bluuebunny/crossref_metadata_2025 huggingface dataset:
Prolonged exposure to ouabain eliminates the greater norepinephrine-dependent calcium sensitivity of resistance vessels in spontaneously hypertensive rats.
Authors: Nilsson H , Mulvany M J
Published: June 2012

The effects of 30 minutes of exposure to ouabain on calcium sensitivity have been investigated in two types of resistance vessels from 12 pairs of spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Branches of the superior mesenteric and femoral arteries, with internal diameters of about 200 micrometer, were mounted as ring preparations in a myograph capable of measuring their isometric wall tension. Dose-response curves for calcium upon norepinephrine stimulation were determined under conditions where neuronal uptake was eliminated. Initially, when stimulated with norepinephrine, the SHR vessels from both locations were more sensitive to calcium and had stronger contractions than their controls. The addition of ouabain (1 mM) to the relaxed vessels immediately elicited a moderate, transient contraction in the branches of the femoral artery, whereas no response was observed in the mesenteric vessels. Although the addition of ouabain to activated vessels produced an immediate potentiation of the response, prolonged (30-minute) exposure to ouabain reduced active tension development upon norepinephrine stimulation in all vessels. The reduction was greatest in the SHR vessels, so that, under these conditions, the norepinephrine-activated calcium sensitivity of corresponding SHR and WKY vessels was similar. By contrast, responses to norepinephrine in high potassium solution were unaffected. The results suggest that under normal conditions, SHR vessels may have a specific increase in the permeability of the norepinephrine-activated calcium channels. Prolonged exposure to ouabain appears to reduce the permeability of these channels, providing an explanation for why this treatment eliminates the difference in calcium sensitivity of the SHR and WKY vessels.
Ultraviolet Light May Contribute to Geographic and Racial Blood Pressure Differences
Authors: Rostand Stephen G.
Published: June 2012

Abstract
Mean systolic and diastolic pressures and the prevalence of hypertension vary throughout the world. Published data suggest a linear rise in blood pressure at increasing distances from the equator. Similarly, blood pressure is higher in winter than summer. Blood pressure also is affected by variations in skin pigmentation. Altered calcium, vitamin D, and parathyroid hormone status is associated with hypertension and may vary with latitude and season. Since changes in UV light affect vitamin D and parathyroid hormone status and UV light intensity are influenced by seasonal change and latitude, these disparate observations suggest an association between blood pressure and ultraviolet light. This discussion presents the hypothesis that reduced epidermal vitamin D
3
photosynthesis associated with high skin melanin content and/or decreased UV light intensity at distances from the equator, alone or when coupled with decreased dietary calcium and vitamin D, may be associated with reduced vitamin D stores and increased parathyroid hormone secretion. These changes may stimulate growth of vascular smooth muscle and enhance its contractility by affecting intracellular calcium, adrenergic responsiveness, and/or endothelial function. Thus, UV light intensity and efficiency of epidermal vitamin D
3
photosynthesis may contribute to geographic and racial variability in blood pressure and the prevalence of hypertension.
Angiotensin II Regulates Vascular Smooth Muscle Cell pH, Contraction, and Growth Via Tyrosine Kinase–Dependent Signaling Pathways
Authors: Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Abstract
Angiotensin II (Ang II), a potent vasoactive peptide with mitogenic potential, influences vascular smooth muscle cell contraction and growth through receptor-linked pathways that increase intracellular free Ca
2+
concentration ([Ca
2+
]
i
) and pH (pH
i
). Activation of these second messengers by Ang II may involve tyrosine kinase-dependent signaling pathways. This study determined the role of tyrosine kinases in Ang II–stimulated pH
i
, and in simultaneously measured contractile and [Ca
2+
]
i
responses, as well as growth in cultured vascular smooth muscle cells from mesenteric arteries of Wistar-Kyoto rats. pH
i
was determined by fluorescent digital imaging using 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM). Vascular smooth muscle cell [Ca
2+
]
i
and contractile responses were assessed simultaneously by fura 2 methodology and by photomicroscopy in cells grown on rat tail collagen gels. Cell growth was determined by DNA and protein synthesis as measured by [
3
H]thymidine and [
3
H]leucine incorporation, respectively. The Ang II receptor subtypes (AT
1
or AT
2
) through which Ang II mediates effects were assessed with [Sar
1
,Ile
8
]Ang II (a nonselective subtype antagonist), losartan (a selective AT
1
antagonist), and PD 123319 (a selective AT
2
antagonist). To determine whether tyrosine kinases influence Ang II–stimulated responses, cells were pretreated with 10
−5
mol/L tyrphostin A-23 (a specific tyrosine kinase inhibitor). Ang II increased pH
i
in a dose-dependent manner (pD
2
, 9.2±0.2) and significantly increased vascular smooth muscle cell contraction (30%) and [Ca
2+
]
i
(pD
2
, 7.4±0.1). Ang II (10
−7
mol/L) increased DNA ([
3
H]thymidine incorporation) and protein synthesis ([
3
H]leucine incorporation). [Sar
1
,Ile
8
]Ang II and losartan but not PD 123319 abolished Ang II–elicited responses. Tyrphostin A-23 significantly attenuated Ang II–stimulated pH
i
responses; it also inhibited [Ca
2+
]
i
and contractile responses and cell growth. The inactive analogue tyrphostin A-1 did not alter Ang II–stimulated actions. These results provide novel evidence for a role of tyrosine kinases in Ang II–mediated pH
i
responses in vascular smooth muscle cells and indicate that tyrosine kinases participate in the regulation of signal transduction associated with AT
1
receptor subtype–mediated contraction and growth.
Asp905Tyr Polymorphism of Protein Phosphatase 1 G Subunit Gene in Hypertension
Authors: Shen Gong-Qing , Ikegami Hiroshi , Fujisawa Tomomi , Hamada Yoichi , Kamide Kei , Rakugi Hiromi , Higaki Jitsuo , Murakami Hideyuki , Shimamoto Kazuaki , Ogihara Toshio
Published: June 2012

Abstract
A possible pathogenic polymorphism in the gene for the G subunit of the glycogen-associated regulatory form of protein phosphatase 1 (PP1 G subunit), causing an Asp-to-Tyr substitution at codon 905 (Asp905Tyr), has been reported to be associated with insulin resistance and hypersecretion of insulin in the white population. Since marked heterogeneity has been reported in the association of mutations of candidate genes with essential hypertension between Japanese and other ethnic groups, we investigated the association of Asp905Tyr with essential hypertension in Japanese subjects. The frequency of the Tyr allele in Japanese control subjects (0.70) was much higher than that in the Danish population (0.10,
P
<1×10
−8
), indicating that the Tyr allele, previously reported as a rare variant in white subjects, is a common allele in our population. The genotype distribution in Japanese hypertensive patients (n=109; Asp/Asp=0.09, Asp/Tyr=0.39, Tyr/Tyr=0.52) was not significantly different (χ
2
=0.7,
df
=2,
P
>.6) from that in normotensive control subjects (n=148; Asp/Asp=0.12, Asp/Tyr=0.36, Tyr/Tyr=0.52). Among subjects with different PP1 G subunit genotypes, there was no difference in blood pressure, serum cholesterol, plasma glucose and insulin levels, and glucose disposal rate estimated by the euglycemic hyperinsulinemic clamp test. These data indicate that the Asp905Tyr polymorphism of the PP1 G subunit is not associated with essential hypertension, nor with insulin resistance and/or hyperinsulinemia in Japanese patients with essential hypertension, suggesting that the polymorphism plays little if any role in susceptibility to insulin resistance or hypertension.
Renal Hemodynamic Response to an Angiotensin II Antagonist, Eprosartan, in Healthy Men
Authors: Price Deborah A. , De’Oliveira Jose Mario , Fisher Naomi D. L. , Hollenberg Norman K.
Published: June 2012

Abstract
In view of the vasodilator potential of angiotensin-converting enzyme (ACE) inhibition via prostaglandins and kinins, we asked why renin inhibition induces a larger renal vasodilator response than ACE inhibitors in healthy humans in earlier studies. One possibility was that there was a more complete blockade of the renin system, which could also be achieved by an angiotensin II antagonist, eprosartan. We measured the hormonal and renal hemodynamic responses to eprosartan doses, from 10 to 400 mg in 9 healthy young men in balance on a 10-mmol/d sodium intake. The threshold eprosartan dose to influence renal perfusion was <10 mg, and the 100-mg dose induced a near-maximal vasodilator response of 135±19.7 mL · min
−1
· 1.73 m
2
. When the dose was increased to 400 mg, there was a modest additional increase of 147±57 mL · min
−1
· 1.73 m
–2
. A highly significant dose-related fall in arterial blood pressure occurred (
r
=−.97;
P
<.001), with no indication of a maximal response at 400 mg. In 6 additional subjects, we compared responses to eprosartan on a high salt and a low salt diet. The renal response to 200 mg eprosartan on a high salt diet, 26.0±6.6 mL · min
−1
· 1.73 m
–2
, was significantly less than that seen with the low salt diet (
P
<.001). There was no renal partial agonist angiotensin-like effect of eprosartan. Eprosartan reduced sharply the pressor, renal vascular, and hormonal responses to exogenous angiotensin II. The renal vasodilator response to the angiotensin II antagonist eprosartan closely resembles responses to renin inhibition and exceeds previously reported responses to ACE inhibitors. Thus, eprosartan probably exerted its effect via the angiotensin receptor. More complete blockade of the renin system can be achieved by pharmacological interruption at this level, a finding that could have therapeutic implications.
Stimulation of Imidazoline Receptors Inhibits Proliferation of Human Coronary Artery Vascular Smooth Muscle Cells
Authors: Regunathan Soundararajan , Reis Donald J.
Published: June 2012

Abstract
Vascular smooth muscle cells of rat aorta express imidazoline receptors whose stimulation, by drugs or an endogenous ligand, agmatine, inhibits serum-stimulated proliferation. We investigated whether imidazoline receptors are expressed in human vascular smooth muscle cells if their stimulation is antiproliferative. Cultured human coronary artery vascular smooth muscle cells express a nonadrenergic binding site for
3
H-idazoxan and an imidazoline receptor–binding protein as revealed by immunocytochemical and immunoblot analyses with a specific antibody. Idazoxan and agmatine dose-dependently inhibited serum-stimulated proliferation of these cells as measured by the incorporation of
3
H-thymidine (IC
50
: 5 and 70 μmol/L, respectively) and serum-stimulated expression of proliferating cell nuclear antigen and cell numbers. The agents inhibited proliferation of human and rat (aorta) smooth muscle cells stimulated by either norepinephrine (6560±440 disintegrations per minute norepinephrine versus 3345±220 norepinephrine and idazoxan), angiotensin II (7680±335 disintegrations per minute angiotensin II versus 3769±450 angiotensin II and idazoxan), or platelet-derived growth factor (IC
50
: 3 μmol/L for idazoxan and 40 μmol/L for agmatine), indicating inhibition of mitosis mediated by G-protein or receptor tyrosine kinase pathways. We conclude that human vascular smooth muscle cells express imidazoline-receptors whose activation inhibits proliferation by interacting at a distal step in an intracellular signal cascade common to G-protein and receptor tyrosine kinase mitogenic pathways. Agmatine, synthesized in endothelium, may act as a paracrine regulator of vascular smooth muscle cell proliferation through imidazoline receptors, and agents acting at this site may be useful in treating vascular hyperplasia.
The Effects of Pathophysiological Increments in Brain Natriuretic Peptide in Left Ventricular Systolic Dysfunction
Authors: Lainchbury John G. , Richards A. Mark , Nicholls M. Gary , Hunt Penny J. , Ikram Hamid , Espiner Eric A. , Yandle Tim G. , Begg Evan
Published: June 2012

Abstract
Plasma levels of brain natriuretic peptide (BNP) are raised in patients with left ventricular impairment and may play a role in the adaptation to left ventricular impairment. Manipulation of BNP levels may have therapeutic potential. The effects of BNP have not been well studied in patients with left ventricular impairment. We studied the effects of low-dose BNP infusion, reproducing the increment in plasma BNP seen with progression from mild to severe heart failure in patients with impaired left ventricular systolic function. BNP was infused in a placebo-controlled, single-blind, crossover design at a rate of 3.3 pmol · kg
–1
· min
–1
over 4 hours to 8 patients with a history of congestive heart failure and persistent impairment of left ventricular systolic function (left ventricular ejection fraction <35%). Endocrine, renal, and hemodynamic effects were measured. Compared with time-matched placebo-control, BNP infusion decreased mean systemic arterial pressure (peak decrease, 17.1 mm Hg;
P
=.04), mean pulmonary artery pressure (peak decrease, 6.1 mm Hg;
P
=.007), mean pulmonary capillary wedge pressure (peak decrease, 5.5 mm Hg;
P
=.04), and systemic vascular resistance (peak decrease, 1400 dyne s
–1
· cm
−5
;
P
=.015), but cardiac output and heart rate were unchanged. Urinary volume and urinary excretion of sodium and potassium were not altered. BNP infusion increased plasma cGMP (2.3-fold change,
P
=.002). Plasma atrial natriuretic peptide levels were increased for the first hour of BNP infusion (peak increase, 11.5 pmol/L;
P
=.005). Plasma aldosterone levels were unchanged during but increased over time-matched control levels after the end of the BNP infusion (peak increase, 90 pmol/L;
P
=.02). Plasma renin activity and cortisol and catecholamine levels were unchanged. Low-dose infusion of BNP causes favorable hemodynamic changes and relative neurohormonal suppression but has attenuated renal effects in patients with impaired left ventricular systolic function.
Role of Angiotensin-(1-7) in the Modulation of the Baroreflex in Renovascular Hypertensive Rats
Authors: Britto Raquel R. , Santos Robson A. S. , Fagundes-Moura Cristiane R. , Khosla Mahesh C. , Campagnole-Santos Maria J.
Published: June 2012

Abstract
In this study, we evaluated the effect produced by lateral ventricle (intracerebroventricular, ICV) infusion of the selective angiotensin (Ang)-(1-7) antagonist,
d
-Ala
7
-Ang-(1-7) (A-779), in the modulation of the baroreflex control of heart rate in two-kidney, one clip renovascular hypertensive rats (2K1C) treated with the angiotensin-converting enzyme (ACE) inhibitor enalapril. Twenty days after the surgery to produce renovascular hypertension, ICV cannulas were implanted in the rats with blood pressure (BP) greater than 145 mm Hg (n=33) and in sham-operated rats (n=32). Five days later, the rats were treated with enalapril (10 mg · kg
−1
· d
−1
; 6 days, in the drinking water) or vehicle (tap water). On the sixth day of treatment, direct continuous BP recording and measurement of reflex changes in heart rate elicited by phenylephrine were made in conscious rats before and at 1 hour of ICV infusion of saline (8 μL/h) or A-779 (4 μg/h). To evaluate the degree of ACE blockade produced by enalapril treatment, the pressor effect of Ang I (50 ng, IV, and 100 ng, ICV) and plasma ACE activity was determined. As expected, enalapril treatment in 2K1C produced a significant fall in BP, significant attenuation in the pressor response of Ang I (IV), and a reduction in plasma ACE activity. In addition, enalapril treatment increased the baroreflex sensitivity (0.76±0.04 versus 0.43±0.04 ms/mm Hg in 2K1C untreated rats). ICV infusion of A-779 reverted the improvement in baroreflex sensitivity produced by enalapril treatment in 2K1C (from 0.80±0.07 to 0.42±0.08 ms/mm Hg) and also attenuated the baroreflex sensitivity in untreated 2K1C (0.36±0.05 versus 0.48±0.06 ms/mm Hg) and untreated sham-operated rats (1.21±0.05 versus 0.78±0.17 ms/mm Hg). These results suggest that central endogenous Ang-(1-7) is involved at least in part in the improvement of baroreflex sensitivity observed in 2K1C after peripheral chronic ACE inhibition.
Angiotensin-Converting Enzyme Gene
I/D
Polymorphism and Carotid Plaques in Japanese
Authors: Watanabe Yasujirou , Ishigami Tomoaki , Kawano Yoshiyuki , Umahara Takahiko , Nakamori Akitoshi , Mizushima Shunsaku , Hibi Kiyoshi , Kobayashi Izumi , Tamura Kouichi , Ochiai Hisao , Umemura Satoshi , Ishii Masao
Published: June 2012

Abstract
To clarify the role of genetic factors in atherosclerotic plaque formation in the carotid artery and magnetic resonance imaging abnormalities in the brain, we investigated the association of these abnormalities with the angiotensin-converting enzyme (ACE) genotype. One hundred sixty-nine subjects (age, 59.2±0.8 years, mean±SE) admitted to our hospital for health checkups underwent brain magnetic resonance imaging to evaluate lacunar infarction. B-mode ultrasound examinations of the carotid arteries were performed to detect atherosclerotic plaque. The
I/D
polymorphism of the ACE gene was determined by the polymerase chain reaction method. Multivariate regression analysis was performed to assess the effects of the following variables on the presence of plaque, mean plaque thickness, and number of plaques: fibrinogen, sex, age, body mass index, mean blood pressure, glycosylated hemoglobin, LDL cholesterol, HDL cholesterol, hematocrit, and the
D
allele of the ACE gene. The frequency of carotid atherosclerotic plaque was significantly (
P
=.034) higher in subjects with the
D
allele than in those without this allele. However, the frequency of lacunar stroke was similar in these groups. A multivariate regression analysis showed that the presence of plaque was independently associated with the
D
allele (odds ratio=3.27,
P
=.016). However, mean plaque thickness and the number of plaques were not associated with the
D
allele. The
D
allele of the ACE gene may be involved in the presence of carotid plaque but not in the extent of this plaque or asymptomatic lacunar stroke in Japanese subjects.
Time-Dependent Effects of Low-Dose Aspirin Administration on Blood Pressure in Pregnant Women
Authors: Hermida Ramón C. , Ayala Diana E. , Iglesias Manuel , Mojón Artemio , Silva Inés , Ucieda Rafael , Fernández José R.
Published: June 2012

Abstract
This study investigated the effects of low-dose acetylsalicylic acid (aspirin) on blood pressure in pregnant women who were at risk of developing gestational hypertension or preeclampsia and who received aspirin at different times of the day according to their rest-activity cycle. A double-blind, randomized, controlled trial was conducted in 100 pregnant women. Blood pressure for each subject was automatically monitored for 2 days every 4 weeks from the day of recruitment until delivery. Women were randomly assigned to one of six groups according to treatment (placebo, 50 subjects or aspirin, 100 mg/d, starting at 12 to 16 weeks of gestation) and the time of treatment: on awakening (time 1), 8 hours after awakening (time 2), or before bedtime (time 3). Results indicated that there was (1) no effect on blood pressure from placebo at any time (
P
>.212) and (2) a highly statistically significant (
P
<.001) time-dependent effect on blood pressure from aspirin. There was no effect of aspirin on blood pressure at time 1 (compared with placebo), but the blood pressure reduction was highly statistically significant after time 2 and, to a greater extent, after time 3 (mean reduction of 12 and 8 mm Hg in 24 hours for systolic and diastolic blood pressure, respectively, at the time of delivery compared with placebo given at the same time). These time-dependent effects of aspirin on blood pressure should be taken into account for the optimization of long-term aspirin administration at low doses for prevention of preeclampsia. In any meta-analysis of aspirin effects, inquiries about the time when the subjects took the drug are indicated and may account for discrepancies in the literature.
Blood Pressure Variability During Gestation in Healthy and Complicated Pregnancies
Authors: Ayala Diana E. , Hermida Ramón C. , Mojón Artemio , Fernández José R. , Silva Inés , Ucieda Rafael , Iglesias Manuel
Published: June 2012

Abstract
The evaluation of predictable variability in blood pressure by the use of ambulatory devices, and the proper processing of the time series thus obtained, can be useful for the early assessment of hypertensive complications in pregnancy. We have used this approach to quantify a predictable pattern of blood pressure and heart rate throughout pregnancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or preeclampsia. We analyzed 503 blood pressure series from 71 healthy pregnant women and 256 series from 42 women who developed gestational hypertension or preeclampsia. Blood pressure monitoring (48-hour) was done once every 4 weeks after the first obstetric consultation. The pattern of variation along gestation of the 24-hour mean of blood pressure for groups of normotensive and hypertensive pregnant women was established by polynomial regression analysis. This method revealed predictable patterns of variation of 24-hour means with gestational age: for normotensive pregnant women, results indicate a steady decrease in blood pressure up to the 21st week of pregnancy, followed by an increase in blood pressure up to the day of delivery. This pattern of variation is not found in pregnancies complicated with gestational hypertension or even preeclampsia: the 24-hour mean of blood pressure is stable until the 22nd week of pregnancy and then correlated with gestational age, indicating a significant linear increase of blood pressure in the second half of pregnancy. For both healthy and complicated pregnancies, heart rate slightly increases until the end of the second trimester, and it is stable thereafter. This study confirms and extends to ambulatory everyday life conditions the predictable pregnancy-associated variability in blood pressure. The differences between uncomplicated and complicated pregnancies offer new end points for an early identification of gestational hypertension and preeclampsia.
Plasma Triglycerides and Red Cell Ion Transport Alterations in Genetically Hypertensive Rats
Authors: Zicha Josef , Dobesová Zdenka , Kunes Jaroslav
Published: June 2012

Abstract
Ion transport abnormalities in essential hypertension are often associated with concomitant changes of lipid metabolism, but this information is missing in rats with genetic hypertension. We therefore studied the alterations of red cell Na
+
and K
+
transport and their relationship to blood pressure and plasma lipids (cholesterol and triglycerides) in Prague hereditary hypertriglyceridemic (HTG) rats, Lyon hypertensive (LH) rats, and HTG×Lewis F
2
hybrids. In both hypertensive models and F
2
hybrids, red cell Na
+
content (Na
+
i
) was positively related to plasma triglycerides but not to plasma cholesterol levels. Na
+
i
elevation was more pronounced in HTG than in LH rats, probably due to higher plasma triglycerides in the former strain. The two hypertensive strains differed in bumetanide-sensitive Na
+
transport, which was augmented in HTG rats with low plasma cholesterol but suppressed in LH rats characterized by high cholesterol levels. In the two genetic models, there was a positive association of blood pressure with Na
+
leak, and this was also confirmed by the cosegregation of these parameters in F
2
hybrids. We conclude that the enhancement of Na
+
leak represents the major ion transport abnormality in rats with genetic hypertension. The alterations in plasma lipids are important determinants of abnormal red cell ion transport in hypertensive models studied. Although the detailed mechanism of their participation in ion transport regulation is still not completely understood, triglyceride-dependent changes in membrane microviscosity seem to be responsible for the modulation of particular ion transport pathways.
Decline in Renal Hemodynamic Function in Aging SHR
Authors: Reckelhoff Jane F. , Zhang Huimin , Granger Joey P.
Published: June 2012

Abstract
Although men and male rats are at increased risk for age-related renal and cardiovascular disease compared with women and female rats, the mechanisms are unknown. However, castration of male normotensive rats protects against age-related glomerular sclerosis, and castration of spontaneously hypertensive rats (SHR) attenuates the age-related progression of hypertension to levels found in female SHR. The present study was performed to determine whether there are differences between male and female renal function in SHR with aging, and if so, the role that androgens play in the age-related changes in renal function in SHR. Renal hemodynamics, glomerular filtration rate (GFR), and proteinuria were measured in anesthetized male and female SHR aged 7 to 8, 14 to 15, and 30 to 32 weeks (n=5 to 7 per sex per age group). Studies were also performed in male SHR that had been castrated at 4 weeks of age and allowed to age to 7 to 8, 14 to 15, and 30 to 32 months of age (n=5 to 9 per age group). At 7 to 8 weeks of age when blood pressures are similar between male, female, and castrated male SHR, there were no differences in renal hemodynamics between male and female SHR. As the rats aged, mean arterial blood pressure increased in all groups and was higher in the intact male SHR than in females. Blood pressure in aging castrated males was similar to the pressure in aging female SHR. With advancing age, GFR in intact male SHR decreased by 20% to 30% at 14 to 15 and 30 to 32 weeks of age, respectively. Renal plasma flow (RPF) also tended to decrease in male SHR but not statistically so. There was no age-related reduction in GFR or RPF in female or castrated male SHR. With advancing age, renal vascular resistance (RVR) increased in all rats. RVR increased by 40% and 60% at 14 to 15 and 30 to 32 weeks in male SHR. In comparison, RVR increased by 20% and 40% in female SHR at similar ages. RVR in castrated male SHR was similar to RVR in females. The levels of urinary protein excretion increased with aging to 14 weeks in the male SHR, but in females and castrated males urinary protein excretion reached a plateau at 6 to 8 weeks that was maintained until 14 weeks of age and was approximately sixfold lower than in male SHR. These data suggest that androgens may play an important role in mediating the hypertension and the age-related alterations in renal function in the male SHR.
Role of Endothelin in Mediating the Attenuated Renal Hemodynamics in Dahl Salt-Sensitive Hypertension
Authors: Kassab Salah , Novak Jackie , Miller Todd , Kirchner Kent , Granger Joey
Published: June 2012

Abstract
The aim of this study was to evaluate the role of endothelin (ET) in the hypertension associated with giving a high sodium diet in Dahl salt-sensitive (DS) rats. To achieve this goal, we examined the effects of intravenous infusion of the nonspecific ET
A
-ET
B
antagonist on arterial pressure and renal function in conscious, chronically instrumented DS and Dahl salt-resistant (DR) rats. After 3 weeks on a high sodium (8%) diet, mean arterial pressure (MAP) in DS rats (166±3 mm Hg) was significantly higher than in DR rats (124±3 mm Hg). Baseline glomerular filtration rate (GFR) and renal plasma flow (RPF) in DS rats (1.92±0.25 mL/min and 7.07±0.80 mL/min) were lower than in DR rats (2.52±0.21 mL/min and 7.98±0.85 mL/min), respectively. Renal vascular resistance was significantly higher in DS rats (32.78±5.88 mm Hg · mL
−1
· min
−1
) than in DR rats (24.60±5.04 mm Hg · mL
−1
· min
−1
). Intravenous infusion of the ET antagonist SB 209670 at a dose of 30 μg · kg
−1
· min
−1
for 75 minutes caused a significant decrease in MAP in DS rats (from 166±3 to 144±4 mm Hg). In contrast, the effect of the ET antagonism on MAP in DR rats was not significant. ET-antagonist infusion tended to improve GFR and RPF in DS but not in DR rats. To determine the renal effects of ET antagonism independent of the systemic hemodynamic responses, we examined the effects of the same ET antagonist in rats chronically implanted with a renal interstitial catheter. Arterial pressure in DS rats (181±5 mm Hg) was significantly higher than in DR rats (135±3 mm Hg). Renal interstitial infusion of SB 209670 at a dose of 200 ng · kg
−1
· min
−1
for 60 minutes caused no change in MAP in DS or DR rats. Intrarenal ET antagonism significantly increased GFR (25%), RPF (30%), urine flow (32%), and urinary sodium excretion (25%) in DS rats, while it had no significant effect in DR rats. Fractional excretion of sodium was not significantly changed by renal interstitial infusion of the ET antagonist in DS rats, indicating that improved renal excretory function in DS rats is most likely due to the associated improvement in renal hemodynamics. We conclude that ET may play a role in the attenuated renal hemodynamics and possibly the development of Dahl salt-sensitive hypertension.
Hemodynamics of Chemoreflex Activation in Unanesthetized Rats
Authors: Franchini Kleber G. , Oliveira Vera L. L. , Krieger Eduardo M.
Published: June 2012

Abstract
Experiments were performed on unanesthetized rats (n=6) to determine the systemic hemodynamics during chemoreflex activation by intravenous KCN. Rats chronically instrumented with ultrasonic flow probes in the ascendant aorta were submitted to KCN injections (30 μg/kg) before and after sequential administration of the autonomic blockers atropine and propranolol. In the control period KCN injections produced a 60% reduction in heart rate (HR) and a 46% elevation in blood pressure (BP), while cardiac output (CO) decreased 76%, stroke volume (SV) decreased 40%, and calculated total peripheral resistance (TPR) increased 900%. Atropine administration increased resting HR, whereas no change was observed in CO or BP. Chemoreflex-induced bradycardia was markedly attenuated (26%), and the pressor response was potentiated (59%) after atropine administration. CO and TPR responses were both attenuated after atropine administration (68% and 718%, respectively). Sequential administration of propranolol decreased HR but did not change the cardiovascular responses to KCN injections compared with the responses observed after atropine administration. In conclusion, CO is greatly reduced during KCN-evoked chemoreflex. Besides the intense bradycardia, a decrease in SV contributed to this reduction. Bradycardic response was most dependent on the cardiac parasympathetic activation, and the reduction in SV was probably most dependent on the increased cardiac afterload due to the sudden increase in BP.
Acute and Chronic Effects of Exercise on Baroreflexes in Spontaneously Hypertensive Rats
Authors: Silva Gustavo José Justo , Brum Patricia Chakur , Negrão Carlos Eduardo , Krieger Eduardo Moacyr
Published: June 2012

Abstract
We studied the effects of acute and chronic exercise on the arterial baroreflex and chemosensitive cardiopulmonary baroreflex (CCB) in spontaneously hypertensive rats (SHR). Arterial baroreflex and CCB were evaluated in normotensive rats (NR, n=11) and SHR (n=5) at rest and after 30 minutes of an acute bout of exercise (45 minutes at 50% of V
o
2
max). In addition, these baroreflexes were evaluated in sedentary (n=5) and exercise-trained (n=9) SHR. Exercise training was performed on a motor treadmill, 5 days/week, during 60 minutes, at 50% of V
o
2
max. Baroreflex bradycardia and tachycardia, analyzed by baroreflex sensitivity index (Δ heart rate/Δ mean arterial pressure), were significantly lower in SHR than in NR (0.7±0.1 versus 2.0±0.1 and 1.8±0.2 versus 3.4±0.1 beats per minute [bpm]/mm Hg, respectively). During the recovery period from acute exercise, baroreflex bradycardia was significantly higher than at rest only in SHR (1.7±0.1 versus 0.7±0.1 bpm/mm Hg). Hypotension and bradycardia induced by CCB stimulation (5-hydroxytryptamine, IV) were similar between SHR and NR, and an acute exercise bout did not change these responses. Exercise training markedly improved baroreflex bradycardia and tachycardia in SHR (1.9±0.1 versus 0.7±0.1 and 2.9±0.1 versus 1.8±0.2 bpm/mm Hg, respectively). Exercise-trained rats had greater bradycardiac (118±26 versus 14±2 and 209±30 versus 19±5 bpm to 1 and 2 μg/kg 5-HT, respectively) and hypotensive (30±6 versus 15±3 and 45±7 versus 17±2 mm Hg to 1 and 2 μg/kg 5-hydroxytryptamine, respectively) responses to CCB stimulation. In conclusion, an acute bout of exercise increases baroreflex bradycardia in SHR, and exercise training attenuates hypertension concomitant with improved arterial baroreflex and CCB sensitivity in SHR.
Localization of the Dopamine D
1
Receptor Protein in the Human Heart and Kidney
Authors: Ozono Ryoji , O’Connell Damian P. , Wang Zhi-Qin , Moore Allan F. , Sanada Hironobu , Felder Robin A. , Carey Robert M.
Published: June 2012

Abstract
The dopamine D
1
receptor has recently been identified in the rat heart and kidney. In the present study, using Western blot analysis and light microscopic immunohistochemistry, we examined D
1
receptor protein expression in the human kidney and heart. Antipeptide polyclonal rabbit antiserum was raised against the third extracellular domain of the native receptor and affinity-purified using a protein-A column. Selectivity of the antiserum was validated by recognition of the D
1
receptor expressed in stably transfected LTK
−
cells and Sf-9 cells. The immunohistochemical staining for D
1
receptor protein was distributed throughout the atrium and ventricular myocardium and in the coronary vessels. In the kidney, positive immunoreactive signal was detected in the proximal and distal tubules, the collecting ducts, and the large intrarenal vasculature, whereas staining was absent in the juxtaglomerular (JG) cells and the glomeruli. D
1
receptor antiserum preadsorbed against the immunizing peptide did not produce significant staining. In Western blot analysis, a single 55-kD band was detected for the D
1
receptor in membranes from the D
1
receptor transfected Sf-9 cells but not in nontransfected cells. In the heart and kidney, we detected a 55-kD band as well as an additional 40-kD band, which may reflect partial degradation of the receptor protein. These results provide the first evidence for the localization of the dopamine D
1
receptor protein in the human heart and kidney. The similar distribution of this subtype receptor in the human heart and kidney to that in the rat supports the possible (patho)physiological significance of the peripheral dopamine system in humans.
Role of Kinins in the Cardioprotective Effect of Preconditioning
Authors: Yang Xiao-Ping , Liu Yun-He , Scicli Gloria M. , Webb Charles R. , Carretero Oscar A.
Published: June 2012

Abstract
Kinins acting on the B
2
receptor appear to be involved in the cardioprotective effect of preconditioning on myocardial ischemia/reperfusion injury. We tested the hypothesis that in mice lacking the gene encoding for the B
2
kinin receptor (B
2
knockout mice; B
2
-KO) as well as in rats deficient in high-molecular-weight (HMW) kininogen (Brown Norway Katholiek rats; BNK), the cardioprotective effect of preconditioning is diminished or abolished. 129SvEvTac (SV129) mice and Brown Norway rats (BN) served as controls. We confirmed that plasma HMW kininogen in BNK rats was 100-fold lower than in BN and 140-fold lower than in Sprague-Dawley rats (33±4 versus 1814±253 and 2397±302 ng/mL,
P
<.01). Each strain of mice was divided into (1) controls (without preconditioning); (2) one cycle of preconditioning (3 minutes ligation and 5 minutes reperfusion); and (3) three cycles of preconditioning. Each strain of rats was divided into (1) controls; and (2) three cycles of preconditioning. All animals were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In SV129 controls, the ratio of infarct size to risk area (IS/AR) was 55.6±4.6%. One and three cycles of preconditioning reduced IS/AR to 38.6±3.2% and 31.1±2.3%, respectively (
P
<.05 and
P
<.01 versus control). This protective effect was absent in B
2
-KO mice: IS/AR was 54.8±2.9% in controls, 58.5±3.6% with one cycle of preconditioning, and 58.5±3.4% with three cycles. In BN rats without preconditioning, IS/AR was 84.7±3.9%; preconditioning reduced it to 61.6±3.4% (
P
<.01). In BNK rats, IS/AR was 87.1±4.8% in controls and 84.3±4.1% with preconditioning. Preconditioning also prevented reperfusion arrhythmias in BN but not BNK rats. Within species, risk area, mean blood pressure, and heart rate were similar between strains. We concluded that (1) preconditioning protects the heart against ischemia/reperfusion injury in mice and rats; (2) activation of prekallikrein, which in turn generates kinins from HMW kininogen, may contribute to the effect of preconditioning; and (3) an intact kallikrein-kinin system is necessary for the cardioprotective effect of preconditioning.
Systolic Function in Hypertensive Men With Concentric Remodeling
Authors: Sadler Diego B. , Aurigemma Gerard P. , Williams David W. , Reda Domenic J. , Materson Barry J. , Gottdiener John S.
Published: June 2012

Abstract
Hypertensive patients with concentric remodeling (relative wall thickness ≥0.45 and normal left ventricular [LV] mass index) may have poor outcomes. It is unclear whether systolic function abnormalities, shown to be present in some patients with concentric LV hypertrophy (increased LV mass index and relative wall thickness ≥0.45), are also present in patients with concentric remodeling. To assess LV pump, chamber, and myocardial function in hypertensive men with concentric remodeling, clinical and echocardiographic data of 118 hypertensive men with concentric remodeling were compared with data from 104 hypertensive men with normal relative wall thickness and normal LV mass index. Chamber function was assessed by relating endocardial fractional shortening to end-systolic circumferential stress, myocardial function was assessed by relating midwall fractional shortening to circumferential stress, and pump performance was assessed by stroke volume (Teichholz method). Compared with hypertensive men with normal relative wall thickness, concentric-remodeling patients had lower stroke volume (84±20 versus 111±20 mL,
P
<.001). Endocardial shortening was no different between the two groups (38±7% versus 40±7%,
P
=NS), but midwall shortening was lower in patients with concentric remodeling (20±3% versus 22±3%,
P
<.001), despite lower end-systolic stress (81±25 versus 117±37 g/cm
2
,
P
<.001). Endocardial and midwall stress-shortening regression plots classified 28% and 42%, respectively, of the concentric remodeling patients below the fifth percentile of hypertensive patients with normal geometry. These data indicate that indexes of chamber and myocardial function are lower than those observed in hypertensive patients with normal geometry. Thus, indices of chamber, myocardial, and pump performance indicate potential abnormalities in systolic function in men with concentric remodeling.
Can Transmitral Doppler E-Waves Differentiate Hypertensive Hearts From Normal?
Authors: Kovács Sándor J. , Rosado Jose , McGuire Abigail L. Manson , Hall Andrew F.
Published: June 2012

Abstract
Physiological models of transmitral flow predict E-wave contour alteration in response to variation of model parameters (stiffness, relaxation, mass) reflecting the physiology of hypertension. Accordingly, analysis of only the E-wave (rather than the E-to-A ratio) should be able to differentiate between hypertensive subjects and control subjects. Conventional versus model-based image processing methods have never been compared in their ability to differentiate E-waves of hypertensive subjects with respect to age-matched control subjects. Digitally acquired transmitral Doppler flow images were analyzed by an automated model-based image processing method. Model-derived indexes were compared with conventional E-wave indexes in 22 subjects: 11 with hypertension and echocardiographically verified ventricular hypertrophy and 11 age-matched nonhypertensive control subjects. Conventional E-wave indexes included peak E, ∫E, and acceleration and deceleration times. Model-based image processing–derived indexes included acceleration and deceleration times, potential energy index, and damping and kinematic constants. Intergroup comparison yielded lower probabilit
y
values for model-based compared with conventional indexes. In the subjects studied, Doppler E-wave images analyzed by this automated method (which eliminates the need for hand-digitizing contours or the manual placement of cursors) demonstrate diastolic function alteration secondary to hypertension made discernible by model-based indexes. The method uses the entire E-wave contour, quantitatively differentiates between hypertensive subjects and control subjects, and has potential for automated noninvasive diastolic function evaluation in large patient populations, such as hypertension and other transmitral flow velocity–altering pathophysiological states.
Reversal of Endothelin-1 Release by Stimulation of Endothelial α
2
-Adrenoceptor Contributes to Cerebral Vasorelaxation
Authors: Thorin Eric , Shreeve S. Martin , Thorin-Trescases Nathalie , Bevan John A.
Published: June 2012

Abstract
Agonists acting on the vascular endothelium can modulate the release of a number of factors that interact with the surrounding smooth muscle cells and influence their tone. One such factor is the vasoconstricting agent endothelin-1 (ET-1), which has been implicated in several disease states, including stroke. However, very little is known about the physiological role of ET-1 in the cerebral circulation. We demonstrate that activation of α
2
-adrenoceptors in human pial artery endothelial cells reduces both constitutive and agonist-stimulated release of immunoreactive ET-1. That this has physiological relevance is supported by our demonstration that in segments of rabbit middle cerebral arteries, α
2
-adrenoceptor activation reduces the release of endothelium-derived ET-1 and causes an endothelium-dependent relaxation. The adrenoceptor-dependent relaxation was not blocked by combined addition of indomethacin and
N
ω
-nitro-
l
-arginine in 25 mmol/L KCl-depolarizing physiological solution but was selectively antagonized by a subthreshold concentration of exogenous ET-1. Our data suggest that activation of endothelial α
2
-adrenoceptor would favor a decrease in ET-1 production and possibly promote vascular relaxation.
NHE-1 Protein in Vascular Smooth Muscle and Lymphocytes From the Spontaneously Hypertensive Rat
Authors: LaPointe Michael S. , Ye Minghao , Bacallao Robert , Batlle Daniel
Published: June 2012

Abstract
The present study examined the abundance of NHE-1 protein in cultured vascular smooth muscle cells (VSMCs), freshly isolated thymocytes, and fresh aortic tissue from spontaneously hypertensive rats (SHRs) and age-matched Wistar-Kyoto (WKY) rats. Two sets of affinity-purified antibodies (Ab
(765-778)
and Ab
(698-711)
) against different epitopes of the NHE-1 isoform of the Na
+
-H
+
antiporter were used. Each set of antibodies recognized a major protein band at 105 to 110 kD that was more abundant in protein lysates prepared from cultured VSMCs from the SHR than those from WKY rats (Ab
(765-778)
0.047±0.011 vs 0.010±0.002 O.D. units/10 μg protein,
P
<.001 for SHR and WKY, respectively; and Ab
(698-711)
0.173±0.026 vs 0.087±0.028 O.D. units/10 μg protein,
P
<.05, for SHR and WKY, respectively). The increase in NHE-1 protein abundance in cultured VSMCs from the SHR was associated with a greater
V
max
of the Na
+
-H
+
antiporter as compared to those from WKY rats (17.93±2.07 vs 8.16±1.05 mmol H
+
/min,
P
<.001, respectively). In contrast to cultured VSMCs, there was no difference in the relative abundance of NHE-1 protein in fresh aortic tissue (0.075±0.018 vs 0.083±0.017 O.D. units/10 μg protein, from SHR and WKY, respectively) or in freshly isolated thymocytes (0.158±0.046 vs 0.226±0.054 O.D. units/10 μg protein, from SHR and WKY, respectively). We conclude that the increase in the
V
max
of the Na
+
-H
+
antiporter in cultured VSMCs from the SHR, compared to those from WKY rats, is due, at least in part, to increased levels of NHE-1 protein.
The Hypertension of Autonomic Failure and Its Treatment
Authors: Shannon John , Jordan Jens , Costa Fernando , Robertson Rose Marie , Biaggioni Italo
Published: June 2012

Abstract
We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure ≥90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92±15 pg/mL) and plasma renin activity (0.3±0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177±6/108±2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36±7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.
Effect of Sympathectomy on Mechanical Properties of Common Carotid and Femoral Arteries
Authors: Mangoni Arduino A. , Mircoli Luca , Giannattasio Cristina , Mancia Giuseppe , Ferrari Alberto U.
Published: June 2012

Abstract
Sympathetic stimulation is accompanied by a reduction of arterial distensibility, but whether and to what extent elastic and muscle-type arterial mechanics is under tonic sympathetic restraint is not known. We addressed this issue by measuring, in the anesthetized rat, the diameters of the common carotid and femoral arteries with an echo-Doppler device (NIUS 01). Blood pressure was measured by a catheter inserted contralaterally and symmetrically to the vessel where the diameter was measured. Arterial distensibility over the systolic-diastolic pressure range was calculated according to the Langewouters formula. Data were collected in 10 intact (vehicle pretreatment) and 9 sympathectomized (6-hydroxydopamine pretreatment) 3-month-old Wistar-Kyoto rats. Compared with the intact animals, sympathectomized rats showed a marked increase in arterial distensibility over the entire systolic-diastolic pressure range. When quantified by the area under the distensibility-pressure curve, the increase was 59% and 62% for the common carotid and femoral arteries, respectively (
P
<.01 for both). In the femoral but not in the common carotid artery, sympathectomy was accompanied also by an increase in arterial diameter (+18%,
P
<.05 versus intact). Therefore, in the anesthetized normotensive rat, sympathetic activity exerts a tonic restraint on large-artery distensibility. This restraint is pronounced in elastic vessels and even more pronounced in muscle-type vessels.