bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered Inotropic Responsiveness and Gene Expression of Hypertrophied Myocardium With Captopril
Authors: Brooks Wesley W. , Bing Oscar H. L. , Boluyt Marvin O. , Malhotra Ashwani , Morgan James P. , Satoh Naoya , Colucci Wilson S. , Conrad Chester H.
Published: June 2012

Abstract
—Inotropic responsiveness to β-adrenergic stimulation is generally found to be impaired in left ventricular (LV) hypertrophy and failure. To investigate the mechanisms by which angiotensin-converting enzyme inhibitor therapy may modulate inotropic responsiveness with long-term pressure overload, we studied the effects of captopril treatment on cardiac gene expression, LV muscle mechanical contraction, and intracellular calcium (Ca
2+
) transients from spontaneously hypertensive rats (SHR). LV papillary muscles from untreated SHR, age-matched normotensive Wistar-Kyoto rats (WKY), and SHR treated with captopril (CAP
Rx
started at 12, 18, and 21 months of age) were studied. All animals were studied at 24 months of age or when heart failure developed. In untreated SHR, α-myosin heavy chain
(MHC)
gene expression and protein were decreased, the Ca
2+
transient (with the bioluminescent indicator aequorin) was prolonged, and abundance of Na
+
/Ca
2+
exchanger mRNA levels increased in comparison to WKY. Active stress development at L
max
and the maximum rate of stress development were depressed and contractile duration prolonged in SHR relative to WKY. Isoproterenol administration further decreased active stress in untreated SHR despite an increase in intracellular Ca
2+
levels. In CAP
Rx
SHR, α-
MHC
gene expression and protein levels were increased, the Ca
2+
transient was not prolonged, Na
+
/Ca
2+
exchanger expression was downregulated, and papillary muscle function demonstrated increased active stress and maximum rate of stress development in response to isoproterenol. The increased abundance of α-
MHC
mRNA in conjunction with an increase in V
1
myosin isozyme suggests that captopril affects transcriptional regulation of cardiac gene expression. Restored LV inotropic responsiveness to β-adrenergic stimulation in CAP
Rx
SHR appears to be coupled to normalization of Na
+
/Ca
2+
exchanger mRNA expression, upregulation of V
1
myosin isozyme levels, and increased speed of contraction.
Peroxisome Proliferator–Activated Receptor-γ Ligands Inhibit Nitric Oxide Synthesis in Vascular Smooth Muscle Cells
Authors: Ikeda Uichi , Shimpo Masahisa , Murakami Yoshiaki , Shimada Kazuyuki
Published: June 2012

Abstract
—Peroxisome proliferator–activated receptor-γ (PPARγ) is a key player in glucose metabolism. If PPARγ ligands modulate nitric oxide (NO) synthesis in the vascular tissue, they may affect the process of plaque formation and postangioplasty restenosis. We investigated the effects of PPARγ ligands on NO synthesis in vascular smooth muscle cells. Incubation of cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in the production of nitrite, a stable metabolite of NO, in cultured rat vascular smooth muscle cells. The PPARγ agonists troglitazone and 15-deoxy-▵
12,14
-prostaglandin J
2
(15d-PG J
2
) dose-dependently inhibited nitrite production by interleukin-1β–stimulated vascular smooth muscle cells. Decreased interleukin-1β–induced nitrite production by the PPARγ agonists was accompanied by decreased inducible NO synthase mRNA and protein accumulation. Interleukin-1β induced nuclear factor-κB activation in vascular smooth muscle cells, and both troglitazone and 15d-PG J
2
markedly suppressed this nuclear factor-κB activation. PPARγ ligands inhibit NO synthesis in cytokine-stimulated vascular smooth muscle cells, suggesting that these agonists may act directly on the vascular smooth muscle and influence the process of atherosclerosis and restenosis.
Bradykinin B
2
Receptor Antagonism Attenuates Blood Pressure Response to Acute Angiotensin-Converting Enzyme Inhibition in Normal Men
Authors: Squire Iain B. , O’Kane Kevin P. J. , Anderson Niall , Reid John L.
Published: June 2012

Abstract
—The physiological effects of angiotensin-converting enzyme (ACE) inhibition may be in part mediated by bradykinin. We investigated the effect of coadministration of the specific bradykinin B
2
receptor antagonist icatibant on hemodynamic and neurohormonal responses to acute intravenous ACE inhibition in normal men on a normal sodium diet. We performed a 4-phase, double-blind, double-dummy, placebo-controlled study in 12 male volunteers. The bradykinin antagonist icatibant (10 mg IV) was coadministered over the first 15 minutes of a 2-hour infusion of the ACE inhibitor perindoprilat (1.5 mg IV). Perindoprilat inhibited ACE activity and elicited the expected changes in active renin concentration and angiotensin peptides. Over the 3 hours after the start of drug infusion, perindoprilat lowered and icatibant increased mean arterial blood pressure (each
P
<0.0005 versus placebo). Coadministration of icatibant attenuated the mean arterial blood pressure response to perindoprilat (
P
<0.0005) but had no effect on neurohormonal responses to perindoprilat. Our study indicates that the bradykinin B
2
receptor antagonist icatibant attenuates the short-term blood pressure–lowering effect of acute ACE inhibition in normal men on a normal sodium diet. Bradykinin B
2
receptor antagonism alone increases resting blood pressure. Bradykinin may be involved in the control of blood pressure in the resting state in humans.
Renal Structural Properties in Prehypertensive Dahl Salt-Sensitive Rats
Authors: Tomoda Fumihiro , Takata Masanobu , Kinuno Hiroyuki , Tomita Shin , Yasumoto Kotaro , Inoue Hiroshi
Published: June 2012

Abstract
—In 10- to 12-week-old Dahl salt-sensitive (DS) and salt-resistant (DR) rats fed a 0.3% salt diet (n=10 in each group), flow-pressure and pressure–glomerular filtration rate (F-P and P-GFR, respectively) relationships were established for maximally vasodilated perfused kidneys. From these relationships, 3 indices of vascular structural properties were estimated: slope of F-P (minimal renal vascular resistance reflecting overall luminal dimensions of preglomerular and postglomerular vasculature), slope of P-GFR (glomerular filtration capability against pressure), and threshold pressure for beginning filtration at P-GFR (preglomerular-to-postglomerular vascular resistance ratio). Thereafter, maximal renal vascular resistance was determined to assess wall-to-lumen ratios of the resistance vessels in half of each group. In the remainder, the kidneys were perfusion-fixed for histological analysis. Mean arterial pressure did not differ between the DS and DR rats. There were no significant differences in the slopes of F-P between the 2 groups. In contrast, the slope of P-GFR was significantly lower (33%) in DS rats than in DR rats, although the DS kidneys began filtering at a threshold pressure similar to that of the DR kidneys. Thus, in DS rats, there were no abnormalities in luminal dimensions at preglomerular and postglomerular vascular segments, but the kidney filtration capacity decreased at any given increase in pressure. Maximal vascular resistance was greater in DS than in DR rats, a finding compatible with the histological appearance, which showed vascular hypertrophy with little, if any, vascular narrowing in the interlobular arteries of DS rats. In conclusion, hypertrophic remodeling without vascular narrowing at preglomerular resistance vessels and structural defects in filtering at the glomeruli could occur in prehypertensive DS rats.
Adrenomedullin and Nitric Oxide Inhibit Human Endothelial Cell Apoptosis via a Cyclic GMP-Independent Mechanism
Authors: Sata Masataka , Kakoki Masao , Nagata Daisuke , Nishimatsu Hiroaki , Suzuki Etsu , Aoyagi Teruhiko , Sugiura Seiryo , Kojima Hirotatsu , Nagano Tetsuo , Kangawa Kenji , Matsuo Hisayuki , Omata Masao , Nagai Ryozo , Hirata Yasunobu
Published: June 2012

Abstract
—Adrenomedullin, which was discovered as a vasodilating peptide, has been reported to be produced in various organs, in which adrenomedullin regulates not only vascular tone but also cell proliferation and differentiation in an autocrine/paracrine manner. We evaluated the effect of adrenomedullin on endothelial cell apoptosis. Human umbilical vein endothelial cells underwent apoptosis when cultured in serum-free medium. Treatment with adrenomedullin reduced the number of cells with pyknotic nuclei (Hoechst 33258 staining) and inhibited cell death (dimethylthiazol-diphenyltetrazolium bromide assay) in a dose-dependent manner. The administration of adrenomedullin did not alter the expression levels of Bcl-2 family proteins. Experiments with analogs of cAMP or a cAMP-elevating agonist demonstrated that elevation of the intracellular cAMP concentration does not mediate the antiapoptotic effect of adrenomedullin. The coadministration of
N
-nitro-
l
-arginine methyl ester (2 mmol/L), an inhibitor of nitric oxide synthase, abrogated the effect of adrenomedullin. Lower doses of sodium nitroprusside (1 to 10 μmol/L), a nitric oxide donor, mimicked the antiapoptotic effect of adrenomedullin. The antiapoptotic effect of sodium nitroprusside was not attenuated by the inhibition of soluble guanylyl cyclase with 1 μmol/L oxadiazolo-quinoxalin-1-one nor could apoptosis be inhibited by the incubation of human umbilical vein endothelial cells with 1 mmol/L 8-bromo-cGMP, a cell-permeant cGMP analog. These results indicate that adrenomedullin and nitric oxide inhibit endothelial cell apoptosis via a cGMP-independent mechanism.
Blood Pressure Is Associated With Body Mass Index in Both Normal and Obese Children
Authors: He Qing , Ding Zong Yi , Fong Daniel Yee-Tak , Karlberg Johan
Published: June 2012

Abstract
—Obesity is associated with elevated blood pressure (BP) both in adults and children. Childhood obesity has become a severe health problem, especially during the last few decades. So far there has not been any large-scale study specifically focusing on the association between obesity and BP in early life. The aim of this study is to examine systematically the association between obesity and BP in preschool Chinese children in mainland China. In 1996, measurements of weight, height, and BP values were collected in a nationwide, case-control study of 748 boys and 574 girls who ranged in age from 0.1 to 6.9 years in 8 cities in mainland China. One obese child and 1 nonobese child were matched for gender and age. The BP differences of the mean-matched pair were ≈5 mm Hg for systolic blood pressure (SBP) and ≈4 mm Hg for diastolic blood pressure (DBP) (
P
<0.05); a higher value was noted in obese children. The BP value of 19.4% children in the obese group and 7.0% children in the nonobese group was higher than the 95th percentile value (
P
<0.0001), which is defined as high BP by the Task Force on Blood Pressure Control in Children. Both SBP and DBP were significantly (
P
<0.05) positively related to body mass index (BMI) values (
P
<0.05) for children in obese and nonobese groups after adjustment for age, gender, and height. To be specific, an increase of 1 BMI unit was associated with, on average, an increase of 0.56 mm Hg and 0.54 mm Hg in SBP and DBP, respectively, for obese children. In nonobese children, the increase in SBP and DBP was 1.22 mm Hg and 1.20 mm Hg, respectively. An increase in the BMI is conclusively associated with elevated SBP and DBP in nonobese children. Furthermore, an increase in the adjusted BMI was associated with an increase in SBP and DBP in obese and nonobese children.
Ascorbic Acid and Glutathione Modulate the Biological Activity of
S-
Nitrosoglutathione
Authors: Xu Aiming , Vita Joseph A. , Keaney John F.
Published: June 2012

Abstract
—Ascorbic acid and glutathione (GSH) are important determinants of the intracellular redox state, and both are known to accelerate the decomposition of
S
-nitrosoglutathione (GSNO), an endogenous adduct of nitric oxide (NO). The implications of these observations for GSNO bioactivity are not yet clear. We investigated the effect of ascorbic acid and GSH on GSNO bioactivity by using a bioassay with isolated segments of guinea pig aorta suspended in organ chambers. Arterial segments demonstrated relaxation to GSNO (0.1 μmol/L) that was significantly enhanced by 300 μmol/L ascorbic acid (71±6% versus 53±6%,
P
<0.05) but not GSH. Both ascorbic acid and GSH significantly shortened the duration of arterial relaxation in response to 0.1 μmol/L GSNO (from >120 minutes to 22.5±3.5 and 36.3±4.3 minutes, respectively;
P
<0.05), consistent with accelerated decomposition of GSNO that was confirmed spectrophotometrically. The effect of ascorbic acid was abrogated by either DTPA or the copper(I)-specific agent bathocuproine but not deferoxamine, indicating a dependence on the availability of redox-active copper. Consistent with this notion, the action of ascorbic acid on GSNO bioactivity was also supported by copper-zinc superoxide dismutase, a physiologically relevant source of copper. In contrast, the effect of GSH on GSNO degradation and GSNO-mediated arterial relaxation was independent of transition metal ions, because DTPA had no effect. These data indicate that both ascorbic acid and GSH modulate GSNO bioactivity and suggest a distinction between the mechanism of GSNO degradation by ascorbic acid or GSH. Whereas both ascorbic acid and GSH accelerate the degradation of GSNO, only ascorbic acid is dependent on the presence of transition metal ions.
Circulating Heat Shock Protein 60 Is Associated With Early Cardiovascular Disease
Authors: Pockley A. Graham , Wu Ruhia , Lemne Carola , Kiessling Rolf , Ulf de Faire  , Frostegård Johan
Published: June 2012

Abstract
—The phylogenetically conserved nature of heat shock proteins (Hsp) has led to the proposition that they may provide a link between infection and the inflammatory component to vascular disease. Hypertension is associated with atherosclerosis. Here, we measured circulating heat shock protein and heat shock protein antibody levels in association with borderline hypertension. Seventy-two men with borderline hypertension patients and 75 normotensive control subjects (diastolic blood pressure 85 to 94 and <80 mm Hg, respectively) were selected from a population-screening program. The levels of Hsp60; Hsp70; and anti–human Hsp60, anti–human Hsp70, and anti–mycobacterial Hsp65 antibodies were determined with enzyme immunoassay. The presence of carotid atherosclerosis and the intima-media thickness values were determined with ultrasonography. A major novel observation in this report was the detection of circulating Hsp60, which was present at a significantly enhanced level in patients with borderline hypertension. Furthermore, serum Hsp60 was associated with intima-media thicknesses (
P
<0.01). Anti-Hsp65 antibody levels were higher in borderline hypertension (
P
<0.001), whereas Hsp70 and anti-Hsp70 antibody levels did not differ. In contrast to anti-Hsp65 antibody, anti-Hsp60 antibody levels were lower in borderline hypertension (
P
<0.03), although the difference was quantitatively small. None of the parameters evaluated were associated with atherosclerosis, metabolic factors, or smoking. We identified elevated Hsp60 levels in patients with borderline hypertension and an association between early atherosclerosis and Hsp60 levels. The physiological role of Hsp60 release has yet to be defined, but given the proinflammatory properties, these proteins could be involved in the induction/progression of both hypertension and atherosclerosis, as well as being markers for early cardiovascular disease.
CC Chemokine Receptor 2 Is Required for Macrophage Infiltration and Vascular Hypertrophy in Angiotensin II–Induced Hypertension
Authors: Bush Errol , Maeda Nobuyo , Kuziel William A. , Dawson Tracey C. , Wilcox Josiah N. , DeLeon Hector , Taylor W. Robert
Published: June 2012

Abstract
—Recent studies have identified the presence of macrophages in the arterial wall of hypertensive animals and suggested that as is the case in atherosclerosis, macrophage products may be important mediators of the adaptive response of the arterial wall. In support of this, we have previously shown that the expression of monocyte chemoattractant protein-1 is upregulated in the arteries of hypertensive animals. We hypothesized that macrophage recruitment is a critical step in the pathogenesis of hypertension. To obtain insights into this potential mechanism, we made use of mice deficient in the CC chemokine receptor 2 (CCR2), the receptor for monocyte chemoattractant protein-1. Hypertension was induced with the subcutaneous administration of angiotensin II (0.75 mg · kg
−1
· d
−1
) for 7 days. Using in situ hybridization with a probe for c-
fms
to identify macrophages, we found that hypertension-induced macrophage infiltration of the arterial wall was virtually eliminated in CCR2-deficient mice. In addition, vascular hypertrophy was reduced by ≈65% compared with wild-type animals. These data demonstrate that CCR2 is essential for the recruitment of macrophages into the arterial wall in the setting of hypertension. Furthermore, the decreased hypertrophic response suggests that vascular hypertrophy occurs in part as a consequence of macrophage infiltration. In angiotensin II–induced hypertension, CCR2-mediated responses are critical to the process of macrophage recruitment and vascular hypertrophy and may represent one mechanism by which at least some forms of hypertension may lead to the development of atherosclerosis.
Species-Specific Pharmacological Properties of Human α
2A
-Adrenoceptors
Authors: Molderings Gerhard J. , Bönisch Heinz , Brüss Michael , Likungu James , Göthert Manfred
Published: June 2012

Abstract
—On the basis of data obtained in rabbits, the imidazoline receptor ligand rilmenidine has been suggested to decrease blood pressure in humans by activating central α
2A
-adrenoceptors. A prerequisite for this hypothesis was the unproved assumption that rabbit and human α
2A
-adrenoceptors are equally activated by rilmenidine. Because α
2A
-adrenoceptors in the brain and on cardiovascular sympathetic nerve terminals are identical, the latter were used as a model for the former to confirm or disprove this assumption. Human atrial appendages and rabbit pulmonary arteries were used to determine the potencies of α
2
-adrenoceptor agonists in inhibiting the electrically (2 Hz) evoked [
3
H]norepinephrine release and of antagonists in counteracting the α
2
-adrenoceptor–mediated inhibition induced by moxonidine. In the rabbit pulmonary artery, rilmenidine and oxymetazoline are potent full agonists, whereas in the human atrial appendages they are antagonists at the α
2
-autoreceptors, sharing this property with rauwolscine, phentolamine, and idazoxan. In contrast, prazosin is ineffective. In addition, a partial nucleotide and amino acid sequence of the rabbit α
2A
-adrenoceptor (a region known to substantially influence the pharmacological characteristics of the α
2
-adrenoceptor) revealed marked differences between the rabbit and the human α
2A
-adrenoceptor. The sympathetic nerves of both the human atrial appendages and rabbit pulmonary artery are endowed with α
2A
-autoreceptors, at which, however, both rilmenidine and oxymetazoline exhibit different properties (antagonism and agonism, respectively). The antagonistic property of rilmenidine at human α
2A
-adrenoceptors indicates that in contrast to the suggestion based on rabbit data, the hypotensive property of the drug in humans is not due to activation of α
2A
-adrenoceptors but other, presumably I
1
-imidazoline receptors, are probably involved.
Association of the Human Y Chromosome With High Blood Pressure in the General Population
Authors: Ellis Justine A. , Stebbing Margaret , Harrap Stephen B.
Published: June 2012

Genetic variation in the Y chromosome has significant effects on male blood pressure in experimental animals, but the effects in humans are unknown. We examined the relationship between blood pressure and a polymorphic
Hin
dIII restriction site in the nonrecombining region of the Y chromosome in 409 randomly selected men from the general population. Carefully standardized measures of systolic and diastolic blood pressures were made. The
Hin
dIII restriction site was significantly more common (43.2%) in men in the lowest decile of the diastolic blood pressure distribution than men in the highest decile (15.9%,
P
=0.007). No significant difference in genotype frequency was observed between the lowest and highest deciles for systolic pressure (32.4% versus 27.8%,
P
=0.66). In the entire group, men with the
Hin
dIII restriction site had significantly lower diastolic blood pressures (81.2 mm Hg, SD:8.3, versus 83.2 mm Hg, SD:8.7,
P
=0.03). No significant differences in systolic blood pressure (130.6 mm Hg, SD:14.7, versus 128.3 mm Hg, SD: 13.6) were observed in relation to genotypes. Our results indicate that genetic variation in the human Y chromosome is associated with high blood pressure and contributes significantly to the quantitative variation of male diastolic blood pressure in the general population.
Fetal Growth and Early Postnatal Growth Are Related to Blood Pressure in Adults
Authors: Cheung Yin Bun , Low Louis , Osmond Clive , Barker David , Karlberg Johan
Published: June 2012

Abstract
—It is commonly agreed that birth weight is associated with blood pressure in adults. However, not much is known about birth length, ponderal index, and early postnatal growth, whose effects on adult blood pressure, if any, can affect the interpretation of the birth weight–blood pressure association. This study examined the association between fetal growth, early postnatal growth, and blood pressure in Chinese adults. One hundred twenty-two subjects born in Hong Kong in 1967 were followed from birth to age 30 years. Multiple linear regression was used to analyze the association between size at birth, postnatal changes in body size, and systolic and diastolic blood pressure at age 30 years. Having adjusted for potential confounders and each other explanatory variable, it is found that birth length standard deviation score (regression coefficient or β=−3.2), ponderal index at birth (β=−1.8), and postnatal changes in ponderal index from age 6 months to 18 months (β=−2.2) were inversely associated with systolic blood pressure (each
P
<0.05). Postnatal changes in length standard deviation score were not significantly associated with systolic blood pressure. Birth length standard deviation score was inversely associated with diastolic blood pressure at age 30 years (β=−2.6;
P
<0.05). Other anthropometric variables were not associated with diastolic blood pressure. The results support the hypotheses that both fetal growth and early postnatal growth may have a long-term impact on blood pressure in adults. It also highlights the importance of differentiating length and weight for length.
Subpressor Dose of L-NAME Unmasks Hypertensive Effect of Chronic Hyperinsulinemia
Authors: Bursztyn Michael , Mekler Judith , Peleg Edna , Bernheim Jacques
Published: June 2012

Abstract
—We previously found that chronic exogenous hyperinsulinemia without sugar supplementation does not elevate blood pressure. This may be partially explained by the ability of insulin to release nitric oxide and cause vasodilatation. To test this hypothesis, we studied 4 groups of rats: 9 rats (body weight, 213±14 g) treated with a gradual increase of a sustained-release subcutaneous insulin pellet; 9 rats (body weight, 213±9 g) treated with
N
G
-nitro-
l
-arginine methyl ester (L-NAME) in drinking water 50 mg/L; 19 rats (body weight, 217±11 g) treated with the combination of L-NAME and insulin; and 9 control rats (body weight, 218±11 g). Blood pressure was followed weekly for 6 weeks, and then rats were studied in metabolic cages. Weight gain was not different during the 6 weeks. Renal function did not differ between the 4 groups, but 24-hour urinary nitrite/nitrate excretion was lower (
P
<0.02) in L-NAME–treated and higher in insulin-treated rats. Plasma insulin doubled (
P
<0.002) in the insulin-treated rats, but there was no hypoglycemia and, by week 6, fructosamine levels were 2.1±0.2, 2.1±0.2, 2.3±0.1, and 2.3±0.2 mmol/L in control rats and rats treated with L-NAME, insulin, and L-NAME plus insulin, respectively. Systolic blood pressure, which did not differ at baseline, at week 3 was 122±17, 118±17, and 118±24 mm Hg in the control, L-NAME, and insulin groups and 136±14 mm Hg (
P
<0.03) in the combination group. At week 6, systolic blood pressure was 128±14, 127±15, and 118±13 mm Hg in the control, L-NAME, and insulin groups, respectively, and 150±14 mm Hg (
P
<0.0005) in the combination group. In a subsequent experiment,
l
-arginine 2 g/L abrogated the effects of L-NAME and insulin combination. In conclusion, chronic exogenous hyperinsulinemia does not affect blood pressure but may cause hypertension when endothelial function is compromised.
Beneficial Renal and Cardiac Effects of Vasopeptidase Inhibition With S21402 in Heart Failure
Authors: Burrell Louise M. , Farina Nicole K. , Balding Leanne C. , Johnston Colin I.
Published: June 2012

S21402 is a vasopeptidase inhibitor that simultaneously inhibits neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE). This study determined whether chronic treatment with S21402 produced different effects on sodium and water excretion, hormonal parameters, and cardiovascular structure compared with selective inhibition of ACE and NEP in a rat model of myocardial infarction–induced congestive heart failure (CHF). CHF rats received the vasopeptidase inhibitor (S21402, 100 mg · kg
−
1
· d
−
1
), an ACE inhibitor (captopril, 50 mg · kg
−
1
· d
−
1
), a NEP inhibitor (
SCH42495
, 60 mg · kg
−
1
· d
−
1
), or vehicle for 4 weeks. S21402 alone caused a diuresis and natriuresis (
P
<0.01) in CHF. After 4 weeks, blood pressure was lowered by captopril but not other treatments (
P
<0.01). Both S21402 and captopril increased plasma renin activity (
P
<0.01), all treatment lowered plasma aldosterone (
P
<0.05) and plasma natriuretic peptide levels were unchanged. In the kidney, S21402 inhibited NEP and ACE (
P
<0.01),
SCH42495
inhibited NEP (
P
<0.01), and captopril inhibited ACE (
P
<0.01). Heart mass was reduced by all active treatments; captopril reduced left ventricular mass (
P
<0.01),
SCH42495
reduced right ventricular mass (
P
<0.01), and S21402 decreased left (
P
<0.05) and right ventricular mass (
P
<0.01), atrial mass (
P
<0.05), and lung mass (
P
<0.01). In CHF, vasopeptidase inhibition with S21402 produces effects that differ from those of selective NEP or ACE inhibition. S21402 improved sodium and water excretion, reduced pulmonary congestion, and attenuated both right and left ventricular remodeling. These effects, which occurred in the absence of any hypotensive action, suggest that S21402 may offer several advantages over ACE inhibition alone in the treatment of heart failure.
Interaction of the
ACE D
Allele and the
GNB3 825T
Allele in Myocardial Infarction
Authors: Naber Christoph K. , Hüsing Johannes , Wolfhard Ulrich , Erbel Raimund , Siffert Winfried
Published: June 2012

Abstract
—In polygenetic disorders, such as ischemic heart disease, the investigation of gene-gene interactions rather than determination of single gene effects is crucial to better understand the contribution of genetic factors. The
825T
allele of the G-protein β
3
-subunit gene (
GNB3
) associated with enhanced G-protein signaling is a candidate to interact with the angiotensin-converting enzyme (
ACE
) deletion/insertion
(D/I)
polymorphism to increase the risk for myocardial infarction (MI). The
ACE
D/I
variant affects the renin-angiotensin system hormones that activate G-protein–coupled receptors. Genotyping at the
ACE
and
GNB3
loci was performed on 585 patients with coronary artery disease with (n=270) or without (n=315) previous MI. Logistic regression analysis demonstrated a significant interaction between the
ACE
D
allele and the
GNB3
825T
allele (
P
<0.001). The odds ratio for MI, associated with the
825T
allele, was not increased in the presence of the
ACE II
genotype (OR 0.5;
P
=0.09) but was significantly higher in
825T
allele carriers with the
ACE DI
genotype (OR 1.9;
P
=0.01) and further increased in individuals with the
ACE DD
genotype (OR 2.4;
P
=0.02). The highest odds ratio was found in homozygous
825T
allele carriers with the
ACE
DD
genotype (OR 7.5;
P
=0.006). Our data suggest a significant interaction of the
GNB3 825T
allele with the
ACE D
allele in MI. These hypothesis-generating data may justify larger prospective studies.
Differential Distribution of Bradykinin B
2
Receptors in the Rat and Human Cardiovascular System
Authors: Figueroa Carlos D. , Marchant Alejandra , Novoa Ulises , Förstermann Ulrich , Jarnagin Kurt , Schölkens Bernward , Müller-Esterl Werner
Published: June 2012

Abstract
—Bradykinin, a major vasodilator peptide, plays an important role in the local regulation of blood pressure, blood flow, and vascular permeability; however, the cellular distribution of the major bradykinin B
2
receptor in the cardiovascular system is not precisely known. Immunoblot analysis with an anti-peptide antibody to the bradykinin B
2
receptor or chemical cross-linkage with [
125
I]Tyr
0
-bradykinin revealed a band of 69±3 kDa at varying intensity in the homogenates of the endothelium and tunica media of the rat aorta and endocardium. Immunostaining showed that the B
2
receptor is abundant in the endothelial linings of the aorta, other elastic arteries, muscular arteries, capillaries, venules, and large veins, where it localizes preferentially to the luminal face of the endothelial cells. In marked contrast, small arterioles (ie, the principal blood–pressure regulating vessels) of the mesenterium, heart, urinary bladder, brain, salivary gland, and kidney had a different staining pattern in which B
2
receptor was prominent in the perivascular smooth muscle cells of the tunica media. A similar distribution pattern was found in mouse as well as in human tissues, indicating that the particular distribution pattern of the B
2
receptor in arterioles is not a species-specific phenomenon. During development, the distribution of B
2
receptor in the heart changes; for example, in the heart of newborn rats, the B
2
receptor was abundant in the myocardium, whereas in the adult heart, the receptor was present in the endocardium of atria, atrioventricular valves, and ventricles but not in the myocardium. Thus, B
2
receptors are localized differentially in different parts of the cardiovascular system: the arterioles have smooth muscle–localized B
2
receptors, and large elastic vessels have endothelium-localized receptors.
Mycophenolate Mofetil Reduces Renal Injury in the Chronic Nitric Oxide Synthase Inhibition Model
Authors: Fujihara Clarice Kazue , Avancini Costa Malheiros Denise Maria , de Lourdes Noronha Irene , De Nucci Gilberto , Zatz Roberto
Published: June 2012

Abstract
—We and others have recently shown that mycophenolate mofetil (MMF) reduces renal inflammation and glomerular and interstitial injury in the 5/6 renal ablation model. In the present study, we investigated whether MMF limits renal injury in a model of chronic nitric oxide (NO) inhibition associated with a high-salt diet and characterized by progressive systemic hypertension, albuminuria, glomerular sclerosis and ischemia, interstitial expansion, and progressive macrophage infiltration. Adult male Münich-Wistar rats were distributed among 3 groups: HS, rats receiving a high-salt diet (3.2% Na); HS+N, HS rats orally treated with the NO inhibitor N
ω
-nitro-
l
-arginine methyl ester (L-NAME), 25 mg · kg
−1
· d
−1
; and HS+N+MMF, HS+N rats orally treated with MMF, 10 mg · kg
−1
· d
−1
. Renal hemodynamics were studied after 15 days of treatment; histological and immunohistochemical studies were conducted after 30 days of treatment. MMF treatment did not reverse the hemodynamic alterations characteristic of this model. Renal injury in the HS+N group was associated with macrophage and lymphocyte infiltration. Treatment with MMF reduced glomerular and interstitial injury and limited macrophage and lymphocyte infiltration. These results suggest that renal inflammation is a strong independent factor in the pathogenesis of the nephropathy associated with the HS+N model.
Alterations of Intrarenal Adrenomedullin and Its Receptor System in Heart Failure Rats
Authors: Yoshihara Fumiki , Nishikimi Toshio , Okano Ichiro , Horio Takeshi , Yutani Chikao , Matsuo Hisayuki , Takishita Shuichi , Ohe Tohru , Kangawa Kenji
Published: June 2012

Calcitonin receptor–like receptor/receptor activity–modifying protein 2 (CRLR/RAMP2) and CRLR/RAMP3 complexes have been reported to be specific adrenomedullin (AM) receptors. In the present study, we evaluated the pathophysiological significance of renal AM and its receptor system in aortocaval shunt (ACS) rats. Renal AM levels were measured serially during 5 weeks after the operation. Renal gene expressions of AM, CRLR, RAMP2, and RAMP3 were measured at 2 weeks (decompensated phase) and 5 weeks (compensated phase) after the operation. Immunohistochemical localizations of renal AM were also evaluated. Furthermore, the relations between urinary sodium excretion (UNaV) and renal AM levels were evaluated. Renal AM levels were higher in ACS than in control animals only at 1, 2, and 3 weeks after the operation. At 2 weeks after the operation, renal AM mRNA expression was also higher in ACS than in control animals. CRLR, RAMP2, and RAMP3 mRNAs were expressed in the kidney, but there were no differences between the 2 groups. Immunohistochemistry revealed the positive AM immunostaining within the renal tubular cells, and it was more intense in ACS than in control animals. There were significant correlations between UNaV and renal AM levels. At 5 weeks after the operation, there were no differences in mRNA levels of AM, CRLR, RAMP2, and RAMP3 between the 2 groups. There was a significant correlation between UNaV and medullary AM levels. The present findings suggest that increased renal AM levels in decompensated heart failure, presumably due to increased AM production in renal tubules, in part, are involved in the regulation of sodium excretion.
Effect of Adrenomedullin on Placental Arteries in Normal and Preeclamptic Pregnancies
Authors: Jerat Sandra , Morrish Donald W. , Davidge Sandra T. , Kaufman Susan
Published: June 2012

Adrenomedullin is a potent vasodilatory peptide with plasma levels that increase during pregnancy. Although fetoplacental adrenomedullin levels are reported to increase in preeclampsia, maternal plasma levels may be elevated or decreased, or they may resemble those in normal pregnancy. In other hypertensive conditions, adrenomedullin increases. Therefore, we hypothesized that maternal plasma adrenomedullin levels would be higher in hypertensive pregnancies than in normotensive pregnancies and that the higher placental resistance found in preeclamptic pregnancies results from blunted activity of adrenomedullin on the vasculature. Adrenomedullin concentrations in plasma from women with normotensive pregnancies, gestational hypertension, and preeclampsia were determined by radioimmunoassay. Stem villous arteries from normotensive and preeclamptic pregnancies were dissected and mounted on a wire myograph system. Arteries were first preconstricted to 80% of their maximum constriction with
U46619
, a thromboxane A
2
mimetic, and exposed to cumulative doses of adrenomedullin (1×10
−
9
to 3×10
−
7
mol/L). Contrary to our hypothesis, there were no significant differences in maternal plasma adrenomedullin levels among patients with normal pregnancies, gestational hypertension, and preeclampsia. Adrenomedullin significantly relaxed arteries from both normal and preeclamptic placentas, but there was no significant difference between the 2 groups. During normal pregnancy, adrenomedullin may contribute to the low placental vascular resistance. This pathway appears to be intact in preeclampsia. We conclude that the increased placental vascular resistance observed in preeclampsia is due neither to reduced adrenomedullin secretion nor to an attenuated vascular responsiveness. Moreover, unlike other hypertensive disorders, there is no compensatory rise in circulating adrenomedullin levels.
Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo
Authors: Verma Subodh , Yao Linfu , Stewart Duncan J. , Dumont Aaron S. , Anderson Todd J. , McNeill John H.
Published: June 2012

The endothelial actions of insulin remain an area of intense research because they relate to both insulin sensitivity and vascular tone. Physiological doses of insulin evoke endothelium-dependent vasorelaxation in humans; however, this remains a pharmacological phenomenon in rat aortas. Because insulin may stimulate the divergent production of both nitric oxide and endothelin-1, we hypothesized that the lack of insulin-induced vasorelaxation at low/subthreshold concentrations may be due to the concurrent production of endothelin-1, which in turn serves to inhibit nitric oxide-dependent, insulin-mediated dilation. To investigate this, we studied the effects of subthreshold concentrations of insulin (100 mU/L) on norepinephrine-induced contraction in rat aortas following short-term and long-term endothelin blockade. In addition, the effects of tetrahydrobiopterin inhibition (with diaminohydroxyprimidine) on norepinephrine-induced contraction in the presence of insulin and endothelin receptor blockade were investigated. Subthreshold concentrations of insulin failed to evoke vasorelaxation in rat aortas. Strikingly, short-term endothelin A/B receptor blockade with bosentan (10
−2
mmol/L) uncovered insulin-mediated dilation; the percent maximum contraction and sensitivity of aortas to norepinephrine were attenuated (% maximum relaxation: bosentan+insulin 74±4%* versus bosentan 92±3%, insulin 107±5%
P
<0.002; pD
2
values: bosentan+insulin 6.87±0.14* versus bosentan 7.40±0.15, insulin 7.63±0.11, *
P
<0.002). This effect was mediated through endothelin A receptors because bosentan and BQ-123 (10
−2
mmol/L) attenuated norepinephrine-induced contraction to a similar degree. In addition, insulin evoked vasorelaxation in aortas isolated from rats after long-term bosentan treatment (100 mg · kg
−1
· d
−1
, 3 weeks). The component of insulin-mediated vasorelaxation uncovered by endothelin receptor blockade was tetrahydrobiopterin-dependent because it was reversed by diaminohydroxyprimidine. These data demonstrate, for the first time, the functional interaction between insulin, endothelin-1, and tetrahydrobiopterin in modulating vascular tone in rat aortas in vitro and in vivo.
Nuclear Factor 1 Is a Negative Regulator of
gadd153
Gene Expression in Vascular Smooth Muscle Cells
Authors: Nakamura Michitsugu , Okura Takafumi , Kitami Yutaka , Hiwada Kunio
Published: June 2012

Growth arrest and DNA damage inducible gene 153 (
gadd153
) is expressed at very low levels in growing cells but is markedly induced in response to cellular stresses, including glucose deprivation, exposure to genotoxic agents, and other growth-arresting situations. Forced expression of GADD153 can induce cell cycle arrest and/or apoptosis in many types of cells. Recently, we reported that GADD153 was induced in vascular smooth muscle cells (VSMCs) in neointimal lesions of balloon-injured carotid arteries. To investigate the underlying molecular mechanisms of
gadd153
gene expression in VSMCs, we isolated and characterized a promoter region of the rat
gadd153
gene. Sequence alignments of this region revealed 1 TATA-like sequence and several well-known
cis
elements. The 5′-deletion analysis for this region showed that a domain spanning −447 through −368 drastically reduced the promoter activity to almost equal levels of promoterless control. Because this domain contained a consensus sequence for the nuclear factor 1 family of proteins (NF1), DNA-binding studies were performed by use of 2 types of NF1 consensus probes. Both probes were specifically shifted by nuclear extracts from proliferating VSMCs and were supershifted by antiserum against CCAAT transcription factor/NF1. In addition, promoter activity of a mutant luciferase vector, which was generated by a point mutation at the NF1 binding motif of the gadd153 gene, was 14-fold higher than that of a wild-type one. These results suggest that
gadd153
gene expression in VSMCs is negatively regulated by an NF1-binding motif, and NF1 may act as an antiapoptotic factor by continuously suppressing
gadd153
gene expression in growing VSMCs.
Marinobufagenin, an Endogenous α-1 Sodium Pump Ligand, in Hypertensive Dahl Salt-Sensitive Rats
Authors: Fedorova Olga V. , Kolodkin Nikolai I. , Agalakova Natalia I. , Lakatta Edward G. , Bagrov Alexei Y.
Published: June 2012

Dahl salt-sensitive rats (DS), which have a mutation in the α-1 subunit of Na
+
/K
+
-ATPase, exhibit impaired pressure natriuresis and on a high-salt diet, retain Na
+
and exhibit increased blood pressure. Recently, we have shown that mammalian tissues contain a bufadienolide Na
+
/K
+
-ATPase inhibitory factor, marinobufagenin (MBG), that exhibits greater affinity for the α-1 than α-3 sodium pump isoform. The present study investigated the possible role of MBG in hypertension in DS on a high NaCl intake. Eight DS and 8 Dahl salt-resistant rats (DR) were placed on an 8% NaCl diet. Within 2 weeks, systolic blood pressure increased in DS (162±9 mm Hg at week 2 versus 110±2 mm Hg in baseline,
P
<0.01), and increased less in DR (124±3 mm Hg at week 2 versus 112±2 mm Hg in baseline). Renal excretion of MBG increased 4-fold (38.9±7.6 pmol versus 9.1±1.3 pmol in baseline,
P
<0.01) in DS, but by only 25% in DR (13.2±0.9 pmol versus 10.3±0.7 pmol in baseline). Excretion of endogenous ouabain did not change in either strain. MBG-immunoreactive material was purified from the urine of hypertensive DS by means of 2 steps of reverse-phase high performance liquid chromatography (HPLC) and compared with plant ouabain and amphibian MBG for its ability to inhibit the Na
+
/K
+
-ATPase from rat kidney (which expresses only α-1 Na
+
/K
+
-ATPase isoform). Unlike ouabain (IC
50
=248 μmol/L), serially diluted, HPLC-purified MBG immunoreactivity from DS and authentic MBG potently inhibited rat kidney Na
+
/K
+
-ATPase (IC
50
=70 and 78 nmol/L, respectively). Our results suggest that an α-1 Na
+
/K
+
-ATPase ligand, MBG, is elaborated to promote natriuresis in hypertensive DS. MBG acts as a selective inhibitor of the ouabain-resistant α-1 Na
+
/K
+
-ATPase subunit, ie, the major sodium pump isoform of the kidneys, as would be expected of a putative natriuretic hormone.
Structure-Activity Relationships for the Hypertensinogenic Activity of Ouabain
Authors: Manunta Paolo , Hamilton Bruce P. , Hamlyn John M.
Published: June 2012

Elevated levels of an endogenous ouabain circulate in many patients with essential hypertension. However, in contrast to ouabain, digoxin does not induce hypertension. This study investigated the hypothesis that within a single cardiac glycoside, the structural elements that induce hypertension differ from those responsible for high potency as a sodium pump inhibitor. Normal male Sprague-Dawley rats received infusions of vehicle (VEH), rhamnose (RHA), ouabain (OUA), ouabagenin (OGN), dihydro-ouabain (DHO), iso-ouabain (ISO), and a lactone ring opened analog (ORO) at 30 μg · kg
−1
· 24 h
−1
for 5 weeks via subcutaneous osmotic pumps. Cuff pressures were taken weekly. At the end of the study, trunk blood was harvested, extracted by C18 column, and subjected to high-performance liquid chromatography. Fractions were analyzed for OUA, OGN, and DHO by immunoassay. In OUA-, OGN-, and DHO-infused rats, 1 main peak of immunoreactivity corresponding to the infused agent was found. No evidence of in vivo conversion to OUA or DHO was found for any analog except ORO. At 5 weeks, systolic blood pressures in VEH, RHA, OUA, OGN, DHO, ISO, and ORO were 132±2.5, 133±1.5, 159±2.6,* 154±4,* 167±4,*† 171±2.2,*† and 169±2.4*† mm Hg, respectively (*
P
<0.01 versus VEH and RHA, †
P
<0.05 versus OUA). The hypertensinogenic activity was greater than OUA in 3 analogs (DHO, ISO, and ORO) in which the lactone was saturated, conformationally restrained by linkage with the oxygen at C14, or opened, respectively. These compounds were weak inhibitors of dog kidney Na,K-ATPase. Thus, RHA and the unsaturated lactone ring are crucial to the high potency of OUA as an inhibitor of the sodium pump but appear to be unrelated to its ability to induce hypertension. The conclusion that this form of hypertension is mediated primarily by the steroid nucleus suggests also that OUA may have a mechanism of action independent of the sodium pump.
Expression of Cell Cycle Proteins in Blood Vessels of Angiotensin II–Infused Rats
Authors: Diep Quy N. , El Mabrouk Mohammed , Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Angiotensin II is an important modulator of cell growth through AT
1
receptors, as demonstrated both in vivo and in vitro. We investigated the role of proteins involved in the cell cycle, including cyclin D1, cyclin-dependent kinase 4 (cdk4), and cyclin-dependent kinase inhibitors p21 and p27 in blood vessels of angiotensin II–infused rats and the effect therein of the AT
1
-receptor antagonist losartan. Male Sprague-Dawley rats were infused for 7 days with angiotensin II (120 ng/kg per minute SC) and/or treated with losartan (10 mg/kg per day orally). DNA synthesis in mesenteric arteries was evaluated by radiolabeled
3
H-thymidine incorporation. The expression of cyclin D1, cdk4, p21, and p27, which play critical roles during the G
1
-phase of the cell cycle process, was examined by Western blot analysis. Tail-cuff systolic blood pressure (mm Hg) was elevated (
P
<0.01, n=9) in angiotensin II–infused rats (161.3±8.2) versus control rats (110.1±5.3) and normalized by losartan (104.4±3.2). Radiolabeled
3
H-thymidine incorporation (cpm/100 μg DNA) showed that angiotensin II infusion significantly increased DNA synthesis (152±5% versus 102±6% of control rats,
P
<0.05). Expression of cyclin D1 and cdk4 was significantly increased in the angiotensin II group to 213.7±8% and 263.6±37% of control animals, respectively, whereas expression of p21 and p27 was significantly decreased in the angiotensin II group to 23.2±10.4% and 10.3±5.3% of control animals, respectively. These effects induced by angiotensin II were normalized in the presence of losartan. Thus, when AT
1
receptors are stimulated in vivo, DNA synthesis is enhanced in blood vessels by activation of cyclin D1 and cdk4. Reduction in cell cycle kinase inhibitors p21 and p27 may contribute to activation of growth induced by in vivo AT
1
receptor stimulation.
Potentiation of Bradykinin by Angiotensin-(1-7) on Arterioles of Spontaneously Hypertensive Rats Studied In Vivo
Authors: Fernandes Liliam , Fortes Zuleica Bruno , Nigro Dorothy , Tostes Rita C. A. , Santos Robson A. S. , Catelli de Carvalho Maria Helena
Published: June 2012

In the present study, we investigated the potentiating effect of angiotensin-(1-7) [Ang-(1-7)] on bradykinin (BK)-induced vasodilation in the mesenteric vascular bed of anesthetized spontaneously hypertensive rats using intravital microscopy. Topical application of BK and Ang-(1-7) induced vasodilation in mesenteric arterioles. The BK-induced effect, but not acetylcholine, sodium nitroprusside, or histamine responses, was potentiated in the presence of Ang-(1-7). This interaction was abolished by BK-B
2
and Ang-(1-7) antagonists (HOE 140 and A-779, respectively), a K
+
channel blocker (tetraethylammonium), and cyclooxygenase inhibitors (indomethacin and diclofenac); however, nitric oxide synthase inhibition (
Nω
-nitro-
l
-arginine methyl ester) did not modify the Ang-(1-7)–potentiating activity. Long-term angiotensin-converting enzyme (ACE) inhibition increased BK and Ang-(1-7)–induced vasodilation. The BK potentiation by Ang-(1-7) was preserved after ACE inhibition, Ang II type 1 receptor blockade, or the combination of both treatments. The most striking finding of this study was the unexpected observation that the potentiation of BK vasodilation in spontaneously hypertensive rats treated short- or long-term with ACE inhibitors was reverted by the Ang-(1-7) antagonist A-779. Our results unmasked a key role for an Ang-(1-7)–related mechanism in mediating BK potentiation by ACE inhibitors.