bluuebunny/crossref_metadata_2025 huggingface dataset:
N-Domain–Specific Substrate and C-Domain Inhibitors of Angiotensin-Converting Enzyme
Authors: Deddish Peter A. , Marcic Branislav , Jackman Herbert L. , Wang Huan-Zhu , Skidgel Randal A. , Erdös Ervin G.
Published: June 2012

Abstract
—We used the isolated N- and C-domains of the angiotensin I–converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1–7 derivative of angiotensin (Ang) II and inhibition by 5-
S
-5-benzamido-4-oxo-6-phenylhexanoyl-
l
-proline (keto-ACE). Ang-(1–7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC
50
of C-ACE with 100 μmol/L Ang I substrate was 1.2 μmol/L and the
K
i
was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38- to 47-times lower concentration than by N-ACE; IC
50
values with C-ACE were 0.5 and 0.04 μmol/L. Furthermore, we investigated how Ang-(1–7) acts via bradykinin and the involvement of its B
2
receptor. Ang-(1–7) was ineffective directly on the human bradykinin B
2
receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1–7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 μmol/L), acting on the B
2
receptor when the cells were cotransfected with cDNAs of both B
2
receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1–7) can potentiate the actions of a ligand of the B
2
receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1–7).
Ethnic Differences in the Hypertensive Heart and 24-Hour Blood Pressure Profile
Authors: Mayet Jamil , Chapman Neil , Li Charles K.-C. , Shahi Manjit , Poulter Neil R. , Sever Peter S. , Foale Rodney A. , Thom Simon A.McG.
Published: June 2012

Abstract
—Black hypertensive persons have been observed to have a greater degree of left ventricular hypertrophy than white hypertensives. However, previous studies have matched groups for blood pressure (BP) measured in the clinic, and it has been demonstrated that black hypertensives have an attenuated nocturnal BP dip. Clinic BPs may thus underestimate mean 24-hour BP in this group. To investigate whether the differences in left ventricular hypertrophy can be accounted for by the greater mean 24-hour BP in black hypertensives, 92 previously untreated hypertensives were studied with 24-hour ambulatory BP monitoring and echocardiography. The 46 black hypertensives (24 men and 22 women) were matched with the 46 white hypertensives for age, gender, and mean 24-hour BP. Despite similar mean 24-hour BPs (blacks, 142/93 mm Hg; whites, 145/92 mm Hg;
P
=.53/.66), the black group had a smaller mean nocturnal dip than the white group (blacks, 8/8 mm Hg; whites, 16/13 mm Hg;
P
<.01). In addition, mean left ventricular mass index (LVMI) was greater (blacks, 130 g/m
2
; whites, 107 g/m
2
;
P
<.001). Mean 24-hour systolic BP was significantly related to LVMI in both groups (blacks,
r
=.45,
P
<.01; whites,
r
=.56,
P
<.01). However, systolic BP dip correlated inversely with LVMI only in the black group (blacks,
r
=−.30,
P
<.04; whites,
r
=.05,
P
=.76). In a multiple regression model, LVMI was independently related to both mean daytime BP and mean nocturnal BP dip in black subjects but only to mean daytime BP in white subjects. In conclusion, the increased left ventricular hypertrophy observed in black hypertensives compared with white hypertensives is not accounted for by differences in mean 24-hour BP. However, LVMI in black hypertensives appears to be more dependent on nocturnal BP than that in white hypertensives; this, coupled with the attenuated BP dip in black hypertensives, suggests that the BP profile rather than 24-hour BP may be important in determining the differences in left ventricular hypertrophy.
Salt Induces Vascular AT
1
Receptor Overexpression In Vitro and In Vivo
Authors: Nickenig Georg , Strehlow Kerstin , Roeling Jörg , Zolk Oliver , Knorr Andreas , Böhm Michael
Published: June 2012

Abstract
—The molecular events governing salt-sensitive hypertension are currently unknown. Because the renin-angiotensin system plays a central role in blood pressure regulation, as well as electrolyte balance, it may be closely involved in the phenomenon of salt sensitivity. Therefore, we examined the effect of a high salt diet (8%) on aortic angiotensin type 1 (AT
1
) receptor expression in Sprague-Dawley rats by means of radioligand binding assays and quantitative polymerase chain reaction. High salt intake caused an increase of AT
1
receptor mRNA and AT
1
receptor density to approximately 160% compared with control levels. Northern analysis revealed that incubation of vascular smooth muscle cells (VSMCs) with an increased concentration of sodium chloride (by 10 mmol/L) caused a time-dependent elevation of AT
1
receptor mRNA levels, with a maximum of 241±28% after 24 hours. There was a similar increase in AT
1
receptor density in VSMCs in response to sodium chloride, as assessed by radioligand binding assays. The salt-induced AT
1
receptor upregulation led to an enhanced functional response of VSMCs on stimulation with angiotensin II, since the angiotensin II–elicited intracellular calcium response was significantly increased in cells preincubated for 24 hours with the high salt concentration. Thus, sodium chloride may directly induce AT
1
receptor upregulation in vitro as well as in vivo; this suggests a potential mechanism participating in salt-induced hypertension because the AT
1
receptor activation is tightly coupled to blood pressure regulation.
Role of Ca
2+
-Activated K
+
Channels in the Protective Effect of ACE Inhibition Against Ischemic Myocardial Injury
Authors: Node Koichi , Kitakaze Masafumi , Kosaka Hiroaki , Minamino Tetsuo , Mori Hidezo , Hori Masatsugu
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) inhibitors increase the production of nitric oxide (NO) and prostacyclin and open Ca
2+
-activated K
+
channels. The effects of these actions of ACE inhibitors on infarct size were investigated in open-chest dogs subjected to myocardial ischemia and reperfusion. Infarct size was assessed 6 hours after the onset of reperfusion, subsequent to 90 minutes of occlusion of the left anterior descending coronary artery. The ACE inhibitor cilazaprilat was administered into the coronary artery 10 minutes before coronary occlusion, and infusion was continued until 1 hour after reperfusion. The bradykinin and NO concentrations in coronary venous blood 10 minutes after the onset of reperfusion were significantly higher in dogs treated with cilazaprilat (3 μg · kg
-1
· min
-1
) than in control animals. Although there were no significant differences in collateral flow during ischemia, infarct size in the cilazaprilat group was smaller than that in the control group (15.1±3.0% versus 46.7±4.2% of the area at risk,
P
<0.0001). The infarct size–limiting effect of cilazaprilat was partially reduced by either
N
G
-nitro-
l
-arginine methyl ester (an inhibitor of NO synthase) or iberiotoxin (a blocker of Ca
2+
-activated K
+
channels) and was abolished by
N
G
-nitro-
l
-arginine methyl ester plus iberiotoxin. Indomethacin (an inhibitor of cyclooxygenase) had no effect on the beneficial action of cilazaprilat. Inhibition of ACE thus reduced myocardial infarct size, an effect that was mediated by NO and the opening of Ca
2+
-activated K
+
channels in canine hearts.
Differential Regulation of Angiotensin II Receptor Subtypes in the Adrenal Gland
Authors: Wang Donna H. , Qiu Jingxin , Hu Zhaoyong
Published: June 2012

Abstract
—It has been shown that aldosterone potentiates the action of angiotensin II (Ang II) in cultured rat vascular smooth muscle cells solely by increasing the number of Ang II receptors. The mechanisms responsible for aldosterone–Ang II interactions in the adrenal gland are unknown. The present study was designed to investigate the effect of aldosterone on expression of Ang II receptor subtypes (AT
1
and AT
2
) in the adrenal gland. Seven-week-old male Wistar rats were treated for 2 weeks with either aldosterone (0.05 μg/h, n=14) or vehicle (n=14) by use of implanted osmotic minipumps. Systolic blood pressure was not altered by aldosterone treatment. Plasma aldosterone levels were higher in aldosterone-treated rats (181±53 pg/mL) compared with vehicle-treated rats (33±21 pg/mL,
P
<0.05). Northern blot analysis and radioligand binding assay showed that adrenal AT
1
mRNA levels and AT
1
receptor density in aldosterone-treated rats were not statistically different from those of vehicle-treated rats. However, immunohistochemical studies showed that the highest adrenal AT
1
receptor expression was shifted from the zona glomerulosa to the zona fasciculata after aldosterone treatment. In contrast, adrenal AT
2
mRNA and AT
2
receptor density in aldosterone-treated rats were decreased by approximately 50% and 40%, respectively, compared with vehicle-treated rats (
P
<0.05). Aldosterone-induced decrease in adrenal AT
2
receptor expression occurred mainly in the medulla. Thus, aldosterone differentially modulates the expression of AT
1
and AT
2
receptors in the adrenal gland. Although the function of the AT
2
receptor in the adrenal gland is largely unknown, our data indicate that aldosterone may modulate the effect of Ang II by altering the location of AT
1
receptors and by reducing the number of AT
2
receptors in the adrenal gland.
Renal Dopamine Receptor Function in Hypertension
Authors: Hussain Tahir , Lokhandwala Mustafa F.
Published: June 2012

Abstract
—Dopamine plays an important role in the regulation of renal sodium excretion. The synthesis of dopamine and the presence of dopamine receptor subtypes (D
1A
, D
1B
as D
1
-like and D
2
, and D
3
as D
2
-like) have been shown within the kidney. The activation of D
1
-like receptors located on the proximal tubules causes inhibition of tubular sodium reabsorption by inhibiting Na,H-exchanger and Na,K-ATPase activity. The D
1
-like receptors are linked to the multiple cellular signaling systems (namely, adenylyl cyclase, phospholipase C, and phospholipase A
2
) in the different regions of the nephron. Defective renal dopamine production and/or dopamine receptor function have been reported in human primary hypertension as well as in genetic models of animal hypertension. There may be a primary defect in D
1
-like receptors and an altered signaling system in the proximal tubules that lead to reduced dopamine-mediated effects on renal sodium excretion in hypertension. Recently, it has been shown in animal models that the disruption of either D
1A
or D
3
receptors at the gene level causes hypertension in mice. Dopamine and dopamine receptor agonists also provide therapeutic potential in treatment of various cardiovascular pathological conditions, including hypertension. However, because of the poor bioavailability of the currently available compounds, the use of D
1
-like agonists is limited to the management of patients with severe hypertension when a rapid reduction of blood pressure is clinically indicated and in acute management of patients with heart failure. In conclusion, there is convincing evidence that dopamine and dopamine receptors play an important role in regulation of renal function, suggesting that a defective dopamine receptor/signaling system may contribute to the development and maintenance of hypertension. Further studies need to be directed toward establishing a direct correlation between defective dopamine receptor gene in the kidney and development of hypertension. Subsequently, it may be possible to use a therapeutic approach to correct the defect in dopamine receptor gene causing the hypertension.
Appropriate Regulation of Human Renin Gene Expression and Secretion in 45-kb Human Renin Transgenic Mice
Authors: Yan Yan , Hu Lufei , Chen Rong , Sealey Jean E. , Laragh John H. , Catanzaro Daniel F.
Published: June 2012

Abstract
—To create physiological models of the human renin-angiotensin system in transgenic animals, the component genes should be expressed in the correct tissues and cells and respond appropriately to physiological stimuli. We recently showed that mice carrying a 45-kb human renin genomic fragment, containing approximately 25 kb 5′-flanking DNA and 6 kb 3′-flanking DNA, express the transgene in a highly cell- and tissue-specific pattern. More importantly, in contrast to previous models, human renin in the circulating plasma of these mice is derived exclusively from the kidneys. In the present study, we tested the responses of both human and mouse renal renin expression and secretion of the 45-kb hREN transgenic mice to a variety of physiological and pharmacological stimuli. A sodium-deficient diet, angiotensin-converting enzyme inhibition, and β
1
-adrenergic stimulation each increased both human and mouse plasma renin concentration significantly, whereas elevated blood pressure and/or increased plasma angiotensin II levels suppressed them. Human and mouse renal renin mRNA levels changed similarly but to a lesser degree. These studies demonstrate that human renin synthesis and secretion respond appropriately in 45-kb hREN mice to physiological stimuli. This most likely results from appropriate cell-specific expression of the transgene conferred by the extended transgene flanking sequences.
Effects of Magnesium Supplementation in Hypertensive Patients
Authors: Kawano Yuhei , Matsuoka Hiroaki , Takishita Shuichi , Omae Teruo
Published: June 2012

Abstract
—An increase in magnesium intake has been suggested to lower blood pressure (BP). However, the results of clinical studies are inconsistent. We studied the effects of magnesium supplementation on office, home, and ambulatory BPs in patients with essential hypertension. Sixty untreated or treated patients (34 men and 26 women, aged 33 to 74 years) with office BP >140/90 mm Hg were assigned to an 8-week magnesium supplementation period or an 8-week control period in a randomized crossover design. The subjects were given 20 mmol/d magnesium in the form of magnesium oxide during the intervention period. In the control period, office, home, and average 24-hour BPs (mean±SE) were 148.6±1.6/90.0±0.9, 136.4±1.3/86.8±0.9, and 133.7±1.3/81.0±0.8 mm Hg, respectively. All of these BPs were significantly lower in the magnesium supplementation period than in the control period, although the differences were small (office, 3.7±1.3/1.7±0.7 mm Hg; home, 2.0±0.8/1.4±0.6 mm Hg; 24-hour, 2.5±1.0/1.4±0.6 mm Hg). Serum concentration and urinary excretion of magnesium increased significantly with magnesium supplementation. Changes in 24-hour systolic and diastolic BPs were correlated negatively with baseline BP or changes in serum magnesium concentration. These results indicate that magnesium supplementation lowers BP in hypertensive subjects and this effect is greater in subjects with higher BP. Our study supports the usefulness of increasing magnesium intake as a lifestyle modification in the management of hypertension, although its antihypertensive effect may be small.
Statistical Base Value of 24-Hour Blood Pressure Distribution in Patients With Essential Hypertension
Authors: Tochikubo Osamu , Hishiki Satoshi , Miyajima Eiji , Ishii Masao
Published: June 2012

Abstract—
The purpose of this study was to calculate statistically the minimum (base) blood pressure (BP) of nighttime (sleep-time) BP values obtained by ambulatory BP monitoring (ABPM) and to investigate its clinical significance. Twenty-four-hour recording of ECG with ABPM was performed directly (n=89) or indirectly (n=117) in 206 patients with essential hypertension. A telemeter was used for the direct method and a multi-biomedical recorder (TM2425) was used for indirect measurement. First, minimum heart rate (HR
0
=60/RR
0
) was determined from sleep-time ECG. The mean product of sleep-time diastolic BP (DBP) and pulse interval (RR) was divided by RR
0
to obtain DBP
0
[DBP
0
=(DBP×RR)s/RR
0
]. The correlation between systolic BP (SBP) and DBP was used to determine SBP
0
corresponding to DBP
0
. Statistical base mean BP (MBP
0
) was calculated from these values, and its reproducibility and relation to hypertension severity were investigated. MBP
0
values were similar to true base values of sleep-time MBP obtained by the direct method (mean±SD difference, 2.0±4.2 mm Hg). Direct MBP
0
criteria predicted hypertension severity (mild, moderate, or severe target organ damage) more accurately (predictive accuracy, 89%) than daytime MBP criteria (53%,
P
<0.01). Almost the same results were obtained using indirect MBP
0
criteria. Day-to-day indirect MBP
0
variation (mean absolute difference) was smaller (2.4±1.8 mm Hg) than day-to-day daytime and nighttime MBP variation (6.3±5.3 and 5.4±3.4 mm Hg, respectively; n=61,
P
<0.01), and the correlation coefficient between day-to-day variations of daytime MBP and physical activity (measured by an acceleration sensor) was 0.38 (
P
<0.05). In conclusion, statistical base BP was almost equal to true base (minimum) BP of sleep-time BP distribution. It was closely related to the severity of hypertensive organ damage, was highly reproducible, and is considered likely to serve stochastically and physiologically as a representative BP value in an individual subject.
MAP Kinase–Independent Signaling in Angiotensin II Regulation of Neuromodulation in SHR Neurons
Authors: Yang Hong , Raizada Mohan K.
Published: June 2012

Abstract
—Angiotensin II (Ang II), via its interaction with the angiotensin type 1 (AT
1
) receptor subtype, causes enhanced stimulation of norepinephrine (NE) neuromodulation. This involves increased transcription of NE transporter, tyrosine hydroxylase, and dopamine β-hydroxylase genes in Wistar-Kyoto rat (WKY) brain neurons. AT
1
receptor–mediated regulation of certain signaling events (such as activation of the Ras-Raf-1–mitogen activated protein (MAP) kinase signaling pathway, nuclear translocation of transcription factors such as Fos and Jun, and the interactions of these factors with AP-1 binding sites) is involved in this NE neuromodulation (Lu et al.
J Cell Biol
. 1996;135:1609–1617). The aim of this study was to compare the signal transduction mechanism of Ang II regulation of NE neuromodulation in WKY and spontaneously hypertensive rat (SHR) brain neurons, in view of the fact that AT
1
receptor expression and Ang II stimulation of NE neuromodulation are higher in SHR neurons compared with WKY neurons. Despite this hyperactivity, Ang II stimulation of Ras, Raf-1, and MAP kinase activities was comparable between the neurons from WKY and SHR. Similarly, central injections of Ang II caused a comparable stimulation of MAP kinase in the hypothalamic and brain stem areas of adult WKY and SHR. Inhibition of MAP kinase by either an MAP kinase kinase inhibitor (PD98059) or an MAP kinase antisense oligonucleotide completely attenuated the stimulatory effects of Ang II on [
3
H]-NE uptake, NE transporter mRNA, and tyrosine hydroxylase mRNA levels in WKY neurons. These treatments resulted in only 43% to 50% inhibition of [
3
H]-NE uptake and NE transporter and tyrosine hydroxylase mRNAs in SHR neurons. Thus, Ang II stimulation of NE neuromodulation was completely blocked by MAP kinase inhibition in WKY neurons and only partially blocked in the SHR neurons. These observations suggest the presence of an additional signal transduction pathway involved in NE neuromodulation in SHR neurons that is independent of the MAP kinase pathway.
ANP and Bradycardic Reflexes in Hypertensive Rats
Authors: Thomas Colleen J. , Head Geoffrey A. , Woods Robyn L.
Published: June 2012

Abstract
—In previous studies we demonstrated that in normotensive rats, but not in spontaneously hypertensive rats (SHR), atrial natriuretic peptide (ANP) enhances bradycardic reflexes through an action on cardiac vagal afferent pathways. The present study aimed to determine whether cardiac hypertrophy, hypertension, or a nonreversible genetic factor accounted for the insensitivity of SHR to ANP action on cardiac reflex pathways. SHR were treated with the angiotensin-converting enzyme (ACE) inhibitor perindopril (3 mg/kg per day) for 6 weeks from 4 to 9 weeks of age (SHR-S, n=10) or for 9 weeks from 4 to 12 weeks of age (SHR-L, n=10) or were untreated (SHR, n=10) to produce differential effects on blood pressure and left ventricle/body weight ratio (LV/BW). Untreated normotensive Wistar-Kyoto rats (WKY, n=10) were also studied. At 13 weeks of age, all rats were instrumented with aortic and jugular catheters, and at 14 weeks we measured heart rate reflexes to rapid intravenous infusions of methoxamine (100 μg/kg, cardiac baroreflex) and serotonin (5 to 60 μg/kg, von Bezold-Jarisch cardiac chemosensitive reflex), with either α-rat ANP (150 ng/kg per minute IV) or saline vehicle (270 μL/h IV) infusion. Perindopril treatment for 6-week (SHR-S) and 9-week (SHR-L) durations maintained blood pressure at normotensive levels in both groups. SHR-S exhibited a small degree of cardiac hypertrophy (LV/BW was 8% higher than in WKY but 11% less than in untreated SHR), but LV/BW was normalized in SHR-L (to within 1% of WKY LV/BW). In WKY, ANP significantly (
P
<0.05) enhanced bradycardic responses to both the cardiac baroreflex (by 42±10%) and von Bezold-Jarisch chemosensitive reflex (by 17±5%) activation but had no effect in SHR. The cardiac reflex action of ANP was restored in SHR-L (ANP enhanced reflex bradycardia by 28±12% and 36±8%, baroreflex and von Bezold-Jarisch reflex, respectively;
P
<0.05), but SHR-S, which developed some cardiac hypertrophy, remained unresponsive to ANP. Our results suggest that the inability of ANP to sensitize cardiac vagal (nonarterial) afferents in SHR was not due to an inherited irreversible component, or the hypertension per se, but was associated with the presence of cardiac hypertrophy. A functional consequence of hypertension-induced cardiac hypertrophy may be the inhibition of the cardioprotective action of ANP through cardiac vagal reflexes.
Carotid Arterial Stiffness as a Predictor of Cardiovascular and All-Cause Mortality in End-Stage Renal Disease
Authors: Blacher Jacques , Pannier Bruno , Guerin Alain P. , Marchais Sylvain J. , Safar Michel E. , London Gérard M.
Published: June 2012

Abstract
—Damage of large arteries is a major contributory factor to the high pulse pressure observed in patients with end-stage renal disease. Whether incremental modulus of elasticity (E
inc
), a classic marker of arterial stiffness, can predict cardiovascular mortality has never been investigated. A cohort of 79 patients with end-stage renal disease undergoing hemodialysis was studied between September 1995 and January 1998. Mean age at entry was 58±15 years. The duration of follow-up was 25±7 months, during which 10 cardiovascular and 8 noncardiovascular fatal events occurred. At entry, carotid E
inc
was calculated from measurements of diameter, thickness (echo-tracking technique), and pulse pressure (tonometry). Based on Cox analyses, 2 dominant factors emerged as predictors of all-cause and cardiovascular mortality: increased E
inc
and decreased diastolic blood pressure. Lipid abnormalities and the presence of previous cardiovascular events interfered to a smaller extent. After adjustment for confounding variables, the odds ratio for E
inc
≥1 kPa
−3
was 9.2 (95% confidence interval, 2.4 to 35.0) for all-cause mortality. These results provide the first direct evidence that in patients with end-stage renal disease undergoing hemodialysis, arterial alterations, as determined from carotid E
inc
, are strong independent predictors of all-cause and cardiovascular mortality.
Successful Isolation of a Rat Chromosome 1 Blood Pressure Quantitative Trait Locus in Reciprocal Congenic Strains
Authors: Frantz Simon A. , Kaiser Michael , Gardiner Sheila M. , Gauguier Dominique , Vincent Madeleine , Thompson John R. , Bennett Terence , Samani Nilesh J.
Published: June 2012

Abstract
—Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the
Sa
gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an
Sa
gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-
Sa
), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-
Sa
). WKY.SHR-
Sa
contains at least ≈26 cM of SHR chromosome 1, between markers
mD7mit206
and
D1Mit2
(and including the SHR allele of the
Sa
gene), and SHR.WKY-
Sa
carries at least ≈15 cM of WKY chromosome 1, between
mD7mit206
and
D1Wox34
(and including the WKY allele of the
Sa
gene). Blood pressure of WKY.SHR-
Sa
rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-
Sa
rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-
Sa
and WKY were +11.5 mm Hg (
P
=0.001) and +11.6 mm Hg mm Hg (
P
<0.001), respectively. The corresponding differences between SHR.WKy-
Sa
and SHR were −11.3 mm Hg (
P
=0.002) and −9.1 mm Hg (
P
=0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal
Sa
mRNA levels in the congenic strains reflected their
Sa
allele with a high level in WKY.SHR-
Sa
and a low level in SHR.WKY-
Sa
, consistent with previous data suggesting that the level of
Sa
expression is primarily determined by
cis
-acting elements in or near the
Sa
gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the
Sa
gene in reciprocal congenic strains derived from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHR×WKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome.
Raised Cerebrovascular Resistance in Idiopathic Orthostatic Intolerance
Authors: Jordan Jens , Shannon John R. , Black Bonnie K. , Paranjape Sachin Y. , Barwise John , Robertson David
Published: June 2012

Abstract
—Patients with idiopathic orthostatic intolerance (IOI) exhibit symptoms suggestive of cerebral hypoperfusion and an excessive decrease in cerebral blood flow associated with standing despite sustained systemic blood pressure. In 9 patients (8 women and 1 man aged 22 to 48 years) with IOI, we tested the hypothesis that volume loading (2000 cc normal saline) and α-adrenoreceptor agonism improve systemic hemodynamics and cerebral perfusion and that the decrease in cerebral blood flow with head-up tilt (HUT) could be attenuated by α-adrenoreceptor blockade with phentolamine. At 5 minutes of HUT, volume loading (−20±3.2 bpm) and phenylephrine (−18±3.4 bpm) significantly reduced upright heart rate compared with placebo; the effect was diminished at the end of HUT. Phentolamine substantially increased upright heart rate at 5 minutes (20±3.7 bpm) and at the end of HUT (14±5 bpm). With placebo, mean cerebral blood flow velocity decreased by 33±6% at the end of HUT. This decrease in cerebral blood flow with HUT was attenuated by all 3 interventions. We conclude that in patients with IOI, HUT causes a substantial decrease in cerebrovascular blood flow velocity. The decrease in blood flow velocity with HUT can be attenuated with interventions that improve systemic hemodynamics and therefore decrease reflex sympathetic activation. Moreover, α-adrenoreceptor blockade also blunts the decrease in cerebral blood flow with HUT but at the price of deteriorated systemic hemodynamics. These observations may suggest that in patients with IOI, excessive sympathetic activity contributes to the paradoxical decrease in cerebral blood flow with upright posture.
Nerve Growth Factor Gene Locus Explains Elevated Renal Nerve Growth Factor mRNA in Young Spontaneously Hypertensive Rats
Authors: Charchar Fadi J. , Kapuscinski Miroslav K. , Harrap Stephen B.
Published: June 2012

Abstract
—Nerve growth factor (NGF) controls the growth of sympathetic nerves and is increased in young spontaneously hypertensive rats (SHR). The NGF gene has been linked genetically with hypertension in the SHR strain and may explain high NGF mRNA levels. To test for genetic linkage between the NGF gene and its expression in vivo, we examined renal NGF mRNA levels in male SHR, control Donryu rats (DRY), and F
2
rats derived from SHR and DRY at ages 2, 4, 10, and 20 weeks. Tail-cuff blood pressure was measured at 4, 10, and 20 weeks of age. NGF mRNA levels in SHR (NGF genotype:
SS
) were higher than those in DRY (NGF genotype:
DD
) at 2, 4, and 10 weeks of age (
P
<0.0001) but the same at 20 weeks of age. In the F
2
generation, the
S
allele was associated with significantly (
P
=0.01) higher renal NGF mRNA levels at 2 weeks of age. Mean NGF mRNA levels fell (
P
=0.01) with age in F
2
rats, and the difference between
SS
and
DD
genotype F
2
rats diminished at older ages and was not significant. In F
2
rats there was a positive correlation between the number of NGF
S
alleles inherited and tail-cuff pressure (
P
<0.007). Our findings indicate that the NGF locus is an important regulator of NGF mRNA levels. It is likely that mutations in or near the NGF gene explain in part high early NGF gene expression in SHR.
Calcium Channel Blockade Enhances Nitric Oxide Synthase Expression by Cultured Endothelial Cells
Authors: Ding Yaoxian , Vaziri Nosratola D.
Published: June 2012

Abstract
—In a recent study, we found marked increases in nitric oxide (NO) production and endothelial and inducible NO synthase (eNOS and iNOS) expressions with calcium channel blockade in rats with chronic renal failure. This study was undertaken to determine whether enhanced NO production with calcium channel blockade is a direct effect of this therapy or a consequence of the associated hemodynamic and humoral changes. We tested the effects of a calcium channel blocker, felodipine (10
−5
, 10
−6
, and 10
−7
mol
/L
), on nitrate and nitrite (NOx) generation, Ca
2+
-dependent and -independent NOS activity, and eNOS and iNOS protein masses in proliferating and quiescent rat aortic endothelial cells in culture. Compared with vehicle alone, felodipine significantly increased NOx generation, Ca
2+
-dependent NOS activity, and eNOS protein mass in proliferating and quiescent endothelial cells. Felodipine did not modify the stimulatory action of 10% fetal calf serum on DNA synthesis (thymidine incorporation) and cell proliferation. Ca
2+
-independent NOS activity and iNOS protein expression were negligible and unaffected by calcium channel blockade. NOx production and NOS expression were greater in proliferating cells than in quiescent cells. Thus, calcium channel blockade upregulates endothelial NO production in vitro, confirming our previous in vivo study. This observation indicates that the reductions in cytosolic [Ca
2+
] and vasodilation with calcium channel blockade are not only due to inhibition of Ca
2+
entry but also to an NO-cGMP–mediated mechanism.
Endothelin-Dependent Tone Limits Acetylcholine-Induced Dilation of Resistance Coronary Vessels After Blockade of NO Formation in Conscious Dogs
Authors: Ming Zhi , Parent Robert , Thorin Éric , Lavallée Michel
Published: June 2012

Abstract
—Nitric oxide (NO) impairs endothelin (ET) formation and/or action in isolated vessels. We hypothesized that ET may magnify the consequences of NO formation blockade on receptor-operated dilation of resistance coronary vessels in conscious dogs. In conscious instrumented dogs, graded intracoronary (IC) doses of acetylcholine (ACh) were delivered before IC administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME), after L-NAME, and after L-NAME plus IC bosentan, an ET
A
/ET
B
receptor blocker. Before L-NAME, ACh (100 ng · kg
−1
· min
−1
) increased coronary blood flow (CBF) by 43±4% from 47±6 mL · min
−1
. After L-NAME, ACh failed to increase CBF (−3±2% from 50±7 mL · min
−1
). CBF responses to ACh were partially restored (+10±2% from 50±7 mL · min
−1
,
P
<0.01) after the addition of bosentan. Bosentan alone (without L-NAME) did not alter CBF responses to ACh. Blockade of ET
A
(Ro 61-1790) but not ET
B
(Ro 46-8443) receptors partially restored CBF responses to ACh after L-NAME. Myocardial immunoreactive ET levels in the perfusion territories of the circumflex and left anterior descending coronary arteries did not differ. ET
A
-dependent tone magnified the inhibitory effects of blockade of NO formation on receptor-operated dilation to ACh in resistance coronary vessels. Presumably, stimulated NO release has an inhibitory action on endogenous ET production and/or action at the level of resistance coronary vessels.
Testosterone Effects on Renal Norepinephrine Content and Release in Rats With Different Y Chromosomes
Authors: Jones Thomas J. , Dunphy Gail , Milsted Amy , Ely Daniel
Published: June 2012

Abstract
—The Y chromosome in spontaneously hypertensive rats (SHR) and stroke-prone rats has been shown to contain a locus that contributes to the hypertensive effect; both the sympathetic nervous system and testosterone may be involved. The objective of this study was to look at the effects of testosterone on renal norepinephrine (NE) release and content in the isolated perfused kidney in different Y chromosome backgrounds. The study involved male SHR, Wistar-Kyoto rats (WKY), and 2 consomic strains with different Y chromosomes (n=5 to 8 per group). Adult animals were castrated, and implants containing testosterone propionate were placed at the base of the neck. Blood testosterone levels were measured by radioimmunoassay 2 weeks after castration. The left kidney was isolated and perfused with oxygenated Krebs solution at a constant flow and temperature with KCl and electrical stimulation of the renal nerves. Perfusate was collected and analyzed for NE by high-performance liquid chromatography. Lactate dehydrogenase analyses were performed as a marker for potential tissue damage. Renal perfusate and renal tissue NE levels were significantly elevated by testosterone. The average NE increase with a single testosterone implant was 13.2 ng/mL, and for a double testosterone implant it was 29.8 ng/mL. The Y chromosome from the SHR produced a significant increase in renal NE release compared with the WKY Y chromosome. Significance was shown between all groups: 1 versus 2 implants,
P
=0.0067; 1 versus sham implants,
P
=0.015; 2 versus sham implants,
P
<0.001. In conclusion, testosterone caused an enhanced renal NE release that was strain-specific, with the Y chromosome raising renal NE content and release.
Pressure Oscillation Regulates Human Mesangial Cell Growth and Collagen Synthesis
Authors: Mertens Peter Rene , Espenkott Volker , Venjakob Birgit , Heintz Bernhard , Handt Stefan , Sieberth Heinz-Günther
Published: June 2012

Abstract
—Experimental renal disease models establish glomerular hypertension as a crucial determinant in glomerulosclerosis progression and demonstrate that glomerular capillary pressure reduction delays sclerosis development. An oscillating pressure (OP) chamber was constructed as an in vitro model to study human mesangial cells. Cell cultures were grown under atmospheric pressure (AP) and a controlled OP corresponding to intraglomerular capillary pressure. We show that OP significantly decreases mesangial cell proliferation within 24 hours and attenuates DNA synthesis throughout a 7-day period. To explore the effects of OP on cell metabolism, cell-associated and medium-secreted extracellular (CA and EC, respectively) collagen synthesis were measured by [
3
H]proline incorporation. In subconfluent cultures, total CA and EC collagen synthesis was unaffected by OP, while in confluent cultures total EC collagen [
3
H]proline incorporation was increased. To determine whether OP influenced mesangial cell growth induction, the effects of increasing glucose in the cell culture media were investigated. Our data show that the high glucose growth stimulatory effect on cell number and DNA synthesis was suppressed by OP. Under high glucose conditions, total CA collagen synthesis was increased in confluent cultures, whereas the EC collagen fraction remained unchanged. In these cultures, OP caused an additional increase in CA collagen synthesis. This study shows that mesangial cell growth and collagen synthesis are influenced by hyperbaric OP, supporting the hypothesis that glomerular capillary pressure plays a role in progressive glomerulosclerosis development.
Early-Onset But Not Late-Onset Endothelin-A–Receptor Blockade Can Modulate Hypertension, Cerebral Edema, and Proteinuria in Stroke-Prone Hypertensive Rats
Authors: Blezer Erwin L. A. , Nicolay Klaas , Goldschmeding Roel , Jansen Gerard H. , Koomans Hein A. , Rabelink Ton J. , Joles Jaap A.
Published: June 2012

Abstract
—The ability of endothelin receptor blockade to prevent and to treat established cerebral and renal injury was explored in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP) with the endothelin receptor subtype-A antagonist
A127722
. SHRSP were subjected to 1% NaCl intake. The start of treatment with
A127722
(35 and 70 mg · kg
−1
· d
−1
, respectively) was either synchronized with salt loading or initiated after the first observation of cerebral edema with T
2
-weighted magnetic resonance imaging. In untreated control animals median survival was 54 days (range, 32 to 80 days) after the start of salt loading. Early-onset
A127722
treatment increased median survival to 233 days (range, 92 to 407 days;
P
<0.05 versus controls) with 35 mg/kg and to 124 days (range, 97 to 169 days;
P
<0.05 versus control) with 70 mg/kg. The development of cerebral edema was prevented, and systolic blood pressure and proteinuria were dose-dependently reduced. However, all rats in the 70-mg/kg treatment group developed hemorrhages in the basal ganglia shortly before death. Late-onset
A127722
treatment failed to affect survival, systolic blood pressure, or proteinuria. Nevertheless, cerebral edema was reduced but not as well as in early-onset treatment. Development of hypertension, cerebral edema, and proteinuria was prevented in SHRSP when
A127722
treatment was initiated at the start of salt-loading. However,
A127722
treatment did not prolong survival in SHRSP with cerebral edema. This suggests that in SHRSP the endothelin A receptor participates actively in the development of increased blood pressure and initiation of organ damage but participates minimally in established malignant hypertension and progression of target-organ damage.
Hormones and Vasoprotection
Authors: Oparil Suzanne
Published: June 2012

Abstract
—There is a strong link between menopause and increased cardiovascular disease incidence in women, and observational studies suggest that postmenopausal hormone replacement therapy reduces cardiovascular disease risk by about half. Observational studies suffer from important limitations, however, and the only published prospective controlled trial of the effects of hormone replacement therapy on cardiovascular outcomes, the Heart Estrogen-Progestin Replacement Study (HERS), showed no net benefit of continuous estrogen plus synthetic progestin treatment in women with established coronary disease. Fundamental mechanistic studies of the cellular and molecular events by which hormones protect (or fail to protect) blood vessels from damage are needed to define the role of postmenopausal hormone replacement therapy in cardiovascular disease prevention. Most studies suggest that estrogen inhibits the neointimal response to acute injury in normal blood vessels, but this vasoprotective effect was not seen in vessels with preexisting atherosclerosis. Studies from our laboratory in the rat carotid injury model have shown that estrogen inhibits neointima formation via effects on all 3 layers of the vascular wall, including inhibition of medial smooth muscle cell migration and proliferation, stimulation of regrowth of endothelium, and inhibition of adventitial cell migration into neointima. Our laboratory is currently using transduced (lacZ) syngeneic fibroblasts as ‘reporter’ cells to delineate the factors that stimulate migration of adventitial cells into neointima after vascular injury and their modulation by estrogen and the other sex hormones. These fundamental studies will establish more rational strategies for therapeutic intervention in vascular diseases, including the basis for future gene therapy.
Angiotensin-(1–7) Reduces Smooth Muscle Growth After Vascular Injury
Authors: Strawn William B. , Ferrario Carlos M. , Tallant E. Ann
Published: June 2012

Abstract
—Regulation of vascular smooth muscle cell growth is critical to the maintenance of normal blood flow and vessel patency. Angiotensin-(1–7) [Ang-(1–7)] inhibits proliferation of vascular smooth muscle cells in vitro and opposes the mitogenic effects of angiotensin II. The present study investigated whether Ang-(1–7) inhibits vascular smooth muscle cell growth in vivo by determining its effect on neointimal formation and medial remodeling in balloon-injured carotid arteries. The carotid arteries of adult male Sprague-Dawley rats were injured with a balloon embolectomy catheter. Ang-(1–7) in saline (24 μg/kg per hour) or saline alone was infused intravenously for 12 days after injury. Pumps containing bromodeoxyuridine were implanted at the same time to determine DNA synthesis. Intravenous infusion increased plasma Ang-(1–7) to 166.0±41.2 fmol/mL (n=6) compared with 46.9±4.2 fmol/mL (n=8) in saline-infused rats. Plasma concentrations of Ang II were not changed by Ang-(1–7) infusion. Elevation in circulating Ang-(1–7) had no effect on either blood pressure or heart rate compared with saline controls. Histomorphometric analysis of carotid arteries indicated that Ang-(1–7) infusion significantly reduced neointimal area compared with rats infused with saline (0.063±0.011 versus 0.100±0.009 mm
2
;
P
<0.05). In contrast, Ang-(1–7) infusion had no effect on medial area of the injured or the contralateral uninjured artery compared with saline controls. Ang-(1–7) infusion also reduced the rate of DNA synthesis in both the neointima and the media of the injured vessels. Therefore, exogenous Ang-(1–7) inhibited vascular smooth muscle cell proliferation associated with balloon-catheter injury. Similar increases in endogenous plasma Ang-(1–7) and inhibition of neointimal growth were observed in rats after angiotensin-converting enzyme inhibitor or angiotensin type 1 receptor antagonist administration, suggesting that Ang-(1–7) may contribute to the in vivo antiproliferative effects of these agents on vascular smooth muscle.
Hypertension-Induced End-Organ Damage
Authors: Luft Friedrich C. , Mervaala Eero , Müller Dominik N. , Gross Volkmar , Schmidt Folke , Park Joon Keun , Schmitz Christian , Lippoldt Andrea , Breu Volker , Dechend Ralph , Dragun Duska , Schneider Wolfgang , Ganten Detlev , Haller Hermann
Published: June 2012

Abstract
—Angiotensin (Ang) II-induced organ damage has fascinated students of hypertension since the work of Wilson and Byrom. We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, and VEGF expression. The expression of TGF-β and deposition of extracellular matrix proteins follows, which is accompanied by fibrinoid vasculitis in small vessels of the heart and kidneys. Angiotensin-converting enzyme inhibitors and AT1 receptor blockers each lowered blood pressure and shifted pressure natriuresis partially leftward by different mechanisms. When combined, they normalized blood pressure, pressure natriuresis, and protected from vasculopathy completely. Renin inhibition lowered blood pressure partially, but protected from vasculopathy completely. Endothelin receptor blockade had no influence on blood pressure but protected from vasculopathy and improved survival. We show evidence that Ang II stimulates oxidative stress directly or indirectly via endothelin 1 and that NFκB is upregulated in this model. We speculate that the transcription factors NFκB and AP-1 are involved with initiating chemokine and cytokine expression, leading to the above cascade. The unique model and our pharmacological probes will enable us to test these hypotheses.
Effect of Chromosome 19 Transfer on Blood Pressure in the Spontaneously Hypertensive Rat
Authors: St. Lezin Elizabeth , Zhang Lei , Yang Ying , Wang Jia-Ming , Wang Ning , Qi Nianing , Steadman J. Sanford , Liu Weizhong , Kren Vladimir , Zidek Vaclav , Krenova Drahomira , Churchill Paul C. , Churchill Monique C. , Pravenec Michal
Published: June 2012

Abstract
—Linkage studies in the spontaneously hypertensive rat (SHR) have suggested that a gene or genes regulating blood pressure may exist on rat chromosome 19 in the vicinity of the angiotensinogen gene. To test this hypothesis, we measured blood pressure in SHR progenitor and congenic strains that are genetically identical except for a segment of chromosome 19 containing the angiotensinogen gene transferred from the normotensive Brown Norway (BN) strain. Transfer of this segment of chromosome 19 from the BN strain onto the genetic background of the SHR induced significant decreases in systolic and diastolic blood pressures in the recipient SHR chromosome 19 congenic strain. To test for differences in angiotensinogen gene expression between the congenic and progenitor strains, we measured angiotensinogen mRNA levels in a variety of tissues, including aorta, brain, kidney, and liver. We found no differences between the progenitor and congenic strains in the angiotensinogen coding sequence or in angiotensinogen expression that would account for the blood pressure differences between the strains. In addition, no significant differences in plasma levels of angiotensinogen or plasma renin activity were detected between the 2 strains. Thus, transfer of a segment of chromosome 19 containing angiotensinogen from the BN rat into the SHR induces a decrease in blood pressure without inducing any major changes in plasma angiotensinogen levels or plasma renin activity. These results indicate that the differential chromosome segment trapped in the SHR chromosome 19 congenic strain contains a quantitative trait locus that influences blood pressure in the SHR but that this blood pressure effect is not explained by differences in plasma angiotensinogen levels or angiotensinogen expression.