bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmentation of Aortic Ring Contractions by Angiotensin II Antisense Peptide
Authors: Dillon Patrick F. , Root-Bernstein Robert S. , Holsworth Daniel D.
Published: June 2012

Abstract
—Previous biochemical experiments have revealed two antisense peptide antagonists to human angiotensin II (Ang II), one encoded in the cDNA in the antiparallel reading, the other in the parallel reading. Neither peptide’s ability to produce physiological antagonism has been demonstrated previously. Both peptides were tested for their ability to antagonize Ang II–induced contractions on rabbit aorta smooth muscle. Neither peptide had any direct contractile activity. The antiparallel Ang II peptide had physiological antagonism to Ang II contractions at a lower sensitivity than reported in biochemical studies, and its antagonist activity was partially blocked by Ang II antiserum, suggesting that it is not an antipeptide but an Ang II homologue. The parallel Ang II antipeptide also required high concentrations for physiological inhibition. Its contractile inhibition was not affected by Ang II antiserum and diminished the Ang II contraction at high micromolar concentrations, findings consistent with physicochemical data showing that it is an Ang II complement. The concentration of either peptide required to produce an antagonistic physiological effect was too high to predict any pharmacological usefulness. The parallel antipeptide, however, significantly increased the force of muscle contractions at high nanomolar concentrations, thus displaying a unique dual augmentation/antagonist activity. This antipeptide seems to have highly sequence-specific activity because other similar parallel antipeptides had no activity. The parallel antipeptide augmentation mimics the shift in the Ang II dose-response curve produced in hypertension studies of the slow pressor effect of Ang II and may be useful in deducing the currently unknown cause of the slow pressor effect. It may also have some uses in migraine studies.
Vascular Smooth Muscle Nitric Oxide Synthase Anomalies in Dahl/Rapp Salt-Sensitive Rats
Authors: Chen Pei Yan , Gladish Reginald D. , Sanders Paul W.
Published: June 2012

Abstract
—Salt-sensitive hypertension in the Dahl/Rapp rat (S strain) is prevented by
l
-arginine. Based on the observations that dexamethasone prevented the antihypertensive effect of
l
-arginine in these animals and the suggestion that a locus in or near an inducible nitric oxide synthase (NOS) gene on chromosome 10 cosegregated with hypertension in some F2 crosses that utilized the S rat, the present study explored the hypothesis that the vascular smooth muscle isoform of inducible NOS (NOS2) was abnormal in S rats. Primary cultures of aortic smooth muscle cells from S rats demonstrated impaired inducible NO production, which improved with increased
l
-arginine in the medium. Sequence analysis identified a single T→C transversion that produced an amino acid substitution (S714P) between the FAD and FMN binding sites and a restriction fragment length polymorphism. This restriction fragment length polymorphism was present only in S rats. The mutation of NOS2 and the role of this enzyme in the pathogenesis of salt-sensitive hypertension in the Dahl/Rapp rat require further investigation.
Enhanced Vascular Reactivity During Inhibition of Nitric Oxide Synthesis in Pregnant Rats
Authors: Khalil Raouf A. , Crews Janice K. , Novak Jacqueline , Kassab Salah , Granger Joey P.
Published: June 2012

Abstract
—Pregnancy-induced hypertension has been suggested to be mediated by several mechanisms, including reduced nitric oxide (NO) synthesis. In this study, the effects of chronic treatment with the NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME) on blood pressure and the underlying changes in vascular reactivity were investigated in virgin and late-pregnancy Sprague-Dawley rats. The systolic blood pressure was 120±2, 124±5, 116±4, and 171±5 mm Hg in untreated virgin, virgin treated with L-NAME, untreated pregnant, and pregnant treated with L-NAME rats, respectively. The rats were killed, and the thoracic aorta was cut into strips for measurement of active stress in response to α
1
-adrenergic stimulation with phenylephrine and membrane depolarization by high KCl. In pregnant rats, the maximal active stress to phenylephrine (0.31±0.03×104 N/m
2
) and the high-KCl–induced active stress (0.55±0.09×10

4

N/m
2
) were smaller than those in virgin rats. By contrast, in the L-NAME–treated pregnant rats, the maximal phenylephrine-induced active stress (0.76±0.1×10

4

N/m
2
) was greater than that in virgin rats (0.52±0.1×10

4

N/m
2
), whereas the high-KCl–induced active stress (1.08±0.14×10

4

N/m
2
) was indistinguishable from that in virgin rats (1.03±0.14×10

4

N/m
2
). Treatment with L-NAME did not affect the phenylephrine-releasable Ca
2+
stores in pregnant rats and had minimal effect on active stress in virgin rats. Thus, reduction of NO synthesis during late pregnancy is associated with a significant increase in blood pressure and vascular responsiveness to α-adrenergic stimulation, which can possibly be explained in part by enhanced Ca
2+
entry from extracellular space. However, other mechanisms such as increased myofilament force sensitivity to Ca
2+
and/or activation of a completely Ca
2+
-independent mechanism cannot be excluded.
N
N
-Nicotinic Blockade as an Acute Human Model of Autonomic Failure
Authors: Jordan Jens , Shannon John R. , Black Bonnie K. , Lance Robert H. , Squillante Mark D. , Costa Fernando , Robertson David
Published: June 2012

Abstract
—Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N
N
-nicotinic receptors with intravenous trimethaphan (6±0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32±3 years, 68±4 kg, 171±5 cm). N
N
-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1±0.12 nmol/L (180±20 pg/mL) at baseline to 0.23±0.05 nmol/L (39±8 pg/mL) with trimethaphan (
P
<.001). There was a more than 16-fold increase in plasma vasopressin (
P
<.01) and no change in plasma renin activity. We conclude that blockade of N
N
-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N
N
-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N
N
-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.
Genetic Markers at the Leptin (
OB
) Locus Are Not Significantly Linked to Hypertension in African Americans
Authors: Onions Kelly L. , Hunt Steven C. , Rutkowski Mark P. , Klanke Charles A. , Su Yan Ru , Reif Max , Menon Anil G.
Published: June 2012

Abstract
—Increased body mass index (BMI) has been correlated with increased blood pressure in human populations. To examine the role of the leptin gene (
OB
) in essential hypertension in African Americans, we performed affected sib pair analysis on a set of 103 hypertensive African American sibships using four highly polymorphic markers at the human leptin locus. No evidence of linkage was detected between these markers and the phenotype of essential hypertension either in these sibships or in a severely obese subset of 46 sibships in which each sibling had a BMI ≥85th percentile for the US population. Using BMI rather than hypertension as a quantitative trait, we found significant linkage for the marker D7S504 (
P
=0.029) but not for the other markers. Significance strengthened in the overweight subset of sibships for this marker (
P
=0.001), and there was a trend of lower
P
values for the other three markers. However, multipoint analysis with the use of all four markers simultaneously to estimate linkage between BMI and the leptin locus did not demonstrate a statistically significant relationship. Analysis of the coding region of the leptin gene (exons 2 and 3) by single-strand conformational polymorphism revealed a rare Ile-Val polymorphism at amino acid 45 but revealed no other alterations. These results suggest that the
OB
gene is not a major contributor to the phenotype of essential hypertension in African Americans, although a minor contribution to the phenotype of extreme obesity in this group cannot be ruled out.
Interactive Nitric Oxide–Angiotensin II Influences on Renal Microcirculation in Angiotensin II–Induced Hypertension
Authors: Ichihara Atsuhiro , Imig John D. , Inscho Edward W. , Navar L. Gabriel
Published: June 2012

Abstract
—The present study was conducted to determine the contribution of nitric oxide to angiotensin II (Ang II) reactivity of afferent and efferent arterioles from Ang II–infused hypertensive rats. Experiments were performed in vitro with the blood-perfused juxtamedullary nephron technique in kidneys harvested from hypertensive Sprague-Dawley rats (181±1 mm Hg) that had received 60 ng/min Ang II subcutaneously for 13 days. Superfusion with 0.1, 1, and 10 nmol/L Ang II reduced afferent arteriolar diameter (18.1±0.6 μm; n=12) by 10.0±0.7%, 28.1±1.7%, and 52.8±1.9%, respectively, and efferent arteriolar diameter (17.2±1.4 μm; n=8) decreased by 9.3±0.7%, 27.0±1.2%, and 50.4±1.6%, respectively. Nitric oxide synthase inhibition with 100 μmol/L
N
ω
-nitro-
l
-arginine (NLA) reduced resting afferent and efferent arteriolar diameters to 14.7±0.4 and 14.3±1.2 μm, respectively, and enhanced afferent but not efferent arteriolar reactivity to Ang II. The enhanced afferent arteriolar reactivity to Ang II was eliminated by addition of the nitric oxide donor
S
-nitroso-
N
-acetylpenicillamine (SNAP, 10 μmol/L), which reversed the NLA-induced decrease in diameter. Addition of 10 μmol/L SNAP, without NLA, blunted efferent but not afferent arteriolar reactivity to Ang II. Afferent (n=7) and efferent arteriolar diameters (n=6) decreased by 48.5±2.2% and 41.0±1.9%, respectively, in response to 10 nmol/L Ang II. These results suggest that in this model of hypertension, maintained nitric oxide production in afferent arterioles counteracts the enhanced afferent arteriolar reactivity that occurs in Ang II–induced hypertension.
Dietary Sodium Restriction Impairs Endothelial Effect of Insulin
Authors: Vecchione Carmine , Morisco Carmine , Fratta Luigi , Argenziano Luigi , Trimarco Bruno , Lembo Giuseppe
Published: June 2012

Abstract
—Hyperinsulinemia and high salt intake represent two independent cardiovascular risk factors. However, it is still unknown whether the change in dietary salt intake may affect the ability of insulin to stimulate whole-body glucose uptake and to modulate endothelial function. Regarding this latter issue, we have recently demonstrated that insulin enhances endothelial-mediated α
2
-adrenergic vasorelaxation. In overnight-fasted, freely moving Wistar-Kyoto rats (10 to 12 weeks old), we assessed whole-body glucose uptake (in milligrams per kilogram per minute) during a euglycemic-hyperinsulinemic clamp (insulin infusion rate, 3 mU · kg
−1
· min
−1
) after 3 weeks of normal (NSD, 2% NaCl), high (HSD, 6% NaCl), and low (LSD, 0.6% NaCl) sodium diet. Three days after the clamp study, rats were killed to assess α
2
-adrenergic vasorelaxation evoked by UK 14,304 (10
−9
to 10
−6
mol/L) in aortic rings in control conditions and after insulin exposure (100 μU/mL). Different sodium intakes did not modify the mean blood pressure or the insulin-stimulated whole-body glucose uptake (NSD: 14±1.2, n=16; HSD: 15.4±1.7, n=14; LSD: 14.8±0.8, n=14; NS). In contrast, we confirmed the ability of insulin to enhance α
2
-adrenergic vasorelaxation during NSD and HSD (Δ% of maximal relaxation, NSD: from 32±3% to 58±3.4%, n=9,
P
<0.01; HSD: from 33±3.8% to 59±3.5%, n=8,
P
<0.01), but this effect was impaired during LSD (Δ% maximal relaxation, from 36±1.5% to 36±3.4%, n=8, NS). In conclusion, our data demonstrate that in Wistar-Kyoto rats, changes in dietary salt intake do not modify the insulin-stimulated whole-body glucose uptake. In contrast, LSD impairs the insulin potentiation of α
2
-adrenergic vasorelaxation, thus suggesting that dietary salt restriction provokes an impairment of insulin effect on endothelial function.
Blood Pressure–Independent Cardiac Hypertrophy Induced by Locally Activated Renin-Angiotensin System
Authors: Mazzolai Lucia , Nussberger Jürg , Aubert Jean-François , Brunner Dorette B. , Gabbiani Giulio , Brunner Hans R. , Pedrazzini Thierry
Published: June 2012

Abstract
—Cardiac hypertrophy is frequent in chronic hypertension. The renin-angiotensin system, via its effector angiotensin II (Ang II), regulates blood pressure and participates in sustaining hypertension. In addition, a growing body of evidence indicates that Ang II acts also as a growth factor. However, it is still a matter of debate whether the trophic effect of Ang II can trigger cardiac hypertrophy in the absence of elevated blood pressure. To address this question, transgenic mice overexpressing the rat angiotensinogen gene, specifically in the heart, were generated to increase the local activity of the renin-angiotensin system and therefore Ang II production. These mice develop myocardial hypertrophy without signs of fibrosis independently from the presence of hypertension, demonstrating that local Ang II production is important in mediating the hypertrophic response in vivo.
Renal Denervation Prevents and Reverses Hyperinsulinemia-Induced Hypertension in Rats
Authors: Huang Wann-Chu , Fang Te-Chao , Cheng Juei-Tang
Published: June 2012

Abstract
—Experiments were performed to evaluate the role of the renal nerves in hyperinsulinemia-induced hypertension. Male Sprague-Dawley rats were made hyperinsulinemic by insulin infusion via osmotic minipumps implanted subcutaneously (3.0 mU/kg per minute for 6 weeks). Rats with vehicle infusion served as controls. Bilateral renal denervation was performed either at the beginning of or 4 weeks after insulin infusion. The systolic blood pressure was measured by the tail-cuff method twice a week. Food and water intake and urine flow were measured daily. The results showed that sustained insulin infusion significantly increased plasma insulin concentrations from 277.7±25.8 pmol/L to 609.9±22.2 and 696.7±23.0 pmol/L by the end of weeks 4 and 6, respectively (
P
<0.05). Systolic blood pressure was significantly increased from 135±3 to 157±3 and 159±2 mm Hg (
P
<0.05) at the corresponding time points. There was a significant increase in the plasma norepinephrine concentration after insulin infusion, whereas no significant changes in plasma triglyceride and glucose concentrations, water intake, urine flow, sodium excretion, sodium gain, and body weight gain were observed. Bilateral renal denervation depleted renal norepinephrine stores and prevented the development of hyperinsulinemia-induced hypertension. After hyperinsulinemia-induced hypertension had been fully established (from 134±2 to 157±2 mm Hg), bilateral renal denervation reversed the elevated systolic blood pressure to normotensive levels within 2 weeks. Transient denervated diuresis and natriuresis were observed. These results indicate that chronic hyperinsulinemia-induced hypertension requires the presence of intact renal nerves in rats.
Early Induction of Transforming Growth Factor-β via Angiotensin II Type 1 Receptors Contributes to Cardiac Fibrosis Induced by Long-term Blockade of Nitric Oxide Synthesis in Rats
Authors: Tomita Hideharu , Egashira Kensuke , Ohara Yuichi , Takemoto Masao , Koyanagi Masamichi , Katoh Makoto , Yamamoto Hiroaki , Tamaki Kiyoshi , Shimokawa Hiroaki , Takeshita Akira
Published: June 2012

Abstract
—We previously reported that the chronic inhibition of nitric oxide (NO) synthesis increases cardiac tissue angiotensin-converting enzyme expression and causes cardiac fibrosis in rats. However, the mechanisms are not known. Transforming growth factor-β (TGF-β) is a key molecule that is responsible for tissue fibrosis. The present study investigated the role of TGF-β in the pathogenesis of cardiac fibrosis. The development of cardiac fibrosis by oral administration of the NO synthesis inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) to normal rats was preceded by increases in mRNA levels of cardiac TGF-β
1
and extracellular matrix (ECM) proteins. TGF-β immunoreactivity was increased in the areas of fibrosis. Treatment with a specific angiotensin II type 1 receptor antagonist, but not with hydralazine, completely prevented the L-NAME–induced increases in the gene expression of TGF-β
1
and ECM proteins and also prevented cardiac fibrosis. Intraperitoneal injection of neutralizing antibody against TGF-β did not affect the L-NAME–induced increase in TGF-β
1
mRNA levels but prevented an increase in the mRNA levels of ECM protein. These results suggest that the early induction of TGF-β
1
via the angiotensin II type 1 receptor plays a major role in the development of cardiac fibrosis in this model.
Erythrocyte Disaggregation Shear Stress, Sialic Acid, and Cell Aging in Humans
Authors: Hadengue Alexandra L. , Del-Pino Muriel , Simon Alain , Levenson Jaime
Published: June 2012

Abstract
—Erythrocyte aggregation, which plays an important role in the physiological behavior of blood fluidity, was found to be enhanced in hypertension and hypercholesterolemia. While the role of macromolecule bridging force has been widely described, cellular factors related to membrane sialic acid content, which might contribute to the negative charge of cell surface causing the repulsion of erythrocytes, have been less studied. Cell age–dependent changes in membrane sialic acid content (in micromoles per gram of integral membrane protein) were investigated in 24 normotensive and 24 hypertensive matched subjects, each divided into 2 identical subgroups according to a cutoff of 6.2 mmol/L serum cholesterol. A progressive and significant (
P
<0.001) decrease in membrane sialic acid content associated with an increase (
P
<0.001) of disaggregation shear rate threshold (laser reflectometry in the presence of dextran) were observed with increased erythrocyte density (erythrocytes fractionated by density using ultracentrifugation) in both normotensive and hypertensive groups regardless of the cholesterol level. However, disaggregation shear rate threshold was significantly higher and sialic acid content was lower (
P
<0.001) in both hypertensive and normotensive subjects with hypercholesterolemia compared with either normotensive or hypertensive subjects with low cholesterol, respectively. A high membrane sialic acid content variance, beginning in the younger erythrocytes, was due mainly to triglyceride and LDL cholesterol levels (
R
2
=0.49 for low,
R
2
=0.43 for middle, and
R
2
=0.54 for high densities, ie, young, mean, and senescent erythrocytes, respectively). We conclude that an early decrease in erythrocyte sialic acid content may influence the rheological properties of blood by increasing the adhesive energy of erythrocyte aggregates.
Microvasculature in Angiotensin II–Dependent Cardiac Hypertrophy in the Rat
Authors: Sabri Abdelkarim , Samuel Jane-Lyse , Marotte Françoise , Poitevin Pierre , Rappaport Lydie , Levy Bernard I.
Published: June 2012

Abstract
—The long-lasting effect of angiotensin II (Ang II) on the microvasculature in the rat left ventricle was studied. Immunolabeling of ventricular cryosections combined with morphometric analysis allowed us to (1) distinguish between capillaries and arterioles and (2) precisely evaluate their respective densities in the endomyocardium. Ang II–induced hypertensive cardiac hypertrophy was associated with an 18% decrease in capillary density (
P
<0.05) and an increase in arteriole density (+54%,
P
<0.001). Treatments with losartan or
PD123319
, the respective antagonists of the angiotensin subtype 1 and subtype 2 receptors, prevented the increase in arteriolar density, whereas only losartan, which restored normal arterial pressure, prevented changes in capillary density. Taken together, these results indicate that Ang II–induced cardiac hypertrophy was associated with capillary rarefaction and arteriolar growth, the 2 processes being independently regulated.
Reproducibility and Clinical Value of the Trough-to-Peak Ratio of the Antihypertensive Effect
Authors: Omboni Stefano , Fogari Roberto , Palatini Paolo , Rappelli Alessandro , Mancia Giuseppe
Published: June 2012

Abstract
—The objectives of our study were to assess the reproducibility of the trough-to-peak ratio (T/P) and to see whether a high T/P is accompanied by more organ protection or vice versa. The study included 175 (mean±SD age, 51±9 years) subjects with mild-moderate essential hypertension who had echocardiographic evidence of left ventricular (LV) hypertrophy taken from the SAMPLE study (Study on Ambulatory Monitoring of Blood Pressure and Lisinopril Evaluation), an open-label multicenter study. The study included a 3-week washout pretreatment period, a 12-month treatment period with lisinopril (n=84) or lisinopril plus hydrochlorothiazide (n=91) once daily, and a 4-week placebo follow-up period. Results of 24-hour ambulatory blood pressure monitoring and echocardiographic determination of left ventricular mass index (LVMI) were obtained before and after 3 and 12 months of treatment. T/Ps were computed in each patient by dividing the systolic and diastolic blood pressure changes at trough (changes in the last 2 hours of the monitoring period) by those at peak (average of the 2 adjacent hours with the maximal blood pressure reduction between the 2nd and 8th hour from drug intake) after 3 and 12 months of treatment. Average 24-hour blood pressure was similarly reduced at 3 and 12 months. Trough blood pressure changes at 3 and 12 months were closely correlated, as were the corresponding peak blood pressure changes. However, the 3- and 12-month T/Ps correlated to a lesser degree (
r
<0.42). Furthermore, the reduction of LVMI induced by treatment was similarly correlated with the treatment-induced reduction in 24-hour average, trough, and peak blood pressures but not with the T/Ps. This was also evident when the contribution to LV hypertrophy regression by 24-hour blood pressure changes and T/Ps was assessed in a multivariate regression analysis. In patients with a T/P ≥0.5 or <0.5, the regression of LVMI was similar. In conclusion, peak and trough blood pressure changes are reproducible and predict the regression of LVMI induced by treatment as well as average 24-hour blood pressure. T/Ps are less reproducible, and their value does not predict regression of organ damage by antihypertensive treatment.
Interaction of mRNAs for Angiotensin II Type 1 and Type 2 Receptors to Vascular Remodeling in Spontaneously Hypertensive Rats
Authors: Otsuka Shoji , Sugano Masahiro , Makino Naoki , Sawada Shojiro , Hata Tomoji , Niho Yoshiyuki
Published: June 2012

Abstract
—We administered angiotensin II (Ang II) receptor type 1 (AT
1
) blockade (losartan, 40 mg · kg
−1
· d
−1
), type II receptor (AT
2
) blockade (PD123319, 100 mg · kg
−1
· d
−1
), or angiotensin-converting enzyme (ACE) inhibitor (enalapril, 30 mg · kg
−1
· d
−1
) to spontaneously hypertensive rats (SHR) from 10 to 20 weeks of age. Control SHR and Wister-Kyoto rats (WKY) received a placebo for the same period. At the end of treatment, losartan and enalapril were both found to have significantly reduced the arterial systolic blood pressure and the collagen concentration to the level of WKY, whereas PD123319 had no effect. Enalapril and PD123319 significantly reduced the media cross-sectional area of the aorta in comparison to that of untreated SHR, which was still larger than that of the WKY; however, losartan did not change it. Using reverse transcription–polymerase chain reaction, we next examined the mRNA expressions for ACE, AT
1
receptor, and AT
2
receptor in experimental animals. We observed significantly enhanced mRNA expression for AT
1
and AT
2
receptors and ACE in untreated SHR compared with WKY. The AT
1
mRNA level was also significantly decreased in the SHR treated with either losartan or enalapril, whereas the AT
2
mRNA level was significantly decreased in the SHR treated with either PD123319 or enalapril in comparison to untreated SHR. The level of ACE mRNA was significantly decreased only in the SHR treated with enalapril. These results indicate that AT
1
receptor, but not AT
2
receptor, plays a crucial role in the remodeling of matrix tissue, while AT
2
receptor may play a role in the development of hypertrophy of smooth muscle in aorta in SHR, and that the reduction of hypertrophy of smooth muscle does not fully account for the suppression of hypertension.
Endothelial Nitric Oxide Synthase Gene Polymorphism and Acute Myocardial Infarction
Authors: Hibi Kiyoshi , Ishigami Tomoaki , Tamura Kouichi , Mizushima Shunsaku , Nyui Nobuo , Fujita Takayuki , Ochiai Hisao , Kosuge Masami , Watanabe Yasujirou , Yoshii Yuzuru , Kihara Minoru , Kimura Kazuo , Ishii Masao , Umemura Satoshi
Published: June 2012

Abstract
—Recently a point mutation of guanine to thymine at nucleotide position 1917 in the endothelial nitric oxide synthase (eNOS) gene has been reported to be associated with coronary artery spasm. In addition, a significant association of the 4a/b polymorphism in intron 4 of the eNOS gene with coronary artery disease has been reported. However, the implications of these polymorphisms with respect to acute myocardial infarction (AMI) remain to be established. We conducted a case-control study of 226 patients with AMI and 357 healthy gender- and age-matched control subjects. In the former group, coronary angiograms were evaluated according to angiographic criteria based on the number of diseased vessels (≥75%) and the number of stenotic lesions (≥50%). Homozygosity for the Glu-Asp298 polymorphism existed in 5 of 226 patients with AMI (2.2%) but not in any of the 357 control subjects (
P
=.0085). However, when we evaluated the coronary angiograms of 226 case patients, there was no difference in the number of diseased vessels or the number of stenotic lesions between the patients with this homozygote and those without it. By contrast, there was no evidence of a significant increase in the risk of AMI or the severity of coronary atherosclerosis among individuals with the a/a genotype of the eNOS4a/b polymorphism. Our results imply that patients who are homozygous for the Glu-Asp298 polymorphism may be genetically predisposed to AMI; however, this mutation apparently is not related to the severity of coronary atherosclerosis. Further studies are needed to confirm our results and characterize the molecular mechanisms by which eNOS is involved in susceptibility to AMI.
Relation Between Coronary Artery Disease, Aortic Stiffness, and Left Ventricular Structure in a Population Sample
Authors: Gatzka Christoph D. , Cameron James D. , Kingwell Bronwyn A. , Dart Anthony M.
Published: June 2012

Abstract
—To elucidate the relationship between coronary artery disease (CAD), aortic stiffness, and left ventricular structure, we recruited 55 subjects (33 men; average age, 63±1 years) with previously unknown CAD from a healthy general population sample, as well as 55 control subjects matched for gender, age, and serum cholesterol level. We measured arterial blood pressure and the systolic expansion of the transverse aorta and left ventricular structure by echocardiography. Aortic stiffness was higher in CAD patients than in controls, with a brachial pulse pressure of 59±3 versus 52±2 mm Hg and stiffness indices of E
p
=212±26 versus 123±13 kN/m
2
and β=16±2 versus 9±1 (all
P
<0.01). Mean arterial pressure was similar in both groups during the measurements (95±2 versus 93±2 mm Hg,
P
=NS). Most CAD patients (61%) were in the highest stiffness quartile defined by the normal control values (
P
<0.05 versus control). Left ventricular mass index was also higher in CAD patients than in matched controls (139±5 versus 123±4 g/m
2
,
P
<0.05). We conclude that aortic stiffness and left ventricular mass are increased in subjects newly diagnosed as having CAD. This might explain previously reported associations of an increased mortality, particularly from CAD, found among subjects with elevated pulse pressures.
Isolation of a Chromosome 1 Region That Contributes to High Blood Pressure and Salt Sensitivity
Authors: Iwai Naoharu , Tsujita Yasuyuki , Kinoshita Masahiko
Published: June 2012

Abstract
—Linkage analyses in the spontaneously hypertensive rat (SHR) suggest that a gene involved in blood pressure regulation may be located on rat chromosome 1, in the
Sa
region. To confirm this possibility, we replaced a region of chromosome 1 in the Wistar-Kyoto rat (WKY) defined by the markers
D1Mit3
and
MTPA
with the corresponding chromosome segment from SHR. Genotyping using 65 polymorphic microsatellite markers throughout the entire genome confirmed the congenic status of this new strain designated WKY.SHR-D1Mit3/Rat57. In male WKY.SHR-D1Mit3/Rat57, mean blood pressures in the daytime and in the nighttime assessed by radiotelemetry were significantly higher than those in male progenitor WKY. Moreover, salt loading significantly increased the mean blood pressure in male WKY.SHR-D1Mit3/Rat57 but not in male progenitor WKY. The present study confirmed the existence of a gene that contributes to high blood pressure and salt sensitivity in this chromosomal segment. This congenic strain represents a new animal model for fine mapping and characterization of the gene in this region involved in salt-sensitive hypertension.
Rapid Communication: Salt-Sensitive Hypertension Induced by Sensory Denervation
Authors: Wang Donna H. , Li Jianping , Qiu Jingxin
Published: June 2012

Abstract
—To test the novel hypothesis that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure, newborn Wistar rats were given 50 mg/kg capsaicin subcutaneously on the 1st and 2nd day of life. Control rats were treated with vehicle. Immediately after the weanling period, male rats were divided into 4 groups and fed different sodium diets for 2 weeks: capsaicin pretreatment plus high sodium diet (4%, CAP-HS), capsaicin plus normal sodium diet (0.5%, CAP-NS), control plus high sodium diet (CON-HS), and control plus normal sodium diet (CON-NS). Both tail-cuff systolic blood pressure and mean arterial pressure with anesthesia were significantly higher in CAP-HS than in CAP-NS, CON-HS, and CON-NS (
P
<0.05), but they were not different among the latter 3 groups. Radioimmunoassay revealed that levels of calcitonin gene–related peptide in dorsal root ganglia were markedly decreased by capsaicin treatment (
P
<0.05). Twenty-four-hour urine volume and urine sodium excretion were significantly lower in CAP-HS than in CON-HS but were higher in CAP-HS and CON-HS compared with CAP-NS and CON-NS (
P
<0.05). Urine potassium excretion was not different among the 4 groups. Thus, this study provides the first evidence that neonatal degeneration of capsaicin-sensitive sensory nerves renders the rat salt-sensitive in terms of blood pressure regulation. Furthermore, our data suggest that neonatal capsaicin treatment may impair renal sodium and water excretion responses to high sodium intake. This model will provide a novel experimental paradigm for exploring underlying molecular mechanisms linked with salt-sensitive hypertension and sensory nerve function.
Nitric Oxide Metabolism in Erythropoietin-Induced Hypertension
Authors: Ni Zhenmin , Wang Xiu Q. , Vaziri Nosratola D.
Published: June 2012

Abstract
—Long-term administration of erythropoietin (EPO) frequently causes hypertension in humans and animals with chronic renal failure (CRF). We recently demonstrated that EPO-induced hypertension is hematocrit independent and accompanied by elevated cytosolic [Ca
2+
]
i
and nitric oxide (NO) resistance. This study was undertaken to examine the effects of therapy with EPO alone or together with calcium channel blockade on NO metabolism. Urinary excretion of NO metabolites (NOx) and thoracic aorta and kidney endothelial and inducible NO synthases (eNOS and iNOS) were studied in 4 groups of 6 nephrectomized rats treated with either placebo, EPO, the calcium channel blocker felodipine, or EPO plus felodipine for 6 weeks. A group of sham-operated placebo-treated animals served as control. The placebo-treated CRF group exhibited moderate hypertension, elevated basal and depressed stimulated platelet [Ca
2+
]
i
, reduced urinary NOx excretion, and diminished vascular and renal eNOS and iNOS proteins. EPO therapy further raised blood pressure and increased resting and stimulated [Ca
2+
]
i
but did not change NOx excretion or NOS proteins. Concurrent administration of felodipine abrogated EPO-induced hypertension, normalized resting and stimulated [Ca
2+
]
i
, and increased NOx excretion and eNOS and iNOS proteins. Thus, EPO therapy leads to marked increases in blood pressure and resting and stimulated [Ca
2+
]
i
. These abnormalities are ameliorated by calcium channel blockade, which restores [Ca
2+
]
i
to normal and increases vascular and renal NOS expression.
Maladaptive Remodeling of Cardiac Myocyte Shape Begins Long Before Failure in Hypertension
Authors: Onodera Tatsuyuki , Tamura Tetsutaro , Said Suleman , McCune Sylvia A. , Gerdes A. Martin
Published: June 2012

Abstract
—Progression to failure in hypertension is associated with ventricular dilation, excessive myocyte lengthening, and an increase in myocyte length/width ratio. The temporal development of these changes in relation to impaired pump performance is unknown. We examined isolated myocytes from 1- to 12-month-old spontaneously hypertensive heart failure (SHHF) rats who develop heart failure at approximately 24 months of age. Left ventricular myocyte cross-sectional area reached a maximum of ≈350 to 400 μm
2
at 3 months of age and did not change significantly thereafter. Nonetheless, LV systolic wall stress, a known stimulus for myocyte transverse growth, increased progressively between 3 and 12 months of age. Unlike the situation in normally aging rats with stable body mass, myocyte length in SHHF rats continued to increase with aging (
P
<0.05 from 9 to 12 months of age). In summary, (1) left ventricular myocyte transverse growth reaches an upper limit by 3 months of age although systolic wall stress continues to rise; and (2) cell length is significantly increased by 12 months of age. This study suggests that maladaptive remodeling of cardiac myocyte shape begins long before pump failure in hypertension. Additionally, it appears that the left ventricle may be robbed of an important adaptive mechanism to normalize wall stress (eg, myocyte transverse growth) early in the progression to failure.
Effect of Vasopressin Antagonism on Structure and Mechanics of Small Arteries and Vascular Expression of Endothelin-1 in Deoxycorticosterone Acetate–Salt Hypertensive Rats
Authors: Intengan Hope D. , He Gang , Schiffrin Ernesto L.
Published: June 2012

Abstract
—The structural and mechanical properties of small arteries are altered in rat models of hypertension. The precise role of humoral factors in these changes has not been determined. In deoxycorticosterone acetate (DOCA)–salt hypertension, endothelin-1 (ET-1) peptide content and gene expression are enhanced in mesenteric resistance arteries. These vessels also present augmented vasoconstrictor responsiveness to vasopressin versus control uninephrectomized rats. To determine whether an interaction exists between vasopressin and ET-1 in the pathogenesis of small-artery structural alterations in DOCA-salt rats, we examined the effect of chronic V
1
vasopressin receptor antagonism (OPC-21268, 30 mg/kg BID) on the structure and mechanical properties of mesenteric resistance arteries using a pressure myograph and the effect on preproendothelin-1 (preproET-1) gene expression, determined by Northern blot analysis of preproET-1 mRNA. Tail-cuff systolic pressures were elevated in DOCA-salt (200±11 mm Hg) versus uninephrectomized rats (109±4 mm Hg) and decreased slightly but significantly by OPC-21268 to 187±7 mm Hg (
P
<0.01). Treatment with DOCA-salt increased vascular media-lumen ratios and media cross-sectional areas and reduced both stress and incremental elastic modulus for a given pressure. However, there was no change in distensibility or incremental elastic modulus versus media stress. OPC-21268 partially attenuated the vascular growth in DOCA-salt rats. PreproET-1 mRNA was increased 2-fold in mesenteric arteries of DOCA-salt rats versus uninephrectomized rats, an effect abrogated by OPC-21268. Thus, DOCA-salt hypertension is associated with altered morphology of the small-arterial wall, without altering stiffness of the arterial wall components. OPC-21268 regressed in part these changes, suggesting the involvement of vasopressin. The concomitant attenuation of enhanced ET-1 expression by OPC-21268 suggests that ET-1 may be involved in mediating in part the vascular effects of vasopressin in DOCA-salt hypertensive rats.
α
1
-Adrenergic Plus Angiotensin Receptor Blockade Reduces Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Makaritsis Konstantinos P. , Gavras Haralambos , Du Yue , Chobanian Aram V. , Brecher Peter
Published: June 2012

Abstract
—We have used the apolipoprotein E (apoE)–deficient mouse model to determine whether both the angiotensin II type 1 (AT
1
) and the α
1
-adrenergic receptors influence arteriosclerotic changes in this hyperlipidemic animal model. Mice were treated with antihypertensive drugs beginning at 9 weeks of age, and aortic atherosclerosis was measured after 12 weeks of treatment. Systolic blood pressure in the untreated apoE-deficient mouse averaged 104 mm Hg throughout the treatment period. Prazosin at a dose of 7.5 mg · kg
−1
· d
−1
was ineffective in attenuating atherosclerosis and did not significantly reduce blood pressure. Losartan, at dosages of either 20 or 30 mg · kg
−1
· d
−1
, also did not influence atherosclerosis and had only a slight blood pressure–lowering effect. However, combined treatment with both prazosin and losartan markedly reduced atherosclerotic lesion development from an average lesion size per section of 2.6 to 1.5×10
5
μm
2
(
P
<0.001) and significantly reduced blood pressure to 85±5 mm Hg. Treatment with
N
G
-nitro-
l
-arginine methyl ester (40 mg · kg
−1
· d
−1
) produced significant elevations of blood pressure (127±3.8 mm Hg) but had no effect on the development of atherosclerosis. None of the treatments used affected plasma cholesterol throughout the 12-week period. These studies suggest that the vascular changes associated with atherosclerosis are influenced by a combination of AT
1
and α
1
-adrenergic receptor activation.
Arachidonate-Induced Tyrosine Phosphorylation of Epidermal Growth Factor Receptor and Shc-Grb2-Sos Association
Authors: Dulin Nickolai O. , Sorokin Andrey , Douglas Janice G.
Published: June 2012

Abstract
—Protein tyrosine phosphorylation induced by arachidonic acid (AA), an important lipid second messenger, was investigated in rabbit renal proximal tubule epithelial cells. AA stimulated tyrosine phosphorylation of a number of proteins with estimated molecular weights of 42, 44, 52, 56, 85, and 170/180 kDa. The phosphoproteins pp44 and pp42 were identified as 2 isoforms of mitogen-activated protein kinase (MAPK). Phosphorylation of MAPK in response to AA was transient, dose-dependent, and accompanied by an increase in its activity. The mechanism of AA-induced MAPK activation in RTE cells was protein kinase C–independent and involved tyrosine phosphorylation of adaptor protein Shc and its association with Grb2-Sos complex. Moreover, stimulation of RTE cells with AA resulted in significant phosphorylation of epidermal growth factor (EGF) receptor and its association with Shc. The effect of AA on EGF receptor phosphorylation, its association with Shc, and MAPK activation was similar to the effect of 1 ng/mL EGF. Tyrphostin AG1478, a specific inhibitor of EGF receptor tyrosine kinase activity, completely blocked the effects of AA and EGF but not phorbol ester on MAPK phosphorylation. These data suggest that in renal tubular epithelial cells, the mechanism of AA-induced MAPK activation involves tyrosine phosphorylation of EGF receptor and its association with Shc and Grb2-Sos complex. Given the critical role of AA in signaling linked to G protein–coupled receptors (GPCRs), these observations provide a mechanism for cross talk between GPCRs linked to phospholipases and the tyrosine kinase receptor signaling cascades.
Role of Chromosome X in the Sabra Rat Model of Salt-Sensitive Hypertension
Authors: Yagil Chana , Sapojnikov Marina , Kreutz Reinhold , Zürcher Heiko , Ganten Detlev , Yagil Yoram
Published: June 2012

Abstract
—We carried out a total genome screen in the Sabra rat model of hypertension to detect salt-susceptibility genes. We previously reported in male animals the presence of 2 major quantitative trait loci (QTLs) on chromosome 1 that together accounted for most of the difference in the blood pressure (BP) response to salt loading between Sabra hypertension-prone rats (SBH/y) and Sabra hypertension-resistant rats (SBN/y). In females, we reported on 2 major QTLs on chromosomes 1 and 17 that together accounted for only two thirds of the difference in the BP response between the strains. On the basis of phenotypic patterns of inheritance in reciprocal F
2
crosses, we proposed a role of the X chromosome. We therefore continued the search for the missing QTL in females that would account for the remaining difference in the BP response between the 2 strains using newly developed microsatellite markers and focusing on chromosome X. We screened an F
2
cross, consisting of 371 females and 336 males, using 19 polymorphic chromosome X microsatellite markers. We analyzed the averages of BP by genotype using ANOVA and the individual data using MAPMAKER/QTL. In female F
2
progeny, we identified a segment on chromosome X that spans over 33.4 cM and shows significant cosegregation (
P
<0.001) of 14 microsatellite markers (demarcated by
DXRat4
and
DXMgh10
) with systolic BP after salt loading. This segment has 2 apparent peaks at
DXRat4
and
DXRat13,
with a BP effect of 14 mm Hg for each. Multipoint linkage analysis with a free model detected 3 peaks (logarithm of the odds ratio [LOD] score >4.3) within the same chromosomal segment: One between
DXMgh9
and
DXMit4
(LOD 4.9; 6.1% of variance), a second between
DXMgh12
and
DXRat8
(LOD 5.2; 7.2% of variance), and a third between
DXRat2
and
DXRat4
(LOD 5.8; 7.5% of variance). On the basis of these findings and until congenic strains become available, our working assumption is that within chromosome X, 1 to 3 genetic loci contribute importantly to the BP response of female Sabra rats to salt. In male F
2
progeny, we detected no significant cosegregation of any region on chromosome X with the BP response to salt loading. We conclude that in the female rat, salt susceptibility is mediated by 3 to 5 gene loci on chromosomes 1, 17, and X, whereas in the male rat, the X chromosome does not affect the BP response to salt.
Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen
Authors: Müller Dominik N. , Hilgers Karl F. , Mathews Salima , Breu Volker , Fischli Walter , Uhlmann Regina , Luft Friedrich C.
Published: June 2012

Abstract
—The physiological role of prorenin is unknown; however, the possibility that prorenin inhibits renin locally has been suggested. We tested the hypothesis that prorenin may be an endogenous competitor for renin uptake in the tissue. We also investigated whether prorenin can be activated to active renin and affect mean arterial pressure (MAP). Isolated perfused hindquarters of rats transgenic for human angiotensinogen were infused with human renin and/or prorenin. The plateau phase of angiotensin (Ang) I release 15 minutes after cessation of infusions was used as a parameter for renin uptake. Renin (10 ng/mL for 15 minutes) caused sustained release of Ang I (153±16 fmol/mL). Coinfusion with a 15-fold excess of prorenin did not affect local Ang I formation (153±19 fmol/mL). Prorenin infusion alone showed no activation to active renin. In addition, we investigated MAP and plasma Ang II levels after injection of saline (ΔMAP, −1±2 mm Hg; 40±5 fmol/mL Ang II), 9 ng renin (ΔMAP, +37±3 mm Hg; 378±39 fmol/mL), and 144 ng prorenin (ΔMAP, +10±5 mm Hg; 61±5 fmol/mL) and the coinjection of renin and prorenin (ΔMAP, +41±4 mm Hg; 305±23 fmol/mL) in anesthetized rats. The data show that prorenin was not activated to active renin and did not affect MAP in short-term experiments. Renin-induced Ang formation was not affected by prorenin. Renin may have been taken up specifically because of its physical and chemical properties or because of nonspecific sequestration in the extravascular space. We conclude that prorenin does not act as an endogenous antagonist for the long-lasting effects of renin in the vascular wall. Moreover, prorenin does not affect acute renin-related effects on blood pressure.
Regulation of Angiotensin II Type 1 Receptor mRNA and Protein in Angiotensin II–Induced Hypertension
Authors: Harrison-Bernard Lisa M. , El-Dahr Samir S. , O’Leary Denise F. , Navar L. Gabriel
Published: June 2012

Abstract
—Chronic elevations of circulating angiotensin II (Ang II) cause sustained hypertension and enhanced accumulation of intrarenal Ang II by an AT
1
receptor–dependent process. The present study tested the hypothesis that chronic elevations in circulating Ang II regulate AT
1
mRNA and protein expression in a tissue-specific manner. Sprague-Dawley rats were infused with Ang II (80 ng/min) or vehicle subcutaneously for 13 days via osmotic minipump. On day 12, systolic blood pressure averaged 186±12 mm Hg in Ang II–infused rats compared with rats given vehicle (121±2 mm Hg). Plasma renin activity was markedly suppressed in the Ang II–infused rats compared with vehicle-infused rats (0.1±0.01 versus 4.9±0.9 ng of Ang I · mL
−1
· h
−1
;
P
<0.05). Semiquantitative reverse transcription polymerase chain reaction using rat AT
1A
- and glyceraldehyde-3-phosphate-dehydrogenase (GAPDH)-specific primers was followed by Southern blot hybridization using specific radiolabeled cDNA or oligonucleotide probes. The results showed that the ratios of AT
1A
/GAPDH mRNA in the kidney (0.19±0.05 versus 0.26±0.03) and liver (2.8±0.9 versus 3.0±0.5) were comparable in Ang II– and vehicle-infused rats. In contrast, AT
1A
/GAPDH mRNA levels were increased in the adrenal glands of Ang II–infused rats (0.49±0.04 versus 0.36±0.02;
P
<0.05). Western blot analysis showed that AT
1
protein levels in the kidney and liver were also similar in the two groups. Therefore, these results indicate that renal and liver AT
1
receptor gene expression is maintained in Ang II–induced hypertension. The failure to downregulate AT
1
receptor mRNA and protein levels thus allows the sustained effects of chronic elevations in Ang II to elicit progressive increases in arterial pressure.