bluuebunny/crossref_metadata_2025 huggingface dataset:
Lisinopril Reverses Left Ventricular Hypertrophy Through Improved Aortic Compliance
Authors: Shimamoto Hiroyuki , Shimamoto Yoriko
Published: June 2012

We treated with nifedipine or lisinopril 38 essential hypertensive patients with left ventricular hypertrophy. The study had a single-blind crossover design; nifedipine or lisinopril was given for the first 24 weeks, and then patients were crossed over to the other antihypertensive agent for another 24 weeks. Both nifedipine and lisinopril significantly decreased mean arterial pressure to the same extent. Although lisinopril decreased left ventricular mass index more rapidly than nifedipine, 48 weeks of antihypertensive treatment with nifedipine or lisinopril reduced the extent of left ventricular hypertrophy to the same level. Stepwise multiple linear regression analysis revealed that the reversal of left ventricular hypertrophy may be mainly due to a reduction in mean arterial pressure during the 24-week nifedipine treatment and due to an improvement of aortic compliance during the lisinopril treatment. Both nifedipine and lisinopril are effective in the reversal of hypertensive left ventricular hypertrophy; however, the agents have disparate actions on hemodynamic factors.
Nitrotyrosine Residues in Placenta
Authors: Myatt Leslie , Rosenfield Richard B. , Eis Annie L.W. , Brockman Diane E. , Greer Ian , Lyall Fiona
Published: June 2012

The interaction of nitric oxide and superoxide produces peroxynitrite anion, a strong, long-lived oxidant with pronounced deleterious effects that may cause vascular damage. The formation and action of peroxynitrite can be detected by immunohistochemical localization of nitrotyrosine residues. We compared the presence and localization of nitrotyrosine and of the endothelial isoform of nitric oxide synthase in placental villous tissue from normotensive pregnancies (n=5) with pregnancies complicated by preeclampsia (n=5), intrauterine growth restriction (n=5), and preeclampsia plus intrauterine growth restriction (n=4), conditions characterized by increases in fetoplacental vascular resistance, fetal platelet consumption, and fetal morbidity and mortality. In all tissues, absent or faint nitrotyrosine immunostaining but prominent nitric oxide synthase immunostaining were found in syncytiotrophoblast. In tissues from normotensive pregnancies, faint nitrotyrosine immunostaining was found in vascular endothelium, and nitric oxide synthase was present in stem villous endothelium but not in the terminal villous capillary endothelium. In contrast, in preeclampsia and/or intrauterine growth restriction, moderate to intense nitrotyrosine immunostaining was seen in villous vascular endothelium, and immunostaining was also seen in surrounding vascular smooth muscle and villous stroma. The intensity of nitrotyrosine immunostaining in preeclampsia (with or without intrauterine growth restriction) was significantly greater than that of controls. Intense nitric oxide synthase staining was seen in endothelium of stem villous vessels and the small muscular arteries of the terminal villous region in these tissues and may be an adaptive response to the increased resistance. The presence of nitrotyrosine residues, particularly in the endothelium, may indicate the formation and action of peroxynitrite, resulting in vascular damage that contributes to the increased placental vascular resistance.
Myocyte Remodeling During the Progression to Failure in Rats With Hypertension
Authors: Gerdes A. Martin , Onodera Tatsuyuki , Wang Xuejun , McCune Sylvia A.
Published: June 2012

Regional changes in cardiac myocyte shape during the progression to failure with hypertension have not been clearly established. To address this issue, we examined left and right ventricular myocytes from lean, female spontaneously hypertensive/heart failure rats with compensated hypertrophy (approximately 12 months of age) and congestive heart failure (approximately 24 months of age). During this period, body weight did not change, but heart weight increased 59% and lung weight increased 93%. Left ventricular function declined with the onset of failure. Left ventricular myocyte volume increased 27% exclusively because of myocyte lengthening (29% increase). The onset of left ventricular failure resulted in a 72% increase in right ventricular myocyte volume. Right ventricular myocyte growth, however, was proportional, with a 23% increase in myocyte length and 18% increase in myocyte width. Changes in left ventricular myocyte shape were virtually identical to data collected previously from patients with similar disease, suggesting that this is a relevant animal model. Evidence suggests that left ventricular myocyte transverse growth is defective because dilation and failure were associated with cell lengthening, without a change in myocyte diameter. Although severe hypertrophy was present in the right ventricle as a result of left ventricular failure, myocyte growth was proportional, suggesting that cell shape was properly regulated in this chamber.
Stress-Induced Laboratory Blood Pressure in Relation to Ambulatory Blood Pressure and Left Ventricular Mass Among Borderline Hypertensive and Normotensive Individuals
Authors: Georgiades Anastasia , Lemne Carola , de Faire Ulf , Lindvall Kaj , Fredrikson Mats
Published: June 2012

Our primary aim in the present study was to investigate the association between blood pressure measured in the laboratory and in the ambulatory state in a group of middle-aged borderline hypertensive men and age-matched normotensive control subjects. In addition, we examined the relation between stress-induced blood pressure measurements and left ventricular mass. Blood pressure and heart rate were measured noninvasively during a standardized laboratory stress protocol and four times per hour throughout 24 hours. Borderline hypertensive subjects had significantly higher systolic and diastolic pressures than normotensive subjects during both the daytime (systolic pressure, 141.1±9.7 versus 130.9±8.6 mm Hg; diastolic pressure, 88.8±7.0 versus 79.4±6.2 mm Hg,
P
<.001) and nighttime (systolic pressure, 114.0±9.9 versus 107.1±8.3 mm Hg; diastolic pressure, 71.5±7.5 versus 64.6±7.2 mm Hg,
P
<.001). The borderline hypertensive group also displayed increased systolic pressure reactivity in the laboratory compared with the normotensive group. The groups did not differ significantly in left ventricular mass (index). In both borderline hypertensive and normotensive individuals, blood pressure levels during stress testing were closely related to ambulatory blood pressure levels (
r
=.51 to .82). Furthermore, stress-induced blood pressure levels were significantly correlated to left ventricular mass in borderline hypertensive (
r
=.33 to .40) but not normotensive subjects. Since stress-induced blood pressure levels were significantly associated with both ambulatory blood pressure levels and left ventricular mass in borderline hypertensive subjects, the addition of standardized stress testing to casual blood pressure measurements may improve risk estimation.
Mechanism of the Hypotensive Action of Anandamide in Anesthetized Rats
Authors: Varga Karoly , Lake Kristy D. , Huangfu Donghai , Guyenet Patrice G. , Kunos George
Published: June 2012

We studied the effects of the endogenous cannabinoid ligand anandamide on blood pressure, single unit activity of barosensitive neurons in the rostral ventrolateral medulla, and postganglionic splanchnic sympathetic nerve discharge in urethane-anesthetized rats. In rats with an intact baroreflex, an intravenous bolus of 4 mg/kg anandamide caused a triphasic blood pressure response: transient hypotension, followed by a brief pressor and more prolonged depressor phase. Anandamide evoked a “primary” increase in neuronal firing coincident with its pressor effect and a “secondary,” baroreflex-mediated rise coincident with its depressor effect at both sites. Pretreatment of rats with phentolamine or trimethaphan did not inhibit either the pressor response or the primary increase in splanchnic nerve discharge elicited by anandamide. In barodenervated rats, electrical stimulation of the rostral ventrolateral medulla increased blood pressure and splanchnic nerve discharge. Anandamide treatment blunted the rise in blood pressure without affecting the increase in splanchnic nerve discharge. Anandamide did not affect the rise in blood pressure in response to an intravenous bolus dose of phenylephrine. The results indicate that (1) the brief pressor response to anandamide is not sympathetically mediated, and (2) the prolonged hypotensive response to anandamide is not initiated in the central nervous system, in ganglia, or at postsynaptic adrenergic receptors but is due to a presynaptic action that inhibits norepinephrine release from sympathetic nerve terminals in the heart and vasculature.
Distinct Factors in Plasma of Preeclamptic Women Increase Endothelial Nitric Oxide or Prostacyclin
Authors: Davidge Sandra T. , Signorella Arthur P. , Hubel Carl A. , Lykins David L. , Roberts James M.
Published: June 2012

The pathogenesis of preeclampsia is proposed to be due to uncharacterized circulating factors that activate endothelial cells. Support for this hypothesis is provided by in vitro activation of endothelial cells by plasma from preeclamptic women, eg, increased nitric oxide and prostacyclin generation. We performed molecular sizing, lipid extraction, and lipoprotein fractionation of plasma from normal pregnant and preeclamptic women and determined the ability of these plasma fractions to increase nitric oxide or prostacyclin generation by endothelial cells. Fractions from plasma of preeclamptic women were consistently more active than fractions from normal pregnant women, although characterization was qualitatively similar. The factors stimulating nitric oxide and prostacyclin were different. The factor (or factors) stimulating nitric oxide generation was extractable by charcoal and present in lipid extracts and lipoprotein isolates with a molecular weight greater that 1.5 million daltons, which is characteristic of a lipoprotein or lipoprotein aggregate. By contrast, activity to stimulate prostacyclin persisted after charcoal stripping or lipoprotein removal, partitioned to the aqueous fraction, and had a molecular weight of approximately 50 000 D. Two distinct factors in the blood of preeclamptic women alter endothelial function in vitro. This information should guide the search for circulating factors contributing to the pathophysiology of preeclampsia.
Left Ventricular Hypertrophy and QT Dispersion in Hypertension
Authors: Mayet Jamil , Shahi Manjit , McGrath Katherine , Poulter Neil R. , Sever Peter S. , Foale Rodney A. , Thom Simon A. McG.
Published: June 2012

The interlead variation in QT length on a standard electrocardiograph reflects regional repolarization differences in the heart. To investigate the association between this interlead variation (QT dispersion) and left ventricular hypertrophy, we subjected 100 untreated subjects to 12-lead electrocardiography and echocardiography. Additionally, 24 previously untreated subjects underwent a 6-month treatment study with ramipril and felodipine. In the cross-sectional part of the study, QT dispersion corrected for heart rate (QTc dispersion) was significantly correlated with left ventricular mass index (
r
=.30,
P
<.01), systolic pressure (
r
=.30,
P
<.01), the ratio of peak flow velocity of the early filling wave to peak flow velocity of the atrial wave (E/A ratio) (
r
=−.22,
P
=.02), isovolumic relaxation time (
r
=.31,
P
<.01), and age (
r
=.21,
P
<.04). In the treatment part of the study, lead-adjusted QTc dispersion decreased from 24 to 19 milliseconds after treatment, and after a subsequent 2 weeks of drug washout remained at 19 milliseconds (
P
<.01). The changes in left ventricular mass index at these stages were 144, 121, and 124 g/m
2
(
P
<.01). Systolic pressure decreased from 175 to 144 mm Hg and increased again to 164 mm Hg after drug washout (
P
<.01).The E/A ratio (0.97, 1.02, and 1.02;
P
=.69) and isovolumic relaxation time (111, 112, and 112;
P
=.97) remained unchanged through the three assessment points. In conclusion, QT dispersion is increased in association with an increased left ventricular mass index in hypertensive individuals. Antihypertensive therapy with ramipril and felodipine reduced both parameters. If an increased QT dispersion is a predictor of sudden death in this group of individuals, then the importance of its reduction is evident.
Subcellular Localization of Angiotensin II Immunoreactivity in the Rat Cerebellar Cortex
Authors: Erdmann Bettina , Fuxe Kjell , Ganten Detlev
Published: June 2012

We localized angiotensin II (Ang II) immunoreactivity in the rat cerebellar cortex with immunogold staining methods. Perfusion fixation with high amounts of glutaraldehyde and the use of cryoultramicrotomy caused remarkable changes in immunostaining versus formaldehyde/picric acid fixation. With the use of monoclonal and polyclonal anti–Ang II, Ang II immunoreactivity was prominent in cerebellar neurons such as Purkinje, granule, basket, and stellate cells. At the subcellular level, the peptide was clearly localized in nuclei, and in some cell types, such as endothelial and granule cells, it was nearly exclusively present in the transcriptionally active euchromatin. Intracellular Ang II immunoreactivity was also detected in vesicle-like structures in cytoplasm and mitochondria and at cell-cell contacts. Additional experiments with liver and adrenal tissue confirmed the nuclear localization of Ang II immunoreactivity, suggesting a role of Ang II in the regulation of gene transcription.
Structure-Activity Studies of B
1
Receptor–Related Peptides
Authors: Gobeil Fernand , Neugebauer Withold , Filteau Catherine , Jukic Daniela , Allogho Susanne Nsa , Pheng Leng Hong , Nguyen-Le Xuan Khai , Blouin Daniel , Regoli Domenico
Published: June 2012

We tested several peptides related to des-Arg
9
-bradykinin as stimulants or inhibitors of B
1
(rabbit aorta, human umbilical vein) and B
2
(rabbit jugular vein, guinea pig ileum, human umbilical vein) receptors. We also incubated the compounds with purified angiotensin-converting enzyme from rabbit lung to test their resistance to degradation. We evaluated apparent affinities (in terms of the affinity constant pA
2
) of compounds and their potential residual agonistic activities (α
E
). Bradykinin and des-Arg
9
-bradykinin were used as agonists for the B
2
and B
1
receptors, respectively. Degradation of peptides by the angiotensin-converting enzyme was prevented in the presence of a
d
-residue in position 7 of des-Arg
9
-bradykinin. Replacement of Pro
7
with
d
-Tic combined with Leu, Ile, Ala, or
d
-Tic in position 8 led to weak B
1
receptor antagonists, some of which had strong residual agonistic activities on the B
2
receptor preparations. The use of
d
-βNal in position 7, combined with Ile in position 8 and AcLys at the N-terminal (eg, AcLys[
d-
βNal
7
,Ile
8
]des-Arg
9
-bradykinin) gave the most active B
1
receptor antagonist (pA
2
of 8.5 on rabbit aorta and human umbilical vein), which is also partially resistant to enzymatic degradation. Extension of the N-terminal end by Sar-Tyr-εAhx (used for labeling purposes) and even cold-labeling of Tyr with iodine were compatible with high, selective, and specific antagonism of the B
1
receptors. We compared some compounds with some already known B
1
receptor antagonists to underline the novelty of new peptidic compounds.
Diurnal Variations in Cardiovascular Function and Glucose Regulation in Normotensive Humans
Authors: Biston Patrick , Van Cauter Eve , Ofek Gilad , Linkowski Paul , Polonsky Kenneth S. , Degaute Jean-Paul
Published: June 2012

To define the physiological relationships between cardiovascular function, glucose regulation, and insulin secretion, we submitted nine young normotensive subjects to ambulatory blood pressure monitoring and blood sampling at 20-minute intervals for 24 hours to measure glucose, insulin, C peptide, cortisol, and growth hormone. Subjects ingested three identical carbohydrate-rich meals in the morning (8:30
am
), early afternoon (2
pm
), and evening (8
pm
). On the following day, they underwent an intravenous glucose tolerance test for quantification of insulin sensitivity. Significant postmeal increases in systolic pressure averaging 18±10 mm Hg in the morning, 18±8 mm Hg in the early afternoon, and 26±19 mm Hg in the evening were observed. Postprandial variations in diastolic pressure and heart rate were significant only for the morning meal. The magnitude of the postprandial increases in systolic pressure was correlated with the amount of insulin secreted in the morning but not later in the day. Pulses of growth hormone consistently occurred 3 to 4 hours after the morning and midday meals, as well as after the onset of sleep. Our findings indicate that under normal conditions, there is a quantitative relationship between postprandial insulin secretion and blood pressure.
Polymorphisms of the Transforming Growth Factor-β1 Gene in Relation to Myocardial Infarction and Blood Pressure
Authors: Cambien François , Ricard Sylvain , Troesch Alain , Mallet Christine , Générénaz Laurence , Evans Alun , Arveiler Dominique , Luc Gérald , Ruidavets Jean-Bernard , Poirier Odette
Published: June 2012

Transforming growth factor-β1 (TGF-β1) plays an important role in the modulation of cellular growth and differentiation and the production and degradation of the extracellular matrix. A number of experimental results suggest that TGF-β1 may be involved in cardiovascular physiopathology. In the present study, we assessed whether the TGF-β1 gene is a candidate gene for coronary heart disease or hypertension. We screened the coding region and 2181 bp upstream of the TGF-β gene for polymorphisms and identified seven polymorphisms: 3 in the upstream region of the gene at positions −988, −800, and −509 from the first transcribed nucleotide; 1 in a nontranslated region at position +72; 2 in the signal peptide sequence Leu
10
→Pro, Arg
25
→Pro; and 1 in the region of the gene coding for the precursor part of the protein not present in the active form, Thr
263
→Ile. We analyzed these TGF-β1 polymorphisms in 563 patients with myocardial infarction and 629 control subjects from four regions in Northern Ireland and France. The Pro
25
allele was more frequent in patients than in control subjects in Belfast (
P
<.01) and Strasbourg (
P
<.05). The TGF-β1 polymorphisms were not associated with the degree of angiographically assessed coronary artery disease in patients. The presence of a Pro
25
allele was associated with a lower systolic pressure in the four control groups (
P
<.002), and a history of hypertension was significantly less frequent in homozygotes or heterozygotes for Pro
25
than in homozygotes for Arg
25
(odds ratio, 0.43; 95% confidence interval, 0.19 to 0.92;
P
<.03). Since the Pro
25
allele was associated with an increased risk of myocardial infarction and a reduced risk of hypertension, we favor a cautious interpretation of these apparently inconsistent results. Other studies will need to verify whether these associations are real.
Chronic Renal Neuroadrenergic Hypertension Is Associated With Increased Renal Norepinephrine Sensitivity and Volume Contraction
Authors: Plato Craig F. , Osborn Jeffrey L.
Published: June 2012

Individuals with essential hypertension have been characterized by increased renal sympathetic vascular tone with decreased plasma volume and normal cardiac output compared with normotensive individuals. We used a servo-controlled intrarenal infusion system to evaluate the hemodynamic, renal excretory, and plasma hormonal responses to 28-day, low-level elevations in the intrarenal adrenergic neurotransmitter norepinephrine. In uninephrectomized dogs (n=6), servo-controlled norepinephrine infusion increased mean arterial pressure from 95.6±3.1 to 115.7±4.9 mm Hg on day 1 without concomitant reductions in renal blood flow. Arterial hypertension was sustained and renal vascular resistance increased during the 28 days of servo-controlled norepinephrine infusion despite significant decreases in the daily dose of intrarenal norepinephrine (1.49±0.23 to 0.47±0.25 mg/d) necessary to maintain renal blood flow constant. Arterial pressure returned to control values with the cessation of servo-controlled norepinephrine, whereas renal blood flow and renal vascular resistance remained slightly decreased and increased, respectively. Cumulative sodium balance exhibited a net 177±37 mmol sodium loss over the 28 days of norepinephrine infusion, indicating that the hypertension did not result from sodium retention or expansion of extracellular fluid volume. Intrarenal norepinephrine did not change plasma epinephrine, norepinephrine, or vasopressin concentrations. Atrial natriuretic factor, however, increased at 7 and 14 days of servo-controlled norepinephrine, and plasma renin activity increased on day 14 of norepinephrine infusion. We conclude that low-level elevation of intrarenal adrenergic neurotransmitter produces sustained arterial hypertension that is independent of expansion in extracellular fluid volume, increases in circulating catecholamines or plasma renin activity, or reductions in renal blood flow. This hypertension may be associated with increased renal vascular sensitivity to norepinephrine and/or other renal vasoactive factors.
Heart Rate and Blood Pressure Variabilities in Salt-Sensitive Hypertension
Authors: Piccirillo Gianfranco , Bucca Carmela , Durante Michele , Santagada Elvira , Munizzi Maria R. , Cacciafesta Mauro , Marigliano Vincenzo
Published: June 2012

In salt-sensitive hypertension, a high sodium intake causes plasma catecholamines to rise and pulmonary baroreceptor plasticity to fall. In salt-sensitive and salt-resistant hypertensive subjects during low and high sodium intakes, we studied autonomic nervous system activity by power spectral analysis of heart rate and arterial pressure variabilities and baroreceptor sensitivity. In all subjects, high sodium intake significantly enhanced the low-frequency power of heart rate and arterial pressures at rest and after sympathetic stress. It also increased heart rate and arterial pressure variabilities. During high sodium intake, salt-sensitive hypertensive subjects had significantly higher low-frequency powers of systolic arterial pressure (7.5 mm Hg
2
,
P
<.05) and of heart rate at rest (59.2±2.4 normalized units [NU],
P
<.001) than salt-resistant subjects (6.6±0.3 mm Hg
2
, 55.0±3.2 NU) and normotensive control subjects (5.1±0.5 mm Hg
2
, 41.6±2.9 NU). In salt-sensitive subjects, low sodium intake significantly reduced low-frequency normalized units (
P
<.001) and the ratio of low- to high-power frequency (
P
<.001). High-sodium intake significantly increased baroreflex sensitivity in control subjects (from 10.0±0.7 to 17.5±0.7 ms/mm Hg,
P
<.001) and salt-resistant subjects (from 6.9±0.7 to 13.9±0.9,
P
<.05) but not in salt-sensitive subjects (7.4±0.3 to 7.9±0.4). In conclusion, a high sodium intake markedly enhances cardiac sympathetic activity in salt-sensitive and salt-resistant hypertension. In contrast, although reduced sodium intake lowers arterial pressure and sympathetic activity, it does so only in salt-sensitive subjects. Hence, in salt-resistant subjects, neither arterial pressure nor sympathetic activity depends on salt intake. During a high sodium intake in normotensive subjects and salt-resistant hypertensive subjects, increased sympathetic activity is probably compensated by enhanced baroreflex sensitivity.
Synthesis and Secretion of Natriuretic Peptides in the Hypertensive TGR(mREN-2)27 Transgenic Rat
Authors: Marttila Minna , Vuolteenaho Olli , Ganten Detlev , Nakao Kazuwa , Ruskoaho Heikki
Published: June 2012

To examine the pathophysiological mechanisms in transgenic rats carrying the murine

Ren-2
d

renin gene, we studied atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression and secretion in 12-week-old hypertensive TGR(mREN-2)27 and normotensive Sprague-Dawley rats. Hypertension and marked left ventricular hypertrophy in TGR(mREN-2)27 rats were associated with high baseline plasma levels of immunoreactive ANP (148±18 versus 34±3 pmol/L, hypertensive versus normotensive rats;
P
<.001), whereas plasma immunoreactive BNP levels did not differ significantly between the strains (19±4 versus 12±3 pmol/L,
P
=.06). ANP mRNA and immunoreactive ANP levels in the left ventricular endocardial and epicardial layers in TGR(mREN-2)27 rats were about 20 to 40 times higher (
P
<.001) than those in normotensive rats. There were no statistically significant differences between atrial and ventricular BNP mRNA levels, but left ventricular immunoreactive BNP concentrations were twofold higher in hypertensive TGR(mREN-2)27 than in normotensive rats. Infusion of [Arg
8
]-vasopressin (0.05 μg/kg per minute IV, for 2 hours) in normotensive rats produced rapid increases (twofold,
P
<.05 to .01) in left ventricular BNP mRNA and immunoreactive BNP levels, whereas ventricular BNP mRNA and peptide levels did not change significantly in hypertensive rats. The increase in left atrial BNP mRNA levels in response to acute pressure overload was also significantly smaller in the hypertensive than normotensive rats (3.5-fold versus 5.2-fold,
P
<.01). Furthermore, the proportional but not absolute (in picomoles per liter) increase in plasma immunoreactive ANP was smaller in transgenic rats in response to acute saline and [Arg
8
]-vasopressin infusions (0.9% NaCl: 1.9-fold increase versus 4.4-fold increase in normotensive rats,
P
<.001; [Arg
8
]-vasopressin: 2.2-fold versus 4.8-fold increase,
P
<.001). These results show that baseline and cardiac overload–induced increases in BNP synthesis are markedly attenuated in transgenic rats carrying the murine

Ren-2
d

renin gene. In addition, acute volume and pressure overload produced a smaller proportional increase in ANP secretion in hypertensive rats than normotensive rats. These alterations in the natriuretic peptide system may contribute to the pathogenesis of hypertension and cardiovascular complications in the TGR(mREN-2)27 rat.
Pressor Effects of Endogenous Opioid System During Acute Episodes of Blood Pressure Increases in Hypertensive Patients
Authors: Fontana Fiorella , Bernardi Pasquale , Spampinato Sante , Boschi Stefano , De Iasio Rosaria , Grossi Gabriele
Published: June 2012

To investigate the involvement of endogenous opioids in acute increases in blood pressure and their functional relationship with atrial natriuretic factor and endothelin-1, we assessed plasma levels of β-endorphin, met-enkephalin, dynorphin B, catecholamines, atrial natriuretic factor, and endothelin-1 before and after administration of the opioid antagonist naloxone hydrochloride (8 mg IV) in 28 hypertensive patients with a stress-induced acute increase in blood pressure. Ten patients with established mild or moderate essential hypertension and 10 normotensive subjects served as control groups. Opioids, atrial natriuretic factor, and endothelin-1 were radioimmunoassayed after chromatographic preextraction; catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Patients with an acute increase in blood pressure (systolic, 203.2±2.2 mm Hg; diastolic, 108.4±1.3) had plasma opioid, catecholamine, and atrial natriuretic factor levels significantly (
P
<.01) higher than hypertensive control patients (systolic pressure, 176.4±1.0 mm Hg; diastolic, 100.0±1.4), who had a hormonal pattern similar to that of normotensive subjects (systolic pressure, 123.2±1.5 mm Hg; diastolic, 75.0±2.0). Endothelin-1 did not differ in any group. In patients with an acute increase in blood pressure, naloxone significantly (
P
<.01) reduced blood pressure, heart rate, opioids, catecholamines, and atrial natriuretic factor 10 minutes after administration. Naloxone effects on blood pressure, heart rate, opioids, and catecholamines wore off within 20 minutes. In control groups, naloxone failed to modify any of the considered parameters. Our findings suggest that pressor effects of opioid peptides mediated by the autonomic nervous system during stress-induced acute episodes of blood pressure increase in hypertensive patients.
Antisense Inhibition and Adeno-Associated Viral Vector Delivery for Reducing Hypertension
Authors: Phillips M. Ian
Published: June 2012

Antisense oligodeoxynucleotides have been designed to inhibit the production of specific proteins. In models of hypertension, we have targeted the renin-angiotensin system at the level of synthesis (angiotensinogen) and the receptor (AT
1
receptor). The design of antisense oligonucleotides requires choosing a site to inhibit mRNA processing or translation. The strategy we use is to make three oligonucleotides of antisense sequences, upstream and downstream from the AUG site and over the AUG site. The oligonucleotides are tested in a screening test. Antisense oligonucleotides to AT
1
-receptor mRNA and to angiotensinogen mRNA reduce blood pressure in spontaneously hypertensive rats when injected into the brain. They significantly reduce the concentration of the appropriate protein. The oligonucleotides are also effective when administered systemically. The decrease in blood pressure with antisense oligonucleotides delivered in blood or brain lasts 3 to 7 days. To prolong the action, direct injection of naked DNA and injection of DNA in liposome carriers have been tested. Viral vectors have been developed to deliver antisense DNA. The viral vectors available include retroviruses and adenovirus, but the adeno-associated virus (AAV) vector is the vector of choice for ultimate use in gene therapy. It offers safety because it is nonpathogenic, has longevity because it integrates into the genome, and has sufficient carrying capacity to carry up to 4.5 kb antisense or gene in a recombinant AAV. Using rAAV-antisense to AT
1
mRNA, there is efficient transfection into cells and an inhibition of AT
1
receptor number. In in vivo tests, rAAV-AS AT
1
-receptor when injected into the brains of SHR reduces blood pressure for more than 2 months. In young rats (3 weeks old), rAAV-AS AT
1
-receptor decreases blood pressure and slows the development of hypertension. While further experiments need to be done on dose-response relationships and on the cellular mechanisms of these effects, the results show the feasibility of AAV as a vector for antisense inhibition, which may ultimately be used in gene therapy for hypertension.
Calcitonin Gene-Related Peptide Is a Depressor in
N
G
-Nitro-
l
-Arginine Methyl Ester-Induced Hypertension During Pregnancy
Authors: Gangula Pandu R. R. , Supowit Scott C. , Wimalawansa Sunil J. , Zhao Huawei , Hallman Diane M. , DiPette Donald J. , Yallampalli Chandrasekhar
Published: June 2012

Inhibition of nitric oxide production with
N

g

-nitro-
l
-arginine methyl ester (L-NAME) increases blood pressure and fetal mortality in pregnant rats. We previously reported that administration of calcitonin gene-related peptide (CGRP) reduces the blood pressure and fetal death produced by L-NAME. To determine the hemodynamic role of endogenous CGRP in this setting, CGRP
8–37
, a CGRP receptor antagonist, was used. In addition, CGRP mRNA and peptide levels were determined in dorsal root ganglia. L-NAME or control rats had intravenous (for drug administration) and arterial (for continuous mean blood pressure monitoring) catheters surgically placed and were studied in the conscious unrestrained state. Baseline blood pressure was higher in the L-NAME than the control rats on days 19, 20, and 21 or pregnancy and postpartum day 1. Vehicle administration did not change blood pressure in any group, and CGRP
8–37
(100 μg) did not change blood pressure in control groups. However, CGRP
8–37
administration to the L-NAME rats further increased blood pressure (
P
<.05) on days 19 (8±1), 20 (12±2), and 21 (7±1) of gestation but was without effect on postpartum day 1. Furthermore, CGRP mRNA or peptide levels in dorsal root ganglia were not different between the L-NAME and control rats at any of the time points studied. These data indicate that in experimental preeclampsia, CGRP is playing a compensatory vasodilator role to attenuate the elevated blood pressure. The mechanism of this effect appears to be an enhanced vascular responsiveness to CGRP that is attenuated after the birth of pups.
Regulation of Potassium Channels in Coronary Arterial Smooth Muscle by Endothelium-Derived Vasodilators
Authors: Li Pin-Lan , Zou Ai-Ping , Campbell William B.
Published: June 2012

Recent studies have suggested that coronary endothelial cells produce and release nitric oxide (NO), prostaglandin I
2
, and epoxyeicosatrienoic acids (EETs). These endothelium-derived vasodilators play an important role in the control of coronary vascular tone. However, the mechanism by which these endothelium-derived vasodilators cause relaxation of coronary arterial smooth muscle has yet to be determined. This study characterized and compared the effects of NO, prostaglandin I
2
, and 11,12-EET on the two main types of potassium channels in small bovine coronary arterial smooth muscle: the large conductance Ca
2+
-activated K
+
channels (K
Ca
) and 4-aminopyridine-sensitive delayed rectifier K
+
channels (K
drf
). In cell-attached patches, non-oate, an NO donor, activated both K
Ca
and K
drf
channels. The open probability of both K
Ca
and K
drf
channels increased 10- to 25-fold when nonoate was added to the bath at concentrations of 10
−6
to 10
−4
mol/L. 11,12-EET (10
−8
to 10
−4
mol/L) also increased the activity of the K
Ca
channels in a concentration-dependent manner, but it had no effect on the activity of the K
drf
channels, even in the highest concentration studied (10
−4
mol/L). In contrast to the effect of 11,12-EET, iloprost, a prostaglandin I
2
analogue (10
−6
to 10
−4
mol/L), produced a concentration-dependent increase in the activity of K
drf
channels without affecting the K
Ca
channels. In conclusion, all three endothelium-derived vasodilators act to open potassium channels; however, the channel types that they affect are different. NO activates both K
Ca
and K
drf
channels; 11,12-EET activates only the K
Ca
channels; and prostaglandin I
2
activates only the K
drf
channels.
Endogenous Estrogen and Acetylcholine-Induced Vasodilation in Normotensive Women
Authors: Pinto Stefania , Virdis Agostino , Ghiadoni Lorenzo , Bernini GianPaolo , Lombardo Maurizio , Petraglia Felice , Genazzani Andrea R. , Taddei Stefano , Salvetti Antonio
Published: June 2012

Acute exogenous estrogen administration enhances endothelial function in postmenopausal women. To evaluate the effect of endogenous estrogen on endothelium-dependent vasodilation, in 10 fertile normotensive women (age range 45 to 51 years) we studied the changes in forearm blood flow (strain-gauge plethysmography) induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, 15 μg·100 mL
−1
·min
−1
), an endothelium-dependent vasodilator, or sodium nitroprusside (1, 2, 4 μg·100 mL
−1
·min
−1
), an endothelium-independent vasodilator, in basal conditions and within 1 month after ovariectomy. As control subjects, 10 matched healthy women were also evaluated. In basal condition, vasodilation to acetylcholine and sodium nitroprusside was similar in patients and control subjects. Ovariectomy was followed by endogenous estrogen deprivation (from 71.6±31.3 to <12 pg/mL) and was associated with a significant (
P
<.01) reduction in acetylcholine-induced vasodilation compared with baseline (maximum percent increase in forearm blood flow: baseline 568.2±47.1%; ovariectomy 309.5±37.4%); the response to sodium nitroprusside was unaffected by ovariectomy (maximum percent increase in forearm blood flow: baseline 526.4±36.5%; ovariectomy 454.7± 47.2%;
P
=NS). In 6 of 10 patients, the study was repeated after 3 months of estrogen replacement therapy (17β-estradiol, 50 μg/d by transdermal patches). Exogenous estrogen restored acetylcholine-induced vasodilation (maximum percent increase in forearm blood flow: 548.9±43.1%;
P
<.01 versus ovariectomy), which was no longer different from baseline, whereas the response to sodium nitroprusside was not affected (maximum percent increase in forearm blood flow: 480.2±39.3%;
P
=NS). These results suggest a protective role of endogenous estrogen on endothelium-dependent vasodilation in the forearm vascular bed of normotensive women.
Converting Enzyme Inhibitor Improves Forearm Reactive Hyperemia in Essential Hypertension
Authors: Iwatsubo Haruhiko , Nagano Masahiro , Sakai Tomoko , Kumamoto Kunihiko , Morita Ryuhei , Higaki Jitsuo , Ogihara Toshio , Hata Takeshi
Published: June 2012

Endothelial function is known to be impaired in essential hypertensive patients. In this study, we examined whether antihypertensive drugs improve forearm vasodilatory response to reactive hyperemia in 26 patients with essential hypertension (62±2 years) without diabetes mellitus, hyperlipidemia, coronary heart disease, or cerebrovascular disease. Antihypertensive drugs were never given or were discontinued for at least 4 weeks before the study. Patients were treated with monotherapy of either temocapril (2 or 4 mg, n= 15) or amlodipine (2.5 or 5 mg, n= 11) for 6 months. Forearm blood flow was measured by strain-gauge plethysmography. Vasodilator response to the release of upper arm compression at 300 mm Hg for 5 minutes and to sublingual administration of nitroglycerin (0.3 mg) were assessed. Changes of forearm blood flow response to reactive hyperemia were significantly less in hypertensive patients (99±18%) than in age-matched normotensive control subjects (150±22%,
P
<.01, n=39). Blood pressure (mm Hg) was similarly decreased by the treatment with temocapril (160±4/94±2 to 139±3/83±3,
P
<.001) or amlodipine (165±5/94±3 to 141±4/82±3,
P
<.001). Response to nitroglycerin was not changed by either drug. Forearm vasodilatory response to reactive hyperemia was improved by temocapril (102±20% to 168±25%,
P
<.01) but not by amlodipine (97±16% to 114±14%, NS). These results indicate that the treatment with the angiotensin-converting enzyme inhibitor temocapril improved forearm vasodilatory response to reactive hyperemia, suggesting its beneficial effect on endothelial function.
Endothelial Adhesion Molecules and Leukocyte Integrins in Preeclamptic Patients
Authors: Haller Hermann , Ziegler Eva-Maria , Homuth Volker , Drab Marek , Eichhorn Jens , Nagy Zsuzsanna , Busjahn Andreas , Vetter Klaus , Luft Friedrich C.
Published: June 2012

Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia, 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca
2+
]
i
in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca
2+
]
i
was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca
2+
]
i
in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca
2+
]
i
concentrations were correlated with the ICAM-1 expression in preeclamptic patients (
r
=.80,
P
<.001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preeclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca
2+
]
i
. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca
2+
]
i
and enhances adhesion molecule expression.
Inhibition of Renal Outer Medullary 20-HETE Production Produces Hypertension in Lewis Rats
Authors: Stec David E. , Mattson David L. , Roman Richard J.
Published: June 2012

Recent studies have indicated that a deficiency in the production of 20-hydroxyeicosatetraenoic acid (20-HETE) in the outer medulla of the kidney may contribute to the abnormalities in the renal handling of sodium and the development of hypertension in Dahl salt-sensitive rats. To determine whether a reduction in 20-HETE production in the outer medulla is sufficient to induce hypertension, an inhibitor of the renal metabolism of arachidonic acid by P450 enzymes, 17-octadecenoic acid (17-ODYA), was chronically infused directly into the outer medulla of the left kidney of uninephrectomized Lewis rats fed a high salt diet. Renal medullary interstitial infusion of 17-ODYA (400 pmol/min) reduced the formation of 20-HETE in the outer medulla of the infused kidney by 70% compared with values seen in the right kidney collected when the rat was uninephrectomized, but it had no effect on the production of 20-HETE in the renal cortex. After 5 days, mean arterial pressure rose from 115±2 to 142±2 mm Hg (n=6) in the rats infused with 17-ODYA, while mean arterial pressure was not significantly altered in the rats infused with vehicle alone (116±1 versus 117±2 mm Hg, n=6). These results suggest that inhibition of the renal metabolism of arachidonic acid by P450 enzymes in the outer medulla of the kidney is sufficient to induce the development of hypertension in Lewis rats fed a high salt diet and support the view that P450 metabolites of arachidonic acid play an important role in the regulation of renal function and the long-term control of arterial pressure.
Dopamine D1-Like Receptor Stimulation Inhibits Hypertrophy Induced by Platelet-Derived Growth Factor in Cultured Rat Renal Vascular Smooth Muscle Cells
Authors: Yasunari Kenichi , Kohno Masakazu , Kano Hiroaki , Yokokawa Koji , Minami Mieko , Yoshikawa Junichi
Published: June 2012

Vascular smooth muscle cell (VSMC) hypertrophy is believed to play some roles in atherosclerosis. To elucidate the role of vascular D1-like receptors in VSMC hypertrophy, the effects of dopamine and specific D1-like receptor agonist SKF 38393 and YM 435 on platelet-derived growth factor (PDGF) BB-mediated VSMC hypertrophy was studied. We observed that cells stimulated by PDGF-BB 5 ng/mL showed increased VSMC hypertrophy. These effects were prevented by coincubation with dopamine, SKF 38393, and YM 435 1-10 μmol/L, and this prevention was reversed by Sch 23390 1 to 10 μmol/L, a specific D1-like receptor antagonist. These actions are mimicked by forskolin 1 to 10 μmol/L, a direct activator of adenylate cyclase and 8-bromo-cAMP 0.1 to 1 mmol/L, and are blocked by a specific protein kinase A (PKA) inhibitor
N
-[2-(P-bromocinnamylamino)ethyl]-5-isoquinoline-sulfonamide (H 89) but not blocked by its negative control. PDGF-BB (5 ng/mL)-mediated mitogen-activated protein kinase (MAPK) activity was significantly suppressed by coincubation with D1-like receptor agonists, which were reversed by PKA inhibitor H 89. These results suggest that vascular D1-like receptor agonists inhibit hypertrophy of VSMC, possibly through PKA activation and suppression of activated MAPK activity.
Neonatal Angiotensin-Converting Enzyme Inhibition in the Rat Induces Persistent Abnormalities in Renal Function and Histology
Authors: Guron Gregor , Adams Michael A. , Sundelin Birgitta , Friberg Peter
Published: June 2012

Recently, we reported that neonatal blockade of the renin-angiotensin system in the rat produces irreversible abnormalities in renal histology associated with increased diuresis. In the present study, we assessed the long-term consequences of neonatal angiotensin-converting enzyme inhibition on renal function. Rats were injected with 10 mg·kg
−1
·d
−1
enalapril or vehicle from day 3 to day 24 after birth. Urine concentrating ability, renal function, and renal histology were assessed in 16-week-old rats. There was a twofold increase in diuresis and water intake in enalapril-treated rats throughout the study course. Urine osmolality after 24 hours of water deprivation was 1008±108 and 2549±48 mOsm·kg
−1
(
P
<.05) in enalapril- and vehicle-treated rats, respectively. Glomerular filtration rate (0.54±0.03 versus 0.75±0.06 mL·min
−1
·100 g body wt
−1
,
P
<.05) and effective renal plasma flow (1.76±0.09 versus 2.19±0.14 mL·min
−1
·100 g body wt
−1
,
P
<.05) were reduced in neonatally enalapril-treated versus control rats. Absolute and fractional urinary sodium excretion values were elevated (
P
<.05) in enalapril-treated rats. Semiquantitative assessment of renal histology demonstrated statistically significant degrees of papillary atrophy, interstitial fibrosis and inflammation, tubular atrophy and dilatation, and focal glomerulosclerosis in neonatally enalapril-treated rats. In conclusion, neonatal angiotensin-converting enzyme inhibition in the rat produces irreversible alterations in renal function and morphology, demonstrating the importance of an intact renin-angiotensin system neonatally for normal renal development.