bluuebunny/crossref_metadata_2025 huggingface dataset:
Interactive Effect of Ethnicity and ACE Insertion/Deletion Polymorphism on Vascular Reactivity
Authors: Gainer James V. , Stein C. Michael , Neal Tami , Vaughan Douglas E. , Brown Nancy J.
Published: June 2012

Abstract
—Bradykinin is a potent endothelium-dependent vasodilator that contributes to the blood pressure lowering effect of angiotensin-converting enzyme inhibition. Angiotensin-converting enzyme inhibitors are widely prescribed for the treatment of hypertension, although the efficacy of this therapy has been reported to vary among different ethnic groups. To determine whether vascular sensitivity to bradykinin is decreased in blacks compared with whites, we measured forearm blood flow with venous plethysmography in response to intraarterially-administered bradykinin (100, 200, and 400 ng/min) under salt-controlled conditions in 28 (14 black, 14 white) normotensive subjects genotyped for the
ACE
insertion/deletion (
I/D
) polymorphism. Acetylcholine (ACh) (15, 30, and 60 μg/min) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 μg/min) were infused as endothelium-dependent and endothelium-independent controls. Compared with whites, blacks exhibited a blunted vasodilator response to bradykinin (maximal blood flow: 20.4±2.5 versus 10.9±1.4 mL · 100 mL
−1
· min
−1
,
P
=0.004) and SNP (14.1±1.6 versus 9.9±1.7 mL · 100 mL
−1
· min
−1
,
P
=0.05) but not to ACh (10.5±2.8 versus 6.6±1.0 mL · 100 mL
−1
· min
−1
,
P
=0.21). White subjects who carried at least 1
ACE D
allele demonstrated significantly greater vasodilator responses to bradykinin compared with those homozygous for the
I
allele (
DD
or
ID
versus
II
, F=5.6,
P
<0.04). In contrast, only blacks homozygous for the
ACE D
allele had a significantly greater vasodilator response to bradykinin than those who carried the
I
allele (
DD
versus
ID
or
II
, F=8.3,
P
=0.01). The ethnic difference was most pronounced in subjects heterozygous at the
ACE I/D
locus in which blacks had a markedly attenuated response to bradykinin compared with whites (F=41.0,
P
<0.001). There was no effect of
ACE I/D
genotype on the vasodilator responses to SNP or ACh in either ethnic group. These data confirm that vascular reactivity to bradykinin and the endothelium-independent vasodilator SNP is decreased in normotensive blacks compared with whites, consistent with attenuated vascular smooth muscle reactivity. The data suggest that genetic variation at the
ACE
gene locus interacts with ethnicity to impact the vascular response to bradykinin.
Upregulated Expression of Rat Heart Intercellular Adhesion Molecule-1 in Angiotensin II– but Not Phenylephrine- Induced Hypertension
Authors: Kiarash Arash , Pagano Patrick J. , Tayeh Mahmoud , Rhaleb Nour-Eddine , Carretero Oscar A.
Published: June 2012

Abstract
—Intercellular adhesion molecule-1 (ICAM-1), part of an immunoglobulin-like superfamily of adhesion molecules, is involved in several cardiovascular diseases. We investigated whether in vivo angiotensin II (Ang II) increases ICAM-1 in rats. Sprague-Dawley rats were infused with vehicle or Ang II (750 μg · kg
−1
· d
−1
SC) for 7 days. The contribution of Ang II receptors to ICAM-1 expression was investigated with a nonpeptide Ang II type 1 (AT
1
) receptor antagonist losartan (30 mg · kg
−1
· d
−1
in drinking water). Systolic blood pressure was elevated in Ang II–treated animals compared with sham-treated controls, and losartan blocked this increase. Tumor necrosis factor (TNF)-α (5 μg/kg IP bolus), a prototype inducer of ICAM-1, was administered as a positive control for ICAM-1 expression. After treatment, hearts were frozen in liquid nitrogen; homogenates were subjected to SDS-PAGE and immunoblotted with an anti-rat ICAM-1 monoclonal antibody. We detected a predominantly high-molecular-weight band in homogenates from non–TNF-α–treated rats, which was enhanced by 80±5% in TNF-α–treated rats. This band measured ≈200 kDa, which is the molecular weight of ICAM-1 in its native dimer form. The same band was detected in homogenates from sham and Ang II–treated rats, with the latter showing a 150±10% increase in ICAM-1 versus sham controls. Immunoprecipitation of rat heart homogenates with anti-rat ICAM-1 antibody resulted in a dominant band of the same molecular weight as samples not treated with antibody. Losartan prevented enhanced expression of ICAM-1 in the presence of Ang II but had no effect on basal ICAM-1 expression. Phenylephrine, an α-agonist (3 mg · kg
−1
· d
−1
), was infused for 1 week but had no effect on ICAM-1 expression, even though systolic blood pressure was elevated to the same level as in rats treated with Ang II. Thus, heart ICAM-1 expression is enhanced via AT
1
receptor activation independent of hypertension. Ang II–induced ICAM-1 expression was time and dose dependent, with maximal expression occurring within 5 to 7 days at 100 to 750 μg/kg Ang II. Immunohistochemical staining demonstrated markedly increased ICAM-1 levels in the perivascular area in Ang II–infused rats. Monocyte/macrophage accumulation was significantly greater in Ang II–treated rat hearts than in sham-treated hearts (10±1;
P
<0.001; n=5). Thus during inflammation, overexpression of ICAM-1 may contribute to cardiovascular damage in diseases characterized by increased activity of the renin-angiotensin system.
Endothelin-1–Independent and Angiotensin II–Independent Induction of Adrenomedullin Gene Expression
Authors: Romppanen Hannu , Puhakka Jutta , Földes Gábor , Szokodi István , Vuolteenaho Olli , Tokola Heikki , Tóth Miklós , Ruskoaho Heikki
Published: June 2012

Abstract
—Adrenomedullin (AM) may function as an autocrine and/or paracrine factor in the heart, but the exact mechanisms regulating cardiac AM gene expression are unknown. The aim of the present study was to characterize the precise time course of induction of atrial and ventricular AM gene expression during pressure overload and to study whether endothelin-1 or angiotensin II plays a causal role in the activation of cardiac AM gene expression. The pressure overload was produced by arginine-vasopressin (AVP, 0.05 μg/kg per minute IV) infusion for 15 minutes, 30 minutes, 1 hour, 2 hours, or 4 hours in conscious rats. A significant increase in left ventricular AM mRNA levels was seen after 2 hours of pressure overload in the left ventricle and after 30 minutes in the left atrium. The left atrial immunoreactive AM (ir-AM) levels decreased significantly after 2 hours of pressure overload. Plasma ir-AM levels increased slightly in response to 4 hours of AVP infusion. Bolus injections of bosentan (mixed ET
A
/ET
B
receptor antagonist, 10 mg/kg IV), losartan (AT
1
receptor antagonist, 10 mg/kg IV), and their combination had no effect on the increase of cardiac AM mRNA and ir-AM levels produced by 2 hours of pressure overload. In addition, losartan, bosentan, and their combination did not affect plasma ir-AM levels in the vehicle-infused and AVP-infused animals. The present study indicates that cardiac AM gene expression is rapidly upregulated in response to pressure. The induction of ventricular and atrial AM gene expression by pressure overload is angiotensin II–independent and endothelin-1–independent.
T Wave Alternans and Ventricular Arrhythmias in Arterial Hypertension
Authors: Hennersdorf Marcus G. , Niebch Verena , Perings Christian , Strauer Bodo-E.
Published: June 2012

Patients with a positive microvolt-level T wave alternans (TWA) are characterized by an increased risk of ventricular tachyarrhythmias. Arterial hypertension leads to an increase of sudden cardiac death risk, particularly if left ventricular hypertrophy is present. The aim of this study was to investigate the value of TWA in patients with arterial hypertension. Fifty-one consecutive patients were included in the study. TWA analysis was performed with patients sitting on a bicycle ergometer and exercising with a gradual increase of workload to maintain a heart rate of at least 105/min. After recording 254 consecutive low-noise-level heartbeats, the exercise test was stopped. The ECG signals were digitally processed by a spectral analysis method. The magnitude of TWA was measured at a frequency of 0.5 cycle per beat. A TWA was defined as positive if the ratio between TWA and noise level was >3.0 and the amplitude of the TWA was >1.8 μV. Eight of the 51 patients (16%) showed a positive TWA. If left ventricular hypertrophy was present, the prevalence of TWA was higher (33.3% versus 8.3%;
P
<0.05). Sensitivity concerning a previous arrhythmic event was 73%, and specificity was 100%. The alternans ratio was significantly higher in patients with a previous event (39.3±62.3 versus 2.4±4.6;
P
<0.001), as was the cumulative alternans voltage (4.7±4.1 versus 1.6±1.9 μV;
P
<0.001). In 16 patients invasively investigated by an electrophysiological study, a significant correlation between inducibility of tachyarrhythmias and a positive TWA result was found (Spearman
R
=0.36,
P
=0.01). We conclude that the arrhythmic risk of patients with arterial hypertension is markedly increased if microvolt-level TWA is present. The prevalence of TWA is higher in patients with left ventricular hypertrophy.
Nitric Oxide and Central Antihypertensive Drugs
Authors: Sy Guata Yoro , Bruban Véronique , Bousquet Pascal , Feldman Josiane
Published: June 2012

NO is known to be involved in the peripheral and central regulation of the cardiovascular function. It plays a neuromodulatory role via a direct action on presynaptic nerve terminals, stimulating the release of γ-aminobutyric acid, glutamate, and norepinephrine. Our aim was to study the possible role of NO in the cardiovascular effects of the central antihypertensive drugs clonidine, rilmenidine, and α-methyl-norepinephrine (α-MNA). Sites and mechanisms of the hypotensive action of these drugs were different; clonidine and rilmenidine acted on imidazoline receptors in the nucleus reticularis lateralis, whereas α-MNA acted upon α
2
-adrenoceptors in the nucleus tractus solitarius. The influence of
N
G
-nitro-
l
-arginine, an NO synthase inhibitor, on the central hypotensive effects of these drugs was investigated in pentobarbital-anesthetized rabbits. The intracisternal (IC) administration of α-MNA (30 μg/kg) induced hypotension (79±2 versus 103±4 mm Hg) and bradycardia (222±8 versus 278±4 bpm) (
P
<0.05) (n=5). Clonidine (0.07 μg/kg IC) also induced hypotension (69±5 versus 99±4 mm Hg) and bradycardia (266±7 versus 306±10 bpm) (
P
<0.05) (n=5). In addition to clonidine, rilmenidine (1 μg/kg IC) induced hypotension (64±4 versus 97±4 mm Hg) and bradycardia (264±11 versus 310±4 bpm) (
P
<0.05) (n=5). Pretreatment with
N
G
-nitro-
l
-arginine (900 μg/kg IC) completely prevented the hypotensive effect of α-MNA but influenced the cardiovascular effects of neither clonidine nor rilmenidine. These results confirm that imidazoline drugs, such as clonidine, rilmenidine, and the catecholamine α
2
-adrenoceptor agonist α-MNA, have distinct mechanisms of action.
Renal Endothelin ET
A
/ET
B
Receptor Imbalance Differentiates Salt-Sensitive From Salt-Resistant Spontaneous Hypertension
Authors: Rothermund Lars , Luckert Susanne , Koßmehl Peter , Paul Martin , Kreutz Reinhold
Published: June 2012

It is unclear why a subgroup of patients with essential hypertension develop salt-sensitive hypertension with progression of target organ damage over time. We evaluated the role of the renal endothelin (ET) system in the stroke-prone spontaneously hypertensive rat (SHRSP) model of salt-sensitive spontaneous hypertension (SS-SH) compared with the spontaneously hypertensive rat (SHR) model of salt-resistant spontaneous hypertension (SR-SH). Both strains were studied after either sham-operation on a normal diet (Sham) or after unilateral nephrectomy and high NaCl loading (NX-NaCl) with 4% NaCl in diet for 6 weeks (n=10, respectively). Systolic blood pressure (SBP) increased only in SHRSP-NX-NaCl compared with SHRSP-Sham (250±6 versus 172±5 mm Hg,
P
<0.0001). SBP remained unchanged in SHR-NX-NaCl compared with SHR-Sham. In SHRSP-NX-NaCl animals, urinary albumin and ET-1 excretion, renal ET-1 mRNA expression, glomerulosclerosis index, and tubulointerstitial damage index were elevated compared with SHRSP-Sham (
P
<0.05, respectively), whereas no significant changes were found in SHR after NX-NaCl. Urinary sodium excretion (U

Na
+

) was significantly reduced by 38% in SHRSP-NX-NaCl compared with SHR-NX-NaCl (
P
<0.005, respectively). SHR animals showed a similar increase in both renal ET
A
and ET
B
receptor densities after NX-NaCl (2.2-fold,
P
<0.05). In contrast, SHRSP-NX-NaCl developed a significantly more pronounced increase in ET
A
compared with ET
B
binding (4.7-fold versus 2.4-fold,
P
<0.05, compared with SHRSP-Sham, respectively), resulting in a significant 2.1-fold increase in ET
A
/ET
B
receptor ratio only in the SHRSP-NX-NaCl (
P
<0.05). Thus, activation of the renal ET system together with an increased ET
A
/ET
B
receptor ratio may contribute to the development and progression of SS-SH.
Reduced Hypoxic Pulmonary Vascular Remodeling by Nitric Oxide From the Endothelium
Authors: Ozaki Masanori , Kawashima Seinosuke , Yamashita Tomoya , Ohashi Yoshitaka , Rikitake Yoshiyuki , Inoue Nobutaka , Hirata Ken-Ichi , Hayashi Yoshitake , Itoh Hiroshi , Yokoyama Mitsuhiro
Published: June 2012

We examined whether overproduction of endogenous nitric oxide (NO) can prevent hypoxia-induced pulmonary hypertension and vascular remodeling by using endothelial NO-overexpressing (eNOS-Tg) mice. Male eNOS-Tg mice and their littermates (wild-type, WT) were maintained in normoxic or 10% hypoxic condition for 3 weeks. In normoxia, eNOS protein levels, Ca
2+
-dependent NOS activity, and cGMP levels in the lung of eNOS-Tg mice were higher than those of WT mice. Activity of eNOS and cGMP production in the lung did not change significantly by hypoxic exposure in either genotype. Chronic hypoxia did not induce iNOS expression nor increase its activity in either genotype. Plasma and lung endothelin-1 levels were increased by chronic hypoxia, but these levels were not significantly different between the 2 genotypes. In hemodynamic analysis, right ventricular systolic pressure (RVSP) in eNOS-Tg mice was similar to that in WT mice in normoxia. Chronic hypoxia increased RVSP and induced right ventricular hypertrophy in both genotypes; however, the degrees of these increases were significantly smaller in eNOS-Tg mice. Histological examination revealed that hypoxic mice showed medial wall thickening in pulmonary arteries. However, the increase of the wall thickening in small arteries (diameter <80 μm) by chronic hypoxia was inhibited in eNOS-Tg mice. Furthermore, muscularization of small arterioles was significantly attenuated in eNOS-Tg mice. Thus, we demonstrated directly that overproduction of eNOS-derived NO can inhibit not only the increase in RVSP associated with pulmonary hypertension but also remodeling of the pulmonary vasculature and right ventricular hypertrophy induced by chronic hypoxia.
Role of Angiotensin and Its Inhibition in Hypertension, Ischemic Heart Disease, and Heart Failure
Authors: Gavras Haralambos , Brunner Hans R.
Published: June 2012

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.
Twins in Cardiovascular Genetic Research
Authors: Luft Friedrich C.
Published: June 2012

Twin studies have been largely responsible for showing the effects of genetic variance on a quantitative trait. The model is based on the fact that monozygotic twins share all genes in common, whereas dizygotic twins are related as siblings and share “on average” half their genes. Environmental confounders are minimized because twin children are usually exposed to similar environments. Blood pressure was first shown to be heritable in a twin study. However, intermediary phenotypes, such as components of the renin-angiotensin system, sympathetic nervous system, renal function, and the facility in excreting electrolytes, are also heritable. The advent of molecular genetics has made twin studies more useful than ever because of the power of quantitative trait loci analyses. Recruitment of the parents of dizygotic twins greatly facilitates this effort. Gene loci linked to blood pressure, intermediate phenotypes, cardiac dimensions, lipid concentrations, and even components of the ECG have been identified. The use of single-nucleotide polymorphisms then allows for novel association approaches within the cohort. Twin studies will continue to gain in importance and utility, particularly in elucidating normal human genetic diversity.
Antisense Inhibition of Brain Renin-Angiotensin System Decreased Blood Pressure in Chronic 2-Kidney, 1 Clip Hypertensive Rats
Authors: Kagiyama Shuntaro , Varela Adrian , Phillips M. Ian , Galli Sara M.
Published: June 2012

The systemic renin-angiotensin system (RAS) plays an important role in blood pressure (BP) regulation during the development of 2-kidney, 1 clip (2K1C) hypertension. Its contributions decrease with time after constriction of the renal artery. During the chronic phase, the peripheral RAS returns to normal, but the hypertension is sustained for months. We hypothesized that in this phase the brain RAS contributes to the maintenance of high BP. To test the hypothesis, we studied the role of brain RAS by decreasing the synthesis of angiotensinogen (AGT) and the angiotensin II (Ang II) type 1a receptor (AT
1
R) with intracerebroventricular injections of antisense oligonucleotides (AS-ODNs). The response of systolic BP (SBP) to AS-ODNs to AGT mRNA was studied in 2K1C rats at 6 months after clipping, and the response to AS-ODNs to AT
1
R mRNA was studied at 10 months after clipping. Intracerebroventricular injection of AS-ODN-AGT (200 μg/kg, n=5) significantly decreased SBP (−22±6 mm Hg,
P
<0.05) compared with the sense ODN (n=5) and saline (n=3) groups. Intracerebroventricular injection of AS-ODN-AGT reduced the elevated hypothalamic Ang II level. The hypothalamic Ang II content in sense ODN and saline groups was significantly (
P
<0.05) higher than in the nonclipped group. Compared with inverted ODN, intracerebroventricular injection of AS-ODN-AT
1
R (250 μg/kg, n=6) significantly decreased SBP (−26±8 mm Hg,
P
<0.05) for 3 days after injection. This was a brain effect because intravenous AS-ODN-AT
1
R at a dose of 250 to 500 μg/kg did not affect SBP. These results suggest that the brain RAS plays an important role in maintaining the elevated SBP in chronic 2K1C hypertension.
Reciprocal Consomic Strains to Evaluate Y Chromosome Effects
Authors: Negrín Cervantes D. , McBride Martin W. , Carswell Hillary V. O. , Graham Delyth , Carr Fiona J. , Clark James S. , Jeffs Baxter , Anderson Niall H. , Macrae I. Mhairi , Dominiczak Anna F.
Published: June 2012

We have previously demonstrated that the SHRSP Y chromosome contains a locus that contributes to hypertension in SHRSP/WKY F2 hybrids and that SHRSP exhibit an increased vulnerability to focal cerebral ischemia after permanent middle cerebral artery occlusion (MCAO). This increased vulnerability is inherited as a codominant trait, and a putative role for the Y chromosome has been suggested in F1 hybrids. The objective of this study was to investigate further the role of Y chromosome in blood pressure (BP) regulation and in the vulnerability to cerebral ischemia. We have constructed consomic strains by selectively replacing the Y chromosome from WKY rats with that of SHRSP, and vice versa, by using a marker-assisted breeding strategy. Permanent MCAO was carried out by electrocoagulation, with infarct volume expressed as a percentage of the ipsilateral hemisphere. Systolic blood pressure was measured by radiotelemetry during a baseline period of 5 weeks followed by a 3-week period of salt loading. We observed that the transfer of the Y chromosome from WKY onto SHRSP background significantly reduced systolic BP in consomic strains, SP.WKYGlaY
w
(n=6) versus SHRSP (n=6) (209.2±10.4 mm Hg versus 241.7±7.7 mm Hg, F=5.88,
P
=0.038) during the salt-loading period. In the reciprocal consomic strain, WKY.SPGlaY
s
(n=5), systolic BP was increased compared with WKY parental strain (n=6) (147.6±2.4 mm Hg versus 132.6±5.1 mm Hg, F=6.11,
P
=0.035) during baseline. Infarct volumes in consomic strains were not significantly different from their respective parental strain: WKY.SPGlaY
s
(n=7) versus WKY (n=7), 22.8±3.7% versus 22.2±8.0%, 95% CI=−12.7, 4.2,
P
=0.3; SP.WKYGlaY
w
(n=7) versus SHRSP (n=6), 37.7±4.4% versus 33.6±7.6%, 95% CI=−20.3, 12.1,
P
=0.5. We conclude that the SHRSP Y chromosome harbors a locus contributing to systolic BP, whereas no contribution to vulnerability to cerebral ischemia can be detected.
Paradoxical Regulation of Short Promoter Human Renin Transgene by Angiotensin II
Authors: Keen Henry L. , Sigmund Curt D.
Published: June 2012

We previously reported the generation of transgenic mice containing the entire human renin gene with a 900-bp promoter. To determine whether all the required elements for angiotensin II–mediated suppression of human renin are present in these mice, angiotensin II was chronically infused by means of osmotic minipump at both low and high doses, 200 and 1000 ng/kg per minute, respectively. Blood pressure was measured by tail-cuff, and kidney renin mRNA levels were quantitated using ribonuclease protection assays. Blood pressure was unchanged in mice receiving either vehicle or low-dose angiotensin II infusion but was increased by approximately 40 mm Hg with the higher dose of angiotensin II. Mouse renin mRNA decreased by >60% during both pressor and nonpressor angiotensin II infusion. Human renin mRNA was not suppressed by nonpressor angiotensin II and was paradoxically increased 1.9-fold by pressor angiotensin II. The lack of upregulation during nonpressor angiotensin II suggested that the increase might be pressure-mediated. To test this, the angiotensin II-induced increase in blood pressure was prevented by coadministration of the vasodilator, hydralazine (15 mg/kg per day). Hydralazine alone decreased blood pressure (−27±3 mm Hg) and increased mouse renin mRNA 2.4-fold. Human renin mRNA was unresponsive to this vasodilator-induced fall in pressure and despite the normalization of blood pressure by hydralazine, high-dose angiotensin II still caused a 2.1-fold increase in human renin mRNA. Thus, the first 900 bp of the human renin promoter does not contain all the elements required for appropriate angiotensin II–mediated suppression of human renin mRNA.
Salt Sensitivity, Pulse Pressure, and Death in Normal and Hypertensive Humans
Authors: Weinberger Myron H. , Fineberg Naomi S. , Fineberg S. Edwin , Weinberger Morris
Published: June 2012

Although factors such as age, blood pressure, and its responsiveness to changes in sodium balance and extracellular fluid volume status (salt sensitivity) are associated with an increased risk of end-organ disease and cardiovascular events in hypertensive subjects, no such relationship with mortality has been demonstrated for salt sensitivity in normotensive subjects. We conducted long-term follow-up of 430 normal and 278 hypertensive subjects in whom assessment of salt sensitivity of blood pressure was performed as long as 27 years ago. We ascertained the status of 596 subjects (85% of the total population), 123 (21%) of whom had died. The following initial measurements were significantly (P
<0.002) associated with subjects who had died compared with subjects known to be alive: age at study, pulse pressure, systolic, diastolic, and mean arterial pressures, hypertension, salt sensitivity, baseline renin levels, and body mass index (but not body weight). A stepwise logistic regression found the following independent predictors of death (odds ratio, 95% CI): age at initial study (1.08, 1.06 to 1.10), baseline blood pressure (1.03, 1.01 to 1.04), sodium sensitivity (1.73, 1.02 to 2.94), and male gender (1.91, 1.15 to 3.17). When survival curves were examined, normotensive salt-sensitive subjects aged >25 years when initially studied were found to have a cumulative mortality similar to that of hypertensive subjects, whereas salt-resistant normotensive subjects had increased survival (
P
<0.001). These observations provide unique evidence of a relationship between salt sensitivity and mortality that is independent of elevated blood pressure.
Endothelin-1 Enhances Eicosanoids-Induced Coronary Smooth Muscle Contraction by Activating Specific Protein Kinase C Isoforms
Authors: Sirous Zohreh N. , Fleming John B. , Khalil Raouf A.
Published: June 2012

Endothelin-1 (ET-1), a potent vasoconstrictor, has been implicated in the pathogenesis of coronary vasospasm by enhancing coronary vasoconstriction to vasoactive eicosanoids; however, the cellular mechanisms involved are unclear. We investigated whether physiological concentrations of ET-1 enhance coronary smooth muscle contraction to vasoactive eicosanoids by activating specific protein kinase C (PKC) isoforms. Cell contraction was measured in single smooth muscle cells isolated from porcine coronary arteries, intracellular free Ca
2+
([Ca
2+
]
i
) was measured in fura-2–loaded cells, and the cytosolic and particulate fractions were examined for PKC activity and reactivity with isoform-specific anti-PKC antibodies using Western blots. In Hanks’ solution (1 mmol/L Ca
2+
), ET-1 (10 pmol/L) did not increase basal [Ca
2+
]
i
(81±2 nmol/L), but it did cause cell contraction (9%) that was inhibited by GF109203X (10
–6
mol/L), an inhibitor of Ca
2+
-dependent and Ca
2+
-indpendent PKC isoforms. The vasoactive eicosanoid prostaglandin F
2α
(PGF
2α
, 10
–7
mol/L) caused increases in cell contraction (11%) and [Ca
2+
]
i
(108±7 nmol/L) that were inhibited by the Ca
2+
channel blocker diltiazem (10
–6
mol/L). Pretreatment with ET-1 (10 pmol/L) for 10 minutes enhanced cell contraction to PGF
2α
(35%) with no additional increase in [Ca
2+
]
i
(112±8 nmol/L). Direct activation of PKC by phorbol 12,13-dibutyrate (PDBu, 10
–7
mol/L) caused cell contraction (10%) and enhanced PGF
2α
contraction (33%) with no additional increase in [Ca
2+
]
i
(115±7 nmol/L). The ET-1–induced enhancement of PGF
2α
contraction was inhibited by Gö6976 (10
–6
mol/L), an inhibitor of Ca
2+
-dependent PKC isoforms. Both ET-1 and PDBu caused an increase in PKC activity in the particulate fraction and a decrease in the cytosolic fraction and increased the particulate/cytosolic PKC activity ratio. Western blots revealed the Ca
2+
-dependent α-PKC and the Ca
2+
-independent δ-, ε-, and ζ-PKC isoforms. In resting tissues, α- and ε-PKC were mainly cytosolic, δ-PKC was mainly in the particulate fraction, and ζ-PKC was equally distributed in the cytosolic and particulate fraction. ET-1 (10 pmol/L) alone or PDBu (10
–7
mol/L) alone caused translocation of ε-PKC from the cytosolic to the particulate fraction, localized δ-PKC more in the particulate fraction, but did not change the distribution of ζ-PKC. PGF
2α
(10
–7
mol/L) alone did not change PKC activity. In tissues pretreated with ET-1 or PDBu, PGF
2α
caused additional increases in α-PKC activity. Thus, the enhancement of PGF
2α
-induced coronary smooth muscle contraction by physiological concentrations of ET-1 involves activation and translocation of α-PKC in addition to δ- and ε-PKC isoforms, and this may represent one possible cellular mechanism by which ET-1 could enhance coronary vasoconstriction to vasoactive eicosanoids in coronary vasospasm.
Evidence That Reduced Renal Medullary Nitric Oxide Synthase Activity of Dahl S Rats Enables Small Elevations of Arginine Vasopressin to Produce Sustained Hypertension
Authors: Yuan Baozhi , Cowley Allen W.
Published: June 2012

On the basis of observations supporting the functional importance of nitric oxide (NO) in the regulation of renal medullary function, and a reduced nitric oxide synthase (NOS) enzyme activity in the outer medulla of the Dahl salt-sensitive (SS/Mcw) rats, we hypothesized that these inbred rats would have reduced capacity to synthesize renal medullary NO. This reduced capacity would sensitize them to the hypertensive effects of small elevations of circulating arginine vasopressin (AVP). SS/Mcw and Brown Norway (BN/Mcw) rats with implanted arterial and venous catheters were fed a 0.4% salt diet and infused intravenously for 14 days with a subpressor dose of AVP (2 ng/kg per min). Mean arterial pressure (MAP) was measured 2 hours daily in unanesthetized rats maintained in their home cages. MAP in SS/Mcw rats increased during day 1 of AVP infusion from a control level of 127±0.9 mm Hg to an average of 147±1.6 mm Hg after 14 days. MAP did not return to control values during the 3 days after the end of AVP infusion. BN/Mcw rats showed no changes of MAP during 14 days of AVP infusion (90.4±0.6 mm Hg and 92.3±0.4 mm Hg). Northern blot analysis of renal tissue from vehicle (saline) -infused rats demonstrated that NOS I and NOS III mRNA expression was significantly less in SS/Mcw rats in the renal outer medulla compared with BN/Mcw rats. We conclude that small, normally subpressor elevations of plasma AVP can produce chronic hypertension in SS/Mcw rats and that this phenomenon is related to the reduced medullary NOS enzyme activity, which in turn reduces the AVP-stimulated NO synthesis.
γ-Aminobutyric Acid
B
Receptor–Mediated Responses in the Nucleus Tractus Solitarius Are Altered in Acute and Chronic Hypertension
Authors: Vitela Melissa , Mifflin Steven W.
Published: June 2012

The increase in mean arterial pressure evoked by injection of the γ-aminobutyric acid (GABA)
B
agonist baclofen into the nucleus tractus solitarius (NTS) is greater in spontaneously hypertensive rats and renal wrap chronically hypertensive (CHT) rats compared with normotensive (NT) controls. We report here that the baclofen-induced pressor response (BIPR) is enhanced after acute hypertension (AHT) of only 30 minutes. Sprague-Dawley rats were anesthetized with Inactin, paralyzed, and artificially ventilated. As we previously reported, after unilateral electrolytic ablation of the NTS, microinjection of 40 pmol baclofen into the contralateral NTS of NT rats resulted in a BIPR of 22±1 mm Hg (n=12). During the infusion of phenylephrine for 30 minutes (AHT), the BIPR was 39±5 mm Hg (n=10), significantly greater than the response in NT rats (
P
<0.01) and no different from the response in CHT rats (39±5 mm Hg, n=7). Baclofen has both presynaptic and postsynaptic effects. To eliminate the presynaptic component of the baclofen response, sinoaortic denervation (SAD) was performed before the microinjections. The magnitude of the BIPR was 12±1 mm Hg in NT-SAD rats (n=8), 12±1 mm Hg in AHT-SAD rats (n=12), and 20±3 mm Hg in CHT-SAD rats (n=7). The BIPR is enhanced in both CHT and AHT rats. It appears that the increase in baroreceptor afferent input to NTS during phenylephrine-induced AHT provides a greater substrate for presynaptic inhibition by baclofen because the postsynaptic component of the baclofen response is the same in NT-SAD and AHT-SAD. The enhanced BIPR in CHT rats appears to be associated with an enhancement of both the presynaptic and postsynaptic components of the response.
Differentiation of Brain Angiotensin Type 1a and 1b Receptor mRNAs
Authors: Chen Yanfang , Morris Mariana
Published: June 2012

The objective was to examine the effect of dehydration on the expression of the angiotensin type 1 (AT
1
) receptor subtype mRNAs in mice by using an in situ hybridization method. The method used free-floating brain sections with
35
S-labeled probes specific for the untranslated 5′ (AT
1a
) and 3′ (AT
1b
) regions. AT
1a
and AT
1b
mRNA levels in the subfornical organ (SFO) and anterior third ventricle (AV3V) were quantified by using a phosphor-imaging system. Emulsion autoradiography with cresyl violet counterstaining was used to show cellular expression. Adult male C57BL mice (25 to 30 g) were given water ad libitum or were deprived of water for 48 hours. Dehydration produced increases in plasma osmolality (349±6 versus 314±4 mOsm/kg) and hematocrit (58±2% versus 47±1%). In situ hybridization showed that there was expression of AT
1a
and of AT
1b
mRNA in SFO and AV3V. Dehydration produced an increase in AT
1a
mRNA in both regions, with no changes noted for AT
1b
. AT
1a
mRNA was increased in the AV3V region from 0.3±0.2 to 0.7±0.2 μCi/g and in the SFO from 0.6±0.3 to 1.0±0.2 μCi/g. These results provide information regarding the localization and physiological importance of a subset of angiotensin receptors that are important in volume and blood pressure regulation. AT
1a
and AT
1b
mRNAs showed a similar pattern of expression in rostral forebrain osmosensitive regions. However, osmotic/volume stimulation with dehydration produced specific activation of AT
1a
receptors. This verifies the role of AT
1a
receptors in volume regulation but raises a question concerning the physiological role of the AT
1b
subtype.
Combination of Hypercholesterolemia and Hypertension Augments Renal Function Abnormalities
Authors: Rodriguez-Porcel Martin , Krier James D. , Lerman Amir , Sheedy Patrick F. , Romero J. Carlos , Napoli Claudio , Lerman Lilach O.
Published: June 2012

Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6±4.7%,
P
=0.002) but not in hypercholesterolemic or hypertensive animals (8.0±7.4% and 8.2±5.9%, respectively;
P
>0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5±4.8%,
P
=0.02) and significantly different from the group fed a normal diet (
P
<0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.
G-Protein β
3
Subunit Gene
(GNB3) 825T Allele Is Associated With Enhanced Renal Perfusion in Early Hypertension
Authors: Zeltner Raoul , Delles Christian , Schneider Markus , Siffert Winfried , Schmieder Roland E.
Published: June 2012

The
C825T
polymorphism of the gene encoding the G-protein β
3
subunit
(GNB3)
is associated with increased intracellular signal transduction and arterial hypertension. The aim of the study was to investigate the impact of this polymorphism on early adaptive processes of the left ventricle and renal hemodynamic changes in young normotensive to mildly hypertensive subjects. Ninety-five white male students with normal or mildly elevated blood pressure were genotyped for the
GNB3 C825T
polymorphism. In each participant, 24-hour ambulatory blood pressure, left ventricular structure and function (2D-guided M-mode echocardiography), renal plasma flow (
para
-aminohippurate clearance), glomerular filtration rate (inulin clearance), and 24-hour urinary sodium excretion were determined. The
GNB3 825T
allele was not associated with casual or ambulatory blood pressure, parameters of left ventricular structure or function, glomerular filtration, or 24-hour urinary sodium excretion. However, in
T
-allele carriers (
CT+TT
), renal plasma flow was higher than in
CC
subjects (
CT/TT
: 659±96 versus CC: 614±91 mL/min,
P
=0.019). ANOVA disclosed that renal plasma flow was independently influenced by both genotype and blood pressure, with hypertensives having a higher renal plasma flow than normotensive subjects. This was the fact irrespective of the criteria used for the definition of hypertension (World Health Organization or 24-hour ambulatory blood pressure criteria). The
GNB3 825T
variant is associated with increased renal perfusion in this study. Because early renal hemodynamic changes play a pivotal role in the pathogenesis of essential hypertension, our data suggest a relevance of increased G-protein activation in the pathogenesis of hypertension.
Vascular Stiffness in Women With Systemic Lupus Erythematosus
Authors: Selzer Faith , Sutton-Tyrrell Kim , Fitzgerald Shirley , Tracy Russell , Kuller Lewis , Manzi Susan
Published: June 2012

Abstract
—Large-vessel manifestations of systemic lupus erythematosus (SLE), a multisystem disease characterized by disturbances in the immune system, include higher than expected rates of hypertension and cardiovascular disease. Reductions in the elasticity of central arteries may act as a marker of early changes that predispose to the development of major vascular disease. This study evaluated risk factors associated with aortic stiffness measured by pulse wave velocity (PWV) in women with SLE. We expected SLE-specific factors, especially variables indicative of inflammation and active disease, to be associated with increasing PWV. The study population included 220 women currently enrolled in the Pittsburgh Lupus Registry. All risk factor data were collected on the day of the ultrasound examinations. PWV waveforms were collected from the right carotid and femoral arteries by Doppler probes. The mean age of the women was 45.5±10.8 years, the median SLE disease duration approximated 9 years, and the mean PWV was 6.1±1.7 m/s. Multiple regression models were stratified by menopausal status. Among postmenopausal women, PWV risk factors were primarily traditional factors and included age, systolic blood pressure, family history of vascular disease, carotid plaque, creatinine, obesity, glucose, white cell count, and cumulative SLE organ damage. Among premenopausal women, PWV risk factors consisted of a mix of SLE-related and traditional variables and included higher C3 levels, presence of ds-DNA antibodies, nonuse of hydroxychloroquine, lower leukocyte count, higher mean arterial pressure, and carotid plaque. SLE-specific variables appeared to be associated with increases in aortic PWV, indicating central artery stiffening. This was seen most clearly among premenopausal women. This finding may partially explain the higher rates of cardiovascular disease and hypertension observed in young women with SLE.
Vasopeptidase Inhibition Exhibits Endothelial Protection in Salt-Induced Hypertension
Authors: Quaschning Thomas , d’Uscio Livius V. , Shaw Sidney , Lüscher Thomas F.
Published: June 2012

Abstract
—Omapatrilat represents a new class of drugs capable of inhibiting both ACE and neutral endopeptidase 24.11, the so-called vasopeptidase inhibitors. It therefore contributes to neurohumoral modulation, which might improve endothelial function in cardiovascular diseases. This study investigated the effect of omapatrilat in comparison to the ACE inhibitor captopril on systolic blood pressure and endothelial function in salt-induced hypertension. Dahl salt-sensitive rats (n=6/group) on standard or salt-enriched (4% NaCl) chow were treated for 8 weeks with either omapatrilat (36±4 mg/kg per day), captopril (94±2 mg/kg per day), or placebo. Aortic rings were then isolated and suspended in organ chambers for isometric tension recording. Systolic blood pressure of salt-fed, placebo-treated animals increased to 196±6 mm Hg, which was prevented by omapatrilat (162±5 mm Hg,
P
<0.05) and captopril (164±7 mm Hg,
P
<0.05) to a comparable degree. In control rats, acetylcholine (10
−10
to 10
−5
mol/L) induced endothelium-dependent relaxation (97±4%), which was reduced by high-salt diet to 30±5% (
P
<0.005; n=6). Omapatrilat improved relaxation to a greater extent (86±5%) than did captopril (57±6%;
P
<0.05). eNOS protein expression and aortic nitrite/nitrate content were reduced in hypertensive rats and improved by both omapatrilat and captopril. Aortic endothelin-1 levels were increased in salt-fed animals and unaffected by omapatrilat or captopril. These data suggest that despite comparable blood pressure, omapatrilat is superior to captopril in improving endothelium-dependent relaxation in salt-sensitive hypertension.
Sodium Intake Influences Hemodynamic and Neural Responses to Angiotensin Receptor Blockade in Rostral Ventrolateral Medulla
Authors: DiBona Gerald F. , Jones S. Y.
Published: June 2012

Abstract
—To determine the effects of physiological alterations in endogenous angiotensin II activity on basal renal sympathetic nerve activity (RSNA) and its arterial baroreflex regulation, angiotensin II type 1 receptor antagonists were microinjected into the rostral ventrolateral medulla of anesthetized rats consuming a low, normal, or high sodium diet that were instrumented for simultaneous measurement of arterial pressure and RSNA. Plasma renin activity was increased in rats fed a low sodium diet and decreased in those fed a high sodium diet. Losartan (50, 100, and 200 pmol) decreased heart rate and RSNA (but not mean arterial pressure) dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a high sodium diet. Candesartan (1, 2, and 10 pmol) decreased mean arterial pressure, heart rate, and RSNA dose-dependently; the responses were significantly greater in rats fed a low sodium diet than in those fed a normal or high sodium diet. [D-Ala
7
]Angiotensin-(1-7) (100, 200, and 1000 pmol) did not affect mean arterial pressure, heart rate, or RSNA in rats fed either a low or a high sodium diet. In rats fed a low sodium diet, candesartan reset the arterial baroreflex control of RSNA to a lower level of arterial pressure, and in rats with congestive heart failure, candesartan increased the arterial baroreflex gain of RSNA. Physiological alterations in the endogenous activity of the renin-angiotensin system influence the bradycardic, vasodepressor, and renal sympathoinhibitory responses to rostral ventrolateral medulla injection of antagonists to angiotensin II type 1 receptors but not to angiotensin-(1-7) receptors.
Angiotensin-(1-7) Downregulates the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells
Authors: Clark Michelle A. , Diz Debra I. , Tallant E. Ann
Published: June 2012

Abstract
—Angiotensin (Ang)-(1-7) is a biologically active peptide of the renin-angiotensin system that has both vasodilatory and antiproliferative activities that are opposite the constrictive and proliferative effects of angiotensin II (Ang II). We studied the actions of Ang-(1-7) on the Ang II type 1 (AT
1
) receptor in cultured rat aortic vascular smooth muscle cells to determine whether the effects of Ang-(1-7) are due to its regulation of the AT
1
receptor. Ang-(1-7) competed poorly for [
125
I]Ang II binding to the AT
1
receptor on vascular smooth muscle cells, with an IC
50
of 2.0 μmol/L compared with 1.9 nmol/L for Ang II. The pretreatment of vascular smooth muscle cells with Ang-(1-7) followed by treatment with acidic glycine to remove surface-bound peptide resulted in a significant decrease in [
125
I]Ang II binding; however, reduced Ang II binding was observed only at micromolar concentrations of Ang-(1-7). Scatchard analysis of vascular smooth muscle cells pretreated with 1 μmol/L Ang-(1-7) showed that the reduction in Ang II binding resulted from a loss of the total number of binding sites [B
max
437.7±261.5 fmol/mg protein in Ang-(1-7)–pretreated cells compared with 607.5±301.2 fmol/mg protein in untreated cells, n=5,
P
<0.05] with no significant effect on the affinity of Ang II for the AT
1
receptor. Pretreatment with the AT
1
receptor antagonist L-158,809 blocked the reduction in [
125
I]Ang II binding by Ang-(1-7) or Ang II. Pretreatment of vascular smooth muscle cells with increasing concentrations of Ang-(1-7) reduced Ang II–stimulated phospholipase C activity; however, the decrease was significant (81.2±6.4%,
P
<0.01, n=5) only at 1 μmol/L Ang-(1-7). These results demonstrate that pharmacological concentrations of Ang-(1-7) in the micromolar range cause a modest downregulation of the AT
1
receptor on vascular cells and a reduction in Ang II–stimulated phospholipase C activity. Because the antiproliferative and vasodilatory effects of Ang-(1-7) are observed at nanomolar concentrations of the heptapeptide, these responses to Ang-(1-7) cannot be explained by competition of Ang-(1-7) at the AT
1
receptor or Ang-(1-7)–mediated downregulation of the vascular AT
1
receptor.
Baroreflex Improvement in SHR After ACE Inhibition Involves Angiotensin-(1-7)
Authors: Heringer-Walther Silvia , Batista Érica N. , Walther Thomas , Khosla Mahesh C. , Santos Robson A. S. , Campagnole-Santos Maria J.
Published: June 2012

Abstract
—ACE inhibitors are extensively used in the treatment of hypertension mainly because of their efficiency in reducing blood pressure levels and decreasing vascular and cardiac hypertrophy. In addition, ACE inhibitors improve baroreceptor reflex control. Chronic inhibition of ACE produces (in addition to decreased angiotensin II levels) a severe increase in angiotensin-(1-7) [Ang-(1-7)] levels in several species. We have previously shown that Ang-(1-7) produces a facilitation of the baroreflex control of heart rate. In this study, we evaluated the participation of endogenous Ang-(1-7) in the improvement of baroreflex sensitivity in spontaneously hypertensive rats after central infusion of ramiprilat, an ACE inhibitor. Reflex changes in heart rate were elicited, in conscious rats, by bolus injections of phenylephrine (baroreflex bradycardia) before and after intracerebroventricular infusion of (1) saline (8 μL/h), 4 hours (n=5); (2) ramiprilat (14 μg/h), 4 hours (n=6); (3) ramiprilat for 2 hours, followed by ramiprilat combined with A-779 (4 μg/h), a selective Ang-(1-7) antagonist, for an additional 2 hours (n=6); and (4) A-779 for 2 hours, followed by A-779 combined with ramiprilat for an additional 2 hours (n=5). Intracerebroventricular infusion of ramiprilat produced an important increase (≈40%) in baroreflex sensitivity (evaluated as the ratio between changes in heart rate and changes in mean arterial pressure) that was completely reversed by A-779. Furthermore, intracerebroventricular infusion of A-779 prevented the improvement of the baroreflex sensitivity produced by ramiprilat. Intracerebroventricular infusion of saline or A-779 alone did not significantly alter the baroreflex sensitivity. These results suggest that endogenous Ang-(1-7) is involved in the improvement of baroreflex sensitivity observed in spontaneously hypertensive rats during central ACE inhibition.