bluuebunny/crossref_metadata_2025 huggingface dataset:
Renal Denervation Attenuates the Sodium Retention and Hypertension Associated With Obesity
Authors: Kassab Salah , Kato Tatsuya , Wilkins F. Clayton , Chen Rong , Hall John E. , Granger Joey P.
Published: June 2012

Abstract
Recent studies have indicated that obesity is associated with hypertension, sodium retention, and increased sympathetic nervous system activity. The purpose of this study was to determine the role of renal nerves in mediating the sodium retention and hypertension associated with obesity. We determined the hemodynamic and renal excretory responses to a high-fat diet in control (n=6) and bilaterally renal-denervated (n=7) chronically instrumented dogs. After a control period of 8 days, dogs were placed on a high-fat diet for 5 weeks. In response to a high-fat diet, body weight increased from 19.9±2.2 to 29.9±2.4 kg in the control group and from 21.1±2.0 to 32.4±1.9 kg in the bilaterally renal-denervated group. Heart rate increased from 81±8 to 113±7 beats per minute in the control group and from 79±7 to 103±8 beats per minute in the bilaterally renal-denervated group. Arterial pressure increased significantly from 95±2 to 109±4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the bilaterally renal-denervated group did not significantly increase arterial pressure (which went from 87±3 to 90±4 mm Hg). Furthermore, the decrease in sodium excretion in response to the high-fat diet was significantly greater in the control group than in the bilaterally renal-denervated group. After 5 weeks of a high-fat diet, cumulative sodium retention was 455±85 mmol in the control group and only 252±47 mmol in the bilaterally renal-denervated group. Similar increases in glomerular filtration rate and renal plasma flow occurred in both groups in response to the high-fat diet. The results of this study indicate that the renal nerves play an important role in mediating the sodium retention and hypertension associated with obesity in dogs.
In Vivo Evidence for Microvascular Oxidative Stress in Spontaneously Hypertensive Rats
Authors: Suzuki Hidekazu , Swei Allen , Zweifach Benjamin W. , Schmid-Schönbein Geert W.
Published: June 2012

Abstract
The factors that predispose to the accelerated organ injury that accompanies the hypertensive syndrome have remained speculative and without a firm experimental basis. Indirect evidence has suggested that a key feature may be related to an enhanced oxygen radical production. The purpose of this study was to refine and use a technique to visualize evidence of spontaneous microvascular oxidative stress in vivo in the spontaneously hypertensive rat (SHR) compared with its normotensive control, the Wistar-Kyoto rat (WKY). We investigated the effects of adrenal glucocorticoids on the microvascular oxidative stress sequence. The mesentery was superfused with hydroethidine, a reduced, nonfluorescent precursor of ethidium bromide. In the presence of oxidative challenge, hydroethidine is transformed intracellularly into the fluorescent compound ethidium bromide, which binds to DNA and can be detected by virtue of its red fluorescence. The fluorescent light emission from freshly exteriorized and otherwise unstimulated mesentery microvessels was recorded by digital microscopy. The number of ethidium bromide–positive nuclei along the arteriolar and venular walls in SHR was found to be significantly increased above the level exhibited by WKY. The elevation in ethidium bromide fluorescence in SHR arterioles could be attenuated by a synthetic glucocorticoid inhibitor and in rats subjected to adrenalectomy. The administration of glucocorticoids after adrenalectomy by injection of dexamethasone restored the oxidative reaction in SHR arterioles. Treatment with dimethylthiourea and with a xanthine oxidase inhibitor attenuated the superoxide formation. Although a nitric oxide synthase inhibitor (
N
G
-nitro-
l
-arginine methyl ester) enhanced the ethidium bromide staining in WKY, it did not affect that in SHR. Our findings suggest an enhancement of spontaneous oxidative stress in the microvascular wall of SHR that appears to be associated with glucocorticoid synthesis.
Measuring Forearm Blood Flow and Interpreting the Responses to Drugs and Mediators
Authors: Benjamin Nigel , Calver Alison , Collier Joe , Robinson Brian , Vallance Patrick , Webb David
Published: June 2012

Abstract
Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.
Twenty-Four–Hour Noninvasive Blood Pressure Monitoring and Pain Perception
Authors: Guasti Luigina , Cattaneo Rossana , Rinaldi Orlando , Rossi Maria Grazia , Bianchi Lorenzo , Gaudio Giovanni , Grandi Anna Maria , Gorini Giovanna , Venco Achille
Published: June 2012

Abstract
Although a hypertension-related hypalgesia has been described, the relation between pain perception and the 24-hour blood pressure trend is still unknown. The ambulatory blood pressure monitoring parameters and dental pain sensitivity were correlated in 67 male subjects. The pulpar test (graded increase of test current of 0 to 0.03 mA) was performed on three healthy teeth, and mean dental pain threshold (occurrence of pulp sensation) and pain tolerance (time when the subjects asked for the test to be stopped) were evaluated. Three groups of subjects with normal (n=34), intermediate (n=13), and high (n=20) blood pressure values were identified according to ambulatory monitoring results. Pain threshold differed among the three groups (
P
<.02), being higher in the group with highest blood pressure. The groups of hypertensive subjects showed higher pain tolerance than the normotensive group (
P
<.02). Pain threshold was correlated with 24-hour, diurnal, and nocturnal blood pressure values. Pain tolerance was also related to 24-hour blood pressure and to diurnal and nocturnal diastolic and mean arterial pressure values. Systolic and diastolic blood pressure loads were significantly associated with pain threshold, and diastolic load was also associated with tolerance. The blood pressure variability (SD) did not relate to pain perception. The 24-hour arterial pressure was more closely associated with pain perception than the blood pressure values obtained before the pulpar test. A close correlation between pain perception and 24-hour ambulatory blood pressure was demonstrated. The 24-hour mean blood pressure and loads, more than dynamic variations, were related to pain sensitivity, suggesting that the cardiovascular modulation of pain perception may be influenced mainly by sustained levels of arterial pressure.
Enhanced Neuronal Expression of Calcitonin Gene–Related Peptide in Mineralocorticoid-Salt Hypertension
Authors: Supowit Scott C. , Gururaj Arjun , Ramana Chilakamarti V. , Westlund Karin N. , DiPette Donald J.
Published: June 2012

Abstract
Dorsal root ganglia neuronal cell bodies synthesize the vasodilator neuropeptide calcitonin gene–related peptide and innervate the blood vessels and spinal cord sites (laminae I and II) involved in blood pressure regulation. We previously demonstrated that calcitonin gene–related peptide mRNA content is significantly decreased in dorsal root ganglia and that immunoreactive calcitonin gene–related peptide levels are reduced in laminae I and II of the dorsal horn of the spinal cord in the spontaneously hypertensive rat compared with Wistar-Kyoto control rats. To determine whether neuronal calcitonin gene–related peptide expression is also altered in mineralocorticoid-salt hypertension, we quantified calcitonin gene–related peptide mRNA levels in dorsal root ganglia and protein content in laminae I and II of the spinal cord in rats with mineralocorticoid-salt–induced hypertension. To control for pellet implantation, saline drinking water, and/or uninephrectomy, four normotensive groups were similarly studied. By Northern hybridization analysis, the ratio of calcitonin gene–related peptide mRNA to 18S rRNA was increased approximately fivefold in hypertensive rats (33±7) compared with each of the four normotensive control groups (average of the four groups, 6±0.5;
P
<.01, mineralocorticoid-salt group versus each group). The density of the peptide, quantified by computer-assisted image analysis, in laminae I and II in the hypertensive rats was also increased (66±1 versus average of the four groups, 46±2 arbitrary units;
P
<.001, mineralocorticoid-salt group versus each group). In conclusion, neuronal levels of calcitonin gene–related peptide mRNA and protein are increased in mineralocorticoid-salt hypertension. Therefore, increased neuronal synthesis and available stores of this potent vasodilator may be compensatory responses to and thus attenuate the blood pressure elevation in this experimental model of hypertension.
Gene Expression of Brain Nitric Oxide Synthase and Soluble Guanylyl Cyclase in Hypothalamus and Medulla of Two-Kidney, One Clip Hypertensive Rats
Authors: Krukoff Teresa L. , Gehlen Frank , Ganten Detlev , Wagner Jürgen
Published: June 2012

Abstract
Nitric oxide may act at autonomic sites in the brain to regulate arterial blood pressure. Our goal was to determine whether gene expressions of the brain isoform of nitric oxide synthase and of the β subunit of soluble guanylyl cyclase, the target of nitric oxide, were altered in discrete autonomic brain regions after induction of hypertension in rats. The two-kidney, one clip model was used to induce hypertension, and measurements were made 3 and 6 weeks after the left renal artery was clipped. Only experimental rats with blood pressures elevated by at least 25 mm Hg were used. Total RNA was purified from microdissected tissue blocks containing hypothalamus, dorsal medulla, rostral ventrolateral medulla, and caudal ventrolateral medulla. Changes in nitric oxide synthase and guanylyl cyclase mRNA were semiquantified in each region by use of reverse transcription–polymerase chain reactions in which known concentrations of deletion mutants of the two genes were coamplified as internal standards. Compared with controls, significant decreases and increases in nitric oxide synthase mRNA were found in the hypothalamus (×2.2) and caudal ventrolateral medulla (×6.4), respectively, of hypertensive rats 3 weeks after clipping. These alterations were reversed in hypertensive rats at 6 weeks; levels increased (×4.6) in the hypothalamus and decreased (×5.5) in the caudal ventrolateral medulla. Changes in guanylyl cyclase expression paralleled those for nitric oxide synthase in some but not all areas at both time points. Changes in nitric oxide synthase gene expression in the hypothalamus and the so-called depressor caudal ventrolateral medulla support the hypothesis that nitric oxide participates in the response of the central nervous system to increases in blood pressure. Reversal of responses at 6 weeks after clipping may be related to the different phases of hypertension that occur in this model. Finally, while guanylyl cyclase is thought to be the primary target of nitric oxide, regional differences in expression of nitric oxide synthase and soluble guanylyl cyclase suggest that the two genes are differentially regulated in some parts of the brain.
In Vivo Characterization of Muscarinic Receptor Subtypes That Mediate Vasodilatation in Patients With Essential Hypertension
Authors: Bruning Tobias A. , Chang Peter C. , Hendriks Maarten G.C. , Vermeij Pieter , Pfaffendorf Martin , van Zwieten Pieter A.
Published: June 2012

Abstract
Attenuated cholinergic vasodilatation has been suggested as an endothelium-related mechanism involved in essential hypertension. We investigated the role of muscarinic (M) receptor subtypes in the forearm resistance vasculature. In eight white men with essential hypertension and eight matched normotensive control subjects (age of both groups, 47±4 years; mean±SEM), we infused the nonselective agonist methacholine in the presence of saline and the antagonists atropine (nonselective), pirenzepine (M
1
-selective), and AF-DX 116 (M
2
-selective) into the brachial artery and measured forearm blood flow and forearm vascular resistance using venous occlusion plethysmography. Affinity constants (pK
b
values) were determined from calculated plasma concentrations of the infused compounds and EC
50
values. Sodium nitroprusside was given as an endothelium-independent control, and minimal forearm vascular resistance after 10 minutes of ischemia was used as a marker of structural vascular changes. Hypertensive patients showed higher minimal forearm vascular resistance, indicating structural vascular changes. However, sodium nitroprusside– and methacholine-induced vasodilatation was similar in both groups, with apparent EC
50
values (log moles per liter; mean±SEM) of −7.32±0.13 and −7.51±0.21 in hypertensive patients and −7.37±0.13 and −7.45±0.02 in control subjects, respectively. Atropine, pirenzepine, and AF-DX 116 caused a shift to the right of the concentration-response curve of methacholine, with apparent pK
b
values of 8.63±0.08, 6.81±0.13, and 5.51±0.29 in hypertensive individuals and 8.62±0.10, 6.98±0.08, and 5.49±0.09 in control subjects, respectively. Again, there were no statistically significant differences in these pharmacological parameters between hypertensive patients and normotensive subjects. The affinity constants and rank order for potency of the muscarinic antagonists, atropine>pirenzepine>AF-DX 116, indicate that cholinergic vasodilatation in the forearm vascular bed is predominantly mediated by the M
3
receptor subtype. Despite indications for structural vascular changes in hypertensive subjects, the vasodilator responses to both sodium nitroprusside and methacholine were unchanged in these patients. Essential hypertension is not associated with changes in the pharmacological characteristics of muscarinic receptors in forearm resistance vasculature.
Modulation of Left and Right Ventricular β-Adrenergic Receptors From Spontaneously Hypertensive Rats With Left Ventricular Hypertrophy and Failure
Authors: Atkins Floyd L. , Bing Oscar H. L. , DiMauro Paul G. , Conrad Chester H. , Robinson Kathleen G. , Brooks Wesley W.
Published: June 2012

Abstract
Inotropic responsiveness to β-adrenergic stimulation is generally found to be depressed in cardiac hypertrophy and failure. To investigate whether inotropic responsiveness is associated with alterations in β-adrenergic receptors in spontaneously hypertensive rats (SHR), we studied left ventricular myocardial contractile responses to isoproterenol and β-adrenergic receptor density and affinity in age-matched rats (18 to 24 months), including SHR without heart failure, SHR with evidence of heart failure, and normotensive control Wistar-Kyoto rats (WKY). In the baseline state, papillary muscles from failing SHR demonstrated decreased isometric tension development and a reduction in maximal rate of tension development relative to normotensive WKY and compensated SHR. Compared with WKY, β-adrenergic receptor density of the left ventricle was unchanged in nonfailing SHR and increased in failing SHR (
P
<.05 versus WKY and nonfailing SHR), and β-adrenergic receptor affinity did not differ among groups. In the right ventricle, β-adrenergic receptor density was decreased in failing SHR relative to WKY and nonfailing SHR, and β-adrenergic receptor affinity was not different among groups. Muscle preparations did not exhibit a positive inotropic response to 10
−8
to 10
−5
mol/L isoproterenol or 6.3 μmol/L forskolin in either failing or nonfailing SHR, whereas a positive inotropic response to both drugs was observed in the normotensive WKY. The lusitropic response to isoproterenol and forskolin was intact and similar in both SHR groups and WKY. The findings suggest that in the SHR model of heart failure, impaired intrinsic left ventricular myocardial function and depressed inotropic responsiveness to β-adrenergic stimulation are not associated with downregulation of the β-adrenergic receptor. Impaired inotropic responses, with intact lusitropic responses, to both isoproterenol and forskolin are consistent with the concept that “downstream” events are responsible for impaired inotropy in response to β-adrenergic stimulation in the SHR with chronic left ventricular hypertrophy and failure.
Heterogeneity in Vascular Smooth Muscle Responsiveness to Angiotensin II
Authors: Chen Lihua , McNeill J. Robert , Wilson Thomas W. , Gopalakrishnan Venkat
Published: June 2012

Abstract
We compared the role of endothelium and of endothelin in mediating the vasoconstrictor responses to angiotensin II (Ang II) in three vascular smooth muscle preparations—aorta, mesenteric artery, and tail artery—isolated from adult male Sprague-Dawley rats. The vasoconstrictor potency for Ang II in blood vessels with endothelium varied in the following rank order: aorta>mesenteric artery>tail artery. Although the maximal tension responses to Ang II were similar for mesenteric and tail arteries, it was significantly lower in aorta. Endothelium removal led to a leftward shift in the concentration-response curves to Ang II in the aorta but a rightward shift in the mesenteric artery. Strikingly, Ang II failed to evoke tension responses in tail artery in the absence of endothelium. The endothelin-A (ET
A
)–selective antagonist BQ-123 blocked the responses to Ang II in a noncompetitive manner, with partial and complete attenuation of responses in the endothelium-intact mesenteric and tail artery preparations, respectively. In contrast, BQ-123 did not affect the responses to Ang II in the aorta. BQ-123 also failed to affect the responses to Ang II in endothelium-denuded mesenteric artery rings. The Ang II type 1 (AT
1
) receptor–selective antagonist losartan competitively blocked the responses to Ang II in the three tissues (pA
2
, 8.3 to 8.7) when endothelium was present. These data suggest that there are endothelium-dependent regional variations in vascular tissue sensitivity to Ang II. The vasoconstrictor response to Ang II in rat aorta involves activation of AT
1
receptors located on vascular smooth muscle cells, whereas the response in mesenteric artery involves activation of both vascular and endothelial AT
1
receptors. In contrast, the responses to Ang II in the tail artery may be mediated by the indirect stimulation of vascular smooth muscle ET
A
receptors subsequent to the activation of endothelial AT
1
receptors likely linked to the release of endothelins.
Kallikreins and Kinins
Authors: Margolius Harry S.
Published: June 2012

Abstract
Kinins can affect many aspects of cellular function, but their roles in human homeostatic mechanisms and disease are just beginning to be understood. In this brief review, some of the interesting new observations about kallikrein-kinin system characteristics, roles in cell behavior, and aberrancy in diseases of relevance to readers interested in hypertension will be discussed. Along the way, questions raised by these observations will be posed. They show that we still have much to learn about the contributions of kinins to human cardiovascular diseases but now have in addition both a strong rationale for asking them and the tools to make them operational.
Nitric Oxide Synthase Inhibition in Spontaneously Hypertensive Rats
Authors: Ono Hidehiko , Ono Yuko , Frohlich Edward D.
Published: June 2012

Abstract
To investigate the prolonged effects of nitric oxide inhibition on systemic, renal, and glomerular hemodynamics, the effects of the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) on cardiac index, renal micropuncture results, urinary excretion, and histology were obtained in 20-week-old male spontaneously hypertensive rats (SHR) that were divided into two groups: untreated and L-NAME–treated (50 mg/L), each followed for 3 weeks. Cardiac index and effective renal plasma flow decreased (
P
<.01) in L-NAME–treated SHR, exhibiting a positive correlation (
r
=.816;
P
<.0001). Single-nephron plasma flow (123±8 versus 80±12 nL/min per gram;
P
<.01) and ultrafiltration coefficient (
P
<.05) were also reduced in L-NAME–treated SHR versus controls. Most notably, the L-NAME–treated SHR had increased afferent (4.4±0.3 versus 9.5±1.3 U;
P
<.01) and efferent (1.4±0.1 versus 2.7±0.3 U;
P
<.01) glomerular arteriolar resistances versus controls. These functional changes were associated with significantly altered afferent arteriolar (
P
<.001) and glomerular (
P
<.005) histological injury scores accompanied by marked proteinuria (
P
<.001). Because of the intense afferent glomerular artery constriction and lesser increase in efferent glomerular arteriolar resistance associated with reduced single-nephron plasma flow, glomerular capillary pressure did not increase in the L-NAME–treated SHR. Thus, L-NAME produced marked proteinuria and severe hypertensive nephrosclerosis manifested by afferent arteriolar fibrinoid necrosis, segmental glomerular hyalinosis and sclerosis, and myocardial fibrosis without any further increase in left ventricular mass, thereby providing a new model for severe hypertensive nephrosclerosis in young SHR without the necessity for surgical reduction of renal mass.
Pulse Pressure and Resistance Artery Structure in the Elderly
Authors: James Martin A. , Watt Pamela A. C. , Potter John F. , Thurston Herbert , Swales John D.
Published: June 2012

Abstract
There has been recent interest in the possibility that resistance vessel structural adaptation in hypertension may be more closely related to pulse pressure than to other blood pressure parameters. We investigated the relation between blood pressure and resistance vessel structure in a group of subjects from an age group (older than 60 years) in which a widening of pulse pressure is a typical finding and characterized blood pressure parameters using 24-hour ambulatory blood pressure monitoring. We studied resistance vessels retrieved from biopsies of skin and subcutaneous fat taken from the gluteal region of 32 subjects under local anesthesia (age, 70±1 years [mean±SEM]), 21 of whom were hypertensive and 11 normotensive. Media-lumen ratio was higher in the hypertensive than the normotensive subjects (18.6±1.6% versus 12.8±1.2%,
P
<.01) and correlated with age (
r
=.44,
P
<.05), clinic systolic pressure (
r
=.35,
P
<.05), 24-hour systolic pressure (
r
=.40,
P
<.05), and 24-hour pulse pressure (
r
=.56,
P
<.001). Stepwise multivariate regression analysis identified clinic and 24-hour pulse pressure as the only significant predictors of media-lumen ratio independent of age, other parameters of clinic blood pressure, and blood pressure variability (
R
2
=41%,
P
<.05). These findings confirm those from animal models of hypertension in demonstrating the importance of pulse pressure in relation to cardiovascular structural adaptation and have important implications for the goals of treatment of hypertension in the elderly.
Aortic Distensibility and Structural Changes in Sinoaortic-Denervated Rats
Authors: Lacolley Patrick , Bezie Yvonnick , Girerd Xavier , Challande Pascal , Benetos Athanase , Boutouyrie Pierre , Ghodsi Newsha , Lucet Bernadette , Azoui Rachida , Laurent Stéphane
Published: June 2012

Abstract
The purpose of the present study was to determine the effects of chronic sinoaortic denervation on the mechanical properties and composition of the abdominal aorta in Wistar rats. We used a high-resolution echotracking system to determine in situ under physiological conditions of blood flow and arterial wall innervation the aortic diameter-, compliance-, and distensibility-pressure curves in 16-week-old anesthetized rats that had been denervated at 10 weeks of age for 6 weeks (n=8). Compared with sham-operated rats (n=8) we observed a marked reduction of baroreflex response and increase in overall mean blood pressure variability as measured by standard deviation and spectral analysis in sinoaortic-denervated rats. Mean blood pressure was not affected by sinoaortic denervation in both conscious and anesthetized rats. Sinoaortic denervation significantly shifted the distensibility-pressure curve toward lower levels of distensibility, indicating a decreased aortic distensibility for a given level of arterial pressure. Sinoaortic denervation produced a significant increase of aortic wall cross-sectional area and collagen content, one of the less-distensible components of the arterial wall. These results suggest that intact arterial baroreceptors are necessary for maintaining normal functional and structural properties of large arteries in rats. The reduction in arterial distensibility in chronic sinoaortic-denervated rats may have resulted from different factors, including the initial hypertensive phase, aortic wall hypertrophy, and increase in collagen content. The changes in aortic wall structure and related reduction in aortic distensibility, in addition to other mechanisms, might have been direct consequences of an increased blood pressure variability.
Arterial Wall Hypertrophy and Stiffness in Essential Hypertensive Patients
Authors: Laurent Stéphane
Published: June 2012

Abstract
The purpose of this article is to review some clinical and fundamental evidence that hypertension-induced arterial wall hypertrophy at the site of large and medium-sized arteries is not necessarily associated with a decreased arterial distensibility and increased elastic modulus, and to demonstrate the opposing effects of aging and hypertension-induced hypertrophy on the arterial mechanics in vivo. In the studies reported here, the elastic properties of large and medium-sized arteries were noninvasively assessed from the simultaneous measurement of internal diameter and blood pressure inside the systolic-diastolic range. The distensibility of a medium-sized artery, the radial artery, in untreated essential hypertensive patients was not significantly different from that of normotensive control subjects when the two groups were compared at their respective mean arterial pressures. Despite increased wall thickness, the stiffness of the radial artery wall material, assessed by the incremental modulus of elasticity (Young’s modulus), was not increased in hypertensive patients. At the site of a larger, more elastic artery, such as the common carotid artery, distensibility of hypertensive patients was significantly lower than that of normotensive subjects when the two groups were compared at their respective mean arterial pressures, but distensibility at 100 mm Hg was not significantly different between the two groups. Aging may alter distensibility independently of blood pressure, because carotid distensibility at 100 mm Hg was negatively correlated with age. In spontaneously hypertensive rats the elastic modulus of the common carotid artery wall material was not significantly different from that of Wistar-Kyoto rats at a given circumferential stress. Therefore, the hypertension-induced wall thickening is not necessarily associated with a reduced arterial distensibility and increased elastic modulus.
Isolated Diastolic Hypertension
Authors: Fang Jing , Madhavan Shantha , Cohen Hillel , Alderman Michael H.
Published: June 2012

Abstract
To identify pretreatment characteristics associated with subsequent myocardial infarction in young and middle-aged previously untreated hypertensive individuals, we examined the experience of 1560 participants in a work-site hypertension control program who were younger than 60 years. Subjects were categorized by initial blood pressure as having isolated diastolic hypertension (<160/≥90 mm Hg, n=965) or combined systolic and diastolic hypertension (≥160/≥90 mm Hg, n=595). During 4.5 years of follow-up, there were 24 myocardial infarctions, yielding an overall incidence of 3.89 per 1000 person-years. Subjects with systolic/diastolic hypertension were older, had higher cholesterol and blood sugar levels, and included more smokers and people with left ventricular hypertrophy on electrocardiogram than those with isolated diastolic hypertension. Age-adjusted incidence rates for myocardial infarction were 5.20 and 2.21 per 1000 person-years in systolic/diastolic hypertension and isolated diastolic hypertension, respectively, and the relative risk of systolic/diastolic hypertension was 2.31 (95% confidence interval, 1.29-4.15). Among subjects with isolated diastolic hypertension, no myocardial infarction occurred in those with systolic pressure less than 140 mm Hg. Cox regression analysis including other known risk factors showed that pulse pressure, as a continuous variable (hazards ratio, 1.54; 95% confidence interval, 1.08-2.20), and type of hypertension, ie, systolic/diastolic hypertension versus isolated diastolic hypertension (hazards ratio, 2.11; 95% confidence interval, 1.08-4.13), were independently associated with myocardial infarction. These results suggest that young and middle-aged treated hypertensive individuals with normal pretreatment systolic pressure enjoy a more favorable prognosis than do those with systolic elevation. This data, based on the outcomes of treated subjects, cannot be extrapolated to define what the experience of individuals with isolated diastolic hypertension might be in the absence of drug therapy.
Vasodilator Response of Mesenteric Arterioles to Histamine in Spontaneously Hypertensive Rats
Authors: Suzuki Hidekazu , Zweifach Benjamin W. , Schmid-Schönbein Geert W.
Published: June 2012

Abstract
Recent evidence suggests that spontaneously hypertensive rats (SHR) exhibit an impaired response to inflammatory mediators. We designed this study to analyze the response of arterioles of SHR after stimulation with a proinflammatory agent, histamine, compared with the response of arterioles of normotensive Wistar-Kyoto (WKY) controls. We observed mesenteric arterioles by intravital microscopy in rats under general anesthesia and measured their lumen diameters after histamine superfusion. To compare the concentration-response curve with histamine, we also studied the effect of an endothelium-dependent vasodilator, acetylcholine, and an independent vasodilator, sodium nitroprusside. At the end of each experiment we applied papaverine topically to determine the maximal diameter for each vessel, from which we computed arteriolar tone. Arteriolar tone in SHR is set at a higher steady state level than in WKY. The concentration required for a 50% dilator response (EC
50
) of histamine in SHR was significantly higher than that in WKY. In SHR the arteriolar response showed the same refractory pattern to histamine as to acetylcholine. In contrast, the EC
50
of sodium nitroprusside in SHR was similar to that in WKY. Our results indicate that SHR exhibit an impaired dilator response to histamine that is due to a blunted endothelium-dependent vasodilation.
Inhibition by Cardiac Natriuretic Peptides of Rat Vascular Endothelial Cell Migration
Authors: Ikeda Miwako , Kohno Masakazu , Takeda Tadanao
Published: June 2012

Abstract
Vascular endothelial cell migration is proposed to be an important process in the initiation and progression of atherosclerosis. We designed the present study to examine the effects of atrial and brain natriuretic peptides on fetal calf serum–stimulated migration of cultured rat aortic endothelial cells using Boyden’s chamber method. Fetal calf serum clearly stimulated migration in a concentration- and time-dependent manner. Rat atrial natriuretic peptide-(1-28) and rat brain natriuretic peptide-45, which are the major circulating forms of atrial and brain natriuretic peptides in rats, inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10
−10
and 10
−6
mol/L. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. The addition of a cGMP analogue 8-bromo-cGMP, significantly inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10
−7
and 10
−3
mol/L. Rat atrial natriuretic peptide-(5-25) was much less effective than atrial natriuretic peptide-(1-28) or rat brain natriuretic peptide-45 with respect to inhibiting migration and increasing cGMP levels. These results indicate that atrial and brain natriuretic peptides inhibit fetal calf serum–stimulated vascular endothelial cell migration, probably through a cGMP-dependent process.
Weight Threshold and Blood Pressure in a Lean Black Population
Authors: Bunker Clareann H. , Ukoli Flora A. , Matthews Karen A. , Kriska Andrea M. , Huston Sara L. , Kuller Lewis H.
Published: June 2012

Abstract
Hypertension is virtually absent in very lean rural African populations but is becoming more common in higher-weight urban African populations and is very common in predominantly obese Westernized black populations. This implies that there is a threshold above which weight is related to blood pressure. We studied urban Nigerian civil servants, a lean population in transition toward a more Westernized lifestyle. Blood pressure, fat-related measurements, fasting insulin, physical activity, alcohol intake, macronutrient intake, and electrolyte excretion were measured in 500 male and 299 female civil servants in Benin City, Nigeria, in 1992. Median body mass index (BMI) was 21.5 kg/m
2
in men and 24.0 kg/m
2
in women. Examination of age-adjusted mean blood pressure across quantiles of BMI in men and women suggested a threshold of 21.5 kg/m
2
below which blood pressure was not correlated with BMI. Above this threshold blood pressure was correlated with BMI. Comparison of groups above and below the lower BMI threshold found that differences in blood pressure–BMI covariation were not explained by differences in alcohol intake, caloric or macronutrient intake, or electrolyte excretion. Physical activity was higher in men below the threshold. Fasting insulin and waist-hip ratio were strongly correlated with BMI even in this very lean population but neither was independently related to blood pressure. We conclude that there is a threshold below which little relationship between blood pressure and weight is observed. Above this threshold even at levels considered lean in US blacks, weight is a major determinant of blood pressure in this population of African blacks, which shares ancestry with US blacks.
Relationship of Arachidonic Acid Release to Porcine Coronary Artery Relaxation
Authors: Weintraub Neal L. , Stephenson Alan H. , Sprague Randy S. , McMurdo Lorraine , Lonigro Andrew J.
Published: June 2012

Abstract
In porcine coronary artery endothelium-dependent relaxation to bradykinin is in part attributed to a chemically unidentified factor, termed endothelium-derived hyperpolarizing factor (EDHF). We hypothesize that arachidonic acid, acting through a cyclooxygenase-independent mechanism, is responsible for EDHF production. To define the relationship between EDHF production and arachidonic acid release, we investigated the role of phospholipase C in bradykinin-induced relaxation and prostaglandin I
2
production (an index of arachidonic acid release) in porcine coronary artery. The phospholipase C inhibitor U73122 (1 μmol/L) abolished bradykinin-induced, nitric oxide–mediated relaxation but did not inhibit either bradykinin-induced, EDHF-mediated relaxation or prostaglandin I
2
production. However, when given at a larger dose (20 μmol/L) U73122 abolished both bradykinin-induced, EDHF-mediated relaxation and prostaglandin I
2
production. Similarly, the calcium-ATPase inhibitor thapsigargin, given at a dose (1 μmol/L) that abolished bradykinin-induced increases in intracellular calcium concentration in cultured porcine coronary artery endothelial cells, eliminated both bradykinin-induced, EDHF-mediated relaxation and prostaglandin I
2
production. Although thapsigargin abolished bradykinin-induced prostaglandin I
2
production, the basal production of prostaglandin I
2
was enhanced, and contraction of endothelium-intact rings was attenuated. These latter responses are most likely related to enhanced basal arachidonic acid release and associated EDHF production. These observations suggest that phospholipase C activation and increased intracellular calcium concentration are required for both bradykinin-induced arachidonic acid release and EDHF production in porcine coronary artery. Moreover, EDHF production in porcine coronary artery appears to be closely associated with arachidonic acid release, thus supporting the hypothesis that arachidonic acid, acting through a cyclooxygenase-independent mechanism, is responsible for EDHF production in porcine coronary artery.
Enhanced Levels of Tissue-Type Plasminogen Activator in Borderline Hypertension
Authors: Wall Ulrika , Jern Christina , Bergbrant Anders , Jern Sverker
Published: June 2012

Abstract
Despite effective antihypertensive therapy, essential hypertension is still associated with considerable residual risk of cardiovascular complications. The aim of the present study was to investigate the state of the endogenous fibrinolytic system in young subjects with borderline hypertension. Thirty-nine young (age, 24 to 34 years) male subjects with borderline hypertension (systolic BP [SBP] 140 to 160 mm Hg and/or diastolic BP [DBP] 85 to 95 mm Hg) and 17 normotensive control subjects (age, 22 to 31 years; SBP 110 to 130 and DBP 60 to 80 mm Hg) were recruited from a population screening. Plasma levels of tissue-type plasminogen activator (t-PA) antigen and activity and plasminogen activator inhibitor 1 (PAI-1) antigen were determined at rest and in response to a venous occlusion test. Borderline-hypertensive subjects had metabolic and anthropometric characteristics similar to normotensive individuals. In comparison with normotensive subjects, borderline-hypertensive subjects had higher plasma concentration of t-PA antigen both at rest and after venous occlusion but similar levels of t-PA activity or PAI-1 antigen. The increase in t-PA antigen and activity in response to venous occlusion was significantly greater in borderline-hypertensive subjects than in normotensive control subjects (
P
<.0001 and
P
=.003, respectively). In stepwise regression analyses, 24-hour mean arterial pressure emerged as the single most powerful predictor of t-PA antigen levels, but body mass index was the most important determinant of t-PA activity and PAI-1 antigen. However, PAI-1 was explained by both body mass index (partial
r
=.48,
P
<.001) and 24-hour mean arterial pressure (partial
r
=.29,
P
<.05). Thus, early hypertension may be associated with significant alterations in endogenous fibrinolysis.
Distinct Mechanisms of Upregulation of Type 1A Angiotensin II Receptor Gene Expression in Kidney and Adrenal Gland
Authors: Wang Donna H. , Du Yong
Published: June 2012

Abstract
We previously demonstrated that type 1A angiotensin II (Ang II) receptor (AT
1A
) is the predominant renal subtype and is upregulated by a low sodium diet. We have now tested the hypothesis that upregulation of AT
1A
mRNA induced by sodium deficiency is renal specific and is mediated by activation of type 1 Ang II receptor (AT
1
). Male Wistar rats were divided into four groups (n=5 each) and treated for 2 weeks with normal sodium diet (0.5%), normal sodium plus 3 mg/kg per day losartan, low sodium diet (0.07%), or low sodium diet plus losartan. At the end of the 2 weeks, body weight and mean arterial pressure were not different among the four groups (
P
>.05). Plasma renin activity was elevated by losartan treatment, sodium restriction, or the combination of the two versus control (
P
<.05). Northern blot analysis showed that the ratio of renal AT
1A
to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA was increased by losartan treatment, sodium restriction, or the combination of the two versus control (
P
<.05). In contrast, the ratio of adrenal AT
1A
to GAPDH mRNA was increased only by sodium restriction versus three other groups (
P
<.05). Thus, sodium deficiency increases AT
1A
mRNA in both kidney and adrenal gland, while Ang II receptor blockade by losartan prevents low sodium–induced AT
1A
mRNA only in adrenal gland. We conclude that the increase in AT
1A
mRNA induced by sodium deficiency is not renal specific and that different mechanisms of regulation exist, ie, in adrenal gland, low sodium–induced upregulation of AT
1A
is dependent upon Ang II activation of the AT
1
receptor, while in kidney, a non-AT
1
–dependent mechanism is operant.
Effect of Copper-Zinc Superoxide Dismutase on Endothelium-Dependent Vasodilation in Patients With Essential Hypertension
Authors: García Carlos E. , Kilcoyne Crescence M. , Cardillo Carmine , Cannon Richard O. , Quyyumi Arshed A. , Panza Julio A.
Published: June 2012

Abstract
Patients with essential hypertension have abnormal endothelium-dependent vasodilation related to decreased nitric oxide activity. The specific mechanism responsible for this abnormality is unknown. Recent studies in hypertensive animals have suggested an augmented destruction of nitric oxide by superoxide anions. Therefore, in the present study we aimed to investigate whether this mechanism is responsible for the abnormal vasodilator function of hypertensive patients. To this end, we studied the vascular responses to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct smooth muscle dilator) before and after combined administration of copper-zinc superoxide dismutase (a scavenger of superoxide anions with poor intracellular penetrance; 6000 U/min) in 20 healthy control subjects (11 men and 9 women; aged 50±6 years) and 20 hypertensive patients (13 men and 7 women; aged 51±9 years). Drugs were infused into the brachial artery, and the response of the forearm vasculature was measured by plethysmography. The vasodilator response to acetylcholine was significantly blunted in hypertensive patients compared with control subjects (maximal flow: 8.2±4 versus 12.7±3 mL/min per 100 mL;
P
<.02); however, no difference was observed in the response to sodium nitroprusside (8.1±4 versus 9.5±3 mL/min per 100 mL). In healthy control subjects superoxide dismutase infusion did not modify the vasodilator response to acetylcholine (maximal flow: 12.7±3 before versus 12.1±3 after superoxide dismutase). Similarly, in hypertensive patients superoxide dismutase infusion did not alter the response to acetylcholine (maximal flow: 8.2±4 versus 7.7±4). Prolonged (up to 60 minutes) infusion of higher doses (24 000 U/min) of copper-zinc superoxide dismustase did not modify the response to acetylcholine in either healthy control subjects or hypertensive patients. The administration of this form of superoxide dismutase did not modify the response to sodium nitroprusside in either group. These findings confirm previous observations of impaired endothelium-dependent vasodilation in patients with essential hypertension and demonstrate that copper-zinc superoxide dismutase does not alter these responses.
Biological Determinants of Aldosterone-Induced Cardiac Fibrosis in Rats
Authors: Robert Valérie , Silvestre Jean-Sebastien , Charlemagne Danièle , Sabri Abdelkarim , Trouvé Pascal , Wassef Michel , Swynghedauw Bernard , Delcayre Claude
Published: June 2012

Abstract
To determine the events leading to cardiac fibrosis in aldosterone-salt hypertensive rats, we studied protein and mRNA accumulation of procollagens I and III for 60 days. After 3 and 7 days of treatment systolic pressure was normal, and no histological or biochemical changes were seen in rat hearts. At day 15 arterial pressure was raised (+40%) and left ventricular hypertrophy was +15%. Cardiac examination after hemalun-eosin staining and immunolabeling with anticollagen I and III antibodies showed no structural alterations, but an 83% increase in right ventricular type III procollagen mRNA levels was found. At 30 and 60 days we found progressive cardiac fibrosis, with inflammatory cells, myocyte necrosis, and elevation of both types I and III procollagen mRNA levels in both ventricles. To determine whether aldosterone had effects on Na,K-ATPase that might lead to ionic disturbances and induce myocyte necrosis, we studied the major cardiac Na,K-ATPase isoform genes. Although Na,K-ATPase α
1
- and β
1
-subunit mRNA levels were elevated in kidney at day 1, neither of these cardiac transcripts nor the specific α
2
isoform was altered between 1 and 15 days. These results show that accumulation of procollagen mRNAs occurs before collagen deposition. Cardiac alterations are late and not preceded by changes in Na,K-ATPase cardiac gene expression, precluding a direct modulation of cardiac collagen synthesis and Na,K-ATPase by aldosterone.
GABAergic and Glutaminergic Modulation of Centrally Evoked Arrhythmias in Rats
Authors: Crambes Anne , Monassier Laurent , Chapleau Denis , Roegel Jean-Christophe , Feldman Josiane , Bousquet Pascal
Published: June 2012

Abstract
A standard electrical stimulus applied to the posterior hypothalamus evoked cardiac arrhythmogenic responses in the spontaneously hypertensive rat. Isolated premature ventricular beats or doublets and nonsustained ventricular tachycardic salvos were observed. This effect was associated with a large rise in blood pressure (79±3 mm Hg). The same stimulus in normotensive Wistar-Kyoto rats produced no significant cardiac arrhythmias, and the rise in blood pressure was smaller (36±2 mm Hg). We investigated the influence of baclofen, a GABA
B
receptor agonist, and two
N
-methyl-
d
-aspartate receptor antagonists on the arrhythmogenic response to hypothalamic stimulation. Intravenous baclofen (3 mg/kg) had no effect in the normotensive Wistar-Kyoto rats, but in the spontaneously hypertensive rats it enhanced the adjusted mean value of the number of extrasystoles from 0.5±0.5 to 18±1 (
P
<.001). This value was also increased (from 3±1 to 17±1,
P
<.001) by an intracisternal injection of baclofen (1 μg/kg). This facilitatory effect of baclofen was prevented by treatment with atenolol (0.5 mg/kg). Two glutamate receptor antagonists, ketamine (7.5 mg/kg IV) and kynurenic acid (200 μg/kg intracerebroventricularly), prevented both the arrhythmogenic response to the hypothalamic stimulation and its facilitation by baclofen. The study confirms that hypothalamic stimulation facilitates the development of arrhythmias through a sympathetic drive and that these arrhythmias are easier to induce in spontaneously hypertensive rats than in normotensive Wistar-Kyoto rats. Both the central GABAergic and the glutamatergic systems are implicated in the development of these ventricular arrhythmias, since baclofen could disinhibit the glutamatergic central pathway. These results could account for the ability of the spontaneously hypertensive rats to develop ventricular arrhythmias of central origin.