bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Hypertension Directly Impairs Endothelium-Dependent Vasodilation of the Human Microvasculature
Authors: Paniagua Oscar A. , Bryant Melissa B. , Panza Julio A.
Published: June 2012

Abstract
—Hypertension is associated with decreased endothelium-dependent vasodilation. However, whether endothelial dysfunction is a cause or a consequence of elevated blood pressure is unknown. Therefore, to determine whether hypertension can directly induce endothelial dysfunction, we investigated the effect of increases in intra-arterial pressure on endothelium-dependent vasodilation of the human microvasculature. Small arteries (internal diameter 202±75 μm) were isolated from gluteal fat biopsies in 12 healthy normotensive subjects (8 men and 4 women; age, 46±10 years). Arteries were cannulated and perfused in chambers oxygenated at 37°C. Endothelium-dependent and -independent responses to acetylcholine (Ach; 10
−
9
to 10
−
4
mol/L) and sodium nitroprusside (SNP; 10
−
9
to 10
−
4
mol/L), respectively, were obtained after incubating the vessel with incremental intravascular pressures of 50, 80, and 120 mm Hg for 60 minutes each. The response to Ach was also obtained in different arteries after 3 consecutive incubation periods at 50 mm Hg. Arterial internal diameter was measured directly from amplified digital images. A significant reduction in the vasodilator response to Ach was observed with increases in intravascular pressure (mean vasodilation, 62%, 49%, and 26% at 50, 80, and 120 mm Hg, respectively;
P
<0.001). In contrast, the response to SNP showed a nonsignificant trend toward greater vasodilation with increases in pressure (mean vasodilation, 40%, 52%, and 57% at 50, 80, and 120 mm Hg, respectively;
P
=0.10). There was no difference in the consecutive dose-response curves to Ach obtained at the same intravascular pressure (mean vasodilation: 48%, 46%, and 49%;
P
=0.61). Transient increases in intravascular pressure significantly depress endothelium-dependent vasodilation in human resistance arteries. These findings suggest that elevated blood pressure per se may cause endothelial dysfunction in humans and have implications for the pathophysiology of endothelial dysfunction in hypertension.
α-Adducin and Angiotensin I–Converting Enzyme Polymorphisms in Essential Hypertension
Authors: Clark Catherine J. , Davies Eleanor , Anderson Niall H. , Farmer Rosemary , Friel Elaine C. , Fraser Robert , Connell John M. C.
Published: June 2012

Abstract
—This study focused on two genes that have previously been implicated in hypertension and may influence renal sodium handling, adducin, and angiotensin I–converting enzyme (ACE). We compared their polymorphic frequencies and interaction in patients with essential hypertension (n=128) and individually age- and gender-matched normotensive control subjects. The α-adducin
G460W
polymorphism was genotyped by DNA amplification and restriction digestion. The
ACE I/D
polymorphism was assayed by a triple-primer method, with a “nested” polymerase chain reaction primer situated completely within the insertion sequence of the
I
allele. The distributions of genotypes and alleles for the two polymorphisms were not significantly different between the case and control populations, and the cross-classification of cases by α-adducin and
ACE
genotype gave a distribution similar to that of control subjects. We have previously reported that the distributions of genotypes for two linked polymorphisms in the aldosterone synthase gene (one in the steroidogenic factor-1
[SF-1]
binding site and the other an intronic conversion
[IC]
) were significantly different between this cohort of essential hypertensives and matched control subjects. The cross-classification of cases by α-adducin and
SF-1,
α-adducin and
IC, ACE
and
SF-1,
and
ACE
and
IC
genotype gave a distribution similar to that of control subjects. Hence, no evidence was found to suggest an association between either the α-adducin
G460W
or the
ACE I/D
polymorphism and hypertension in a careful case-control study. Furthermore, the α-adducin
G460W, ACE I/D,
and aldosterone synthase
SF-1
and
IC
polymorphisms do not appear to interact in our hypertensive population.
Adrenomedullin Gene Delivery Attenuates Hypertension, Cardiac Remodeling, and Renal Injury in Deoxycorticosterone Acetate-Salt Hypertensive Rats
Authors: Dobrzynski Eric , Wang Cindy , Chao Julie , Chao Lee
Published: June 2012

Abstract
—Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide that plays an important role in cardiorenal function. In this study, we explored the potential protective role of AM in volume-dependent hypertension by somatic gene delivery. Adenovirus containing the human AM cDNA under the control of the cytomegalovirus promoter/enhancer was administered into deoxycorticosterone acetate (DOCA)-salt hypertensive rats via tail vein injection. A single injection of the human AM gene resulted in a prolonged reduction of blood pressure with a maximal reduction of 41 mm Hg 9 days after gene delivery. Human AM gene delivery enhanced renal function, as indicated by a 3-fold increase in renal blood flow and a 2-fold increase in glomerular filtration rate (n=5,
P
<0.05). Histological examination of the kidney revealed a significant reduction in glomerular sclerosis, tubular injury, luminol protein cast accumulation, and interstitial fibrosis as well as urinary protein. Human AM gene delivery caused significant decreases in left ventricular weight and cardiomyocyte diameter, which were accompanied by reduced interstitial fibrosis and extracellular matrix formation within the heart. Expression of human AM mRNA was detected in the kidney, adrenal gland, heart, aorta, lung, and liver; immunoreactive human AM levels were measured in urine and plasma. Significant increases in urinary and cardiac cAMP levels were observed in DOCA-salt rats receiving the human AM gene, indicating activation of the AM receptor. These findings showed that AM gene delivery attenuates hypertension, protects against cardiac remodeling and renal damage in volume-overload hypertension, and may have significance in therapeutic applications in cardiovascular and renal diseases.
Evaluating a Model of an NRE Mediated Tissue-Specific Expression of Murine Renin Genes
Authors: Abonia J. Pablo , Howles Philip N. , Abel Kenneth J. , Black Thomas A. , Jones Craig A. , Gross Kenneth W.
Published: June 2012

Abstract
—We have used comparative sequence analysis to evaluate a putative silencer element that has been proposed to be involved in the differential tissue-expression of the murine renin genes:
Ren-1
and
Ren-2
. In the mouse, these genes share a similar pattern of tissue-specific renin expression. One significant difference is seen in the submandibular gland (SMG) where renin expression from the
Ren-2
locus is 100-fold greater than the expression from the
Ren-1
locus. One model proposes that this differential expression arises from the interplay among a negative regulatory element and a cAMP responsive element, their respective binding factors, and the disruption of the negative regulatory element by an insertion (M2) that is found in
Ren-2
but not in
Ren-1
. The abrogation of the negative regulatory element’s function as a result of the M2 insertion was proposed to be specifically responsible for the higher level of
Ren-2
expression in the SMG as compared with
Ren-1
. We have assessed this hypothesis by looking at an allelic variant in the closely related mouse species
M. hortulanus
. This species shares the same high level of
Ren-2
expression in the SMG as seen in other
Ren-2
positive mouse strains. However, the
Ren-2 M. hortulanus
allele does not appear to contain the disruptive M2 element according to restriction-enzyme mapping. Our sequence analysis confirms that the
M. hortulanus Ren-2
allele contains the same sequence elements present in the DBA/2
Ren-2
allele except for the M2 element. Moreover, the proposed negative regulatory element is intact at the sequence level in
Ren-2
M. hortulanus
allele. This analysis suggests that any involvement of the negative regulatory element in differential
Ren-1
and
Ren-2
expression in the SMG is not as straightforward as previously hypothesized.
Antibodies to Lysophosphatidylcholine Are Decreased in Borderline Hypertension
Authors: Wu Ruihua , Lemne Carola , de Faire Ulf , Frostegård Johan
Published: June 2012

Abstract
—Atherosclerosis is characterized by infiltration in the lesions of cytokine-producing T cells and macrophages, where oxidized LDL may play an important role. However, little is known about the role of the immune system in the development of hypertension. Lysophosphatidylcholine (LPC) is formed by phospholipase A
2
–induced hydrolysis and/or by oxidation of LDL and other phospholipid-containing membranes. The objective of the present study was to investigate the role of antibodies to LPC in borderline hypertension (BHT). Seventy-five men with BHT were compared with 75 age-matched normotensive (NT) men (diastolic blood pressure 85 to 94 and <80 mm Hg, respectively). Antibody levels to LPC of IgM and IgG isotypes and IgG subclasses were determined with ELISAs. BHT men had significantly lower anti-LPC antibody levels of both IgG class (
P
=0.0002) and IgM class (
P
=0.0003) than did NT controls. Subclass analysis indicated that IgG
1
(
P
=0.0005), but not IgG
2
, was decreased. Anti-LPC antibodies or immunoglobulin subclasses thereof were negatively associated with atherosclerosis on the basis of intima-media thickness (
P
=0.02), metabolic factors (
P
=0.02), smoking (
P
=0.02), and endothelin (
P
=0.03). LPC has proinflammatory properties and is toxic at higher concentrations and thus may play a role in atherogenesis. Furthermore, LPC functions as a vasoconstrictor in experimental systems by inhibiting NO-mediated vasorelaxation. An intriguing possibility is that anti-LPC antibodies counteract these effects. Taken together, our data indicate that anti-LPC antibodies may constitute a novel factor in the development of hypertension and atherosclerosis.
Hemodynamic Overload–Induced Activation of Myocardial Mitogen-Activated Protein Kinases In Vivo
Authors: Aoyagi Teruhiko , Izumo Seigo
Published: June 2012

Mitogen-activated protein (MAP) kinases have been shown to be activated by various growth factors in cultured or isolated cardiomyocytes. However, little is known about the regulation of MAP kinases in vivo, especially in clinically important conditions, such as hypertension and senescence. In this study, we assessed mechanical overload–induced activation of myocardial MAP kinases in beating hearts from hypertensive or senescent rats. Fifteen minutes of left ventricular hemodynamic overload activated MAP kinase activity by 2.2-fold (
P
<0.05) in 4-week-old Wistar-Kyoto rats. The age-matched spontaneously hypertensive rats had greater MAP kinase activity than did Wistar-Kyoto rats both at baseline (1.4 times,
P
<0.05) and after the hemodynamic overload (1.7 times,
P
<0.05). Myocardial MAP kinase protein level, assessed by Western blot analysis, was also higher (1.6 times,
P
<0.01) in spontaneously hypertensive rats. In contrast, aged (18-month-old) Fischer 344 rats, which were known to have a diminished capacity of hypertrophy in response to mechanical stress, had lower MAP kinase activity both at baseline (63%,
P
<0.01) and after the hemodynamic overload (52%,
P
<0.05). Their MAP kinase protein level was lower (38%,
P
<0.01) than that in young (6-month-old) adults. Alterations in MAP kinase may contribute to changes in hypertrophic response in these animals.
Angiotensin-(1-7)–Stimulated Nitric Oxide and Superoxide Release From Endothelial Cells
Authors: Heitsch Holger , Brovkovych Svitlana , Malinski Tadeusz , Wiemer Gabriele
Published: June 2012

Abstract
—The stimulation of endothelium-dependent NO release by angiotensin-(1-7) [Ang-(1-7)] has been indirectly shown in terms of vasodilation, which was diminished by NO synthase inhibition or removal of the endothelium. However, direct measurement of endothelium-derived NO has not been analyzed. With a selective porphyrinic microsensor, NO release was directly assessed from single primary cultured bovine aortic endothelial cells. Ang-(1-7) caused a concentration-dependent release of NO of 1 to 10 μmol/L, which was attenuated by NO synthase inhibition. [
d
-Ala
7
]Ang-(1-7) (5 μmol/L), described as a selective antagonist of Ang-(1-7) receptors, inhibited Ang-(1-7)–induced NO release only by ≈50%, whereas preincubation of bovine aortic endothelial cells with the angiotensin II subtype 1 and 2 receptor antagonists EXP 3174 and PD 123,177 (both at 0.1 μmol/L) led to an inhibition of 60% and 90%, respectively. A complete blockade of the Ang-(1-7)–induced NO release was observed on preincubation of the cells with 1 μmol/L concentration of the bradykinin subtype 2 receptor antagonist icatibant (HOE 140), suggesting an important role of local kinins in the action of Ang-(1-7). Simultaneous direct measurement of superoxide (O
2
−
) detected by an O
2
−
-sensitive microsensor revealed that the moderately Ang-(1-7)–stimulated NO release was accompanied by a very slow concomitant O
2
−
production with a relative low peak concentration in comparison to the O
2
−
production of the strong NO releasers bradykinin and, especially, calcium ionophore. Thus, Ang-(1-7) might preserve the vascular system, among others, due to its low formation of cytotoxic peroxynitrite by the reaction between NO and O
2
−
.
Exercise Intolerance in Rats With Hypertensive Heart Disease Is Associated With Impaired Diastolic Relaxation
Authors: Guazzi Marco , Brenner Daniel A. , Apstein Carl S. , Saupe Kurt W.
Published: June 2012

Abstract
—A decrease in functional capacity is one of the most important clinical manifestations of hypertensive heart disease, but its cause is poorly understood. Our purpose was to evaluate potential causes of hypertension-induced exercise intolerance, focusing on identifying the type(s) of cardiac dysfunction associated with the first signs of exercise intolerance during the course of hypertensive heart disease. Exercise capacity was measured weekly in Dahl salt-sensitive rats as they developed hypertension as well as in Dahl salt-resistant control rats. Exercise capacity was unchanged from baseline during the first 8 weeks of hypertension, suggesting that hypertension itself did not cause exercise intolerance. After 9 to 12 weeks of hypertension, exercise capacity decreased in salt-sensitive rats but not in control rats. After 10 weeks of hypertension, indices of diastolic function (early truncation of the E wave), as assessed by echocardiography at rest, were decreased in the salt-sensitive rats. When exercise capacity had decreased by ≈25% in a rat, the heart was isolated, and left ventricular (LV) compliance and systolic function were measured. At that time point, LV hypertrophy was modest (an ≈20% increase in LV mass), and systolic function was normal or supernormal, indicating that exercise intolerance began during “compensated” LV hypertrophy. Passive LV compliance remained normal in salt-sensitive rats. Thus, in this model of hypertensive heart disease, exercise intolerance develops during the compensated stage of LV hypertrophy and appears to be due to changes in diastolic rather than systolic function. However, studies in which LV function is assessed during exercise are needed to conclusively define the roles of systolic and diastolic dysfunction in causing exercise intolerance.
Mortality After Coronary Artery Occlusion in Different Models of Cardiac Hypertrophy in Rats
Authors: Leenen Frans H. H. , Yuan Baoxue
Published: June 2012

Chronic treatment with minoxidil induces cardiac trophic and sympathetic responses, which may increase the propensity for lethal arrhythmias. To test this hypothesis, acute coronary artery occlusion was performed in conscious normotensive rats treated for 2 or 5 weeks with minoxidil with the use of a 2-stage approach to cause a myocardial infarction. For comparison, rats with aortocaval (A-V) shunts and spontaneously hypertensive rats (SHR) were studied. Minoxidil increased left ventricular and right ventricular weights by 15% to 20%, and the A-V shunt increased these weights by 30% to 40%. In SHR, left ventricular weight was increased by 50%, and right ventricular weight was increased by 25%. In rats treated with minoxidil for 5 weeks, coronary artery occlusion caused a rapid and marked mortality, and 4 hours after myocardial infarction, only 18% of these rats were alive versus 61% of the control rats. In rats with the A-V shunt, coronary artery occlusion was also associated with increased mortality, and after 6 hours, 33% were still alive compared with 59% of the control rats. In contrast, SHR with marked hypertension and cardiac hypertrophy showed only a minor increase in mortality (survival rates were 53% versus 60% in SHR versus Wistar-Kyoto rats, respectively). Mortality was preceded by high arrhythmia scores, and ventricular fibrillation was the cause of death. Discontinuation of minoxidil for 1 week, sympathetic blockade with nadolol or clonidine, or blockade of the renin-angiotensin system with enalapril or losartan did not improve minoxidil-induced excess mortality. We conclude that ventricular stretch and other mechanisms (eg, cardiac vagal activity) in rats appear to be more potent than hypertension-induced left ventricular hypertrophy in predisposing for lethal arrhythmias in the setting of acute ischemia.
Structural Vascular Changes in Hypertension
Authors: Simon Geza , Illyes Gyorgy
Published: June 2012

Elevated circulating angiotensin (Ang) II levels, dietary sodium, and sympathetic stimulation are recurrent themes of hypertension research, but their in vivo interaction in physiologically meaningful doses has not been adequately investigated. In this study, the interaction of a subpressor dose of Ang II (50 ng · kg
−1
· min
−1
SC), 2% NaCl diet, and sympathetic stimulation in the form of overnight cold exposure was investigated in the development of hypertension and of structural vascular changes in male Sprague-Dawley rats. There were 8 experimental groups: sham operation and treatment (control), Ang II, 2% NaCl diet, cold exposure (5°C), Ang II plus 2% NaCl diet, Ang II plus cold exposure, cold exposure plus 2% NaCl diet, and Ang II plus 2% NaCl diet plus cold exposure (triple treatment). For each group, the duration of treatment was 12 weeks. Morphometric measurements of maximally dilated, in situ fixed, second-order (250 to 320 μm OD), intermediate-size (100 to 150 μm OD), and small (50 to 100 μm OD) mesenteric arteries were performed, and wall-to-lumen ratios (W/L) were calculated. During the 12-week study, the blood pressure (BP) load (the area under the systolic BP curve) of rats receiving the combined treatment of Ang II and 2% NaCl diet was increased (
P
<0.05), and that of rats receiving the combined treatment of cold exposure and 2% NaCl diet was decreased (
P
<0.05); there were no BP changes in the remaining groups of rats. The most pronounced changes among groups occurred in W/L of small resistance arteries. The W/L of small arteries increased in Ang II–treated (
P
<0.01) and in cold-stressed rats (
P
<0.01). The effect of Ang II was potentiated by the addition of a 2% NaCl diet. In contrast, the addition of 2% NaCl diet to cold stress reduced the W/L of small arteries (
P
<0.01). No other positive or negative synergism occurred among groups, including the rats receiving triple treatment. The findings confirm the potentiation of the hypertensinogenic and vascular trophic effects of Ang II by a high-sodium diet but do not provide evidence for synergism between Ang II and sympathetic stimulation. The finding of hypotension and reduced W/L of small resistance arteries in rats receiving the combined treatment of cold stress and high-sodium diet is unique because there are few known nonpharmacological vascular “hypotrophic” stimuli. The ultimate test of the hypertensinogenic potential of pressor stimuli alone or in combination is their long-term administration in physiologically meaningful doses to experimental animals.
Attenuation of Hypertension and Heart Hypertrophy by Adeno-Associated Virus Delivering Angiotensinogen Antisense
Authors: Kimura Birgitta , Mohuczy Dagmara , Tang Xiaoping , Phillips M. Ian
Published: June 2012

Angiotensinogen (AGT), one of the major components in the renin-angiotensin system, has been linked to hypertension in humans and animals. We have previously systemically administered antisense oligonucleotides and plasmid vectors with DNA that targeted AGT and attenuated hypertension in spontaneously hypertensive rats. The aim of the present study was to prolong the effect of antisense treatment by the use of a recombinant adeno-associated viral (rAAV) vector targeted to AGT. Using a model of lifelong hypertension in which 5-day-old spontaneously hypertensive rats are treated, a single intracardiac injection of rAAV-AGT-antisense (rAAV-AGT-AS) delayed the onset of hypertension for 91 days and significantly attenuated hypertension in adulthood for up to 6 months. Systolic blood pressure was always lower, by up to 23 mm Hg in the AS-treated group. The vector was stable and expressed a reporter gene in liver, kidney, and heart. The rAAV-AGT-AS treatment significantly decreased left ventricular hypertrophy (
P
=0.01) and also lowered levels of AGT in the liver (2.78±0.61 μg/g tissue versus 5.23±0.41 μg/g tissue for the sense-treated group,
P
<0.01). Measurement of liver transaminases showed no evidence for liver toxicity. We conclude that rAAV-AGT-AS offers a safe, stable approach for gene therapy of hypertension.
Renin Gene Transfer Restores Angiogenesis and Vascular Endothelial Growth Factor Expression in Dahl S Rats
Authors: Amaral Sandra L. , Roman Richard J. , Greene Andrew S.
Published: June 2012

In a previous study, we demonstrated that Dahl S rats (SS group) have low plasma renin activity, whereas transfer of a region of chromosome 13 containing the renin gene from Dahl R onto a congenic strain of Dahl SS/Jr/Hsd/MCW rats (S/ren

RR

group) restores renin secretory responses. In the present study, we compared the angiogenic responses to electrical stimulation in the SS and S/ren

RR

groups to explore the hypotheses that the renin-angiotensin system is involved in vascular endothelial growth factor (VEGF) expression and angiogenesis in skeletal muscle. Congenic SS and S/ren

RR

rats fed a 0.4% or 4% salt diet were surgically prepared by chronic implantation of an electrical stimulator. Another group of S/ren

RR

rats was treated with lisinopril 2 days before the surgery and throughout the stimulation protocol. The right tibialis anterior (TA) and extensor digitorum longus (EDL) were stimulated for 8 hours per day for 7 days. The contralateral muscles served as controls. Western blot analysis was performed to identify VEGF protein expression in these muscles. Electrical stimulation produced no change in vessel density of the SS group fed a 0.4% salt diet (change 5.50% and 8.14% for EDL and TA, respectively). Transfer of a region containing the renin gene restored the angiogenic response (change 16% and 30% for EDL and TA, respectively) despite a significantly higher blood pressure. Blockade of the renin-angiotensin system by lisinopril or high salt restored the responses observed in the SS group fed a low salt diet. In addition, increases in VEGF expression to electrical stimulation were observed only in the S/ren

RR

group fed a low salt diet. These results suggest that renin gene transfer restores angiogenesis and VEGF expression in the skeletal muscle of Dahl S rats.
Sodium-Lithium Countertransport Activity Is Linked to Chromosome 5 in Baboons
Authors: Kammerer Candace M. , Cox Laura A. , Mahaney Michael C. , Rogers Jeffrey , Shade Robert E.
Published: June 2012

The genes involved in the regulation of cellular sodium transport characteristics, which are correlated with some forms of essential hypertension, have not yet been identified. We are studying the genes and environmental factors that affect red blood cell sodium-lithium countertransport (SLC) activity and intracellular sodium (ICNa) concentration in 634 baboons that comprise 11 pedigrees of 2 and 3 generations each. To detect and locate possible quantitative trait loci (QTLs) that affect SLC activity and ICNa concentration, we performed a genome screen by using a maximum likelihood–based variance-components linkage analysis program (SOLAR). SLC and ICNa phenotypes as well as genotypes on 281 microsatellite loci were available for all pedigreed animals. Both SLC and ICNa traits were highly heritable (residual heritability 0.593±0.083 [
P
<0.0001] and 0.739±0.082 [
P
<0.0001], respectively). We obtained evidence that a possible QTL for SLC activity is located on the baboon homologue of human chromosome 4 between D4S2456 and D4S2365 with a maximum multipoint lod score of 9.3 (
P
<10
−
10
) near D4S1645. This QTL accounts for approximately two thirds of the total additive genetic variation in SLC activity in baboons. Although ICNa concentration was highly heritable, we found no evidence for linkage to a QTL with use of this methodology. Thus, we have evidence that a gene located on the baboon homologue of human chromosome 4 (baboon chromosome 5) affects cell sodium transport in baboons.
Epoxyeicosatrienoic Acid–Mediated Renal Vasodilation to Arachidonic Acid Is Enhanced in SHR
Authors: Pomposiello Silvia I. , Carroll Mairead A. , Falck John R. , McGiff John C.
Published: June 2012

We tested the hypothesis that cyclooxygenase-independent vasodilation produced by arachidonic acid (AA) is mediated by epoxyeicosatrienoic acids (EETs) and is blunted in the spontaneously hypertensive rat (SHR). At normal perfusion pressure (PP; 70 to 90 mm Hg), AA constricted the renal vasculature in both SHR and normotensive Wistar-Kyoto rats, an effect abolished by cyclooxygenase inhibition, and converted to vasodilation when PP was raised to ≈200 mm Hg. Unexpectedly, renal vasodilation elicited by AA was greater in the SHR at high PP; for example, 2.5, 5, and 10 μg of AA produced PP declines of 54±9, 92±10, and 112±5 mm Hg, respectively, in SHR compared with 26±3, 45±5, and 77±6 mm Hg in Wistar-Kyoto rats (
P
<0.01). However, the renal vasodilator responses to acetylcholine (0.1 μg) and sodium nitroprusside (1 μg) did not differ between strains, indicating that vascular responsiveness to AA was independent of intrinsic changes in vascular smooth muscle. Hyperresponsiveness of the renal vasculature to AA may be unique for the SHR, because it did not occur in Sprague-Dawley rats with angiotensin II–induced hypertension. 5,8,11,14-Eicosatetraynoic acid (ETYA; 4 μmol/L), an inhibitor of all AA pathways, attenuated the vasodilator responses to AA, as did treatment with stannous chloride, which depletes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA metabolite mediated the renal vasodilation.
N
-Methylsulfonyl-12,12-dibromododec-11-en-amide (DDMS; 2 μmol/L), a selective ω-hydroxylase inhibitor, did not affect AA-induced vasodilation, whereas selective inhibition of epoxygenases with either miconazole (0.3 μmol/L) or
N
-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH; 12 μmol/L) did, indicating that one or more EETs were involved in the renal vasodilator action of AA at high PP. This conclusion was supported by the demonstration that AA greatly enhanced the renal efflux of EETs at high PP but not at basal PP.
Determinants of Spontaneous Baroreflex Sensitivity in a Healthy Working Population
Authors: Kardos Attila , Watterich Gusztáv , de Menezes Renee , Csanády Miklós , Casadei Barbara , Rudas László
Published: June 2012

Baroreflex sensitivity (BRS) by the spontaneous sequence technique has been widely used as a cardiac autonomic index for a variety of pathological conditions. However, little information is available on determinants of the variability of spontaneous BRS and on age-related reference values of this measurement in a healthy population. We evaluated BRS as the slope of spontaneous changes in systolic blood pressure (BP) and pulse interval from 10 minutes BP (Finapres) and ECG recordings in 1134 healthy volunteers 18 to 60 years of age. Measurement of BRS could be obtained in 90% of subjects. Those with unmeasurable spontaneous BRS had a slightly lower heart rate but were otherwise not different from the rest of the population. BRS was inversely related to age (lnBRS, 3.24−0.03×age;
r
2
=0.23;
P
<0.0001) in both genders. In addition, univariate analysis revealed a significant inverse correlation between BRS and heart rate, body mass index, and BP. Sedentary lifestyle and regular alcohol consumption were also associated with lower BRS. However, only age, heart rate, systolic and diastolic BP, body mass index, smoking, and gender were independent predictors of BRS in a multivariate model, accounting for 47% of the variance of BRS. The present study provides reference values for spontaneous BRS in a healthy white population. Only approximately half of the variability of BRS could be explained by anthropometric variables and common risk factors, which suggests that a significant proportion of interindividual differences may reflect genetic heterogeneity.
Adenosine, a Metabolic Trigger of the Exercise Pressor Reflex in Humans
Authors: Costa Fernando , Diedrich Andre , Johnson Benjamin , Sulur Paulgun , Farley Ginnie , Biaggioni Italo
Published: June 2012

There is substantial evidence that adenosine activates muscle afferent nerve fibers leading to sympathetic stimulation, but the issue remains controversial. To further test this hypothesis, we used local injections of adenosine into the brachial artery while monitoring systemic muscle sympathetic nerve activity (MSNA) with peroneal microneurography. The increase in MSNA induced by 3 mg intrabrachial adenosine (106±32%) was abolished if forearm afferent traffic was interrupted by axillary ganglionic blockade (21±19%, n=5,
P
<0.05). Furthermore, the increase in MSNA induced by intravenous adenosine was 3.7-fold lower and later (onset latency 20.9±4.8 seconds versus 8.5±1 seconds) than intrabrachial adenosine. Finally, we used forearm exercise (dynamic handgrip at 50% and 15% maximal voluntary contraction, MVC), with or without superimposed ischemia, to modulate interstitial levels of adenosine (estimated with microdialysis) while monitoring MSNA. Fifteen minutes of intense (50% MVC) and moderate (15% MVC) exercise increased adenosine dialysate concentrations from 0.31±0.1 to 1.24±0.4 μmol/L (528±292%) and from 0.1±0.02 to 0.419±0.16 μmol/L (303±99%), respectively (n=7,
P
<0.01). MSNA increased 88±25% and 38±28%, respectively. Five minutes of moderate exercise increased adenosine from 0.095±0.02 to 0.25±0.12 μmol/L, and from 0.095±0.02 to 0.48±0.19 μmol/L when ischemia was superimposed on exercise (n=7,
P
=0.01). The percent increase in MSNA induced by the various interventions correlated with the percent increase in dialysate adenosine levels (
r
=0.96). We conclude that adenosine activates muscle afferent nerves, triggering reflex sympathetic activation.
Leptin Acts in the Central Nervous System to Produce Dose-Dependent Changes in Arterial Pressure
Authors: Correia Marcelo L. G. , Morgan Donald A. , Sivitz William I. , Mark Allyn L. , Haynes William G.
Published: June 2012

Systemic leptin increases energy expenditure through sympathetic mechanisms, decreases appetite, and increases arterial pressure. We tested the hypothesis that the pressor action of leptin is mediated by the central nervous system. The interaction of dietary salt with leptin was also studied. Leptin was infused for 2 to 4 weeks into the third cerebral ventricle of Sprague-Dawley rats. Arterial pressure was measured by radiotelemetry. To control for the effects of leptin on body weight, vehicle-treated rats were pair-fed to the leptin group. Intracerebroventricular infusion of leptin at 200 ng/h in salt-depleted rats caused a reduction in food intake, weight loss, tachycardia, and decreased arterial pressure. Leptin at 1000 ng/h caused further reduction in food intake, weight loss, and tachycardia and prevented the hypotensive effect of weight loss observed in pair-fed, vehicle-treated animals. Intracerebroventricular leptin at 1000 ng/h in high-salt–fed rats also caused a sustained pressor response (+3±1 mm Hg), but high-salt intake did not potentiate the pressor effect of leptin. Intracerebroventricular leptin potentiated the pressor effect of air-jet stress. Intravenous administration of the same dose of leptin (1000 ng/h) did not change weight or arterial pressure, suggesting a direct central nervous system action. In contrast, a high dose of intravenous leptin (18 000 ng/h) caused weight loss and prevented the depressor effect of weight loss. In conclusion, this study demonstrates that high-dose leptin increases arterial pressure and heart rate through central neural mechanisms but leptin does not enhance salt sensitivity of arterial pressure. Leptin appears to oppose the depressor effect of weight loss.
Ascorbic Acid–Induced Modulation of Venous Tone in Humans
Authors: Grossmann Matthias , Dobrev Dobromir , Himmel Herbert M. , Ravens Ursula , Kirch Wilhelm
Published: June 2012

Ascorbic acid appears to have vasodilatory properties, but the underlying mechanisms are not well understood. The aims of this study were to define the acute effects of locally infused ascorbic acid in human veins and to explore underlying mechanisms by using pharmacological tools in vivo. Ascorbic acid was infused in dorsal hand veins submaximally preconstricted with the α
1
-adrenoceptor agonist phenylephrine or with prostaglandin F
2α
in 23 healthy male nonsmokers, and the venodilator response was measured. Ascorbic acid produced dose-dependent dilation with maximum reversal of constriction of 38±4% in phenylephrine-preconstricted veins and of 51±13% in prostaglandin F
2α
–preconstricted veins. Oral pretreatment with the cyclooxygenase inhibitor acetylsalicylic acid or local coinfusion of ascorbic acid and the nitric oxide synthase inhibitor
N
G
-monomethyl-
l
-arginine had no effect, but coinfusion of ascorbic acid and methylene blue (to inhibit cGMP generation) abolished venodilation. Coinfusion of ascorbic acid and the nonselective potassium channel blocker quinidine abolished venodilation, whereas the inhibitor of ATP-dependent potassium channels glibenclamide had no effect. In cultured bovine endothelial cells, ascorbic acid did not affect intracellular calcium concentration but blunted the response to ATP or digitonin exposure. Ascorbic acid, in millimolar concentrations, dilates human hand veins, presumably by activation of vascular smooth muscle potassium channels through cGMP. This activation is independent of eNOS-mediated nitric oxide synthesis and cyclooxygenase products and does not involve ATP-dependent potassium channels.
Src Tyrosine Kinases and Extracellular Signal–Regulated Kinase 1/2 Mitogen-Activated Protein Kinases Mediate Pressure-Induced C-Fos Expression in Cannulated Rat Mesenteric Small Arteries
Authors: Wesselman Jos P. M. , Dobrian Anca D. , Schriver Suzanne D. , Prewitt Russell L.
Published: June 2012

Chronic hypertension is associated with remodeling of small arteries. There is evidence that the high pressure itself may cause these structural changes, but the responsible mechanisms are not clearly defined. Previously we showed that pressure-induced c-fos expression in intact cannulated rat mesenteric small arteries was inhibited by genistein, a general tyrosine kinase inhibitor. The purpose of this study was to further unravel the underlying signal transduction mechanisms, and we particularly tested the involvement of src tyrosine kinases and extracellular signal–regulated kinase (ERK). Rat mesenteric small arteries were cannulated in a dual-vessel chamber. After a 60-minute equilibration period, the pressure in 1 artery was increased to 140 mm Hg, while the other artery remained at 90 mm Hg. Semiquantitative reverse transcriptase–polymerase chain reaction was used to determine c-fos expression, and Western blotting was used to examine levels of ERK phosphorylation. The involvement of src and ERK was tested with the inhibitors herbimycin A (1 μmol/L), PP1 (10 μmol/L), PP2 (10 μmol/L), and PD98059 (30 μmol/L). One-hour exposure to 140 mm Hg increased the c-fos/cyclophilin ratio 3.6-fold, from 0.29±0.07 to 1.06±0.25. All the tested inhibitors suppressed the pressure-induced increase of c-fos expression. A 5-minute exposure period to 140 mm Hg increased ERK phosphorylation, and this was abolished in the presence of PP1. The results suggest that pressure-induced c-fos expression in intact cannulated rat mesenteric small arteries may be mediated, at least in part, by src tyrosine kinases and ERK.
Silent ST Depression and Cardiovascular End-Organ Damage in Newly Found, Older Hypertensives
Authors: Terpstra Willem F. , May Johan F. , Smit Andries J. , de Graeff Pieter A. , Schuurman Frits H. , Jong Betty Meyboom-de , Crijns Harry J. G. M.
Published: June 2012

Abstract
—In hypertension, both reduced vascular supply and increased cardiac demand contribute to the development of (silent) myocardial ischemia. Our aim was to determine the prevalence of ST-segment depression and to analyze contributing factors in asymptomatic, previously untreated, older hypertensives. From a population survey, in 184 patients with mild hypertension (4 times systolic blood pressure ≥160 mm Hg and/or diastolic blood pressure ≥95 mm Hg), 60 to 75 years of age, cardiovascular end-organ damage was measured. Episodes of ST-segment depression were measured by 48-hour ambulatory Holter monitoring and were observed in 21 hypertensives (12%). They showed a significantly higher combined far-wall intima-media thickness of carotid and femoral arteries and more arterial plaques as measured by B-mode ultrasound compared with hypertensives without ST depression (0.00098±0.00021 versus 0.00088±0.00016 mm and 5.2±3.7 versus 3.7±2.8 plaques,
P
<0.05, respectively), whereas left ventricular mass index was not different (111±18 versus 104±24 g/m
2
;
P
=0.18, respectively). In hypertensives with transient ST-segment depression, a significant relation was found between left ventricular mass and ischemic burden (
r
=0.51,
P
=0.02). Approximately 1 of 8 unselected and previously untreated older hypertensives show asymptomatic ST-segment depression, suggestive of silent myocardial ischemia. These data suggest that vascular factors mainly determine the occurrence of ischemic ST-segment depression and cardiac factors determine the ischemic burden in older hypertensives.
Y-Chromosome Transfer Induces Changes in Blood Pressure and Blood Lipids in SHR
Authors: Kren Vladimir , Qi Nianning , Krenova Drahomira , Zidek Vaclav , Sladká Milada , Jáchymová Marie , Míková Blanka , Horky Karel , Bonne Anita , Van Lith Hein A. , Van Zutphen Bert F. M. , Lau Yun-Fai Chris , Pravenec Michal , St. Lezin Elizabeth
Published: June 2012

Abstract
—Previous studies with chromosome-Y consomic strains of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats suggest that a quantitative trait locus for blood pressure regulation exists on chromosome Y. To test this hypothesis in the SHR–Brown Norway (BN) model and to study the effects of chromosome Y on lipid and carbohydrate metabolism, we produced a new consomic strain of SHR carrying the Y chromosome transferred from the BN rat. We found that replacing the SHR Y chromosome with the BN Y chromosome resulted in significant decreases in systolic and diastolic blood pressures in the SHR.BN-Y consomic strain (
P
<0.05). To elicit possible dietary-induced variation in lipid and glucose metabolism between the SHR progenitor and chromosome-Y consomic strains, we fed rats a high-fructose diet for 15 days in addition to the normal diet. On the high-fructose diet, the SHR.BN-Y consomic rats exhibited significantly increased levels of serum triglycerides and decreased levels of serum HDL cholesterol versus the SHR progenitor rats. Glucose tolerance and insulin/glucose ratios, however, were similar in both strains on both normal and high-fructose diets. These findings provide direct evidence that a gene or genes on chromosome Y contribute to the pathogenesis of spontaneous hypertension in the SHR-BN model. These results also indicate that transfer of the Y chromosome from the BN rat onto the SHR background exacerbates dietary-induced dyslipidemia in SHR. Thus, genetic variation in genes on the Y chromosome may contribute to variation in blood pressure and lipid levels and may influence the risk for cardiovascular disease.
Decreased Renal Expression of Nitric Oxide Synthase Isoforms in Adrenocorticotropin-Induced and Corticosterone-Induced Hypertension
Authors: Lou Yi-kun , Wen Cheng , Li Ming , Adams David J. , Wang Min-xia , Yang Feng , Morris Brian J. , Whitworth Judith A.
Published: June 2012

Abstract
—Administration of adrenocorticotropic hormone (ACTH) leads to the development of hypertension. Because glucocorticoids can affect the nitric oxide system at several sites, the present study tested the hypothesis that nitric oxide synthase (NOS) expression may be altered in ACTH-induced and corticosterone-induced hypertension in the rat. This was addressed by measuring
Nos1
,
Nos2
, and
Nos3
mRNA in the kidney, adrenal gland, heart, and hypothalamus of 16 ACTH-treated and 16 vehicle-treated rats as well as in 10 corticosterone-treated and 10 control rats. In addition, in situ hybridization and immunohistochemistry were used to confirm changes by detection of
Nos
in RNA and NOS protein in tissues. Systolic blood pressure of ACTH and corticosterone rats was elevated (165±6 and 162±11 mm Hg;
P
<0.001 versus control). Each
Nos
isoform mRNA was measured by reverse transcriptase-polymerase chain reaction technique. In ACTH rats, mRNA for
Nos2
was reduced in renal cortex by 58±5% and in medulla by 68±7%; for
Nos3
, mRNA reductions of 59±6% and 51±11% were seen (
P
<0.001 after Hochberg correction for multiple comparisons). In corticosterone rats,
Nos2
mRNA decreased in cortex by 68±5% and in medulla by 62±6%;
Nos3
mRNA by 50±8% in cortex, and
Nos1
by 29±7% in medulla (all
P
<0.001 after Hochberg correction). Reductions seen in kidney were supported by in situ hybridization and immunohistochemistry. Apart from a 62±2% decrease in
Nos2
mRNA in adrenal of ACTH rats (corrected
P
<0.05), no significant changes were seen in the other nonrenal tissues for any isoform. In conclusion, we have shown for the first time that the physiological components of glucocorticoid action (ACTH and corticosterone) when given chronically in vivo reduce
Nos2
and
Nos3
expression in the kidney. Such changes are consistent with a role in hypertension for ACTH and corticosterone.
Angiotensin Type 1 Receptor Antagonism and ACE Inhibition Produce Similar Renoprotection in
N

ω

-Nitro-
l
>-Arginine Methyl Ester/Spontaneously Hypertensive Rats
Authors: Nakamura Yasuyuki , Ono Hidehiko , Zhou Xiaoyan , Frohlich Edward D.
Published: June 2012

Abstract
—This study was conducted to determine potentially differential effects between an angiotensin II type 1 (AT
1
) receptor antagonist and an ACE inhibitor on systemic, renal, and glomerular hemodynamics and pathological changes in spontaneously hypertensive rats (SHR) with
N

ω

-nitro-
l
>-arginine methyl ester (L-NAME)–exacerbated nephrosclerosis. The hemodynamic, renal micropuncture, and pathological studies were performed in 9 groups of 17-week-old male SHR treated as follows: group 1, controls (n=16); group 2, candesartan (10 mg/kg per day for 3 weeks) (n=7); group 3, enalapril (30 mg/kg per day for 3 weeks) (n=8); group 4, candesartan (5 mg/kg per day) plus enalapril (15 mg/kg per day for 3 weeks) (n=9); group 5, L-NAME (50 mg/L in drinking water for 3 weeks) (n=17); group 6, L-NAME (50 mg/L) plus candesartan (10 mg/kg per day for 3 weeks) (n=7); group 7, L-NAME (50 mg/L) for 3 weeks followed by candesartan (10 mg/kg per day) for another 3 weeks (n=8); group 8, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day for 3 weeks) (n=7); and group 9, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day) and the bradykinin antagonist icatibant (500 μg/kg SC per day via osmotic minipump for 3 weeks) (n=7). Both candesartan and enalapril similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances as well as glomerular capillary pressure. Histopathologically, the glomerular and arterial injury scores were decreased significantly, and left ventricular and aortic masses also were diminished significantly in all treated groups. L-NAME–induced urinary protein excretion was prevented by both candesartan and enalapril. Thus, both AT
1
receptor and ACE inhibition prevented and reversed the pathophysiological alterations of L-NAME–exacerbated nephrosclerosis in SHR. Itatibant only blunted the antihypertensive effects of enalapril but did not attenuate the beneficial effects of ACE inhibition on the L-NAME–induced nephrosclerosis. Thus, the AT
1
receptor antagonism and ACE inhibition have similar renal preventive effects, which most likely were achieved through reduction in the effects of angiotensin II, and ACE inhibition of bradykinin degradation demonstrated little evidence of renoprotection.
Comparative Effects of Selective T- and L-Type Calcium Channel Blockers in the Remnant Kidney Model
Authors: Griffin Karen A. , Picken Maria , Bakris George L. , Bidani Anil K.
Published: June 2012

Abstract
—We have previously reported that the dihydropyridine L-type calcium channel blockers (CCBs) have an adverse impact on glomerulosclerosis (GS) in the remnant kidney model despite significant blood pressure (BP) reduction, because of the concurrent deleterious effects on renal autoregulation. The effects of the CCB mibefradil, which is ≈10-fold more selective for T- than L-type channels, were compared with the L-type selective amlodipine. One week after 5/6 ablation, rats were left untreated or received mibefradil or amlodipine. Systolic BP was monitored by continuous radiotelemetry. At 7 weeks, proteinuria and percent GS were quantitated. Average BP was significantly and comparably reduced after mibefradil (141±3 mm Hg) and amlodipine (143±5 mm Hg) compared with untreated rats (188±5 mm Hg). Despite the reduction in BP, proteinuria and percent GS in the mibefradil- or amlodipine-treated groups were not significantly different from those in the untreated rats. Excellent correlations were observed between BP and GS in each group (
r
=0.74 to 0.85,
P
<0.02). However, the slope of the relationship between GS and BP (increase in percent GS/mm Hg increase in average BP) was made significantly steeper by both mibefradil (2.7+0.6) and amlodipine (1.9+0.6) as compared with untreated rats (0.7±0.2;
P
<0.01). Thus, at any given BP elevation, greater GS was seen in mibefradil- and amlodipine-treated rats as compared with untreated rats. Additional studies performed at 3 weeks after renal ablation showed that the ability to autoregulate renal blood flow, already impaired in untreated rats, was essentially abolished by both mibefradil and amlodipine, thus providing an explanation for the shift in the slope of the relationship between BP and GS. These data indicate that CCBs with selectivity for either the T- or L-type calcium channel fail to protect against GS despite significant BP reductions because of the similar adverse effects on renal autoregulation and BP transmission.