
<.01). Renal interstitial immunoreactive angiotensin decreased significantly to 124±37 nmol (
P
<.01) in response to intrarenal renin inhibition at the end of day 5 of sodium depletion. Plasma immunoreactive angiotensin increased significantly (
P
<.01) in response to sodium depletion, and no change occurred during intrarenal renin inhibition. We conclude that anesthesia, epinephrine, sodium depletion, and renin inhibition modulate renal interstitial angiotensin, which may serve as an important physiological regulator.
Spontaneous Cardiac Baroreflex in Humans
Authors: Parlow Joel , Viale Jean-Paul , Annat Guy , Hughson Richard , Quintin Luc
Published: June 2012

Abstract
We compared two methods of assessment of baroreflex sensitivity in eight supine healthy volunteers during repeated baseline measurements and various conditions of cardiac autonomic blockade. The spontaneous baroreflex method involved computer scanning of recordings of continuous finger arterial pressure and electrocardiogram to locate sequences of three or more beats in which pressure spontaneously increased or decreased, with parallel changes in pulse intervals. The mean regression slope of all these sequences during each study condition was considered to represent the mean spontaneous baroreflex slope. In the drug-induced method, sigmoidal curves were constructed from data obtained by bolus injections of phenylephrine and nitroprusside; the tangents taken at the resting pressure of each of these curves were compared with the mean spontaneous baroreflex slopes. The two methods yielded slopes that were highly correlated (
r
=.96,
P
<.001), with significant but similar intraindividual baseline variability. Atropine virtually eliminated the baroreflex slope; subsequent addition of propranolol did not alter it further. Propranolol or clonidine alone increased average baroreflex slope to the extent that they increased resting pulse interval (
r
=.69 to .83). The spontaneous baroreflex method provides a reliable, noninvasive assessment of human vagal cardiac baroreflex sensitivity within its physiological operating range.
Effect of Circulating Epinephrine on Platelet Function and Hematocrit
Authors: Kjeldsen Sverre E. , Weder Alan B. , Egan Brent , Neubig Richard , Zweifler Andrew J. , Julius Stevo
Published: June 2012

Abstract
We investigated the effect of raising arterial plasma epinephrine within the lower pathophysiological concentration range on various indicators of blood platelet function and hematocrit. Epinephrine was raised over 60 minutes by a stepwise increasing intravenous infusion in 40 healthy men aged 20 to 40 years. Platelet count increased progressively with increasing arterial epinephrine to a maximal change of 69±6 ×10
9
/L in EDTA-anticoagulated blood and a maximal change of 42±6 ×10
9
/L in acid-citrate-dextrose (ACD)–anticoagulated blood, and the weight of circulating platelets increased by 29% (
P
<.001). Platelet size increased significantly in EDTA and decreased in ACD, and the difference between EDTA and ACD was significant (
P
<.0001) for both count and size, suggesting that epinephrine not only recruits platelets into the circulation but also induces some microaggregation in vivo or adhesion ex vivo. Aggregation of platelets in vitro induced by epinephrine decreased (
P
<.003 for Δoptical density and
P
=.038 for maximal optical density) after epinephrine infusion compared with saline but did not change when stimulated with ADP or collagen. These findings suggest a selective downregulation of the epinephrine-activating mechanisms concomitant with a rise in the platelet content of epinephrine by 81% (
P
<.001) and no change in the platelet sodium-proton membrane exchange. The release of granular content (β-thromboglobulin and platelet factor 4) to the circulation in response to epinephrine was not significant. Thus, under acute conditions it seems that the platelets may protect themselves against inappropriate overstimulation by epinephrine. The importance of platelet epinephrine uptake is still unknown, but sodium-proton exchange does not seem to be involved in regulating the effects of circulating epinephrine on platelet function. Epinephrine has a pronounced effect on raising hematocrit (maximal change of 1.74±0.13 ×10
−2
,
P
<.0001).
Relationship of Alcohol Intake With Blood Pressure in Young Adults
Authors: Gillman Matthew W. , Cook Nancy R. , Evans Denis A. , Rosner Bernard , Hennekens Charles H.
Published: June 2012

Abstract
The objective of this study was to examine the relationship of usual current alcohol intake with systolic and diastolic pressures among young adults. Participants were 316 men and women, aged 18 to 26 years, from East Boston, Mass. At each of three weekly visits we obtained three blood pressure measurements on each subject using a random-zero sphygmomanometer. Using an interviewer-administered questionnaire, we obtained information about quantity and frequency of alcohol intake during the previous month. The lowest systolic pressure levels were in subjects consuming 1 to <2 drinks per day. Adjusted for age, sex, and body mass index, systolic pressure was higher by 4.0 mm Hg (95% confidence interval [CI], 0.5 to 7.6 mm Hg) in abstainers, 3.6 mm Hg (95% CI, 0.5 to 6.6 mm Hg) in those who drank <1 drink per day, 0.4 mm Hg (95% CI, −4.7 to 5.5 mm Hg) in those who drank 2 to <3 drinks per day, and 8.1 mm Hg (95% CI, 2.9 to 13.4 mm Hg) in those who drank ≥3 drinks per day. Levels of diastolic pressure were lowest in those consuming 2 to <3 drinks per day. Adjustment for pulse rate, smoking, medication use, and family history of hypertension did not alter the results. These results suggest a J-shaped association of alcohol intake with blood pressure level in young adults, with the lowest levels in consumers of 1 to 3 drinks per day.
Angiotensin II Increases Vascular Permeability Factor Gene Expression by Human Vascular Smooth Muscle Cells
Authors: Williams Bryan , Baker Anne Quinn , Gallacher Barbara , Lodwick David
Published: June 2012

Abstract
Angiotensin II (Ang II) has been implicated in the pathogenesis of the vascular injury associated with hypertension and diabetes mellitus. Increased vascular permeability is an important early manifestation of endothelial dysfunction and the pathogenesis of atherosclerosis. How Ang II contributes to endothelial dysfunction and promotes an increase in vascular permeability is unknown but is classically attributed to its pressor actions. We demonstrate that human vascular smooth muscle cells express abundant mRNA for vascular permeability/endothelial growth factor. Vascular permeability factor is a 34- to 42-kD glycoprotein that markedly increases vascular endothelial permeability and is a potent endothelial mitogen. Ang II potently induced a concentration-dependent (maximal, 10
−7
mol/L) and time-dependent increase in vascular permeability factor mRNA expression by human vascular smooth muscle cells that was maximal after 3 hours and diminished by 24 hours. Ang II–induced vascular permeability factor mRNA expression by human vascular smooth muscle cells was inhibited by the specific Ang II receptor antagonist losartan (DuP 753), confirming that this is an Ang II receptor subtype 1–mediated event. These results describe a new action of Ang II on human vascular smooth muscle, notably the induction of vascular permeability factor mRNA expression. The wide spectrum and potent activity of vascular permeability factor suggest a novel mechanism whereby Ang II could locally and directly influence the permeability, growth, and function of the vascular endothelium independent of changes in hemodynamics.
Enhanced Predictability of Myocardial Infarction in Japanese by Combined Genotype Analysis
Authors: Kamitani Atsushi , Rakugi Hiromi , Higaki Jitsuo , Ohishi Mitsuru , Shi Shang-Jin , Takami Seiju , Nakata Yukiko , Higashino Yorihiko , Fujii Kenshi , Mikami Hiroshi , Miki Tetsuro , Ogihara Toshio
Published: June 2012

Abstract
To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n=103) and control subjects (n=103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-
TT
genotype (
T
indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (
P
<.05). The ACE-
DD
genotype (
D
indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (
P
<.0001). The odds ratio estimated by the combined analysis of the angiotensinogen-
TT
and ACE-
DD
genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-
TT
(1.75) or ACE-
DD
(4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-
TT
genotype did not enhance the predictability of myocardial infarction from the ACE-
DD
genotype. In conclusion, the angiotensinogen-
TT
genotype is a predictor for myocardial infarction, as well as the ACE-
DD
genotype, and the combined analysis of the angiotensinogen-
TT
and ACE-
DD
genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.
Low Urinary Sodium Is Associated With Greater Risk of Myocardial Infarction Among Treated Hypertensive Men
Authors: Alderman Michael H. , Madhavan Shantha , Cohen Hillel , Sealey Jean E. , Laragh John H.
Published: June 2012

Abstract
A sodium-reduced diet is frequently recommended for hypertensive individuals. To determine the relationship of sodium intake to subsequent cardiovascular disease, we assessed the experience of participants in a worksite-based cohort of hypertensive subjects. The 24-hour urinary excretion of sodium (U
Na
V), potassium, creatinine, and plasma renin activity was measured in 2937 mildly and moderately hypertensive subjects who were unmedicated for at least 3-4 weeks. Morbidity and mortality in these systematically treated subjects were ascertained. Men and women were stratified according to sex-specific quartiles of U
Na
V. Subjects in these strata were similar in race, cardiovascular status, and pretreatment and intreatment blood pressure. Subjects with lower U
Na
V were thinner, excreted less potassium, and had higher plasma renin activity. During an average 3.8 years of follow-up, a total of 55 myocardial infarctions occurred. Myocardial infarction and U
Na
V were inversely associated in the total population and in men but not in women, who sustained only nine events. In men, age- and race-adjusted myocardial infarction incidence in the lowest versus highest U
Na
V quartile was 11.5 versus 2.5 (relative risk, 4.3, 95% confidence interval, 1.7-10.6). No association was observed between non–cardiovascular disease mortality (n=11) and U
Na
V. There was a significant linear trend in proportions of myocardial infarction by U
Na
V quartile, with a break point after the lowest U
Na
V quartile. In the Cox multivariate analysis, log plasma renin activity, age, systolic pressure, and cholesterol as continuous variables as well as left ventricular hypertrophy and smoking had a direct association, and U
Na
V (
P
=.036) had an inverse, independent association with the incidence of myocardial infarction among these treated hypertensive men.
Influence of Blood Pressure on Left Atrial Size
Authors: Vaziri Sonya M. , Larson Martin G. , Lauer Michael S. , Benjamin Emelia J. , Levy Daniel
Published: June 2012

Abstract
Increased left atrial size has been identified as a precursor of atrial fibrillation and of stroke once atrial fibrillation is manifest. Conflicting data exist regarding the effect of high blood pressure on left atrial size. Our objective was to evaluate the association of contemporary and long-term measures of blood pressure with echocardiographically determined left atrial size in a large, population-based cohort. The study sample consisted of 1849 male and 2152 female participants of the Framingham Heart Study and Framingham Offspring Study. All analyses were sex specific. In correlation analyses, systolic and pulse pressures were identified as statistically significant determinants of left atrial size after adjustment for age and body mass index, although the magnitudes of these relations were very modest (partial
r
≤.10). Multivariable linear regression models showed the relative contributions of the pressure variables to the prediction of left atrial size to be substantially less than those of age and, in particular, body mass index. Furthermore, inclusion of left ventricular mass in these multivariable models eliminated or attenuated the associations of the pressure variables with left atrial size. In logistic analyses, increasing levels of the pressure variables were significantly predictive of left atrial enlargement. Subjects with 8-year average systolic pressure of 140 mm Hg or higher were twice as likely to have left atrial enlargement as those with values of 110 mm Hg or lower. Overall, in this population-based study sample, increased levels of systolic and pulse pressures (but not diastolic or mean arterial pressures) were significantly associated with increased left atrial size. However, the magnitude of these associations was quite modest, particularly after controlling for age and body mass index.
Effects of Head-Down Tilt on Atrial Natriuretic Peptide and the Renin System in Pregnancy
Authors: Poulsen Hedvig , Olofsson Per , Stjernquist Martin
Published: June 2012

Abstract
We studied the effects of head-down tilt to 10° for 30 minutes on plasma atrial natriuretic peptide and the renin-aldosterone system in 8 preeclamptic pregnant women, 8 healthy pregnant women, and 11 nonpregnant women of fertile age. Mean arterial blood pressure did not change in the pregnant groups but increased significantly in the nonpregnant control subjects. Heart rate decreased significantly in preeclamptic women but remained unchanged in both control groups. Baseline atrial natriuretic peptide concentration was significantly higher in both preeclamptic (66±4 pmol/L) and pregnant (54±6 pmol/L) control subjects compared with nonpregnant subjects (40±2 pmol/L), but the difference between the pregnant groups was not significant. Head-down tilting induced a significant increase in atrial natriuretic peptide only in healthy pregnant women. Baseline plasma renin activity and aldosterone concentrations were significantly higher in pregnant control subjects compared with both the preeclamptic and nonpregnant groups. The differences between the preeclamptic and nonpregnant control groups were nonsignificant. After head-down tilting, plasma renin activity decreased significantly only in nonpregnant control subjects, whereas aldosterone decreased significantly in preeclamptic and nonpregnant control subjects. In preeclampsia, atrial natriuretic peptide release followed blood pressure and not changes in cardiac output. When all 27 women were studied, a correlation between atrial natriuretic peptide and mean arterial pressure was found in the left lateral supine position. The results suggest that pregnant women developing preeclampsia lose their usual hemodynamic control and show reactions resembling the nonpregnant state when subjected to head-down tilt.
Angiotensin II Induces Cardiac Phenotypic Modulation and Remodeling In Vivo in Rats
Authors: Kim Shokei , Ohta Kensuke , Hamaguchi Akinori , Yukimura Tokihito , Miura Katsuyuki , Iwao Hiroshi
Published: June 2012

Abstract
Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype–related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal α-actin, β-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular α-myosin heavy chain and smooth muscle α-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-β1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II–induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II. This study demonstrates that Ang II in vivo, via the type 1 receptor, directly induces a shift to the fetal phenotype of cardiac myocytes and cardiac remodeling independent of blood pressure elevation. Thus, Ang II may play an important role in the modulation of cardiac performance in pathological cardiac hypertrophy.
Opposing Actions of Angiotensin-(1-7) and Angiotensin II in the Brain of Transgenic Hypertensive Rats
Authors: Moriguchi Atsushi , Tallant E. Ann , Matsumura Kiyoshi , Reilly Thomas M. , Walton Harry , Ganten Detlev , Ferrario Carlos M.
Published: June 2012

Abstract
Lack of specific antagonists to the amino-terminal heptapeptide angiotensin-(1-7) [Ang-(1-7)] prompted us to evaluate the central effects of delivering a specific affinity-purified Ang-(1-7) antibody on the blood pressure and heart rate of 12-week-old conscious homozygous female rats (n=12) expressing the mouse submandibular
Ren-2

d

gene [(m
Ren-2

d

)27] in their genome. Another group of transgenic hypertensive and strain-matched Sprague-Dawley controls were injected with a specific Ang II monoclonal antibody (KAA8). Cerebroventricular administration of the affinity-purified Ang-(1-7) antibody in conscious transgenic hypertensive rats caused significant dose-related elevations in blood pressure associated with tachycardia. The hypertensive response was augmented in transgenic rats studied 7 to 10 days after cessation of lisinopril therapy. Neutralization of Ang II with the Ang II antibody caused a hemodynamic response opposite to that obtained with the Ang-(1-7) antibody. All doses of the Ang II antibody produced hypotension and bradycardia. The magnitude of the depressor response was significantly augmented in transgenic rats weaned off lisinopril therapy. In contrast, central administration of either the Ang-(1-7) or Ang II antibodies had no effect on normotensive rats. Central injections of an affinity-purified IgG fraction were ineffective in both control and transgene-positive rats. These data suggest that in the brain of transgenic hypertensive rats, Ang-(1-7) opposes the action of Ang II on the central mechanism or mechanisms that contribute to the maintenance of this model of hypertension. In addition, these studies showed an important contribution of the brain renin-angiotensin system to the maintenance of this form of monogenetic hypertension.
Serum
N
-Acetyl-β-
d
-Glucosaminidase Activity in Predicting the Development of Hypertension
Authors: Hashimoto Ryuichi , Adachi Hisashi , Nishida Hidemi , Tsuruta Makoto , Nomura Gakuji
Published: June 2012

Abstract
We conducted a prospective study in residents of a small farming community in southwestern Japan to determine whether elevated serum
N
-acetyl-β-
d
-glucosaminidase (NAG) activity would predict future hypertension. The 505 normotensive subjects (blood pressure, <140/90 mm Hg; mean age, 52±12 years) were reexamined after 7 years; 111 (22%) had become hypertensive (defined as blood pressure ≥140/90 mm Hg and/or taking antihypertensive medication at follow-up). After adjustment for age and sex, the development of hypertension was significantly related to body mass index (
P
<.002), the sum of skinfolds (
P
<.001), baseline blood pressure (
P
<.0001), serum cholesterol (
P
<.01), serum uric acid level (
P
<.0001), and serum NAG activity (
P
<.005). Elevated NAG activity showed an independent relationship to future hypertension (
P
<.005) after adjustments for age, sex, baseline blood pressure (systolic, diastolic, or mean), uric acid level, and the sum of skinfolds. Therefore, elevated serum NAG activity was an effective indicator of future hypertension, and it might therefore be related to functional and/or structural changes in the cardiovascular system.
The Arterial System in Hypertension
Authors: Safar Michel E. , Frohlich Edward D.
Published: June 2012

Abstract
Hypertension has long been considered a hemodynamic disorder, the hallmark of which is an increased total peripheral resistance that is more or less uniformly distributed in the arterioles of the component organ circulations. In recent years, because of the introduction of innovative technologies and methods, it is now possible to obtain a meaningful assessment of the physiological role of the larger arteries, thereby providing an index of arterial distensibility and compliance and a new means to assess the role of pulsatile pressure and arterial stiffening in hypertension and its comorbid diseases (eg, arteriosclerosis, diabetes mellitus). This discussion addresses these newer methodological aspects in assessing arterial stiffening in systemic hypertension and other cardiovascular disorders. In addition, the epidemiological, the molecular biological, and genetic, as well as certain therapeutic, aspects of pulse pressure in these circumstances are discussed.
Influence of Angiotensin II Type 1 Receptor Polymorphism on Aortic Stiffness in Never-Treated Hypertensive Patients
Authors: Benetos Athanase , Topouchian Jirar , Ricard Sylvain , Gautier Sylvie , Bonnardeaux Alain , Asmar Roland , Poirier Odile , Soubrier Florent , Safar Michel , Cambien François
Published: June 2012

Abstract
Several clinical and experimental studies have suggested a significant role of angiotensin II in the development of alterations of small and large arteries. The present study was designed to assess the contribution of polymorphism (corresponding to an A
1166
→C transversion) of the angiotensin II type 1 receptor (AT
1
) gene to aortic stiffness. One hundred thirty-four never-treated hypertensive patients were included in the study. Aortic distensibility was evaluated by measuring carotid-femoral pulse wave velocity. Age, systolic and diastolic pressure, and metabolic parameters were similar in the three genotypes. Pulse wave velocity was 11.4±2.5 m/s in AT
1
AA homozygotes, 12.5±3.2 m/s in AC heterozygotes, and 14.7±4.0 m/s in CC homozygotes (
P
=.003,
P
<.001 after adjustment for age, blood pressure, and body mass index). Moreover, an interaction was found between AT
1
genotype and the ratio of total to high-density lipoprotein cholesterol in terms of the development of aortic stiffness. Thus, a positive correlation was observed between the ratio of total to high-density lipoprotein cholesterol and pulse wave velocity in AC and CC (
r
=.42,
P
<.001) but not AA patients. These results suggest that the AT
1
gene is involved in the development of aortic stiffness in hypertensive patients and could modulate the effects of lipids on large arteries.
Circadian Profile of Systemic Hemodynamics
Authors: Veerman Derk P. , Imholz Ben P.M. , Wieling Wouter , Wesseling Karel H. , van Montfrans Gert A.
Published: June 2012

Abstract
We determined the continuous 24-hour profile of mean arterial pressure, heart rate, stroke volume, cardiac output, and total peripheral resistance in eight healthy ambulatory volunteers. Beat-to-beat intra-arterial blood pressure was recorded with the Oxford system; subjects were ambulant during daytime and slept at night. Beat-to-beat stroke volume was determined by the pulse contour method from the arterial pulse wave. During the nighttime, compared with the daytime average, there was a decrease in blood pressure (9 mm Hg), heart rate (18 beats per minute), and cardiac output (29%); stroke volume showed a small decrease (7%), and total peripheral resistance increased unexpectedly by 22%. When subjects arose in the morning a steep increase in cardiac output and decrease in total peripheral resistance were found. Comparable changes were seen during a period of supine resting in the afternoon, whereas physical exercise caused opposite changes in hemodynamics. This pattern was observed in all subjects. We conclude that the circadian pattern of cardiac output and total peripheral resistance originates from the day-night pattern in physical activity: during the nighttime, blood flow to the skeletal muscles is decreased through local autoregulation, which increases total peripheral resistance and decreases cardiac output compared with the daytime.
Trends in the Prevalence, Awareness, Treatment, and Control of Hypertension in the Adult US Population
Authors: Burt Vicki L. , Cutler Jeffrey A. , Higgins Millicent , Horan Michael J. , Labarthe Darwin , Whelton Paul , Brown Clarice , Roccella Edward J.
Published: June 2012

Abstract
The objective of this study was to describe secular trends in the distribution of blood pressure and prevalence of hypertension in US adults and changes in rates of awareness, treatment, and control of hypertension. The study design comprised nationally representative cross-sectional surveys with both an in-person interview and a medical examination that included blood pressure measurement. Between 6530 and 13 645 adults, aged 18 through 74 years, were examined in each of four separate national surveys during 1960-1962, 1971-1974, 1976-1980, and 1988-1991. Protocols for blood pressure measurement varied significantly across the surveys and are presented in detail. Between the first (1971-1974) and second (1976-1980) National Health and Nutrition Examination Surveys (NHANES I and NHANES II, respectively), age-adjusted prevalence of hypertension at ≥160/95 mm Hg remained stable at approximately 20%. In NHANES III (1988-1991), it was 14.2%. Age-adjusted prevalence at ≥140/90 mm Hg peaked at 36.3% in NHANES I and declined to 20.4% in NHANES III. Age-specific prevalence rates have decreased for every age-sex-race subgroup except for black men aged 50 and older. Age-adjusted mean systolic pressures declined progressively from 131 mm Hg at the NHANES I examination to 119 mm Hg at the NHANES III examination. The mean systolic and diastolic pressures of every sex-race subgroup declined between NHANES II and III (3 to 6 mm Hg systolic, 6 to 9 mm Hg diastolic). During the interval between NHANES II and III, the threshold for defining hypertension was changed from 160/95 to 140/90 mm Hg. Hypertension awareness has increased substantially at both thresholds, to 89% and 73% for 160/1995 and 140/90 mm Hg, respectively. Compared with only 16% of all people with hypertension being <160/95 mm Hg in 1960-1962 and 1971-1974, 64% of all people with hypertension now have it controlled to below the 160/95 mm Hg threshold but only 29% to below 140/90 mm Hg. For people with treated hypertension, the rate of control (<140/90 mm Hg) ranges from 47% of black men to 60% of white women. Hypertension prevalence in the United States has declined progressively since 1971, and the distributions of systolic and diastolic pressures have shifted downward during the approximately 30-year period between 1960-1962 and 1988-1991. Variation in blood pressure measurement techniques may explain some of the decline in prevalence and the downward shift in distribution. Hypertension awareness, treatment, and control also have improved tremendously during the same period, accounting for much of the shift at the upper end of the distribution. Despite these favorable trends, many people with hypertension are unaware of their condition, and many more are untreated or inadequately treated.
Plasma From Women With Preeclampsia Increases Endothelial Cell Nitric Oxide Production
Authors: Baker Philip N. , Davidge Sandra T. , Roberts James M.
Published: June 2012

Abstract
In preeclampsia, a factor in the maternal circulation alters endothelial function via a reduction in nitric oxide synthesis. We measured the in vitro effects of 2% plasma from women with preeclampsia, compared with 2% plasma from normotensive pregnant women, on cultured endothelial cell nitrite production and nitric oxide synthase activity. On finding differential effects, we measured the effects on cellular viability (assessed by lactate dehydrogenase levels) and performed a time course study. Endothelial cell nitrite production was found to be higher after exposure to plasma from the preeclamptic group than the normotensive pregnant group. The effects of long-term exposure (120 hours) were similar to those of short-term exposure (24 hours). In addition, nitric oxide synthase activity was significantly greater after exposure to preeclamptic plasma than after exposure to normotensive pregnant plasma. No differential effect on cellular viability was found. Contrary to our hypothesis, exposure of endothelial cells to preeclamptic plasma resulted in increased nitric oxide production and nitric oxide synthase activity.
Effects of Human Renin in the Vasculature of Rats Transgenic for Human Angiotensinogen
Authors: Müller Dominik N. , Hilgers Karl F. , Bohlender Jürgen , Lippoldt Andrea , Wagner Jürgen , Fischli Walter , Ganten Detlev , Mann Johannes F. E. , Luft Friedrich C.
Published: June 2012

Abstract
Transgenic rats, which express the human angiotensinogen gene, provide a unique model for studying local vascular effects of human renin. We examined the cleavage of human angiotensinogen to angiotensin I (Ang I) by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from such rats. Perfusion resulted in the sustained release of human angiotensinogen, which decreased from 19.4 to 11.8 pmol/mL over 45 minutes. Active human renin at doses of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I release from undetectable levels (mean±SEM) to 31.9±3.3, 147.1±26.2, and 206.4±17.1 fmol/mL, respectively, by 9 minutes. In separate experiments aimed at the quantification of renin-induced vasoconstriction, captopril decreased the perfusion pressure and lowered Ang II concentrations to nondetectable levels, whereas Ang I values increased sharply. When renin (30 ng/mL) was infused for 15 minutes, renin values in the perfusate decreased to barely detectable levels within minutes after termination of the infusion. However, Ang I values remained high for at least 30 minutes thereafter. The addition of a human renin inhibitor during renin infusion caused Ang I values to promptly decrease within minutes to undetectable levels. Hindlimbs from nontransgenic control rats released no detectable amounts of Ang I, with or without human renin. Finally, by in situ hybridization we documented the presence of human angiotensinogen message in the vessels of the hindlimb. We conclude that renin acts on angiotensinogen at a site in the vascular wall. The cleavage depends on renin and not on other lysosomal proteases. Transgenic rats are a novel model that may be used to test the functional importance of the local human renin-angiotensin system in experimental animals.
Contribution of Systemic Blood Pressure to Myocardial Remodeling in Uremic Rats
Authors: Fabris Bruno , Carretta Renzo , Fischetti Fabio , Candido Riccardo , Calci Mario , Castellano Maurizio , Bardelli Moreno , Campanacci Luciano
Published: June 2012

Abstract
Left ventricular hypertrophy with diffuse intermyocardiocytic fibrosis is a feature of uremia. The role of blood pressure and/or other cardiovascular uremic risk factors in cardiac remodeling is still uncertain. To determine the extent to which improvement of kidney function and the control of uremia-related risk factors are associated with a reduction of myocardial injury, we evaluated the effect of dietary protein restriction or the angiotensin-converting enzyme inhibitor lisinopril on cardiac structure in remnant kidney rats. One week after subtotal nephrectomy, Wistar rats were allocated to receive drinking water solution (group 1), 5 mg/kg per day lisinopril (group 2), or a low-protein diet (6%) (group 3) for 12 weeks. Groups 2 and 3 showed a comparable efficacy in preventing the expected rise in creatininemia, urinary protein excretion, and glomerulosclerosis. However, hypertension development was prevented only in group 2. Groups 1 and 3 developed a significant (
P
<.01) increase in left ventricular weight (2.45±0.1 and 2.5±0.5 mg/g body wt, respectively) compared with group 2 (1.9±0.06 mg/g body wt). Cardiac hydroxyproline concentration was also lower in group 2 compared with group 1 (2.07±0.16 versus 2.73±0.17 mg/g left ventricular weight,
P
<.05) but not compared with group 3 (2.59±0.19 mg/g left ventricular weight). The effect of angiotensin-converting enzyme inhibition on left ventricular mass and intracardiac collagen content appeared to be dissociated from anemia, sympathetic activity, and hyperlipidemia. There was a close relationship between systolic pressure and left ventricular mass; however, no relationship between the degree of cardiac fibrosis and systolic pressure could be determined. Compared with other uremia-related risk factors, control of systemic blood pressure is an essential component of the prevention of left ventricular hypertrophy, and the limitation of interstitial fibrosis may occur by a mechanism other than blood pressure control.