bluuebunny/crossref_metadata_2025 huggingface dataset:
Heart Rate Variability and Baroreceptor Function in Chronic Diabetic Rats
Authors: Fazan Rubens , Ballejo Gustavo , Salgado Maria Cristina O. , Moraes Márcio F.D. , Salgado Helio C.
Published: June 2012

Abstract
In conscious chronic (12 to 18 weeks) streptozotocin diabetic rats, we examined the changes in basal heart rate, with particular attention to heart rate variability assessed by evaluating the standard deviation (bpm) of the lengths of adjacent pulse pressure. We also investigated in anesthetized rats the ability of the aortic baroreceptors to acutely (30 minutes) reset to hypertensive levels. For this purpose, pressure-nerve activity curves for the baroreceptors were obtained, and gain (slope of the curve) and mean arterial pressure at 50% of maximal baroreceptor activity were calculated. The shift of the pressure-nerve activity curve was used as an index of resetting. Conscious diabetic rats (n=6) exhibited lower mean arterial pressure (93±6 versus 109±4 mm Hg), heart rate (272±25 versus 359±11 bpm), and heart rate variability (18±7 versus 36±6 bpm) than control rats (n=7). Under anesthesia, diabetic rats (n=7) and control rats (n=8) exhibited similar mean arterial pressure (113±6 versus 109±7 mm Hg in control rats ), mean arterial pressure at 50% of maximal baroreceptor activity (117±5 versus 107±6 bpm), gain (1.66±0.08 versus 1.81±0.05%/mm Hg), and extent of resetting (44±12 versus 49±9%) to hypertensive levels. The present study demonstrated that conscious chronic diabetic rats presented lower heart rate variability than control rats. On the other hand, chronic diabetes was not associated with alterations in baroreceptor function or its ability to rapidly reset to hypertensive levels.
Plasma Adrenomedullin Concentrations and Cardiac and Arterial Hypertrophy in Hypertension
Authors: Sumimoto Takumi , Nishikimi Toshio , Mukai Mikio , Matsuzaki Keisuke , Murakami Eiki , Takishita Shuichi , Miyata Atsuro , Matsuo Hisayuki , Kangawa Kenji
Published: June 2012

Abstract
It has been reported that plasma concentrations of adrenomedullin (AM), a novel vasodilator peptide, are higher in patients with essential hypertension than those in normotensive subjects. To clarify the clinical significance of increased levels of AM in patients with essential hypertension, in this study we examined the relationship between plasma concentrations of AM and the structure of the left ventricle or carotid artery. Plasma AM concentrations; renin activity; and norepinephrine, epinephrine, and creatinine concentrations in 50 patients with untreated essential hypertension without renal dysfunction and heart failure were measured. We also measured the mean wall thickness of the left ventricle and left ventricular mass index by M-mode echocardiography and intimal-medial thickness and arterial distensibility of the carotid artery by ultrasonography. Hypertensive patients were divided into two groups: hypertensives with and those without left ventricular hypertrophy. Plasma AM concentrations in hypertensive patients with left ventricular hypertrophy were significantly higher than in hypertensive patients without left ventricular hypertrophy (7.87±2.70 vs 5.74±1.65 fmol/mL,
P
<.01). In all hypertensive patients, plasma AM concentrations were not correlated with blood pressure, plasma renin activity, plasma norepinephrine, plasma epinephrine, or plasma creatinine concentration. Plasma AM concentrations were positively correlated with left ventricular mass index or mean wall thickness (
r
=.37,
P
=.009;
r
=.40,
P
=.004, respectively) and inversely correlated with carotid artery distensibility (
r
=−.33,
P
=.02), whereas plasma AM concentrations were not correlated with intimal-medial thickness. These results suggest that the observed elevation of plasma AM in patients with essential hypertension with normal renal function may be partly related to cardiac hypertrophy and decreased carotid artery distensibility.
Endothelin Mediation of Insulin and Glucose-Induced Changes in Vascular Contractility
Authors: Nava María Pilar , Collados Teresa , Massó Felipe , Guarner Verónica
Published: June 2012

Abstract
Although the prevalence of hypertension in diabetic patients is high and many factors participate, hyperinsulinemia cannot be discarded as a contributing factor. Insulin could act directly on smooth muscle altering intracellular calcium levels that mediate contraction and glucose transport or could induce the secretion of endothelin by the endothelial cells lining the vessels. The aim of the present report was to study the effect of different glucose and insulin concentrations on rat vascular smooth-muscle contractile characteristics and to determine whether insulin effects are mediated by endothelin. Femoral arteries obtained from Wistar rats were placed in an in vitro chamber and superfused with different glucose and/or insulin solutions. The contractile response to KCl 80 mmol/L, measured by the force generated, showed a significant decrease with high extracellular glucose concentrations (11 mmol/L). Insulin caused a dose-dependent increase in arterial contraction induced by KCl. This increase was significant when arteries were stimulated with 80 mmol/L KCl in the presence of 5.5 mmol/L glucose, but when 40 mmol/L KCl was used, an increase was observed with both 5.5 and 11 mmol/L glucose. The insulin-induced contraction was significantly reduced in the presence of hyperimmune anti-endothelin serum and in the presence of endothelin receptor ET
A
and ET
B
antagonists PD 151,242 and BQ-788, respectively. These results suggest that hyperinsulinemia and hyperglycemia may contribute to hypertension in diabetes and that responses to insulin are mediated partially by endothelin, thus explaining why non–insulin-dependent diabetes mellitus patients show an increase in arterial pressure before the onset of nephropathy.
Enalapril and Renal Function in Hypertensive Rats Transgenic for Mouse Renin Gene
Authors: Springate James E. , Feld Leonard G. , Ganten Detlev
Published: June 2012

Abstract
We examined the effect of long-term enalapril treatment on renal function and histology in the monogenetically hypertensive TGR(mRen2)27 rat strain. Untreated transgenic rats had significantly (
P
<.01) higher blood pressures than treated transgenic and control animals throughout the study. Urinary nitric oxide metabolite excretion was significantly lower in young transgenic rats and rose with enalapril, suggesting abnormal TGR nitric oxide production and its correction by enalapril. Converting enzyme inhibition produced preferential preglomerular vasodilatation and increased renal blood flow (6.5±0.5 versus 9.0±0.7 mL/min per gram kidney weight,
P
<.05) without altering whole-kidney and single-nephron glomerular filtration rates in TGR(mRen2)27. Glomerular capillary pressure fell modestly in treated transgenic animals (54±1 versus 50±1 mm Hg,
P
<.05). These hemodynamic changes were associated with reductions in albuminuria (59±6 versus 9±2 mg/d,
P
<.01) and glomerulosclerosis in TGR. However, urinary albumin excretion (15±3 versus 3±1 mg/d,
P
<.05) and glomerulosclerosis also declined in treated control animals in the absence of significant alterations in glomerular hemodynamics. The mechanism of the beneficial effect of enalapril on the TGR(mRen2)27 kidney is unclear but could involve either control of hypertension or suppression of the intrarenal renin-angiotensin system.
Parathyroid Hormone–Related Protein Upregulates Interleukin-1β–Induced Nitric Oxide Synthesis
Authors: Jiang Bingbing , Morimoto Shigeto , Yang Jin , Fukuo Keisuke , Hirotani Atsushi , Kitano Shoichi , Ogihara Toshio
Published: June 2012

Abstract
The effect of parathyroid hormone–related protein on interleukin-1β–induced nitric oxide production was studied in rat vascular smooth muscle cells. Interleukin-1β time- and dose-dependently enhanced the production of nitrite, a stable metabolite of nitric oxide. Parathyroid hormone–related protein(1-34) alone up to 10
−7
mol/L had no obvious effect, but significantly increased the cytokine-induced nitrite production. RNA analysis revealed that the synergistic effect of parathyroid hormone–related protein(1-34) resulted from a potentiation of the expression of inducible nitric oxide synthase and GTP-cyclohydrolase I, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, which is a cofactor of nitric oxide synthase. The increased nitric oxide release induced by interleukin-1β or interleukin-1β with parathyroid hormone–related protein(1-34) was completely inhibited by coincubation with 3×10
−3
mol/L
N
G
-monomethyl-l-arginine, a competitive inhibitor of nitric oxide synthase, or with 10
−3
mol/L 2,4-diamino-6-hydroxypyrimidine, an inhibitor of GTP-cyclohydrolase I. Endothelin-1 potentiated interleukin-1β induction of nitric oxide, which might be mediated by endogenous parathyroid hormone–related protein. Neutralization of exogenous or endogenous parathyroid hormone–related protein with antibody attenuated the synergistic effect of parathyroid hormone–related protein, but did not affect interleukin-1β induction of nitric oxide. These results suggest that locally produced parathyroid hormone–related protein acts as a synergistic regulator upregulating interleukin-1β–induced nitric oxide synthesis in the cardiovascular system, and thereby may affect vascular tone and/or vascular remodeling after vascular injury in some pathological processes such as atherosclerosis and hypertension.
Heritability of Left Ventricular Mass
Authors: Post Wendy S. , Larson Martin G. , Myers Richard H. , Galderisi Maurizio , Levy Daniel
Published: June 2012

Abstract
Left ventricular hypertrophy is associated with an increased risk for cardiovascular disease. The known determinants of left ventricular hypertrophy only partially explain its variability. The purpose of this study was to estimate heritability of left ventricular mass. The study sample included adults in the original Framingham Heart Study and the Framingham Offspring Study who were not receiving antihypertensive medications and who were free of coronary heart disease, congestive heart failure, diabetes mellitus, renal insufficiency, valvular heart disease, and severe left ventricular hypertrophy. Intraclass correlations for left ventricular mass among first-degree relatives, second-degree relatives, and unrelated spouse pairs were calculated to determine the contribution of heredity to the variability in left ventricular mass. After adjustments for age, height, weight, and systolic blood pressure, the intraclass correlations between first-degree relatives were .15 (parent-child,
P
<.001) to .16 (siblings,
P
<.001), between second-degree relatives the correlation was .06 (
P
=NS), and between spouses it was .05 (
P
=NS). The estimated heritability of adjusted left ventricular mass was between .24 and .32. The proportion of the variance in sex-specific left ventricular mass explained by age, height, weight, and systolic blood pressure was .26 in men and .34 in women. On the basis of intraclass correlations for left ventricular mass, incorporation of adjusted left ventricular mass of a parent or sibling would increase the explained variance by an additional .02 to .03. Heredity explains a small, but discernible proportion of the variance in left ventricular mass. Studies are currently under way to identify genetic markers that predict an individual’s predisposition to left ventricular hypertrophy. This knowledge may lead to advances in the prevention of left ventricular hypertrophy, which is strongly associated with cardiovascular morbidity and mortality.
Reflex Effects on Renal Nerve Activity Characteristics in Spontaneously Hypertensive Rats
Authors: DiBona Gerald F. , Jones Susan Y. , Sawin Linda L.
Published: June 2012

Abstract
The effects of arterial and cardiac baroreflex activation on the discharge characteristics of renal sympathetic nerve activity were evaluated in conscious spontaneously hypertensive and Wistar-Kyoto rats. In spontaneously hypertensive rats compared with Wistar-Kyoto rats, (1) arterial baroreflex regulation of renal sympathetic nerve activity was reset to a higher arterial pressure and the gain was decreased and (2) cardiac baroreflex regulation of renal sympathetic nerve activity exhibited a lower gain. With the use of sympathetic peak detection analysis, the inhibition of integrated renal sympathetic nerve activity, which occurred during both increased arterial pressure (arterial baroreflex) and right atrial pressure (cardiac baroreflex), was due to parallel decreases in peak height with little change in peak frequency in both spontaneously hypertensive and Wistar-Kyoto rats. Arterial and cardiac baroreflex inhibition of renal sympathetic nerve activity in Wistar-Kyoto and spontaneously hypertensive rats is due to a parallel reduction in the number of active renal sympathetic nerve fibers.
Prevalence and Clinical Correlates of Microalbuminuria in Essential Hypertension
Authors: Pontremoli Roberto , Sofia Antonella , Ravera Maura , Nicolella Clizia , Viazzi Francesca , Tirotta Angelito , Ruello Natia , Tomolillo Cinzia , Castello Cristoforo , Grillo Giuliano , Sacchi Giorgio , Deferrari Giacomo
Published: June 2012

Abstract
The prevalence of microalbuminuria and its relationship with several cardiovascular risk factors and target organ damage were evaluated in a cohort of 787 untreated patients with essential hypertension. Albuminuria was measured as the albumin-to-creatinine ratio in three nonconsecutive, first morning urine samples. The prevalence of microalbuminuria was 6.7%. Albuminuric patients were more likely to be men and to be characterized by higher blood pressure, body mass index, and uric acid levels and lower HDL cholesterol and HDL cholesterol−to−LDL cholesterol ratio. Piecewise linear regression analysis demonstrated that uric acid and diastolic blood pressure significantly influence albuminuria and together account for a large part of its variations. K-means cluster analysis performed on the entire cohort of patients confirmed that microalbuminuria is associated with a worse cardiovascular risk profile. Furthermore, microalbuminuria was associated with the presence of target organ damage (eg, electrocardiographic [ECG] abnormalities and retinal vascular changes). Age and the presence of microalbuminuria act as independent risk factors for the development of ECG abnormalities and retinal vascular changes. Cluster analysis allowed us to identify three subgroups of patients who differed in the presence or absence of microalbuminuria, retinopathy, and ECG abnormalities. We conclude that the prevalence of microalbuminuria in essential hypertension is lower than previously reported. Increased urinary albumin excretion is associated with a worse cardiovascular risk profile and is a concomitant indicator of early target organ damage.
Sodium, Blood Pressure, and Arterial Distensibility in Insulin-Dependent Diabetes Mellitus
Authors: Lambert Jan , Pijpers Rik , van Ittersum Frans J. , Comans Emile F.I. , Aarsen Mieke , Pieper Erik J. , Donker Ab J.M. , Stehouwer Coen D.A.
Published: June 2012

Abstract
We investigated 24-hour ambulatory blood pressure and arterial distensibility, a marker of biophysical vessel wall properties, in 32 normoalbuminuric type I diabetic patients and 32 healthy control subjects on diets containing 50 mmol and 200 mmol sodium per day. The increase in daytime diastolic blood pressure from 50 to 200 mmol sodium was significantly higher in the diabetic patients than in the control subjects (2.3±4.9 versus 0.2±3.7 mm Hg,
P
<.05). On a high sodium regimen, femoral artery distensibility was decreased in the diabetic patients compared with the control subjects (19.2±7.6 versus 24.1±9.3 10
−3
/kPa,
P
<.05). Angiotensin-converting enzyme inhibition in the diabetic patients on a high sodium diet decreased daytime diastolic blood pressure and increased femoral artery distensibility. The blood pressure decrease in response to angiotensin-converting enzyme inhibition correlated significantly with the blood pressure increase to sodium (for 24-hour systolic and diastolic blood pressure,
r
=.72,
P
<.001 and
r
=.76,
P
<.001). In addition, we found that in the diabetic patients on a high sodium diet, the renal blood flow response to exogenous angiotensin II was not bimodally distributed, as is the case in essential hypertension, in which a subgroup of the patients are characterized by sodium sensitivity of the blood pressure and an abnormal renal blood flow response to exogenous angiotensin II (“nonmodulator phenotype”). These results show that blood pressure in insulin-dependent diabetes mellitus is sodium sensitive, but that this is not related to the nonmodulator phenotype, and suggest that in IDDM a relatively high sodium intake may be a factor that predisposes to the development of diabetic vascular disease.
Association Between the Angiotensinogen 235T-Variant and Essential Hypertension in Whites
Authors: Kunz Regina , Kreutz Reinhold , Beige Joachim , Distler Armin , Sharma Arya M.
Published: June 2012

Abstract
Recently, an allelic variant of the angiotensinogen gene (
AGT
235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the
AGT
235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the
AGT
235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The
AGT
235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29;
P
<.0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61,
P
<.0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62,
P
<.0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47,
P
<.0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the
AGT
235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension.
On-line Synthesis of the Human Ascending Aortic Pressure Pulse From the Finger Pulse
Authors: Karamanoglu Mustafa , Feneley Michael P.
Published: June 2012

Abstract
Although systolic pressure in the ascending aorta (AA) can be determined accurately from the radial arterial waveform using a single generalized transfer function (TF) of the upper limb, a better on-line methods is needed for accurate noninvasive synthesis of the AA pressure contour to characterize left ventricular contractile function and ventricular-vascular coupling. AA, tonometric carotid (CA), and photoplethysmographic finger (FA) arterial pressure waveforms were recorded in 12 subjects (10 male, aged 59.1±10.3 years, mean±SD) during cardiac catheterization. The AA-FA TF was estimated using (1) a single generalized TF (GAA), (2) individualized TFs directly determined from CA-FA recordings in each patient (DAA), and (3) individualized TFs computed from CA-FA recordings in each patient with a mathematical model of the human upper limb (MAA). AA pressure waveforms were synthesized from FA recordings in real time using convolution windows derived from these TFs. Under steady state conditions, the root mean square error (RMSE) between measured and synthesized AA was lower by DAA (3.3±1.3 mm Hg) and MAA (3.9±1.2 mmHg) than by GAA (4.8±2.0 mm Hg,
P
<.05). During dynamic load alteration induced by the Valsalva maneuver, however, the MAA method performed better (5.4±2.8 mm Hg) than both the GAA (5.8±3.3 mm Hg,
P
<.05) and DAA (6.5±2.7 mm Hg,
P
<.01) methods. The beat-to-beat AA contour can be accurately and noninvasively synthesized on-line using individualized TFs. During dynamic load alteration, individualized TFs derived with an upper limb arterial model provide greater accuracy.
Growth Factors Mediate Intracellular Signaling in Vascular Smooth Muscle Cells Through Protein Kinase C–Linked Pathways
Authors: Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Abstract
Intracellular Ca
2+
and pH are potent modulators of growth factor–induced mitogenesis and contraction. This study examined platelet-derived growth factor–(PDGF-BB) and insulin-like growth factor (IGF-1)–mediated signal transduction in primary cultured unpassaged vascular smooth muscle cells (VSMC) from mesenteric arteries of Sprague-Dawley rats. Intracellular free Ca
2+
concentration ([Ca
2+
]
i
) and intracellular pH (pH
i
) were measured by fluorescence digital imaging using fura-2 AM and 2′7′-bis(2-carboxyethyl)-5
6
-carboxyfluorescein, respectively. Characteristics of [Ca
2+
]
i
transients were determined by pre-exposing cells to Ca
2+
-free buffer, and involvement of the Na
+
/Ca
2+
exchanger was assessed by withdrawal of extracellular Na
+
and by exposure to dimethylbenzamil (Na
+
/Ca
2+
exchange blocker). To determine whether pH
i
responses were mediated via the Na
+
/H
+
exchanger, cells were preincubated with 10
−5
mol
/L
5-(N-ethyl-N-isopropyl)amiloride (a selective Na
+
/H
+
exchange blocker). The role of protein kinase C (PKC) and tyrosine kinases in growth factor signaling was assessed by pre-exposing cells to calphostin C and chelerythrine chloride (selective PKC inhibitors; 10
−5
mol
/L
) and tyrphostin A23 (a selective tyrosine kinase inhibitor; 10
−5
mol
/L
). PDGF-BB and IGF-1 (1 to 10 ng/mL) increased [Ca
2+
]
i
and pH
i
in a dose-dependent manner. At concentrations greater than 1 ng/mL both growth factors induced a biphasic [Ca
2+
]
i
response with an initial transient peak followed by a sustained elevation. At 5 ng/mL PDGF-BB and IGF-1 significantly increased [Ca
2+
]
i
from 95±3 nmol/L to 328±28 and 251±18 nmol/L, respectively. Ca
2+
withdrawal abolished the second phase of [Ca
2+
]
i
elevation. Agonist-induced [Ca
2+
]
i
responses were similarly altered by Na
+
withdrawal, by Na
+
/Ca
2+
exchange blockade, and by PKC inhibition; latency, the period from stimulus application to the first [Ca
2+
]
i
peak, was increased, the initial [Ca
2+
]
i
peak was attenuated, and the sustained phase was prolonged. PDGF-BB and IGF-1 (10 ng/mL) significantly increased pH
i
from 6.89±0.04 nmol/L to 7.11±0.01 and 7.09±0.02 nmol/L, respectively. EIPA and calphostin C completely inhibited agonist-elicited alkalinization. Tyrphostin A-23 abolished second-messenger responses to PDGF-BB and IGF-1, whose receptors have tyrosine kinase activity. In conclusion, PDGF-BB and IGF-1 elicit significant [Ca
2+
]
i
and pH
i
responses in VSMC. The underlying pathways that mediate these responses are partially dependent on Na
+
/Ca
2+
transporters and the Na
+
/H
+
exchanger, both of which are linked to PKC activation.
AT
1
Receptor Antagonist Treatment Caused Persistent Arterial Functional Changes in Young Spontaneously Hypertensive Rats
Authors: Gillies Leesa K. , Lu Mei , Wang Hong , Lee Robert M. K. W.
Published: June 2012

Abstract
The effects of chronic treatment with an AT
1
receptor antagonist (L-158,809) on hypertension development and cardiovascular changes were studied in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). L-158,809 treatment (0.6 mg/kg PO) was initiated at 3 weeks of age and lasted 12 weeks, to 15 weeks of age. The treatment prevented hypertension development in the SHR (systolic blood pressure, BP, of 136±1 mm Hg compared with 198±3 mm Hg in control SHR), and lowered the BP of WKY (99±2 vs 128±1 mm Hg in control WKY). Treatment significantly reduced the heart weight in SHR and WKY. Ten weeks after treatment withdrawal (25 weeks of age), BP had increased in SHR and WKY to 172±8 and 117±3 mm Hg, respectively. Body weight and kidney weight were not affected by the treatment. Mesenteric arteries from treated SHR were less responsive than control SHR arteries to periarterial nerve stimulations at transmural pressures higher than 80 mm Hg (15 and 25 weeks). Control WKY arteries were less responsive than control SHR arteries at almost all transmural pressures tested (15 weeks) and to pressures greater than 80 mm Hg (25 weeks). Pretreatment of arteries with 10
−8
mol/L angiotensin II enhanced their response to nerve stimulation in vessels from control SHR and WKY (25 weeks) but not from treatment-withdrawn SHR and WKY. Treatment did not alter arterial reactivity in response to norepinephrine. Alteration in arterial structure due to L-158,809 treatment was found only when measured at a transmural pressure of 100 mm Hg. In conclusion, L-158,809 was effective in preventing hypertension during the treatment period, in reducing hypertension severity during the withdrawal period, and in persistently decreasing the reactivity of the arteries.
Regional Renal Nitric Oxide Release in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Zuckerman Andrea , Chander Praveen N. , Zeballos Guillermo A. , Stier Charles T.
Published: June 2012

Abstract
Diminished nitric oxide (NO) production has been implicated in the pathogenesis of salt-sensitive hypertension. We questioned whether such a defect is responsible for the malignant hypertension and nephrosclerosis in stroke-prone spontaneously hypertensive rats (SHRSP) fed a high-salt/stroke-prone diet (S) versus a regular diet (R). NO release from 30-minute incubates of cortex and outer and inner medulla were studied in SHRSP at 10, 12, and 16 weeks of age on the S diet versus R diet. SHRSP-S (n=16) exhibited a marked age-dependent increase in NO release, especially in the cortex. Increases were only modest in SHRSP-R (n=21). At 16 weeks, cortical NO was 93±25 versus 6±1 pmol/mg tissue in SHRSP-S versus SHRSP-R (
P
<.001). Immunohistochemical staining increased mostly for neuronal, slightly for endothelial, and negligibly for inducible isoforms of NO synthase and was predominantly in the cortex of SHRSP-S versus SHRSP-R. Despite similar hypertension in SHRSP-S versus SHRSP-R (mean arterial pressure, 174±7 versus 177±2 mm Hg), malignant nephrosclerosis was seen only in SHRSP-S, affecting 22±6% of glomeruli and 23±4 vessels per 100 glomeruli by 16 weeks.
N
ω
-nitro-
l
-arginine (15 mg/kg per day) in SHRSP-S (n=6) abrogated the increase in cortical NO but further augmented the hypertension and accelerated lesion development. Wistar-Kyoto rats at 16 weeks on the R diet (n=8) had NO levels similar to those of SHRSP-R, showed increased cortical NO to only 28±10 pmol/mg on the S diet (n=9) (
P
<.05 versus SHRSP-S), but remained normotensive and lesion-free. We conclude that hypertension and lesion development in SHRSP are not due to deficient renal NO. Accelerated onset of malignant nephrosclerosis by NO synthase inhibition suggests that NO is protective in these animals, mitigating the effects of hypertension and S diet on renal pathology.
Autonomic Nervous System Dysfunction in Elderly Hypertensive Patients With Abnormal Diurnal Blood Pressure Variation
Authors: Kario Kazuomi , Motai Keiji , Mitsuhashi Takeshi , Suzuki Takaaki , Nakagawa Yukinori , Ikeda Uichi , Matsuo Takefumi , Nakayama Toshio , Shimada Kazuyuki
Published: June 2012

Abstract
To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both
P
<.01). There was no significant relationship between the BP level and any HRV parameter for either the daytime or nighttime period. The asleep/awake ratio for systolic BP was significantly correlated with the asleep/awake ratio for HF (
r
=−.363,
P
<.01) and with the asleep/awake ratio for the LF/HF ratio (
r
=.540,
P
<.001), regardless of whether multiple lacunar infarction was present. In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of the diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease.
Relationship Between Blood Pressure and Body Mass Index in Lean Populations
Authors: Kaufman Jay S. , Asuzu Michael C. , Mufunda Jacob , Forrester Terrence , Wilks Rainford , Luke Amy , Long Andrew E. , Cooper Richard S.
Published: June 2012

Abstract
Associations between body mass index (BMI) and blood pressure (BP) have been consistently observed, but remain poorly understood. One unresolved question is whether there is a linear relationship across the entire BMI range. We investigated this question among 11 235 adult men and women from seven low-BMI populations in Africa and the Caribbean. We used kernel smoothing and multivariate linear and spline regression modeling to examine gender differences in the relationship and to test for a threshold. Age-adjusted slopes of BP on BMI were uniformly higher in men than women, with pooled slope ratios of 2.00 and 2.20 for systolic and diastolic BPs, respectively. Men displayed no evidence of age modification or nonlinearity in the relationship, and the age-adjusted slope of systolic BP on BMI was 0.90 (95% confidence interval [CI], 0.76 to 1.04). Women demonstrated both age modification and nonlinearity. For both younger (<45 years) and older (45+ years) women, the optimal change point for a single threshold model was found to be 21 kg/m.
2
Slopes of systolic BP on BMI above this threshold were positive and significant: 0.68 (95% CI, 0.54 to 0.81) and 0.53 (95% CI, 0.29 to 0.76) for younger and older women, respectively. Slopes below the threshold were essentially zero for both groups of women, and the difference between the slopes above and below the threshold was significant for younger women (
P
=.019). In summary, we observed a threshold at 21 kg/m
2
in the relationship between BMI and BP for women but not for men. This contributes to the effort to identify the mechanisms that underlie this relationship and how they differ by gender.
Maintenance of Maternal Diet-Induced Hypertension in the Rat Is Dependent on Glucocorticoids
Authors: Gardner David S. , Jackson Alan A. , Langley-Evans Simon C.
Published: June 2012

Abstract
Recent epidemiological evidence suggests that adult cardiovascular risk is determined by birth weight and factors that influence birth weight, such as maternal nutrition. Data from animal models suggest that an interaction between nutrition and glucocorticoid hormones “programs” increased risk of adult hypertension. Increased fetal exposure to maternal glucocorticoids that is proposed to occur from a reduction in the placental barrier to maternal glucocorticoid, 11β-hydroxysteroid dehydrogenase, is suggested to program hypertension in the resultant offspring from both glucocorticoid-treated and maternally protein–restricted rats. The extent to which postnatal glucocorticoid stimulation may influence the progression of hypertension in the offspring from protein-restricted rat dams was assessed in 6-week-old male Wistar rats, prenatally exposed to either an 18% casein (control) or 9% casein (low protein) diet. Rats from each dietary group were sham operated, adrenalectomized or adrenalectomized, and treated with 20 mg corticosterone/kg body weight per day. Before surgery, systolic blood pressure was significantly higher in the low protein–exposed rats compared with controls (165±3.8 versus 142±3.3 mm Hg,
P
<.0001). Adrenalectomy of the low protein–exposed animals significantly reduced the blood pressure to control levels, while corticosterone replacement restored the hypertensive state. No effect of adrenalectomy on blood pressure was observed in 18% casein controls. In both dietary groups adrenalectomy decreased brain, but not hepatic, glucocorticoid-sensitive enzyme activities and corticosterone treatment elevated activities of all enzymes. The data suggest that maternal diet–induced hypertension is dependent on an intact adrenal gland postnatally and that glucocorticoids are key trophic agents in maintaining the high blood pressure.
Dopamine D
3
Receptor in Peripheral Mononuclear Cells of Essential Hypertensives
Authors: Ricci Alberto , Bronzetti Elena , Mulatero Paolo , Schena Marina , Veglio Franco , Amenta Francesco
Published: June 2012

Abstract
Dopamine D
3
receptor was studied in peripheral mononuclear cells of high-normal, stage 1, stage 2, and stage 3 essential hypertensives using a radioligand binding assay technique with [
3
H]-7-hydroxy-
N,N
-di-n-propyl-2-aminotetraline (7-OH-DPAT) as a radioligand. A group of de novo Parkinsonian patients was also examined as a reference group of impaired dopaminergic function. [
3
H]-7-OH-DPAT was bound specifically to human peripheral mononuclear cells in a manner consistent with the labeling of a dopamine D
3
receptor. No changes in free dopamine, norepinephrine, epinephrine and aldosterone levels, renin activity, dissociation constant of [
3
H]-7-OH-DPAT binding, or the pharmacological profile of [
3
H]-7-OH-DPAT binding were found between normotensive control subjects and essential hypertensives or Parkinsonians. The density of peripheral mononuclear cell [
3
H]-7-OH-DPAT binding sites increased in essential hypertensives parallel to blood pressure value augmentation. A higher density of [
3
H]-7-OH-DPAT binding sites was found in Parkinsonians. In these patients, the density of [
3
H]-7-OH-DPAT binding sites was similar to that observed in high-normal subjects and in stage 1 essential hypertensives. The increased density of peripheral mononuclear cell dopamine D
3
receptor in hypertension as well as in Parkinson’s disease may represent an upregulation mechanism consequent to impaired dopaminergic function. In view of the difficulty in identifying markers of peripheral dopamine function, analysis of dopamine D
3
receptor in peripheral mononuclear cells may help evaluate whether the dopaminergic system is involved in hypertension.
Prevention of the Cardiovascular and Renal Effects of Angiotensin II by Endothelin Blockade
Authors: Herizi Abderraouf , Jover Bernard , Bouriquet Nathalie , Mimran Albert
Published: June 2012

Abstract
—Angiotensin II (Ang II) stimulates the release and gene expression of endothelin-1 in isolated vascular smooth muscle cells. In 47 Sprague-Dawley rats, we assessed the influence of concomitant treatment by the mixed ET
A
/ET
B
endothelin receptor antagonist bosentan (30 mg/kg per day, gavage) on the effect of a 10-day infusion of Ang II (200 ng/kg per minute, SC, osmotic pump) on arterial pressure, renal hemodynamics (microsphere method), albuminuria, cardiac weight, and carotid structure. Ang II increased systolic arterial pressure (SAP) by 49±7 mm Hg. Although bosentan alone did not affect SAP, the development of Ang II–induced hypertension was entirely prevented by the endothelin antagonist. In addition, the reduction in renal blood flow induced by Ang II (4.9±0.3 versus 7.4±0.2 mL · min
−1
· g
−1
in control rats) was prevented by concomitant administration of bosentan (8.8±0.8 mL · min
−1
· g
−1
). The marked increase in albuminuria observed in rats infused with Ang II (2524±961 versus 91±6 μg/24 h in control rats) was prevented by bosentan. Similarly, bosentan abolished the increase in heart weight index (from 2.96±0.03 to 3.41±0.08 mg/g body weight) and carotid media thickness (from 73±14 to 108±6 μm) induced by Ang II infusion. Of interest, the dipsogenic action of Ang II was not influenced by bosentan. In conclusion, endogenous endothelin contributes to the cardiovascular and renal effects of Ang II.
Salt Susceptibility Maps to Chromosomes 1 and 17 With Sex Specificity in the Sabra Rat Model of Hypertension
Authors: Yagil Chana , Sapojnikov Marina , Kreutz Reinhold , Katni Gurion , Lindpaintner Klaus , Ganten Detlev , Yagil Yoram
Published: June 2012

Abstract
—Random genome screening was initiated in the Sabra rat model of hypertension in search of genes that account for salt sensitivity or salt resistance in terms of the development of hypertension. Female salt-sensitive Sabra hypertension-prone (SBH/y) rats were crossed with male salt-resistant Sabra hypertension-resistant (SBN/y) rats, resulting in an F2 cohort consisting of 100 males and 132 females. Systolic blood pressure (BP) was measured in rats at 6 weeks of age under basal conditions and after 4 weeks of salt loading. Genotypes for 24 polymorphic microsatellite markers localized to chromosome 1 and for 8 markers localized to chromosome 17 were determined in F2 and cosegregation with BP was evaluated by ANOVA and multipoint linkage analysis. Basal BP did not cosegregate with any locus on chromosomes 1 or 17. In contrast, BP after salt loading showed significant cosegregation with three QTLs, two on chromosome 1 and one on chromosome 17, designated
SS1a, SS1b
, and
SS17
, respectively; the maximal logarithm of the odds (LOD) scores were 4.71, 4.91, and 3.43, respectively. Further analysis revealed sexual dimorphism. In male F2, BP response to salt loading cosegregated with one QTL (LOD score 4.52) and a second QTL (LOD score 2.98), both on chromosome 1 and coinciding with
SS1a
and
SS1b
, respectively. In female rats, BP response cosegregated with one QTL on chromosome 1 (LOD score 3.08) coinciding with
SS1b
, and with a second QTL on chromosome 17 (LOD score 3.66) coinciding with
SS17
. In males, the additive effects of the two QTLs on chromosome 1 accounted for most of the BP variance to salt loading, whereas in females the additive effects of the QTLs on chromosomes 1 and 17 accounted for over two thirds of the variance. These results identify three putative gene loci on chromosomes 1 and 17 that contribute importantly to salt sensitivity and/or resistance and uncover sex specificity in the role that salt susceptibility genes fulfill in the development of hypertension.
Influence of Venular Prostaglandin Release on Arteriolar Diameter During Functional Hyperemia
Authors: McKay Mary K. , Gardner Angela L. , Boyd Daniel , Hester Robert L.
Published: June 2012

Indomethacin treatment or removal of the venular endothelium will attenuate functional arteriolar vasodilation in the hamster cremaster muscle. We tested the hypothesis that prostanoid release from venular endothelial cells was responsible for the functional vasodilation of the paired arteriole. The hamster cremaster muscle was prepared for in vivo microscopy and stimulated for 1 minute (10V, 40 μsec, 1 Hz). Before a second muscle stimulation, the venular endothelium was removed by perfusing the venule with several air bubbles. A third muscle stimulation was performed during prostaglandin inhibition (28 μmol/L indomethacin superfusion). Arterioles (n=9, 55±5 μm) dilated 25±4% during the initial muscle stimulation. After removal of the endothelium from the paired venules, there was no effect on resting arteriolar diameters (53±4 μm), but the functional arteriolar dilation was attenuated to 15±5% (
P
<.05). The additional indomethacin treatment had a significant effect on resting diameter (50±4 μm) but did not alter the magnitude of the functional vasodilation (11±4%,
P
>.05). In a second set of experiments, the order of the experimental protocol was reversed. Muscle stimulation resulted in a 23±2% increase in diameter (47±2 to 57±2 μm). Indomethacin treatment significantly attenuated the functional dilation to 8±3% (45±2 to 48±2 μm). Arteriolar diameter was significantly smaller after disruption of the venular endothelium with air bubbles (40±2 μm), but there was no effect on the functional vasodilation, 8±3% increase in diameter (to 43±2 μm). These results suggest that the arteriolar dilatory response to muscle stimulation is mediated, in part, by prostanoid release from the venular endothelium.
Induction of P4504A Activity Improves Pressure-Natriuresis in Dahl S Rats
Authors: Alonso-Galicia Magdalena , Frohlich Bruce , Roman Richard J.
Published: June 2012

Clofibrate has been reported to prevent the development of hypertension in Dahl S rats, but its mechanism of action remains to be determined. The present study examined the effects of clofibrate on renal P4504A activity and the pressure natriuresis relationship in Dahl S rats. Dahl S and R rats fed a low-salt diet (0.4% NaCl) were given either clofibrate (240 mg/kg/d) or vehicle (20 mmol/L Na
2
CO
3
) in their drinking water for 1 week and then switched to a high salt diet (8% NaCl) while continuing drug treatment. After 3 weeks, mean arterial pressure in ketamine-Inactin anesthetized rats averaged 121±2 (n=8) in Dahl R, 173±8 (n=6) in Dahl S, and 139±4 mm Hg (n=7) in clofibrate-treated Dahl S rats. Increasing renal perfusion pressure (RPP) from 100 to 150 mm Hg in Dahl R rats increased sodium excretion (U
Na
V) from 2.9±0.7 to 9.7±3.2 μmol/min/g kwt. In contrast, the pressure natriuresis relation was blunted in Dahl S rats and U
Na
V only increased from 2.7±0.9 to 6.1±1.3 μmol/min/g kwt. The pressure natriuresis relation was improved in clofibrate-treated Dahl S rats and U
Na
V increased from 5.1±1.3 to 16.7±2.6 μmol/min/g kwt. At similar levels of RPP, the fractional excretion of sodium tended to be higher in clofibrate-treated than in vehicle-treated Dahl S rats, but not significantly. Glomerular filtration rate (GFR) was 40% higher in clofibrate-compared to vehicle-treated Dahl S rats (0.9±0.2 versus 0.6±0.2 mL/min/g kwt), and was not significantly different from the values seen in Dahl R rats (0.9±0.1 mL/min/g kwt). Clofibrate induced the expression of P4504A protein in the renal cortex and outer medulla of Dahl S rats. These data suggest that induction of renal P4504A activity with clofibrate improves the pressure natriuresis relation in Dahl S rats by primarily increasing GFR.
20-HETE Relaxes Bovine Coronary Arteries Through the Release of Prostacyclin
Authors: Pratt Phillip F. , Falck John R. , Reddy Komandla M. , Kurian Jason B. , Campbell William B.
Published: June 2012

Neutrophils respond to ischemic injury by infiltrating the myocardium via the vascular wall. During this process, neutrophils are activated and release inflammatory mediators. Some of these mediators are metabolites of arachidonic acid. We have reported that neutrophils metabolize arachidonic acid to 20-HETE, a cytochrome P
450
metabolite. We investigated the effects of 20-HETE on coronary vascular tone by examining 20-HETE-induced changes in isometric tension in bovine coronary artery rings precontracted with the thromboxane-mimetic, U46619. 20-HETE relaxed precontracted coronary rings in a concentration-dependent manner (EC
50
of 3 × 10
−7
mol/L). Pretreatment with indomethacin, a cyclooxygenase inhibitor, shifted the concentration-response curve to the right (EC
50
of 1 × 10
−6
mol/L); maximal relaxations were not affected. This suggested that 20-HETE-induced relaxations were, in part, dependent on the cyclooxygenase pathway. Relaxations to 20-HETE were not significantly changed in endothelium-denuded rings. To determine whether metabolism of 20-HETE to a vasoactive compound might explain the relaxations caused by 20-HETE, rings of coronary artery were incubated with [
3
H] 20-HETE. The incubation buffer was extracted and the [
3
H] products resolved on reverse-phase HPLC. Both denuded and intact arteries failed to metabolize [
3
H] 20-HETE. To investigate whether 20-HETE-induced relaxations were related to release of prostacyclin, we measured the release of 6-keto PGF
1α
, the stable metabolite of prostacyclin, from bovine coronary arteries. 20-HETE (1 × 10
−6
mol/L) stimulated an increase in 6-keto PGF
1α
in intact vessels (908 ± 138 pg/mL versus 1402 ± 157 pg/mL, basal versus stimulated). Thus, 20-HETE-induced relaxations are due, in part, to the stimulation of the release of the dilatory prostanoid, prostacyclin.
Nitric Oxide Synthase Activity and Renal Injury in Genetic Hypertension
Authors: Hayakawa Hiroshi , Raij Leopoldo
Published: June 2012

Nitric oxide (NO) is an endogenous vasodilator synthesized in the endothelium by constitutive NO synthase (cNOS). We have shown that upregulation of cNOS activity in hypertension may contribute to forestalling left ventricular and aortic hypertrophy (Hypertension. 29: 235, 1997). NO has been shown to inhibit growth-related responses affecting vascular smooth muscle, and mesangial cells, as well as reduce production of extracellular matrix in response to injury. Here, we investigated the relationship between renal cNOS activity (conversion of [
14
C] L-arginine to [
14
C] L-citrulline) and glomerular (GIS) and tubulointerstitial (TIS) injury scores and urinary protein excretion, indices of renal injury, in age and blood pressure matched spontaneously hypertensive rats (SHR, SBP 220±9 mm Hg) fed 0.5% NaCl diet and Dahl salt-sensitive (DS) rats fed 4% NaCl diet (DS-4%, SBP 228±8 mm Hg) as well as their normotensive counterparts Wistar Kyoto rats fed 0.5% NaCl diet (WKY, 137±3 mm Hg) and DS rats fed 0.5% NaCl diet (DS-0.5%, SBP 135±4 mm Hg). In SHR, renal medullary cNOS activity was 89% higher than in WKY (8.91±0.98 vs 4.71±0.37 nmol/min/g protein,
P
<0.05) whereas, in hypertensive DS-4% rats cNOS activity was 43% lower than in DS-0.5% rats (1.98±0.16 vs 3.48±0.29 nmol/min/g protein,
P
<0.05). Renal cortical cNOS was lower than in medulla but similar in all groups; inducible NOS activity was not detected. Despite hypertension of similar severity and duration, hypertensive DS-4% developed 9 fold more GIS (190±42 vs 21±11), 20 fold more TIS (4.0±0.7 vs 0.2±0.3), and 5 fold more proteinuria (54±11 vs 8.5±3.0 mg/day), all
P
<0.05. The current studies, in conjunction with our recent studies in heart and aorta, strongly suggest that in hypertension, increased cNOS activity may provide a protective homeostatic role in all the end-organs that are targets of hypertensive injury.