bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Endothelium-Derived Metabolites of Arachidonic Acid in Enhanced Pulmonary Artery Contractions in Female Rabbits
Authors: Pfister Sandra L. , Campbell William B.
Published: June 2012

Abstract
Previous studies reported sex differences in production of endothelium-derived substances and suggested that these compounds may be involved in regulation of vascular tone under both normal and pathological conditions. The present study was designed to compare the effects of endothelium-dependent contractions in pulmonary artery vessels obtained from male and female rabbits. Rings of intrapulmonary arteries were suspended under isometric tension in oxygenated Krebs’ buffer. In male rabbit pulmonary artery, arachidonic acid and methacholine elicited endothelium-dependent, concentration-related contractions (maximal contraction, 79±4% and 54±4% of the KCl contractions, respectively). In contrast, endothelium-dependent arachidonic acid– and methacholine-induced contractions were greater in female pulmonary arteries (maximal response, 113±7% and 101±6% of the KCl contractions, respectively). There was no difference in KCl-induced contractions in female and male pulmonary arteries (1.2±0.1 versus 1.3±0.1 g, respectively). In male rabbits, the vasoconstrictor responses to arachidonic acid and methacholine were inhibited by the cyclooxygenase inhibitor indomethacin. We have previously identified thromboxane A
2
as the endothelium-dependent contracting factor in male rabbits. However, indomethacin only partially inhibited arachidonic acid–induced contractions in female pulmonary arteries (maximal inhibition, 46% of the control response) suggesting that a noncyclooxygenase metabolite of arachidonic acid mediates contraction in female rabbits. Likewise, indomethacin only partially inhibited methacholine-induced contractions of female pulmonary arteries. The combined cyclooxygenase/lipoxygenase inhibitor BW 755C and the lipoxygenase inhibitor nordihydroguaiaretic acid completely blocked arachidonic acid–induced contractions in females. Furthermore, both basal and stimulated production of thromboxane B
2
, as measured by radioimmunoassay, were similar in female and male pulmonary arteries. When segments of pulmonary arteries obtained from female and male rabbits were incubated with
14
C-arachidonic acid and the extracted metabolites were resolved by reverse-phase high-performance liquid chromatography, there was an enhanced production of metabolites in females. Pretreatment with indomethacin attenuated metabolism of all products in the males but enhanced production of some compounds in vessels from the females. These observations suggest that the enhanced vasoconstrictor response to arachidonic acid in female pulmonary arteries is due to a lipoxygenase metabolite of arachidonic acid.
Effects of Increased Pulse Pressure on Cerebral Arterioles
Authors: Baumbach Gary L.
Published: June 2012

Abstract
The goal of this study was to examine the hypothesis that increases in pulse pressure produce hypertrophy of cerebral arterioles, even in the absence of increases in mean pressure. Sprague-Dawley rats underwent creation of an arteriovenous fistula and clipping of one carotid artery at 1 month of age. Rats that underwent exposure of the abdominal aorta without fistula production and unilateral carotid clipping served as controls. At about 6 months of age, the mechanics of sham and clipped pial arterioles were examined in vivo in anesthetized rats. Stress-strain relations were calculated from measurements of pial arteriolar pressure (servo null) and diameter and cross-sectional area of the arteriolar wall. Point counting stereology was used to quantify individual components in the arteriolar wall. Before deactivation of smooth muscle with EDTA, cross-sectional areas of the vessel wall and pulse pressures in sham pial arterioles were significantly greater (
P
<.05) in arteriovenous fistula rats than in control rats (cross-sectional area, 1468±100 versus 1129±104 μm
2
; pulse pressure, 26±1 versus 14±1 mm Hg). In contrast, systolic and mean pressures in sham arterioles were not significantly different and diastolic pressure was significantly less in arteriovenous fistula rats (systolic pressure, 69±1 versus 67±4 mm Hg; mean pressure, 52±2 versus 57±3 mm Hg; diastolic pressure, 43±2 versus 53±3 mm Hg). Carotid clipping normalized cross-sectional area of the vessel wall (1083±86 μm
2
) and pulse pressure (12±1 mm Hg) in pial arterioles of arteriovenous fistula rats. During maximal dilatation, the stress-strain curve in sham arterioles of arteriovenous fistula rats was shifted to the right of the curve in control rats, which indicates that arteriovenous fistulae increase passive distensibility of cerebral arterioles. The proportion of distensible components in the vessel wall (smooth muscle, elastin, and endothelium) was increased in sham arterioles of arteriovenous fistula rats. These findings (1) suggest that increases in pulse pressure, even in the absence of increases in mean pressure, are sufficient to produce hypertrophy of cerebral arterioles and (2) provide support for the concept that increases in distensibility of cerebral arterioles in association with hypertrophy of the vessel wall may be related to alterations in wall composition.
Validation of Carotid Artery Tonometry as a Means of Estimating Augmentation Index of Ascending Aortic Pressure
Authors: Chen Chen-Huan , Ting Chih-Tai , Nussbacher Amit , Nevo Erez , Kass David A. , Pak Peter , Wang Shih-Pu , Chang Mau-Song , Yin Frank C.P.
Published: June 2012

Abstract
Our objective was to validate a carotid artery tonometry–derived augmentation index as a means to estimate augmentation index (AI) of ascending aortic pressure under various physiological conditions. A total of 66 patients (50 men, 16 women; mean age, 55 years; range, 21 to 78 years; 44 in Taiwan and 22 in the Unites States) undergoing diagnostic catheterization were studied. Arterial pressure contours were obtained simultaneously from the right common carotid artery by applanation tonometry with an external micromanometer-tipped probe and from the ascending aorta by a micromanometer-tipped catheter at baseline (n=62), after handgrip (n=36), or after sublingual nitroglycerin administration (n=17). The AI (expressed as percentage values) was calculated as the ratio of amplitude of the pressure wave above its systolic shoulder to the total pulse pressure. The carotid AI was consistently lower than the aortic AI, but the two were highly correlated at baseline and after both handgrip and nitroglycerin. Mean±SD and correlation coefficients were baseline (14±16, 28
+
±17, .77), handgrip (18±19, 32
+
±15, .86), and nitroglycerin (7±12, 18
+
±13, .52). In addition, after adjusting for age, sex, height, blood pressure, heart rate, and study site, the changes of both AIs from baseline values with handgrip or nitroglycerin were highly associated such that the aortic AI could be approximated from the carotid AI with appropriate regression equations. The high correlations and predictable changes after interventions between the central AI and those estimated from noninvasive carotid tonometry suggest that this technique may have wide applicability for many cardiovascular studies.
ACE Inhibition Prevents and Reverses L-NAMEExacerbated Nephrosclerosis in Spontaneously Hypertensive Rats
Authors: Ono Hidehiko , Ono Yuko , Frohlich Edward D.
Published: June 2012

Abstract
Chronic nitric oxide inhibition exacerbates hypertension and nephrosclerosis in spontaneously hypertensive rats (SHRs). In this study, we determined whether angiotensin-converting enzyme (ACE) inhibition could prevent or reverse the systemic, renal, and glomerular hemodynamic alterations and the pathological changes of nephrosclerosis. Four groups of 20-week-old SHRs were studied: group 1, untreated controls; group 2, treated with
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, 50 mg/L for 3 weeks); group 3, L-NAME cotreated with quinapril (3 mg·kg
−1
·d
−1
for 3 weeks); and group 4, L-NAME for 3 weeks followed by quinapril for 3 weeks (same doses). The results of this study demonstrated that both cotreatment (group 3) and posttreatment (group 4) with quinapril reduced mean arterial pressure (186±9 and 192±9 mm Hg, respectively, compared with group 2 SHRs, 221±5 mm Hg) and total peripheral resistance index associated with significant reductions in afferent and efferent arteriolar resistances; nephrosclerosis pathological scores; and urinary protein excretion (all at least
P
<.01). ACE inhibition also significantly increased stroke index, single-nephron glomerular filtration rate, and ultrafiltration coefficient compared with the L-NAME SHRs. Most notable were the findings that cotreatment with quinapril completely prevented the renal glomerular hemodynamic alterations with reduced glomerular capillary hydrostatic pressure and efferent arteriolar resistance compared with both the untreated and the L-NAME–treated SHRs (all at least
P
<.01). Posttreatment with quinapril also reversed the glomerular injury (subcapsular, −83%; juxtamedullary, −56%) and arteriolar (−87%) injury scores obtained from renal biopsy specimens (
P
<.005 and
P
<.0001, respectively). These changes were associated with decreased periarteriolar fibronectin and increased afferent arteriolar α-smooth muscle actin deposition (immunohistochemistry). These data, therefore, demonstrate that ACE inhibition not only prevents but also reverses L-NAME–exacerbated severe nephrosclerosis in SHRs, as indicated by improved systemic, renal, and glomerular hemodynamic changes, proteinuria, and histological alterations.
Increased Vasoconstrictor Sensitivity to Glucocorticoids in Essential Hypertension
Authors: Walker Brian R. , Best Ruth , Shackleton Cedric H.L. , Padfield Paul L. , Edwards Christopher R.W.
Published: June 2012

Abstract
Glucocorticoids raise blood pressure but were thought not to play a pathophysiological role in essential hypertension when it was demonstrated that cortisol secretion rates and circulating concentrations are normal in this disease. However, recent observations suggest that increased tissue sensitivity to cortisol, mediated by either abnormal glucocorticoid receptors or impaired inactivation of cortisol by 11β-dehydrogenase, may allow cortisol to raise blood pressure despite normal circulating concentrations. We studied 11 patients with essential hypertension and 11 matched normotensive control subjects. Dermal vasoconstriction after topical application of both cortisol (16±4 versus 32±5 U, control subjects versus hypertensive patients;
P
<.02) and beclomethasone dipropionate (75±10 versus 100±7 U;
P
<.05) was increased in the hypertensive patients. Hypothalamic-pituitary glucocorticoid receptor sensitivity was normal, as judged by basal cortisol secretion rates and suppression of plasma cortisol during sequential overnight dexamethasone suppression tests. 11β-Dehydrogenase activity was impaired in essential hypertension, as judged by prolonged half-lives of [11α-
3
H]cortisol (44±4 versus 58±4 minutes, control subjects versus hypertensive patients;
P
<.02). However, this did not correlate with the dermal vasoconstrictor response. We conclude that vasoconstrictor sensitivity to glucocorticoids is increased in essential hypertension and that this may initiate and/or sustain the increased peripheral vascular resistance that characterizes this disease. The mechanism of increased sensitivity remains uncertain, but it will be important to establish whether it relates to genetic abnormalities of the glucocorticoid receptor that have been observed in animal models and young individuals who are predisposed to essential hypertension.
Pathophysiological Consequences of Changes in the Coupling Ratio of Na,K-ATPase for Renal Sodium Reabsorption and Its Implications for Hypertension
Authors: Orosz David E. , Hopfer Ulrich
Published: June 2012

Abstract
Recent reports indicate that α1-Na,K-ATPase from Dahl salt-sensitive (DS) rats contains a glutamine for leucine substitution associated with increased Na-K coupling at unchanged maximal velocity. Genetic analyses suggest that α1-Na,K-ATPase is a potential hypertension gene. Therefore, we investigated whether renal Na
+
metabolism could constitute a pathophysiological link between the molecular/functional change in Na,K-ATPase and hypertension. We simulated the consequences of increased Na-K coupling on overall Na-bicarbonate reabsorption in a proximal tubular transport model that incorporates apical Na-H exchanger and basolateral Na-bicarbonate cotransporter, K
+
channel, and Na,K-ATPase. As expected, increases in the levels of the former three transport pathways yielded higher Na
+
reabsorption. In contrast, increases in the maximal velocity of the Na,K-ATPase with a normal 3:2 (Na-K) coupling ratio did not increase Na
+
reabsorption when apical Na-H exchange activity was limiting overall absorption. However, an increase in the Na-K coupling from 3:2 to 3:1, reported for the mutant α1-Na,K-ATPase in DS rats, was associated with greater Na
+
reabsorption. This increase is a consequence of lower cytosolic pH and secondary stimulation of the Na-H exchanger at its allosteric H
+
site. Decreased pH results from activation of Na-bicarbonate cotransport by Na,K-ATPase–dependent membrane hyperpolarization due to greater charge movement in 3:1 Na-K coupling. Thus, an increase in the Na-K coupling ratio results in an altered set point for cellular Na
+
metabolism, with higher sodium reabsorption at unchanged Na,K-ATPase levels. The simulations thereby lend support for a unifying explanation for the salt sensitivity of DS rats, which has been proposed to stem from a mutation in the α1-Na,K-ATPase.
Protein Kinase C Modulation of Cardiomyocyte Angiotensin II and Vasopressin Receptor Desensitization
Authors: Zhang Min , Turnbaugh Donald , Cofie Daniel , Dogan Selami , Koshida Hideo , Fugate Robert , Kem David C.
Published: June 2012

Abstract
Angiotensin II (Ang II) and arginine vasopressin (AVP) increased intracellular free Ca
2+
concentration [Ca
2+
]
i
and/or the [Ca
2+
]
i
transient rate (CaTR) in cultured neonatal rat cardiomyocytes. These agents increased membrane-bound protein kinase C (PKC) with peak activity at 5 and 10 minutes, respectively. Two-minute exposure to Ang II produced homologous desensitization to a repeated stimulation with Ang II and heterologous desensitization to AVP. Two-minute exposure to AVP also produced homologous desensitization to AVP but not heterologous desensitization to Ang II. When the AVP exposure time was increased from 2 to 10 minutes coincident with maximal AVP-mediated PKC activation, heterologous desensitization to Ang II was also observed. Acute activation (15 minutes) of PKC by phorbol 12-myristate 13-acetate (PMA) blocked responsiveness to both Ang II and AVP. When PKC activation was inhibited by 20 hours of prior exposure to PMA, as confirmed by PKC assay, homologous desensitization of Ang II still occurred, confirming an alternative mechanism(s) for homologous desensitization in the cardiomyocytes. In contrast, 20-hour PMA suppression of PKC markedly diminished the ability of the cardiomyocytes to exhibit AVP-mediated heterologous desensitization for Ang II. These data indicate that PKC activation plays a primary role in mediating vasopressin V
1
receptor–induced heterologous desensitization of the Ang II receptor and participates in a hierarchy of two or more kinase systems mediating homologous desensitization of the Ang II receptor in cardiomyocytes.
Serum Fatty Acids and Blood Pressure
Authors: Simon Joel A. , Fong Josephine , Bernert John T.
Published: June 2012

Abstract
To examine the relation between serum fatty acids and blood pressure, we conducted a cross-sectional study of 156 men who were enrolled in the Multiple Risk Factor Intervention Trial. After confirming the stability of the stored serum samples, we measured serum fatty acid levels by gas-liquid chromatography and examined their association with blood pressure. Using stepwise linear regression, we determined that each SD increase (1.9%) in the serum level of cholesterol ester palmitoleic acid (16:1) was associated with a systolic pressure increase of 3.3 mm Hg (95% confidence interval, 0.9 to 5.6 mm Hg) and each SD increase (0.1%) in phospholipid ω9 eicosatrienoic acid (20:3) was associated with a diastolic pressure increase of 1.7 mm Hg (95% confidence interval, 0.5 to 2.9 mm Hg). Serum level of cholesterol ester stearic acid (18:0) was inversely associated with diastolic pressure: each SD increase (0.2%) was associated with a decrease of 1.4 mm Hg (95% confidence interval, −2.5 to –0.2 mm Hg). In multivariate models that included dietary fat intake, cholesterol ester dihomogammalinolenic acid (20:3) was also associated with diastolic pressure: each SD increase (0.16%) was associated with an increase of 1.2 mm Hg (95% confidence interval, 0.1 to 2.4 mm Hg). Our results indicate that three nonessential fatty acids—stearic acid, palmitoleic acid, and ω9 eicosatrienoic acid, and one essential fatty acid—dihomogammalinolenic acid, are independent correlates of blood pressure among middle-aged American men at high risk of coronary heart disease.
Weights at Birth and in Early Infancy, Systolic Pressure, and Left Ventricular Structure in Subjects Aged 8 to 24 Years
Authors: Zureik Mahmoud , Bonithon-Kopp Claire , Lecomte Edith , Siest Gérard , Ducimetière Pierre
Published: June 2012

Abstract
The objective of this study was to determine whether systolic pressure and left ventricular mass in children, adolescents, and young adults are related to fetal and infant growth. Blood pressure measurements and M-mode echocardiography were performed in 210 subjects aged 8 to 24 years whose information on weights at birth and in early infancy, written by physicians, was obtained from the children’s health record booklets. Systolic pressure, adjusted for sex and current height or for sex, current age, weight, and height, was the highest in subjects with low birth weight. No association was observed between systolic pressure and weight at either 9 months or 2 years. Left ventricular mass, adjusted for sex and current height or for sex, current age, weight, and height, increased with decreasing weight at 9 months or 2 years, independent of systolic pressure. Increased ventricular mass associated with reduced infant growth was concentric, resulting from a proportionate thickening of the posterior wall and interventricular septum. Left ventricular mass was not related to birth weight. These findings were observed in both sexes and in all age subgroups and were independent of gestational age, birth order, and parental risk factors. This study supports the hypothesis that systolic pressure and left ventricular mass might be partly determined during fetal life and early infancy. The mechanisms that underlie the associations of blood pressure and left ventricular structure with weights at birth and in early infancy should be studied thoroughly.
Sodium Intake Markedly Alters Renal Interstitial Fluid Adenosine
Authors: Siragy Helmy M. , Linden Joel
Published: June 2012

Abstract
Adenosine is produced locally in the kidney. Accumulating data suggest that adenosine plays a role in regulating renal functions. Using a microdialysis technique, we monitored adenosine levels in cortical and medullary renal interstitial fluid and urine after 5 days of diets containing low (0.15%), normal (0.28%), and high (4.0%) sodium. Samples were collected from anesthetized rats (n=5 for each diet). Microdialysis fluid was infused at a rate of 1 μL/min. Adenosine, measured by radioimmunoassay, was stable in the dialysate. During normal sodium intake, renal interstitial fluid adenosine estimated from the concentration in dialysate leaving the cortex was 63±6 nmol/L, which was significantly lower than in dialysate leaving the medulla (157±6 nmol/L,
P
<.01). The concentration of interstitial medullary adenosine was estimated to be 190 nmol/L. In rats consuming a low sodium diet, renal cortical and medullary dialysate adenosine concentrations were significantly decreased (
P
<.01) by 62.6% and 64.9%, respectively. Rats consuming a high sodium diet had renal cortical and medullary dialysate adenosine concentrations that were increased 18.2- and 18.9-fold, respectively (
P
<.01), compared with levels in rats on a low sodium diet. Similar to changes in dialysate adenosine, urinary adenosine concentration decreased during low sodium intake (
P
<.01) and increased during high sodium intake (
P
<.01). The higher adenosine levels in renal medullary than in cortical interstitial fluid may reflect its major renal site of generation. The changes in renal adenosine generation with sodium intake may reflect renal energy expenditure.
Factors That Affect Calorie-Sensitive and Calorie-Insensitive Reduction in Blood Pressure During Short-term Calorie Restriction in Overweight Hypertensive Women
Authors: Kawamura Minoru , Adachi Toshiyuki , Nakajima Jun , Fujiwara Takuya , Hiramori Katsuhiko
Published: June 2012

Abstract
This study was performed to elucidate the factors that affect the reduction in blood pressure produced by calorie restriction in overweight women with essential hypertension. Fifty-one subjects were admitted to the metabolic ward of the hospital. After being fed a standard diet (6.3 to 8.4 MJ/d) for 2 weeks, the calorie-restricted group (n=34) was fed a low-calorie diet (1.9 MJ/d) for an additional 2 weeks. The calorie-nonrestricted group (n=17) was fed the standard diet for 4 weeks. Sodium and potassium intake was kept constant, as was the level of exercise activity. The calorie-restricted group was subdivided into “calorie-sensitive” and “calorie-insensitive” groups based on an average 5 mm Hg reduction in mean blood pressure during the low-calorie diet. The mean age was 51±6 years (mean±SD) in the calorie-sensitive group (n=16), which was significantly lower than the mean age of 61±6 years in the calorie-insensitive group (n=18). Multiple regression analysis indicated that age and change in body weight exhibited significant correlations with blood pressure reduction produced by calorie restriction among 17 parameters. Findings suggest that age can predict the extent of blood pressure reduction that would be obtained during 2 weeks of calorie restriction in overweight hypertensive women. The reduction in blood pressure may be related in part to the amount of weight loss.
Ambulatory Monitoring Uncorrected for Placebo Overestimates Long-term Antihypertensive Action
Authors: Staessen Jan A. , Thijs Lutgarde , Bieniaszewski Leszek , O’Brien Eoin T. , Palatini Paolo , Davidson Christopher , Dobovisek Jurij , Jääskivi Matti , Laks Tovio , Lehtonen Aapo , Vanhanen Hannu , Webster John , Fagard on Behalf of the Systolic Hypertension in Europe (SYS Robert
Published: June 2012

Abstract
This study compares blood pressure (BP) changes during active antihypertensive treatment and placebo as assessed by conventional and ambulatory BP measurement. Older patients (≥60 years, n=337) with isolated systolic hypertension by conventional sphygmomanometry at the clinic were randomized to placebo or active treatment consisting of nitrendipine (10 to 40 mg/d), with the possible addition of enalapril (5 to 20 mg/d) and/or hydrochlorothiazide (12.5 to 25 mg/d). At baseline, clinic systolic/diastolic BP averaged 175/86 mm Hg and 24-hour and daytime ambulatory BPs averaged 148/80 and 154/85 mm Hg, respectively. After 13 months (median) of active treatment, clinic BP had dropped by 22.7/7.0 mm Hg and 24-hour and daytime BPs by 10.5/4.5 and 9.7/4.3 mm Hg, respectively (
P
<.001 for all). However, clinic (9.8/1.6 mm Hg), 24-hour (2.1/1.1 mm Hg), and daytime (2.9/1.0 mm Hg) BPs decreased also during placebo (
P
<.05, except for daytime diastolic BP); these decreases represented 43%/23%, 20%/24%, and 30%/23% of the corresponding BP fall during active treatment. After subtraction of placebo effects, the net BP reductions during active treatment averaged only 12.9/5.4, 8.3/3.4, and 6.8/3.2 mm Hg for clinic, 24-hour, and daytime BPs, respectively. The effect of active treatment was also subject to diurnal variation (
P
<.05). Changes during placebo in hourly systolic and diastolic BP means amounted to (median) 21% (range, −1% to 42%) and 25% (−3% to 72%), respectively, of the corresponding changes during active treatment. In conclusion, expressed in millimeters of mercury, the effect of antihypertensive treatment on BP is larger with conventional than with ambulatory measurement. Regardless of whether BP is measured by conventional sphygmomanometry or ambulatory monitoring, a substantial proportion of the long-term BP changes observed during active treatment may be attributed to placebo effects. Thus, ambulatory monitoring uncorrected for placebo or control observations, like conventional sphygmomanometry, overestimates BP responses in clinical trials of long duration.
Antihypertensive Properties of the Novel Calcium Antagonist Mibefradil (Ro 40-5967)
Authors: Bernink Peter J.L.M. , Prager Gerold , Schelling Arie , Kobrin Isaac
Published: June 2012

Abstract
Preclinical and initial clinical studies suggest that the novel calcium antagonist mibefradil has a unique combination of properties. Mibefradil was evaluated in a multicenter, double-blind, placebo-controlled, parallel group trial. After 4 weeks of a placebo run-in period, 202 eligible patients with mild to moderate hypertension were randomized to receive doses of 25, 50, 100, or 150 mg mibefradil or placebo once a day for 4 weeks. Blood pressure and heart rate were measured repeatedly at trough and peak (24 and 2 to 6 hours postdose, respectively) at the end of each period. Concentration-effect relationships were evaluated at trough on the last treatment day. A significant (
P
<.01 versus placebo) drop in blood pressure (diastolic and systolic) was observed at trough and peak in all mibefradil groups, with a trough-peak ratio greater than 0.8, high response rate, and a significant dose-response relationship (
P
<.001). The full antihypertensive effect of mibefradil was achieved within 1 to 2 weeks and was associated with a slight dose-dependent decrease in heart rate and increase in PQ time. Clear dissociation was observed between the effect on blood pressure and PQ time when concentration-effect relationships were evaluated. These results indicate that mibefradil is an effective and well-tolerated antihypertensive compound at doses of 25, 50, and 100 mg once daily. The incidence of treatment-related adverse events observed in the 25-, 50-, and 100-mg dose groups was lower than in the placebo group, but it was slightly higher in the 150-mg dose group, and three patients from this group were prematurely withdrawn because of an adverse event.
Altered c
-fos
in Rostral Medulla and Spinal Cord of Spontaneously Hypertensive Rats
Authors: Minson Jane , Arnolda Leonard , Llewellyn-Smith Ida , Pilowsky Paul , Chalmers John
Published: June 2012

Abstract
Neurons immunoreactive for Fos, the protein product of the immediate early gene c-
fos
, have been compared in the rostral ventral medulla and spinal cord of conscious normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) after baroreceptor unloading. Hypotension induced by a 60-minute intravenous infusion of sodium nitroprusside reduced baroreceptor activity; controls received intravenous saline. In WKY, 474±56 (n=6) Fos-positive neurons were identified in the rostral ventral medulla after nitroprusside infusion, a fivefold increase from controls; 50% of the tyrosine hydroxylase–containing neurons in the rostral ventral medulla were activated by this hypotension. Sympathetic preganglionic neurons, mainly sympathoadrenal neurons, were Fos positive after nitroprusside, but Fos-positive sympathetic preganglionic neurons were not observed in control WKY. In SHR, Fos immunoreactivity in the rostral ventral medulla was elevated in the control group compared with the WKY controls (236±31 and 93±15, respectively, n=6 for both). Nitroprusside hypotension did not further increase Fos immunoreactivity in the rostral ventral medulla, although the number of Fos-positive spinal sympathetic neurons increased. Our results have identified different neuronal activities between WKY and SHR in sites that are critical to sympathetic outflow. In WKY, nitroprusside effects are consistent with an activation of rostral ventral medulla neurons, including bulbospinal neurons, that are normally inhibited by baroreceptor activity. In SHR, basal nerve activity is increased, so even at rest, rostral ventral medulla neurons and sympathetic preganglionic neurons, mainly sympathoadrenal neurons, are Fos immunoreactive. These activated neurons are likely to contribute to the elevated blood pressure in this rat strain.
Correlations of Na
+
-Li
+
Exchange Activity With Na
+
and Li
+
Binding and Phospholipid Composition in Erythrocyte Membranes of White Hypertensive and Normotensive Individuals
Authors: Chi Yuling , de Freitas Duarte Mota , Sikora Mary , Bansal Vinod K.
Published: June 2012

Abstract
Enhanced Na
+
-Li
+
exchange activity has been reported in red blood cells (RBCs) of white patients with essential hypertension compared with RBCs of normotensive individuals. To understand the factors responsible for this finding, we applied novel and conventional spectroscopic and kinetic methods to blood samples from 10 hypertensive and 10 normotensive individuals. We measured the kinetic parameters (
V
std
,
V
max
, and
K
m
) for RBC Na
+
-Li
+
exchange by atomic absorption spectrophotometry and used
23
Na and
7
Li nuclear magnetic resonance relaxation methods to measure Na
+
and Li
+
binding to RBC membranes as well as
31
P nuclear magnetic resonance spectroscopy to measure membrane phospholipid compositions. We found significant differences between the two groups for the affinity of Na
+
for the RBC membrane (0.202±0.054 mmol/L
−1
for hypertensive patients versus 0.296±0.071 mmol/L
−1
for normotensive subjects,
P
<.005). The kinetic parameters of RBC Na
+
-Li
+
exchange (
V
std
,
V
max
, and
K
m
) were 0.32±0.09 and 0.66±0.17 mmol Li
+
/L cell·h and 160±62 mmol/L, respectively, for hypertensive patients versus 0.21±0.06 and 0.32±0.14 mmol Li
+
/L cell·h and 86±69 mmol/L for normotensive subjects (
P
<.05). The fractions of phosphatidylserine and phosphatidylethanolamine were 0.153±0.009 and 0.294±0.016 for hypertensive patients versus 0.138±0.013 and 0.325±0.018 for normotensive subjects (
P
<.05). The Na
+
binding constants were negatively correlated with the
K
m
values for both the hypertensive (
r
=−.61,
P
=.01) and normotensive (
r
=−.43,
P
=.04) groups. Changes in lipid-protein interactions in the RBC membranes of hypertensive patients appear to be responsible for weaker Na
+
binding to the membrane and for the faster rates of RBC Na
+
-Li
+
exchange.
cDNA Cloning and Gene Expression of Human Type Iα cGMP-Dependent Protein Kinase
Authors: Tamura Naohisa , Itoh Hiroshi , Ogawa Yoshihiro , Nakagawa Osamu , Harada Masaki , Chun Tae-Hwa , Suga Shin-ichi , Yoshimasa Takaaki , Nakao Kazuwa
Published: June 2012

Abstract
The type I cGMP-dependent protein kinase (cGK) is one of the major pathways for the cGMP cascade and has been demonstrated to inhibit platelet aggregation, relax smooth muscle cells, and control cardiocyte contractility. There are two subtypes of the type I cGK, cGKIα and cGKIβ. The former is more sensitive to cGMP than the latter. In humans, cGKIβ cDNA was isolated, but the full structure and tissue-specific gene expression of cGKIα have not been determined. The significance of cGK in human cardiovascular diseases has not been investigated at the molecular level. In the present study, we isolated the full-length human cGKIα cDNA (−36 to +2177; the translation start site: +1) encoding the 671–amino acid protein. Nucleotides +267 to +2177 of the isolated cDNA were identical to the corresponding nucleotides of human cGKIβ cDNA. Southern blot analysis suggested that human cGKIα and cGKIβ are generated by alternative splicing of a single gene assigned to chromosome 10. By Northern blot analysis, we detected abundant human cGKIα mRNA (7.0 kb) in the aorta, heart, kidneys, and adrenals. In contrast, human cGKIβ mRNA (7.0 kb) was detected abundantly only in the uterus. In cultured vascular smooth muscle cells, the type I cGK mRNA concentration was reduced to 10% of the basal level by 4×10
−10
mol/L platelet-derived growth factor. Angiotensin II (10
−8
mol/L), transforming growth factor-β (4×10
−11
mol/L), and tumor necrosis factor-α (6×10
−6
mol/L) also exhibited an inhibitory effect on type I cGK gene expression. These findings suggest a pathophysiological implication of the type I cGK in cardiovascular diseases, including hypertension and atherosclerosis.
Cytochrome P4504A Genotype Cosegregates With Hypertension in Dahl S Rats
Authors: Stec David E. , Deng Alan Y. , Rapp John P. , Roman Richard J.
Published: June 2012

Abstract
Recent studies indicate that the production of 20-HETE by a P4504A2 enzyme in the outer medulla of the kidney is reduced in Dahl salt-sensitive (SS/Jr) rats, but the contribution of this abnormality to the elevation in loop Cl
−
transport and development of hypertension in this model is unknown. The present study found that alleles at the locus for the
P4504A2
gene cosegregate with blood pressure in an F
2
population (n=151) derived from a cross between SS/Jr and Lewis rats (
P
<.0001). The P4504A2 locus is located in a region on rat chromosome 5 where a blood pressure quantitative trait locus was previously detected. Systolic blood pressure averaged 201±6 mm Hg in rats with the SS genotype (n=36), 192±4 mm Hg in SL genotype rats (n=77), and 169±3 mm Hg in LL genotype rats (n=38). In further studies, we confirmed that there are phenotypic differences in the expression of the
P4504A2
gene in the kidneys of SS/Jr and Lewis rats. Although the production of 20-HETE from
14
C-arachidonic acid was similar in microsomes prepared from the renal cortex of SS/Jr and Lewis rats (54±3 versus 55±3 pmol·min
−1
·mg protein
−1
), the production of 20-HETE in microsomes prepared from the outer medulla (OM) was markedly reduced in SS/Jr rats (2.8±0.8 versus 6.7±1 pmol·min
−1
·mg protein
−1
). The diminished production of 20-HETE in the OM was due to a threefold reduction in the level of P4504A2 protein. These results suggest that an altered expression of the P4504A2 enzyme in the OM may contribute to the development of hypertension in SS/Jr rats.
Role of Renal Nerves in Mediating the Hypertensive Effects of Nitric Oxide Synthesis Inhibition
Authors: Granger Joey , Novak Jacqueline , Schnackenberg Christine , Williams Stuart , Reinhart Glenn A.
Published: June 2012

Abstract
Recent studies suggest that enhanced renal sympathetic nervous activity plays an important role in mediating the renal hemodynamic and electrolyte excretion changes associated with acute inhibition of NO synthesis. The purpose of this study was to determine the importance of renal nerves in mediating the long-term hypertensive and renal actions of NO synthesis blockade. To achieve this goal, we infused
N
G
-nitro-
l
-arginine methyl ester (L-NAME) at a rate of 25 μg/kg per minute for 2 weeks in control dogs and in bilaterally renal-denervated dogs. NO synthesis blockade in control dogs increased arterial pressure by 18%, from 94±3 to 111±4 mm Hg, and decreased heart rate from 74±4 to 57±4 beats per minute (bpm). L-NAME also decreased renal plasma flow from 195±18 to 166±18 mL/min while having no effect on glomerular filtration rate (67±7 versus 63±6 mL/min). In the renal-denervated dogs, inhibition of NO synthesis increased arterial pressure by 14%, from 92±4 to 105±5 mm Hg, and decreased heart rate from 80±4 to 65±5 bpm. Renal plasma flow in this group decreased from 195±20 to 165±20 mL/min, whereas glomerular filtration rate remained unchanged (66±6 versus 64±6 mL/min). In addition, renal excretion of sodium and water in response to L-NAME was similar in each group. The results of this study indicate that the long-term hypertensive and renal effects of NO synthesis inhibition in the dog are not dependent on activation of the renal sympathetic nervous system.
Mechanism of the Nitric Oxide-Induced Blockade of Collecting Duct Water Permeability
Authors: García Néstor H. , Stoos Barbara A. , Carretero Oscar A. , Garvin Jeffrey L.
Published: June 2012

Abstract
Nitric oxide has a diuretic effect in vivo. We have shown that nitric oxide inhibits antidiuretic hormone–stimulated osmotic water permeability in the collecting duct; however, the mechanism by which this occurs is unknown. We hypothesized that inhibition of antidiuretic hormone–stimulated water permeability by nitric oxide in the collecting duct is the result of activation of cGMP-dependent protein kinase, which in turn decreases intracellular cAMP. To test this hypothesis, we microperfused cortical collecting ducts. Antidiuretic hormone–stimulated water permeability was 317±47 μm/s (
P
<.001). Addition of spermine NONOate, a nitric oxide donor, to the bath decreased water permeability to 74±38 μm/s (
P
<.002). In the presence of LY 83583, an inhibitor of soluble guanylate cyclase, spermine NONOate did not change water permeability. Addition of spermine NONOate increased cGMP production (
P
<.01). In the presence of the cGMP-dependent protein kinase inhibitor, spermine NONOate did not change water permeability. Since antidiuretic hormone increases water permeability by increasing cAMP, we hypothesized that nitric oxide inhibits water permeability by decreasing cAMP. In tubules pretreated with antidiuretic hormone, intracellular cAMP was 18.9±3.9 fmol/mm. In tubules treated with antidiuretic hormone and spermine NONOate, cAMP was 9.3±1.7 fmol/mm (
P
<.03). We also examined the effect of spermine NONOate on dibutyryl-cAMP–stimulated water permeability. In the presence of dibutyryl-cAMP, water permeability was 388±30 μm/s. Addition of spermine NONOate had no significant effect on water permeability. Time controls and inhibitors by themselves did not change antidiuretic hormone–stimulated water permeability. We concluded that nitric oxide decreases antidiuretic hormone–stimulated water permeability by increasing cGMP via soluble guanylate cyclase, activating cGMP-dependent protein kinase and decreasing cAMP.
Tissue-Specific Expression of the Human Brain Natriuretic Peptide Gene in Cardiac Myocytes
Authors: LaPointe Margot C. , Wu Guiyun , Garami Miklós , Yang Xiao-Ping , Gardner David G.
Published: June 2012

Abstract
Brain natriuretic peptide (BNP) is a cardiac hormone constitutively expressed in the adult heart. To identify the
cis
-acting elements involved in regulation of the human BNP gene, we subcloned the full-length promoter (−1818 to +100) and deletions thereof upstream from a luciferase reporter gene and transiently transfected them into primary cultures of neonatal rat atrial and ventricular myocytes and myocardial fibroblasts. Luciferase activity of the full-length construct was higher in ventricular (39 064±8488 relative light units, n=11) and atrial (11 225±1907, n=17) myocytes than myocardial fibroblasts (329±113, n=5). Maximal promoter activity in ventricular and atrial myocytes was maintained by sequences positioned between −1818 and −1283 relative to the transcription start site. Deletion to −1175 resulted in a decrease, whereas further deletion to −500 effected an increase in reporter activity in both cell types. In ventricular and atrial myocytes, deletion from −500 to −40 reduced luciferase activity 20-fold and 2-fold, respectively, whereas in myocardial fibroblasts, deletion to −40 upregulated the BNP promoter 2-fold. Of note, deleting 16 bp between −127 and −111 reduced luciferase activity 7-fold and 4-fold in ventricular and atrial myocytes, respectively, but had essentially no effect on luciferase activity in fibroblasts. Placement of sequences lying between −127 and −40 upstream from a heterologous thymidine kinase promoter resulted in reporter expression that was 7.4-fold greater than the vector alone in ventricular myocytes, approximately 2-fold greater in atrial myocytes, and equivalent to the vector alone in fibroblasts. For study of activity of the human BNP promoter in adult myocytes, either 408 or 97 bp of 5′ flanking sequence coupled to the luciferase reporter gene was injected into the apex of adult male Sprague-Dawley rat hearts. After 7 days, luciferase activity in the injected myocardium was 9.8-fold higher for the longer construct (70 683±14 744 versus 7223±3920, n=4,
P
<.01), consistent with our in vitro data. These data indicate that (1) the full-length human BNP promoter is more active in ventricular versus atrial myocytes and essentially inactive in fibroblasts, (2) the distal BNP promoter contains both positive and negative regulatory elements, (3) a region of the proximal BNP promoter located between −127 and −40 confers tissue specificity, and (4) the BNP promoter is active after injection into the adult rat heart.
Antihypertensive Mechanism of Diuretics Based on Pressure-Natriuresis Relationship
Authors: Saito Fumio , Kimura Genjiro
Published: June 2012

Abstract
We analyzed the hypotensive mechanisms of a thiazide-type diuretic, mefruside, on the basis of the pressure-natriuresis relationship. We performed a 5-week study in eight patients with essential hypertension who were given a high sodium diet (15 to 18 g NaCl per day) during the 1st and 5th weeks, a severely sodium-restricted diet (1 to 3 g/d) during the 2nd week, and a mildly sodium-restricted diet (5 to 7 g/d) during the 3rd and 4th weeks. Mefruside (25 mg/d) was administered during the 4th and 5th weeks. Urinary sodium excretion rate and mean arterial pressure were measured at the end of each week, and the pressure-natriuresis relationship was drawn by plotting urinary sodium excretion rate on the ordinate and mean arterial pressure on the abscissa before and after mefruside treatment. Before treatment, the pressure-natriuresis relationship was linear, and mean arterial pressure was changed as a consequence of sodium intake alteration (1st week, 117±9 mm Hg; 2nd week, 105±7; 3rd week, 109±9). After treatment, however, the change in mean arterial pressure was very small (4th week, 102±8 mm Hg; 5th week, 104±7). Mefruside steepened the slope of the relationship (20.8±10.5 versus 143±85 [mmol/d]/mm Hg,
P
<.005) without significantly shifting the
x
intercept (104±6 versus 101±9 mm Hg,
P
=NS) of the relationship. The increase in the slope was greater in patients whose slope had been depressed and blood pressure was sodium sensitive before mefruside treatment. The hypotensive effect of mefruside during a high sodium diet correlated positively with both the hypotensive effect of sodium restriction (
r
=.84,
P
<.01) and the increase in the slope by mefruside (
r
=.83,
P
<.02). Thus, mefruside lowers blood pressure especially in patients with high sodium sensitivity mainly by making blood pressure sodium insensitive through its diuretic action. Strict sodium restriction seems unnecessary when diuretics are administered for blood pressure control.
Hypothalamic Lesions Induce Obesity and Sex-Dependent Glomerular Damage and Increases in Blood Pressure in Rats
Authors: Baylis Chris , Samsell Lennie , Racusen Lorraine , Gladfelter Wil
Published: June 2012

Abstract
Placement of two symmetrical lesions in the ventromedial hypothalamus of the rat causes massive overeating and obesity. We have studied male (n=8) and female (n=5) Munich-Wistar rats 7 months after induction of obesity and compared them with age-matched controls. Body weight and kidney weight were greater in control males versus females (396±7 and 1.5±0.1 g versus 229±4 and 1.0±0.1 g, respectively; both
P
<.001). Both obese males and females were heavier than lean counterparts (592±30 and 361±19 g, both
P
<.001), whereas kidney weight was similar between obese and control rats of each sex (obese males, 1.5±0.1 g; obese females, 1.1±0.1 g). Blood pressure was higher in obese versus control males; there were no differences between other groups. Single-nephron glomerular filtration rate was similar in control females and males and obese females but depressed in obese males. Glomerular blood pressure was normal in all groups. Urinary protein excretion and the percentage of sclerosed glomeruli were similar in control females and males and obese females but elevated in obese males. Plasma triglyceride levels were elevated in obesity, particularly in males. We conclude that hypothalamic lesioning induces overeating and obesity and selectively in the male causes hypertension and glomerular damage as well as declines in renal function. This injury is not hemodynamically mediated (glomerular blood pressure is normal) but may be related to the elevation in plasma triglyceride levels, which has previously been causally linked to glomerular damage in genetically obese rats.
Plasma and Renal Prorenin/Renin, Renin mRNA, and Blood Pressure in Dahl Salt-Sensitive and Salt-Resistant Rats
Authors: Campbell Wallace G. , Gahnem Fuad , Catanzaro Daniel F. , James Gary D. , Camargo Maria J. F. , Laragh John H. , Sealey Jean E.
Published: June 2012

Abstract
We measured plasma prorenin and renin levels, renal renin mRNA, renal anti-renin and anti–prorenin-prosequence immunoreactivity, and blood pressure in maturing Brookhaven Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats during 14 days of low (0%), medium (0.4%), or high (4%) NaCl diets. Blood pressure was higher in Dahl S rats and did not increase with high NaCl. Seven-week-old Dahl R rats had twofold and sixfold higher levels of plasma prorenin and renal prosequence immunoreactivity, respectively, which by 9 weeks were the same as in Dahl S rats. The anti-renin antiserum, BR1-5, was found to detect prorenin better than renin; Dahl S rats had suppressed renal anti-renin immunoreactivity relative to Dahl-R rats. Dahl R rats were unresponsive to high NaCl, whereas in Dahl S rats, plasma renin and renal prosequence immunoreactivity fell by 90% (
P
<.01), renal anti-renin immunoreactivity and renal renin mRNA fell by 35% (
P
<.05 for both), and plasma prorenin fell by 30% (
P
=NS). NaCl depletion increased prorenin/renin parameters similarly in both strains. There were direct relationships among all of the prorenin/renin parameters. Between low and high salt diets in Dahl S rats, plasma renin increased 20-fold, plasma total renin (renin plus prorenin) and renal renin mRNA both increased threefold, and plasma prorenin increased twofold. The results indicate that under steady-state conditions, plasma and renal renin/prorenin parameters change concordantly and that plasma total renin (renin plus prorenin) reflects changes in renal renin mRNA. The lower blood pressure of Dahl R rats is associated with later maturation-related declines in plasma and renal prorenin. Suppression of plasma renin may delay the salt-induced blood pressure rise in Dahl S rats. Finally, the renin system and blood pressure of Dahl R rats have remarkable disregard for a high salt diet.