bluuebunny/crossref_metadata_2025 huggingface dataset:
Genes Encoding Atrial and Brain Natriuretic Peptides as Candidates for Sensitivity to Brain Ischemia in Stroke-Prone Hypertensive Rats
Authors: Brosnan M. Julia , Clark James S. , Jeffs Baxter , Negrin Cervantes D. , Van Vooren Pascale , Arribas Silvia M. , Carswell Hilary , Aitman Timothy J. , Szpirer Claude , Macrae I. Mhairi , Dominiczak Anna F.
Published: June 2012

Abstract
—Previous studies suggested that atrial natriuretic peptide gene (
Anp)
and brain natriuretic peptide gene (
Bnp)
are plausible candidate genes for susceptibility to stroke and for sensitivity to brain ischemia in the stroke-prone spontaneously hypertensive rat (SHRSP). We performed structural and functional analyses of these 2 genes in SHRSP from Glasgow colonies (SHRSP
Gla
) and Wistar-Kyoto rats from Glasgow colonies (WKY
Gla
) and developed a radiation hybrid map of the relevant region of rat chromosome 5. Sequencing of the coding regions of the
Anp
and
Bnp
genes revealed no difference between the 2 strains. Expression studies in brain tissue showed no differences at baseline and at 24 hours after middle cerebral artery occlusion. Plasma concentrations of atrial natriuretic peptide (ANP) did not differ between the SHRSP
Gla
and WKY
Gla
, whereas concentrations of brain natriuretic peptide were significantly higher in the SHRSP
Gla
as compared with the WKY
Gla
(n=11 to 14; 163±21 pg/mL and 78±14 pg/mL; 95% confidence interval 31 to 138,
P
=0.003). We did not detect any attenuation of endothelium-dependent relaxations to bradykinin or ANP in middle cerebral arteries from the SHRSP
Gla
; indeed the sensitivity to ANP was significantly increased in arteries harvested from this strain (WKY
Gla
: n=8; pD
2
=7.3±0.2 and SHRSP
Gla
: n=8; pD
2
=8.2±0.15;
P
<0.01). Moreover, radiation hybrid mapping and fluorescence in situ hybridization allowed us to map the
Anf
marker in the telomeric position of rat chromosome 5 in close proximity to D5Rat48, D5Rat47, D5Mgh15, and D5Mgh16. These results exclude
Anp
and
Bnp
as candidate genes for the sensitivity to brain ischemia and pave the way to further congenic and physical mapping strategies.
Effect of ACE Inhibitor on DOCA-Salt– and Aortic Coarctation–Induced Hypertension in Mice
Authors: Rhaleb Nour-Eddine , Peng Hongmei , Alfie Marcos E. , Shesely Edward G. , Carretero Oscar A.
Published: June 2012

Abstract
—Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B
2
receptor gene (B
2
-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B
2
-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg · kg
−1
· d
−1
) are mediated by B
2
receptors in aortic coarctation (6 weeks)– and DOCA-salt (4 weeks)–induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B
2
-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B
2
-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt– or aortic coarctation–induced hypertension. We found that B
2
receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B
2
-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B
2
receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.
The Myocardial β-Adrenergic System in Spontaneously Hypertensive Heart Failure (SHHF) Rats
Authors: Anderson Karen M. , Eckhart Andrea D. , Willette Robert N. , Koch Walter J.
Published: June 2012

Abstract
—Responsiveness to β-adrenergic stimulation is reduced in the failing human myocardium. This results principally from reduced β-adrenergic receptor (βAR) density, elevated β-adrenergic receptor kinase 1 (βARK1) levels, and functional uncoupling of remaining receptors. The temporal nature of changes in the human myocardial β-adrenergic system relative to onset of symptomatic heart failure (HF) has been difficult to discern. A relatively new model of HF, the spontaneously hypertensive heart failure (SHHF) rat spontaneously and reproducibly develops left ventricular hypertrophy (LVH) and progresses to HF, thus enabling longitudinal studies to examine the cellular and molecular bases for hypertension-induced cardiac hypertrophy and subsequent HF. The purpose of this study was to examine age-dependent changes in the βAR system in this model. Lean male SHHF rats at 3, 7, 14, and 20 months were compared with age-matched Sprague-Dawley (SD) control rats ([C]; 4 animals/group). At all ages the SHHF rats had elevated blood pressures and left ventricular end-diastolic pressure relative to the SD control rats (
P
<0.05). Compared with age-matched SD control rats, LVH was evident by 3 months in SHHF rats; 20-month-old SHHF rats had significantly greater LVH compared with the other SHHF rat groups. β-adrenergic responsiveness (maximal heart rate to isoproterenol) was reduced only in 20-month-old SHHF rats. βARK1 protein levels and activity were elevated at 14 months (162±10% and 195±20% C, respectively), and βARK1 protein remained elevated at 20 months (140±14% C). In contrast, G protein–coupled receptor kinase 5, a second receptor kinase in the heart, remained unchanged at all ages. βAR density did not change with age in the SD control rats and was similar in the SHHF rats until 20 months of age when the receptor number was reduced (30±1%). These data indicate that cardiac dysfunction is coincident with reduced βAR density. Importantly, cardiac dysfunction was preceded by elevated βARK1 levels and activity, thus suggesting that βARK1 may be a precipitating factor in the transition from hypertension-induced compensatory cardiac hypertrophy to HF. Furthermore, these results indicate that the SHHF rat is a powerful model for use in examination of the mechanisms involved in alterations of β-adrenergic signaling that occur in human HF.
Two-Week Administration of Tempol Attenuates Both Hypertension and Renal Excretion of 8-Iso Prostaglandin F
2α
Authors: Schnackenberg Christine G. , Wilcox Christopher S.
Published: June 2012

Abstract
—8-Iso prostaglandin F
2α
(8-ISO) is formed nonenzymatically from the attack of superoxide radical on arachidonic acid. Therefore, 8-ISO is a marker of oxidative stress in vivo. We have recently shown that short-term administration of the membrane-permeable, metal-independent superoxide dismutase mimetic tempol (4-hydroxy-2, 2, 6, 6-tetramethyl piperidinoxyl) normalizes blood pressure in spontaneously hypertensive rats (SHR). The present study was designed to test whether prolonged administration of tempol ameliorates oxidative stress and hypertension in SHR. In control SHR (n=8), mean arterial pressure and heart rate were increased and renal blood flow and glomerular filtration rate were reduced compared with control Wistar-Kyoto rats (WKY) (n=7). Twenty-four-hour renal excretion of 8-ISO was significantly increased in SHR compared with WKY. Two weeks of tempol administration in the drinking water (1 mmol/L) to SHR (n=8) decreased mean arterial pressure by 18% (162±8 to 134±6 mm Hg,
P
<0.05), increased glomerular filtration rate by 17% (1.6±0.2 to 1.9±0.3 mL/min), and decreased renal excretion of 8-ISO by 39% (9.8±0.7 to 6.0±0.7 ng/24 hours,
P
<0.05). In contrast, tempol administration to WKY (n=6) had no significant effect on mean arterial pressure (115±5 versus 118±8 mm Hg), glomerular filtration rate (3.0±0.4 versus 2.5±0.5 mL/min), or renal excretion of 8-ISO (7.9±0.4 versus 6.8±0.7 ng/24 hours). In conclusion, the SHR is a model of hypertension and renal vasoconstriction associated with oxidative stress. Because long-term administration of a superoxide scavenger reduces blood pressure and oxidative stress in vivo, this study suggests a role for oxygen radicals in the maintenance of hypertension in SHR.
Local Renal Medullary L-NAME Infusion Enhances the Effect of Long-Term Angiotensin II Treatment
Authors: Szentiványi Mátyás , Maeda Celso Y. , Cowley Allen W.
Published: June 2012

Abstract
—We hypothesized that the relatively high doses of angiotensin (Ang) II required to produce hypertension in rats were related to stimulation of renal medullary nitric oxide production, which in turn blunted reductions in medullary blood flow and the development of hypertension. Ang II was infused (5 days at 3 ng · kg
−1
· min
−1
IV) to uninephrectomized Sprague-Dawley rats in the presence and absence of a continuous medullary interstitial
N
G
-nitro-
l
-arginine methyl ester (L-NAME) infusion. Renal cortical and medullary blood flows were determined with the use of implanted optical fibers and laser-Doppler flowmetry. Ang II in the absence of medullary nitric oxide synthase inhibition did not change cortical or medullary blood flow or mean arterial pressure. A threshold dose of L-NAME was determined (75 μg · kg
−1
· h
−1
) that did not produce significant short- or long-term changes in medullary blood flow and mean arterial pressure. In rats with blunted medullary nitric oxide synthase activity, Ang II infused intravenously resulted in a 30% reduction in medullary blood flow (from 1.3 to 0.9±0.2V) and ≈20 mm Hg increase in mean arterial pressure with Ang II infusion over 5 days. During 70 minutes after the start of intravenous Ang II, there was an immediate reduction in medullary blood flow, with no changes in cortical blood flow or mean arterial pressure. We conclude that the relative insensitivity of rats to long-term elevations of circulating Ang II is due to the potent counterregulatory actions of the nitric oxide system, specifically within the renal medulla. The results provide novel insights of how the organism attempts to protect itself from the hypertensive effects of Ang II.
Role of Neuronal Nitric Oxide Synthase in Dahl Salt-Sensitive Hypertension
Authors: Tan Dunyong Y. , Meng Shumei , Manning R. Davis
Published: June 2012

Abstract
—The goal of this study was to determine the role of neuronal nitric oxide synthase (nNOS) in the arterial pressure, renal hemodynamic, and renal excretory changes that occur in Dahl salt-resistant (DR) and salt-sensitive (DS) rats during changes in Na intake. Fifty-three DR and DS rats/Rapp strain of 7 to 8 weeks of age with indwelling arterial and venous catheters were subjected to low (0.87 mmol/d) or high (20.6 mmol/d) Na intake beginning 2 days before the start of the control period. Measurements were made during a 5-day control period followed by a 5-day period of nNOS inhibition with intravenous 7-nitroindazole (7NI, 1.67 mg · kg
−1
· h
−1
) or vehicle infusion. After 5 days of 7NI, mean arterial pressure increased to 120±6% control in the DR-high Na, 7NI rats compared with 98±1% control (
P
<0.05) in the DR-high Na alone rats. After 5 days of 7NI, DS-high Na rats, which had a control arterial pressure 31 mm Hg higher than the comparable DR rats, increased their arterial pressure to 114±3% control, which was not significantly different from the DS-high Na alone pressure of 110±2% control. No significant changes occurred in glomerular filtration rate, effective renal plasma flow, urinary Na excretion, or urine volume because of 7NI. However, plasma renin activity decreased significantly in DR and DS rats on low Na intake with 7NI infusion. The data demonstrate that the highly salt-resistant DR rat became salt-sensitive during nNOS inhibition with 7NI. However, the arterial pressure of the DS rat was not affected by 7NI. This suggests that nitric oxide produced by nNOS in the DR rat normally helps to prevent salt-sensitive hypertension and that low functional levels of nNOS in the DS rat may contribute to its salt-sensitivity.
Renal Nerves Promote Sodium Excretion During Long-Term Increases in Salt Intake
Authors: Lohmeier Thomas E. , Hildebrandt Drew A. , Hood W. Ashley
Published: June 2012

Abstract
—To determine whether the renal nerves contribute to sodium homeostasis during long-term increments in sodium intake, studies were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. They were fed a low sodium diet and continuously infused with isotonic saline (350 mL/d) to provide a daily sodium intake of ≈60 mmol. After control measurements, sodium intake was increased to 470 mmol/d by increasing the rate of isotonic saline infusion to 3000 mL/d for 5 days; this was followed by a 5-day recovery period. Twenty-four-hour control values for mean arterial pressure and ratios for urinary sodium, potassium, and creatinine excretion from denervated and innervated kidneys (DEN/INN) were 96±3, 1.06±0.04, 1.00±0.04, and 1.01±0.02 mm Hg, respectively. During the ≈8-fold increase in sodium intake, there was no long-term change in mean arterial pressure, and daily sodium balance was achieved within 48 hours. Moreover, during the first day of high salt intake, there were significant reductions in the DEN/INN for sodium and potassium excretion, which persisted for the entire 5-day period of increased sodium intake; on day 5, the DEN/INN for sodium and potassium excretion was 0.86±0.03 and 0.86±0.04, respectively. In contrast, the DEN/INN for creatinine excretion remained at control levels during high salt intake. Furthermore, similar long-term reductions in the DEN/INN for sodium and potassium excretion occurred in a second group of dogs administered adrenergic receptor–blocking agents for 5 days to interrupt the functional effects of the renal nerves. These data indicate that sustained renal sympathoinhibition promotes sodium and potassium excretion during long-term increments in sodium intake by inhibiting tubular reabsorption of these electrolytes.
Enhanced γ-Aminobutyric Acid–B Receptor Agonist Responses and mRNA Within the Nucleus of the Solitary Tract in Hypertension
Authors: Durgam Vijayender Rao , Vitela Melissa , Mifflin Steven W.
Published: June 2012

Abstract
—γ-Aminobutyric acid–B (GABA
B
) receptor function and regulation in the nucleus of the solitary tract (NTS) was examined in Sprague-Dawley rats made chronically (4 to 5 weeks) hypertensive with the one-kidney, figure-8 renal wrap model of hypertension. NTS microinjection of the GABA
B
agonist baclofen produced a pressor response that was enhanced in hypertensive rats compared with the response observed in sham-operated normotensive rats (36±4 mm Hg increase in mean arterial pressure in 8 hypertensive rats compared with 21±2 mm Hg increase in 7 sham-operated normotensive rats,
P
=0.03). Responses to microinjection of GABA
B
antagonists (CGP-55845A and SCH-90511), the GABA
A
agonist muscimol, the GABA
A
antagonist bicuculline, and the GABA reuptake inhibitor nipecotic acid were not different comparing normotensive sham-operated and hypertensive rats. Renal sympathetic nerve responses to NTS microinjection of these drugs were not different in hypertensive compared with normotensive rats. Micropunches of the NTS were homogenized and reverse transcriptase–polymerase chain reaction was performed to examine mRNA levels for the GABA
B
receptor. There was a 3-fold increase in GABA
B
receptor mRNA levels in the caudal NTS of 7 chronically hypertensive rats compared with levels measured in 8 sham-operated normotensive rats (
P
=0.01). In conclusion, chronic hypertension is associated with an upregulation of GABA
B
receptor function; however, the tonic activity of the system does not appear to be different between normotensive and hypertensive rats. The upregulation of GABA
B
receptor function might be due to an increased number of receptors, as suggested by the elevated levels of GABA
B
receptor mRNA measured in the NTS of hypertensive rats. All of these alterations suggest that hypertension is associated with dynamic changes in receptor-mediated mechanisms within the NTS, and these alterations could modify baroreflex regulation of cardiovascular function in hypertension.
Effects of Smoking Cessation on Blood Pressure and Heart Rate Variability in Habitual Smokers
Authors: Minami Junichi , Ishimitsu Toshihiko , Matsuoka Hiroaki
Published: June 2012

Abstract
—We investigated the effects of 1-week of smoking cessation on ambulatory blood pressure, heart rate, and heart rate variability in 39 normotensive male habitual smokers (mean±SEM, 32.5±1.0 years). The ambulatory blood pressure, heart rate, and ECG R-R intervals were measured during a 24-hour period with a portable recorder (TM-2425) on the last day of 1-week smoking and nonsmoking periods. The order of the 2 periods was randomized. In the smoking period, the subjects were instructed to smoke cigarettes according to their usual smoking patterns. A power-spectral analysis of R-R intervals was performed to obtain the low-frequency (LF) and high-frequency (HF) components. The percentage of differences between adjacent normal R-R intervals >50 milliseconds (pNN50) was used as a time-domain measure of heart rate variability. The 24-hour ambulatory blood pressure was significantly lower in the nonsmoking period than in the smoking period, by 3.5±1.1 mm Hg systole [
P
<0.01] and by 1.9±0.7 mm Hg diastole [
P
<0.05], whereas the nighttime blood pressure did not differ significantly between the 2 periods. The 24-hour heart rate was significantly lower in the nonsmoking period than in the smoking period, by 7.3±1.0 beats/min (
P
<0.0001). The pNN50 and the 24-hour HF component were significantly higher in the nonsmoking period than in the smoking period (
P
<0.0001 for each). The plasma norepinephrine and epinephrine concentrations were significantly lower in the nonsmoking period than in the smoking period (
P
<0.05 for each). These results demonstrate the substantial and immediate benefits of smoking cessation on these cardiovascular indices.
Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension
Authors: Higashi Yukihito , Sasaki Shota , Sasaki Nobuo , Nakagawa Keigo , Ueda Tomohiro , Yoshimizu Atsunori , Kurisu Satoshi , Matsuura Hideo , Kajiyama Goro , Oshima Tetsuya
Published: June 2012

Abstract
—The effects of long-term aerobic exercise on endothelial function in patients with essential hypertension remain unclear. To determine whether endothelial function relating to forearm hemodynamics in these patients differs from normotensive subjects and whether endothelial function can be modified by continued physical exercise, we randomized patients with essential hypertension into a group that engaged in 30 minutes of brisk walking 5 to 7 times weekly for 12 weeks (n=20) or a group that underwent no activity modifications (control group, n=7). Forearm blood flow was measured using strain-gauge plethysmography during reactive hyperemia to test for endothelium-dependent vasodilation and after sublingual nitroglycerin administration to test endothelium-independent vasodilation. Forearm blood flow in hypertensive patients during reactive hyperemia was significantly less than that in normotensive subjects (n=17). Increases in forearm blood flow after nitroglycerin were similar between hypertensive and normotensive subjects. Exercise lowered mean blood pressure from 115.7±5.3 to 110.2±5.1 mm Hg (
P
<0.01) and forearm vascular resistance from 25.6±3.2 to 23.2±2.8 mm Hg/mL per minute per 100 mL tissue (
P
<0.01); no change occurred in controls. Basal forearm blood flow, body weight, and heart rate did not differ with exercise. After 12 weeks of exercise, maximal forearm blood flow response during reactive hyperemia increased significantly, from 38.4±4.6 to 47.1±4.9 mL/min per 100 mL tissue (
P
<0.05); this increase was not seen in controls. Changes in forearm blood flow after sublingual nitroglycerin administration were similar before and after 12 weeks of exercise. Intra-arterial infusion of the nitric oxide synthase inhibitor
N
G
-monomethyl-L-arginine abolished the enhancement of reactive hyperemia induced by 12 weeks of exercise. These findings suggest that through increased release of nitric oxide, continued physical exercise alleviates impairment of reactive hyperemia in patients with essential hypertension.
Binge Drinking and Ambulatory Blood Pressure
Authors: Seppä Kaija , Sillanaukee Pekka
Published: June 2012

Abstract
—The effect of alcohol drinking in raising blood pressure (BP) is rapidly reversible. However, there is only limited information on the effect of binge drinking on BP values. In this study, 20 healthy men who were all social drinkers drank alcohol (2.2 g/kg) in controlled circumstances on a Saturday evening. Ambulatory BP measurement (ABPM) values were compared with ABPM values of the same subjects during the previous sober Saturday, separately throughout 6 hours of intoxication, throughout 6 hours when blood alcohol levels decreased, and throughout 6 hangover hours. During the intoxication period, both mean systolic BP and mean diastolic BP were 5 mm Hg higher (
P
=0.0183 and
P
=0.0529, respectively) and the pulse was 18 beats per minute faster (
P
=0.0001) compared with the corresponding sober period during the previous weekend. While blood alcohol levels decreased after drinking, mean systolic BP was 4 mm Hg lower (
P
=0.0331), diastolic BP was 5 mm Hg lower (
P
=0.0058), and pulse was 15 bpm faster (
P
=0.0001) than during the sober weekend. No statistically significant difference was found between the weekends in BP values during the hangover period. Drinking seems to increase both systolic and diastolic BP during intoxication but not during hangover. During the period when blood alcohol levels are decreasing, usually at night, both pressure levels fall to less than the basic level. These major and rapid changes in BP values might increase the likelihood of strokes, which are seen in increased numbers among young adults, especially during weekends and holidays.
Differential Regulation of Renal Angiotensin Subtype AT
1A
and AT
2
Receptor Protein in Rats With Angiotensin-Dependent Hypertension
Authors: Wang Zhi-Qin , Millatt Lesley J. , Heiderstadt Nicholas T. , Siragy Helmy M. , Johns Roger A. , Carey Robert M.
Published: June 2012

Abstract
—This study was designed to investigate distribution and regulation of the renal AT
1A
and AT
2
subtype receptors in rats with either systemic angiotensin II (Ang II)–induced hypertension or acute phase renal hypertension (2-kidney, 1-clip [2K1C] or 2-kidney, 1-figure-of-8-wrap [2K1W]). In normal rat kidneys, positive immunostaining for the AT
1A
receptor was observed in the intrarenal vasculature, glomeruli, proximal and distal tubules, and collecting ducts. The AT
2
receptor was localized mainly to the glomeruli. The AT
1A
but not AT
2
receptor protein expression was significantly reduced in rats with 10-day systemic Ang II–induced hypertension. In both 7-day 2K1C and 3-day 2K1W rats, the AT
1A
receptor was significantly reduced in ischemic and contralateral kidneys compared with sham-operated control rats. Reduction in AT
2
receptor expression was observed only in the ischemic kidneys in 2K1C and 2K1W renal hypertensive rats. These results demonstrate that the AT
1A
receptor is widely distributed in the glomerulus and all other nephron segments of the rat kidney. Renal AT
1A
but not AT
2
receptor protein is downregulated in rats with Ang II–induced hypertension. In renal hypertensive rats, the AT
1A
receptor is bilaterally downregulated and the AT
2
receptor is downregulated only in the ischemic kidney.
Heart Rate and Subsequent Blood Pressure in Young Adults
Authors: Kim Jang-Rak , Kiefe Catarina I. , Liu Kiang , Williams O. Dale , Jacobs David R. , Oberman Albert
Published: June 2012

Abstract
—The objective of the present study was to examine the hypothesis that baseline heart rate (HR) predicts subsequent blood pressure (BP) independently of baseline BP. In the multicenter longitudinal Coronary Artery Risk Development in Young Adults study of black and white men and women initially aged 18 to 30 years, we studied 4762 participants who were not current users of antihypertensive drugs and had no history of heart problems at the baseline examination (1985–1986). In each race-sex subgroup, we estimated the effect of baseline HR on BP 2, 5, 7, and 10 years later by use of repeated measures regression analysis, adjusting for baseline BP, age, education, body fatness, physical fitness, fasting insulin, parental hypertension, cigarette smoking, alcohol consumption, oral contraceptive use, and change of body mass index from baseline. The association between baseline HR and subsequent systolic BP (SBP) was explained by multivariable adjustment. However, HR was an independent predictor of subsequent diastolic BP (DBP) regardless of initial BP and other confounders in white men, white women, and black men (0.7 mm Hg increase per 10 bpm). We incorporated the part of the association that was already present at baseline by not adjusting for baseline DBP: the mean increase in subsequent DBP was 1.3 mm Hg per 10 bpm in white men, white women, and black men. A high HR may be considered a risk factor for subsequent high DBP in young persons.
Low Calorie Diet Enhances Renal, Hemodynamic, and Humoral Effects of Exogenous Atrial Natriuretic Peptide in Obese Hypertensives
Authors: Dessı̀-Fulgheri Paolo , Sarzani Riccardo , Serenelli Massimiliano , Tamburrini Paola , Spagnolo Diego , Giantomassi Laura , Espinosa Emma , Rappelli Alessandro
Published: June 2012

Abstract
—The expression of the natriuretic peptide clearance receptor is abundant in human and rat adipose tissue, where it is specifically inhibited by fasting. In obese hypertensives, plasma atrial natriuretic peptide (ANP) levels were found to be lower than in obese normotensives. Therefore, the increased adipose mass might influence ANP levels and/or its biological activity. The aim of the present study was to evaluate whether the humoral, hemodynamic, and renal effects of exogenous ANP in obese hypertensives might be enhanced by a very low calorie diet. Eight obese hypertensives received a bolus injection of ANP (0.6 mg/kg) after 2 weeks of a normal calorie/normal sodium diet, and blood pressure (BP), heart rate, ANP, cGMP, plasma renin activity, and aldosterone were evaluated for 2 hours before and after the injection. Diuresis and natriuresis were measured every 30 minutes. The patients then started a low calorie/normal sodium diet (510 kcal/150 mmol/d) for 4 days, and then the ANP injection protocol was repeated. The low calorie diet induced a slight weight loss (from 90.6±1.1 to 87.7±1.2 kg;
P
<0.01), which was accompanied by increase of cGMP excretion (from 146.0±10.1 to 154.5±9.5 nmol/24 h;
P
<0.05) together with a reduction of BP (
P
<0.01 versus basal levels). ANP injection after diet was followed by an increase of ANP levels similar to that observed before diet, but plasma cGMP, diuresis, and natriuresis increased significantly only after diet. Similarly, the decrease of BP after ANP administration was significantly higher after diet (change in mean arterial pressure, −6.4±0.7 versus −4.0±0.6 mm Hg;
P
<0.05) as well as that of aldosterone (
P
<0.01). These data show that a low calorie diet enhances the humoral, renal, and hemodynamic effects of ANP in obese hypertensives and confirm the importance of caloric intake in modulating the biological activity of ANP, suggesting that the natriuretic peptide system can play a role in the acute changes of natriuresis and diuresis associated with caloric restriction.
Gender-Related Differences in Myocyte Remodeling in Progression to Heart Failure
Authors: Tamura Tetsutaro , Said Suleman , Gerdes A. Martin
Published: June 2012

Abstract
—Gender-related differences responsible for the better prognosis of females with heart failure have not been clearly established. To address this issue, we investigated potential gender-related differences in myocyte remodeling in spontaneously hypertensive heart failure rats. Echocardiograms and myocyte growth were compared between males and females at compensated (2, 4, and 6 months) and decompensated (18 months in males and 24 months in females) stages of cardiac hypertrophy. Although left ventricular diastolic dimensions did not differ significantly between failing male and female rats, fractional shortening declined significantly only in failing males. Myocyte cross-sectional area did not change after 4 months of age in both genders, which is likely to be responsible for the absence of a change in left ventricular wall thickness during the progression to heart failure. Myocyte volume and cross-sectional area were significantly larger in males than females at 2, 4, and 6 months of age, although there were no significant differences at the failing stage. Reduced adaptive hypertrophic reserve was observed in males, which is likely to contribute to the higher morbidity and mortality of males with chronic heart failure.
Loss of Endothelium and Receptor-Mediated Dilation in Pial Arterioles of Rats Fed a Short-Term High Salt Diet
Authors: Liu Yanping , Rusch Nancy J. , Lombard Julian H.
Published: June 2012

Abstract
—A high salt diet often is regarded as an accessory risk factor in hypertension, coincidental to the deleterious effect of high blood pressure on vasodilator function. The aim of this study was to determine whether short-term ingestion of a high salt diet per se impairs vasodilator function in the cerebral circulation independent of blood pressure changes. Adult Sprague-Dawley rats were fed a normal salt (0.8%) or high salt (4%) diet for 3 days. Mean arterial pressures were similar in the normal and high salt groups (123±2 and 125±2 mm Hg, respectively). Subsequently, the responses of the in situ pial arterioles to acetylcholine, iloprost, and sodium nitroprusside were determined in cranial windows using intravital videomicroscopy. Pial arterioles of rats fed normal and high salt diets showed similar resting diameters of 69±2 and 72±3 μm, respectively, but their reactivity patterns to vasodilator stimuli were markedly different. Arterioles of rats fed a normal salt diet dilated progressively up to 17±3% in response to the endothelium-dependent agent acetylcholine (10
−9
to 10
−6
mol/L) and dilated by 22±2% in response to the prostaglandin I
2
receptor agonist iloprost (3×10
−11
mol/L). In contrast, pial arterioles of rats fed a high salt diet constricted by 4±3% and 8±2% in response to acetylcholine and iloprost, respectively. Sodium nitroprusside (10
−6
mol/L), a nitric oxide donor, dilated pial arterioles of rats fed low and high salt diets by a similar amount (19±3% and 16±2%, respectively), suggesting that signaling mechanisms for dilation distal to the vascular smooth muscle membrane were intact after high salt intake. These results provide the first evidence that the short-term ingestion of a high salt diet may severely impair the vasodilator function of the in situ cerebral microcirculation independent of blood pressure elevation.
Role of Endothelin in the Increased Vascular Tone of Patients With Essential Hypertension
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Waclawiw Myron , Cannon Richard O. , Panza Julio A.
Published: June 2012

Abstract
—We investigated the possible role of endothelin in the increased vasoconstrictor tone of hypertensive patients using antagonists of endothelin receptors. Forearm blood flow (FBF) responses (strain-gauge plethysmography) to intraarterial infusion of blockers of endothelin-A (ET
A
) (BQ-123) and endothelin-B (ET
B
) (BQ-788) receptors, separately and in combination, were measured in hypertensive patients and normotensive control subjects. In healthy subjects, BQ-123 alone or in combination with BQ-788 did not significantly modify FBF (
P
=0.78 and
P
=0.63, respectively). In hypertensive patients, in contrast, BQ-123 increased FBF by 33±7% (
P
<0.001 versus baseline), and the combination of BQ-123 and BQ-788 resulted in a greater vasodilator response (63±12%;
P
=0.006 versus BQ-123 alone in the same subjects). BQ-788 produced a divergent vasoactive effect in the two groups, with a decrease of FBF (17±5%;
P
=0.004 versus baseline) in control subjects and transient vasodilation (15±7% after 20 minutes) in hypertensive patients (
P
<0.001, hypertensives versus controls). The vasoconstrictor response to endothelin-1 was slightly higher (
P
=0.04) in hypertensive patients (46±4%) than in control subjects (32±4%). Our data indicate that patients with essential hypertension have increased vascular endothelin activity, which may be of pathophysiological relevance to their increased vascular tone. In these patients, nonselective ET
A
and ET
B
blockade seems to produce a greater vasodilator effect than selective ET
A
blockade.
Enhancement of Bradykinin and Resensitization of Its B
2
Receptor
Authors: Marcic Branislav , Deddish Peter A. , Jackman Herbert L. , Erdös Ervin G.
Published: June 2012

Abstract
—We studied the enhancement of the effects of bradykinin B
2
receptor agonists by agents that react with active centers of angiotensin-converting enzyme (ACE) independent of enzymatic inactivation. The potentiation and the desensitization and resensitization of B
2
receptor were assessed by measuring [
3
H]arachidonic acid release and [Ca
2+
]
i
mobilization in Chinese hamster ovary cells transfected to express human ACE and B
2
receptor, or in endothelial cells with constitutively expressed ACE and receptor. Administration of bradykinin or its ACE-resistant analogue desensitized the receptor, but it was resensitized (arachidonic acid release or [Ca
2+
]
i
mobilization) by agents such as enalaprilat (1 μmol/L). Enalaprilat was inactive in the absence of ACE expression. La
3+
(100 μmol/L) inhibited the apparent resensitization, probably by blocking the entry of extracellular calcium. Enalaprilat resensitized the receptor via ACE to release arachidonic acid by bradykinin at a lower concentration (5 nmol/L) than required to mobilize [Ca
2+
]
i
(1 μmol/L). Monoclonal antibodies inhibiting the ACE N-domain active center and polyclonal antiserum potentiated bradykinin. The snake venom peptide BPP5a and metabolites of angiotensin and bradykinin (angiotensin-[1–9], angiotensin-[1–7], bradykinin-[1–8]; 1 μmol/L) enhanced arachidonic acid release by bradykinin. Angiotensin-(1–9) and -(1–7) also resensitized the receptor. Enalaprilat potentiated the bradykinin effect in cells expressing a mutant ACE with a single N-domain active site. Agents that reacted with a single active site, on the N-domain or on the C-domain, potentiated bradykinin not by blocking its inactivation but by inducing crosstalk between ACE and the receptor. Enalaprilat enhanced signaling via ACE by Gα
i
in lower concentration than by Gα
q
-coupled receptor.
Evidence for Involvement of the Type 1 Angiotensin II Receptor Locus in Essential Hypertension
Authors: Kainulainen Katariina , Perola Markus , Terwilliger Joseph , Kaprio Jaakko , Koskenvuo Markku , Syvänen Ann-Christine , Vartiainen Erkki , Peltonen Leena , Kontula Kimmo
Published: June 2012

Abstract
—Components of the renin-angiotensin system play an important role in the normal regulation of blood pressure. We carried out a comprehensive genetic linkage study of the genes involved in the renin-angiotensin cascade in Finnish hypertensive twins and their affected siblings. We found no evidence for linkage between essential hypertension and the genes coding for renin, angiotensinogen, angiotensin-converting enzyme, or kallikrein 1 in the 329 hypertensive individuals of 142 families studied. In contrast, two intragenic markers for the type 1 angiotensin II receptor (AT
1
) showed some evidence for linkage in the total sample. A closer examination of this gene locus was carried out using subgroups of nonobese sibpairs with early onset of hypertension and uniform geographical origin. These stratifications yielded suggestive evidence for linkage of hypertension to the genetic area containing the AT
1
gene, with a maximal multipoint logarithm of the odds (LOD) score of 2.9. A genetic association study carried out in an independent series of 50 hypertensive cases and 122 normotensive controls showed an increase in the frequency of the A1166→C allele of the AT
1
gene in the hypertensive individuals. In a novel variant of model-free multipoint linkage analysis allowing linkage disequilibrium in the calculations, an LOD score of 5.13 was obtained. Sequence analyses of the entire coding region and 848 bp of promoter region in the DNA sample on 8 index samples did not reveal previously unpublished sequence variations. The data provide evidence that a common genetic variant of the AT
1
gene locus influences the risk of essential hypertension in the Finnish population.
Effects of Coffee on Ambulatory Blood Pressure in Older Men and Women
Authors: Rakic Valentina , Burke Valerie , Beilin Lawrence J.
Published: June 2012

Abstract
—This study assessed the effects of regular coffee drinking on 24-hour ambulatory blood pressure (ABP) in normotensive and hypertensive older men and women. Twenty-two normotensive and 26 hypertensive, nonsmoking men and women, with a mean age of 72.1 years (range, 54 to 89 years), took part in the study. After 2 weeks of a caffeine-free diet, subjects were randomized to continue with the caffeine-free diet and abstain from caffeine-containing drinks or drink instant coffee (5 cups per day, equivalent to 300 mg caffeine per day) in addition to the caffeine-free diet for a further 2 weeks. Change in systolic and diastolic blood pressures (SBP, DBP) determined by 24-hour ambulatory BP monitoring showed significant interactions between coffee drinking and hypertension status. In the hypertensive group, rise in mean 24-hour SBP was greater by 4.8 (SEM, 1.3) mm Hg (
P
=0.031) and increase in mean 24-hour DBP was higher by 3.0 (1.0) mm Hg (
P
=0.010) in coffee drinkers than in abstainers. There were no significant differences between abstainers and coffee drinkers in the normotensive group for 24-hour, daytime, or nighttime SBP or DBP. In older men and women with treated or untreated hypertension, ABP increased in coffee drinkers and decreased in abstainers. Restriction of coffee intake may be beneficial in older hypertensive individuals.
Renal and Metabolic Clearance of
N
-Acetyl-Seryl-Aspartyl-Lysyl-Proline (AcSDKP) During Angiotensin-Converting Enzyme Inhibition in Humans
Authors: Azizi Michel , Ezan Eric , Reny Jean-Luc , Wdzieczak-Bakala Joanna , Gerineau Vincent , Ménard Joël
Published: June 2012

Abstract
—We investigated the contributions of angiotensin-converting enzyme (ACE) and glomerular filtration to creating the new metabolic balance of the hemoregulatory peptide
N
-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) that occurs during acute and chronic ACE inhibition in healthy subjects. We also studied the effect of chronic renal failure on the plasma concentration of AcSDKP during long-term ACE inhibitor (ACEI) treatment or in its absence. In healthy subjects, a single oral dose of 50 mg captopril (n=32) and a 7-day administration of 50 mg captopril BID (n=10) resulted in a respective 42-fold (range, 18- to 265-fold) and 34-fold (range, 24-fold to 45-fold) increase in the ratio of urinary AcSDKP to creatinine accompanied by a 4-fold (range, 2- to 6.8-fold) and 4.8-fold (range, 2.6- to 11.8-fold) increase in plasma AcSDKP levels. Changes in plasma AcSDKP and in vitro ACE activity over time showed an intermittent reactivation of ACE between each captopril dose. In subjects with chronic renal failure (creatinine clearance<60 mL/min per 1.73 m
2
), plasma AcSDKP levels were 22 times higher (95% confidence interval, 15 to 33) in the ACEI group (n=35) than the control group (n=23); in subjects with normal renal function, they were only 4.1 times higher (95% confidence interval, 3.2 to 5.3) in the ACEI group (n=19) than the non-ACEI group (n=21). Renal failure itself led to a slight increase in plasma AcSDKP concentration. In conclusion, intermittent reactivation of ACE between doses of an ACEI is the major mechanism accounting for the lack of major AcSDKP accumulation during chronic ACE inhibition in subjects with normal renal function.
Chronic ET
A
Receptor Blockade Attenuates Cardiac Hypertrophy Independently of Blood Pressure Effects in Renovascular Hypertensive Rats
Authors: Ehmke Heimo , Faulhaber Jörg , Münter Klaus , Kirchengast Michael , Wiesner Rudolf J.
Published: June 2012

Abstract
—In isolated cardiac myocytes, the direct effects of angiotensin II on cellular growth and gene expression were shown to be mediated by endothelin via the endothelin subtype A (ET
A
) receptor. To determine whether this pathway is also involved in the cardiovascular adaptations to a chronic activation of the renin-angiotensin system in vivo, the effects of a selective ET
A
receptor antagonist (LU 127043) were investigated in adult rats with renal artery stenosis. Four groups of rats (n=107) were studied over a period of 10 days after surgery: (1) sham-operated animals with saline administration, (2) rats subjected to left renal artery clipping with saline administration, (3) sham-operated rats with LU 127043 administration, and (4) rats subjected to left renal artery clipping with LU 127043 administration. LU 127043 (50 mg/kg) or saline was given by gavage twice daily starting 1 day before the operation. In clipped rats with saline administration, plasma renin activity, the ratio of left ventricular weight to body weight, and mRNAs for β-myosin heavy chain and atrial natriuretic peptide were significantly elevated as early as 2 days after surgery. Blood pressure started to rise on the third postoperative day and attained a steady state hypertensive level by day 6. Blockade of ET
A
receptors had no effects on plasma renin activity or the time course of hypertension in clipped animals but completely prevented left ventricular hypertrophy and the re-expression of the β-myosin heavy chain and atrial natriuretic peptide genes on day 2. While the expressions of the β-myosin heavy chain and atrial natriuretic peptide genes were not different from saline-treated, clipped animals after day 4, the development of left ventricular hypertrophy remained markedly blunted (−50%) during ET
A
receptor blockade until day 10. These results show that a continuous blockade of ET
A
receptors significantly attenuates the development of left ventricular hypertrophy and, more transiently, fetal gene expression in the early phase of renovascular hypertension. Since neither blood pressure nor the increase in plasma renin activity was significantly altered by ET
A
receptor blockade, the inhibitory influences of the ET
A
receptor antagonist on left ventricular hypertrophy and gene expression were mediated most likely through a direct blockade of myocardial ET
A
receptors.
Enhanced Natriuretic Response to Neutral Endopeptidase Inhibition in Heart-Transplant Recipients
Authors: Geny Bernard , Hardy Hélène , Lonsdorfer Jean , Eisenmann Bernard , Haberey Pascal , Piquard François
Published: June 2012

Abstract
—Heart-transplant recipients (Htx) generally present with body fluid and sodium handling abnormalities and hypertension. To investigate whether neutral endopeptidase inhibition (NEP-I) increases endogenous atrial natriuretic peptide (ANP) and enhances natriuresis and diuresis after heart transplantation, ecadotril was given orally to 8 control subjects and 8 matched Htx, and levels of volume-regulating hormones and renal water, electrolyte, and cyclic guanosine monophosphate (cGMP) excretions were monitored for 210 minutes. Baseline plasma ANP, brain natriuretic peptide (BNP), and cGMP were elevated in Htx, but renin and aldosterone, like urinary parameters, did not differ between groups. NEP-I increased plasma ANP (Htx, 20.6±2.3 to 33.2±5.9 pmol/L,
P
<0.01; controls, 7.7±1.2 to 10.6±2.6 pmol/L) and cGMP, but not BNP. Renin decreased similarly in both groups, whereas aldosterone decreased significantly only in Htx. Enhanced urinary sodium (1650±370% versus 450±150%,
P
=0.01), cGMP, and water excretions were observed in Htx and urinary cGMP positively correlated with natriuresis in 6 of the Htx subjects. Consistent with a normal circadian rhythm of blood pressure, without excluding a possible effect of NEP-I, mean systemic blood pressure increased similarly in both groups at the end of the study (6.9±2.0% versus 7.4±2.8% in controls and Htx). Thus, systemic hypertension, mild renal impairment, and raised plasma ANP levels are possible contributory factors in the enhanced natriuresis and diuresis with NEP-I in Htx. These results support a physiological role for the cardiac hormone after heart transplantation and suggest that long-term studies may be useful to determine the potential of NEP-I in the treatment of sodium retention and water retention after heart transplantation.
Central Adrenomedullin Augments the Baroreceptor Reflex in Conscious Rabbits
Authors: Matsumura Kiyoshi , Abe Isao , Tsuchihashi Takuya , Fujishima Masatoshi
Published: June 2012

Abstract
—We examined the roles of central adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP), and calcitonin gene–related peptide (CGRP) on the baroreceptor reflex in conscious rabbits. Intracerebroventricular injection of adrenomedullin (0.2 and 1 nmol/80 μL) elicited dose-related increases in arterial pressure and renal sympathetic nerve activity. On the other hand, a subpressor dose of intracerebroventricular infusion of adrenomedullin (1 nmol/300 μL per hour) caused significant increases in baroreflex sensitivities assessed by renal sympathetic nerve activity and heart rate compared with vehicle infusion (G
max
; −14.9±1.7 versus −8.0±0.7%/mm Hg,
P
<0.01, and −8.1±0.8 versus −5.1±0.5 bpm/mm Hg,
P
<0.01, respectively). Intracerebroventricular infusion of CGRP (1 nmol/300 μL per hour), which is structurally homologous to adrenomedullin, also enhanced the baroreflex controls of renal sympathetic nerve activity and heart rate. However, the intracerebroventricular infusion of PAMP (30 nmol/300 μL per hour) failed to alter the baseline levels of arterial pressure and baroreflex sensitivities. These results suggest that central adrenomedullin and CGRP, but not PAMP, participate in cardiovascular regulation to augment the baroreflex controls of renal sympathetic nerve activity and heart rate in conscious rabbits.