bluuebunny/crossref_metadata_2025 huggingface dataset:
Ethnic Differences in Insulinemia and Sympathetic Tone as Links Between Obesity and Blood Pressure
Authors: Weyer Christian , Pratley Richard E. , Snitker Soren , Spraul Maximilian , Ravussin Eric , Tataranni P. Antonio
Published: June 2012

Abstract
—Hyperinsulinemia and increased sympathetic nervous system (SNS) activity are thought to be pathophysiological links between obesity and hypertension. In the present study, we examined the relation among heart rate (HR), blood pressure (BP), and percent body fat (hydrodensitometry or DEXA), fasting plasma insulin concentration, and muscle sympathetic nerve activity (MSNA, microneurography) in male, normotensive whites (n=42) and Pima Indians (n=77). Pima Indians have a high prevalence of obesity and hyperinsulinemia but a relatively low prevalence of hypertension. Compared with whites, Pima Indian men had a higher percent body fat (28% versus 21%) and higher fasting insulin concentrations (210 versus 132 pmol/L) but lower MSNA (27 versus 33 bursts/min) (all
P
<0.001). In both ethnic groups, HR and BP were positively related to percent body fat and MSNA, and both were significant independent determinants of HR and BP in multiple regression analyses. However, MSNA was positively related to percent body fat and the fasting insulin concentration in whites (
r
=0.60 and
r
=0.47, both
P
<0.01) but not in Pima Indians (
r
=0.15 and
r
=0.03, NS) (
P
<0.01 for ethnic differences in the slope of the regression lines). These results confirm the physiological importance of the SNS in normal BP regulation but indicate that the roles of hyperinsulinemia and increased SNS activity as mediators for the relation between obesity and hypertension can differ between different ethnic groups. The lack of an increase in SNS activity with increasing adiposity and insulinemia in Pima Indians may contribute to the low prevalence of hypertension in this population.
Adrenergic and Reflex Abnormalities in Obesity-Related Hypertension
Authors: Grassi Guido , Seravalle Gino , Dell’Oro Raffaella , Turri Carlo , Bolla Giovanni Battista , Mancia Giuseppe
Published: June 2012

Abstract
—Previous studies have shown that essential hypertension and obesity are both characterized by sympathetic activation coupled with a baroreflex impairment. The present study was aimed at determining the effects of the concomitant presence of the 2 above-mentioned conditions on sympathetic activity as well as on baroreflex cardiovascular control. In 14 normotensive lean subjects (aged 33.5±2.2 years, body mass index 22.8±0.7 kg/m
2
[mean±SEM]), 16 normotensive obese subjects (body mass index 37.2±1.3 kg/m
2
), 13 lean hypertensive subjects (body mass index 24.0±0.8 kg/m
2
), and 16 obese hypertensive subjects (body mass index 37.5±1.3 kg/m
2
), all age-matched, we measured beat-to-beat arterial blood pressure (by Finapres device), heart rate (HR, by ECG), and postganglionic muscle sympathetic nerve activity (MSNA, by microneurography) at rest and during baroreceptor stimulation and deactivation induced by stepwise intravenous infusions of phenylephrine and nitroprusside, respectively. Blood pressure values were higher in lean hypertensive and obese hypertensive subjects than in normotensive lean and obese subjects. MSNA was significantly (
P
<0.01) greater in obese normotensive subjects (49.1±3.0 bursts per 100 heart beats) and in lean hypertensive subjects (44.5±3.3 bursts per 100 heart beats) than in lean normotensive control subjects (32.2±2.5 bursts per 100 heart beats); a further increase was detectable in individuals with the concomitant presence of obesity and hypertension (62.1±3.4 bursts per 100 heart beats). Furthermore, whereas in lean hypertensive subjects, only baroreflex control of HR was impaired, in obese normotensive subjects, both HR and MSNA baroreflex changes were attenuated, with a further attenuation being observed in obese hypertensive patients. Thus, the association between obesity and hypertension triggers a sympathetic activation and an impairment in baroreflex cardiovascular control that are greater in magnitude than those found in either of the above-mentioned abnormal conditions alone.
Development of Hypertension Induced by Subpressor Infusion of Angiotensin II
Authors: Wu Wei , Zhang Yong , Ballew Jennifer R. , Fink Gregory , Wang Donna H.
Published: June 2012

Abstract
—Long-term administration of a subpressor dose of angiotensin II (Ang II) leads to pressor hyperresponsiveness and slow development of hypertension. Our preliminary data show that mRNA expression for calcitonin-gene related peptide in dorsal root ganglia was significantly increased by subpressor infusion of Ang II. To determine the role of sensory nerves in the development of hypertension induced by subpressor infusion of Ang II, newborn Wistar rats were given 50 mg/kg SC capsaicin on the 1st and 2nd days of life. After the weaning period, male rats were divided into 4 groups and subjected to the following treatments for 2 weeks: capsaicin+Ang II (150 ng · kg
−
1
· min
−
1
SC by osmotic pumps, CAP-AII), capsaicin+vehicle (CAP), control+Ang II (CON-AII), and control+vehicle (CON). The results show that mean arterial pressure was significantly elevated in both Ang II–infused rats compared with non–Ang II–treated rats (
P
<0.05), and it was higher in CAP-AII than in CON-AII rats (
P
<0.05). The 24-hour urinary and sodium excretions were lower in CAP-AII than in CON-AII, CAP, and CON rats (
P
<0.05). These data demonstrated that sensory denervation exacerbates the development of hypertension and impairs renal excretory function when a subpressor dose of Ang II is given. These results indicate that activation of sensory nerves, either by Ang II or by other hormonal or hemodynamic factors, plays a compensatory role in promoting urine and sodium excretion and attenuating elevated blood pressure initiated by Ang II.
Renin-Angiotensin System Blockade Improves Endothelial Dysfunction in Hypertension
Authors: Goto Kenichi , Fujii Koji , Onaka Uran , Abe Isao , Fujishima Masatoshi
Published: June 2012

Abstract
—Angiotensin-converting enzyme (ACE) inhibitor improves the impaired hyperpolarization and relaxation to acetylcholine (ACh) via endothelium-derived hyperpolarizing factor (EDHF) in arteries of spontaneously hypertensive rats (SHR). We tested whether the angiotensin type 1 (AT
1
) receptor antagonist also improves EDHF-mediated responses and whether the combined AT
1
receptor blockade and ACE inhibition exert any additional effects. SHR were treated with either AT
1
receptor antagonist TCV-116 (5 mg · kg
−
1
· d
−
1
) (SHR-T), enalapril (40 mg · kg
−
1
· d
−
1
) (SHR-E), or their combination (SHR-T&E) from 8 to 11 months of age. Age-matched, untreated SHR (SHR-C) and Wistar Kyoto (WKY) rats served as controls (n=8 to 12 in each group). Three treatments lowered blood pressure comparably. EDHF-mediated hyperpolarization to ACh in mesenteric arteries in the absence or presence of norepinephrine was significantly improved in all treated SHR. In addition, the hyperpolarization in the presence of norepinephrine was significantly greater in SHR-T&E than in SHR-E (ACh 10
−
5
mol/L with norepinephrine: SHR-C −7; SHR-T −19; SHR-E −15; SHR-T&E −22; WKY −14 mV). EDHF-mediated relaxation, assessed in the presence of indomethacin and
N
G
-nitro-
l
-arginine, was markedly improved in all treated SHR. Hyperpolarization and relaxation to levcromakalim, a direct opener of ATP-sensitive K
+
-channel, were similar in all groups. These findings suggest that AT
1
receptor antagonists are as effective as ACE inhibitors in improving EDHF-mediated responses in SHR. The beneficial effects of the combined AT
1
receptor blockade and ACE inhibition appears to be for the most part similar to those of each intervention.
Differential Control of Systolic and Diastolic Blood Pressure
Authors: Lloyd-Jones Donald M. , Evans Jane C. , Larson Martin G. , O’Donnell Christopher J. , Roccella Edward J. , Levy Daniel
Published: June 2012

Abstract
—Data from the Third National Health and Nutrition Examination Survey, phase 2 (1991 to 1994), indicate that among hypertensive individuals in the United States, 53.6% are treated and only 27.4% are controlled to goal levels. We sought to determine whether poor hypertension control is due to lack of systolic or diastolic blood pressure control, or both. We studied Framingham Heart Study participants examined between 1990 and 1995 and determined rates of control to systolic goal (<140 mm Hg), diastolic goal (<90 mm Hg), or both (systolic <140 and diastolic <90 mm Hg). Of 1959 hypertensive subjects (mean age 66 years, 54% women), 32.7% were controlled to systolic goal, 82.9% were controlled to diastolic goal, and only 29.0% were controlled to both. Among the 1189 subjects who were receiving antihypertensive therapy (60.7% of all hypertensive subjects), 49.0% were controlled to systolic goal, 89.7% were controlled to diastolic goal, and only 47.8% were controlled to both. Thus, poor systolic blood pressure control was overwhelmingly responsible for poor rates of overall control to goal. Covariates associated with lack of systolic control in treated subjects included older age (OR for age 61 to 75 years, 2.43, 95% CI 1.79 to 3.29; OR for age >75 years, 4.34, 95% CI 3.10 to 6.09), left ventricular hypertrophy (OR 1.63, 95% CI 1.04 to 2.54), and obesity (OR for body mass index ≥30 versus <25 kg/m
2
, 1.49, 95% CI 1.08 to 2.06). In this community-based sample of middle-aged and older subjects, overall rates of hypertension control were remarkably similar to those in the Third National Health and Nutrition Examination Survey. Poor blood pressure control was overwhelmingly due to lack of systolic control, even among treated subjects. Therefore, clinicians and policymakers should place greater emphasis on the achievement of goal systolic levels in all hypertensive patients, especially those who are older or obese or have target organ damage.
Cytochrome P450–Dependent Renal Arachidonic Acid Metabolism in Desoxycorticosterone Acetate–Salt Hypertensive Mice
Authors: Honeck Horst , Gross Volkmar , Erdmann Bettina , Kärgel Eva , Neunaber Ralf , Milia Anna Franca , Schneider Wolfgang , Luft Friedrich C. , Schunck Wolf-Hagen
Published: June 2012

Abstract
—Cytochrome P450 (P450)-dependent arachidonic acid metabolites may act as mediators in the regulation of vascular tone and renal function. We studied arachidonic acid hydroxylase activities in renal microsomes from normotensive NMRI mice, desoxycorticosterone acetate (DOCA)-salt hypertensive mice, and DOCA-salt mice treated with either lovastatin or bezafibrate, both of which improve hemodynamics in this model. Control renal microsomes had arachidonic acid hydroxylase activities of 175±12 pmol · min
−1
· mg
−1
. The metabolites formed were 20- and 19-hydroxyarachidonic acid, representing ≈80% and ≈20% of the total hydroxylation. Treatment with DOCA-salt resulted in significantly decreased hydroxylase activities (to 84±4 pmol · min
−1
· mg
−1
) of the total microsomal P450 content and a decrease in immunodetectable Cyp4a proteins. Lovastatin had no effect on these variables, whereas bezafibrate increased arachidonic acid hydroxylase activities to 163±12 pmol · min
−1
· mg
−1
. In situ hybridization with probes for Cyp4a-10, 12, and 14 revealed that Cyp4a-14 was the P450 isoform most strongly induced by bezafibrate. The expression was concentrated in the cortical medullary junction and was localized predominantly in the proximal tubules. In conclusion, these results suggest that the capacity to produce 20-hydroxyarachidonic acid is impaired in the kidneys of DOCA-salt hypertensive mice. Furthermore, bezafibrate may ameliorate hemodynamics in this model by restoring P450-dependent arachidonic acid hydroxylase activities. Lovastatin, on the other hand, exerts its effects via P450-independent mechanisms.
Nifedipine Prevents Changes in Nitric Oxide Synthase mRNA Levels Induced by Cyclosporine
Authors: Sánchez-Lozada Laura G. , Gamba Gerardo , Bolio Alexis , Jiménez Fabiola , Herrera-Acosta Jaime , Bobadilla Norma A.
Published: June 2012

Abstract
—Cyclosporine toxicity mainly affects kidney and liver function. We have previously shown that cyclosporine nephrotoxicity alters kidney nitric oxide synthase mRNA pattern of expression. To determine if nitric oxide synthase expression changes are mediated directly by cyclosporine or by secondary hemodynamic alterations induced by cyclosporine, we evaluated if these effects are tissue specific and if nifedipine-induced vasodilation prevents these alterations. Uninephrectomized Wistar rats treated for 7 days with olive oil, cyclosporine (30 mg/kg), nifedipine (3 mg/kg), and nifedipine+cyclosporine were studied. In vehicle and cyclosporine groups, the gene expression of the neuronal, inducible, and endothelial nitric oxide synthases in cerebellum, heart, intestine, liver, renal cortex, and medulla was evaluated. The administration of cyclosporine was associated with nephrotoxicity and hepatotoxicity, increased endothelial nitric oxide synthase mRNA levels in renal cortex and liver, and a decrease in inducible nitric oxide synthase and neuronal nitric oxide synthase in renal medulla. The mRNA levels of the 3 nitric oxide synthase isoforms were not affected in any other tissue. Nifedipine did not alter nitric oxide synthase expression in the control group but prevented changes associated with cyclosporine. These results suggest that cyclosporine-induced changes in the pattern of expression of the nitric oxide synthases may be secondary to its hemodynamic effects.
Reduction in Left Ventricular Messenger RNA for Transforming Growth Factor β
1
Attenuates Left Ventricular Fibrosis and Improves Survival Without Lowering Blood Pressure in the Hypertensive TGR(mRen2)27 Rat
Authors: Pinto Yigal M. , Pinto-Sietsma Sara-Joan , Philipp Tobias , Engler Sonja , Koβmehl Peter , Hocher Berthold , Marquardt Heike , Sethmann Svenja , Lauster Roland , Merker Hans-Joachim , Paul Martin
Published: June 2012

Abstract
—Angiotensin II recruits transforming growth factor β
1
(TGFβ
1
) and is related to left ventricular fibrosis. However, it is unclear whether chronic in vivo reduction in left ventricular TGFβ
1
expression blunts fibrosis and improves outcome in angiotensin II–dependent hypertension. Four-week-old male hypertensive TGR(mRen2)27 (Ren2) rats received either normal food, low-dose losartan (0.5 mg · kg
−1
· d
−1
), or tranilast (a nonspecific TGFβ inhibitor; 400 mg · kg
−1
· d
−1
) (n=10 for each group) for 12 weeks and were compared with Sprague-Dawley control rats. The effect of tranilast on survival was evaluated in 34 additional untreated homozygous Ren2 rats. Tranilast or low-dose losartan did not lower blood pressure. However, the increase in left ventricular weight (Ren2 versus SD 3.1±0.16 versus 2.1± 0.06 mg/g body wt;
P
<0.05) was significantly (
P
<0.05) blunted by both tranilast (2.7±0.05) and losartan (2.7±0.07). Both drugs prevented the increase in left ventricular TGFβ
1
mRNA and fibronectin mRNA and blunted the increase in hydroxyproline content and the increase in perivascular fibrosis. The perivascular fibrosis score correlated significantly with the level of expression of TGFβ
1
(
r
=0.62;
P
=0.019). In situ hybridization demonstrated increases in TGFβ
1
mRNA, predominantly in perivascular and nonmyocyte areas. Both drugs did not prevent the decrease in systolic or diastolic dP/dt, but tranilast significantly improved the survival of untreated Ren2 rats (
P
=0.029). In conclusion, TGFβ
1
mRNA expression is increased predominantly in nonmyocyte regions in the hypertrophied left ventricle in this angiotensin II–dependent model of hypertension. This increase is probably due to high angiotensin II levels rather than to hypertension. This is the first study to suggest that chronic inhibition of TGFβ
1
expression attenuates left ventricular hypertrophy and fibrosis, even without lowering blood pressure.
Normal TGF Responsiveness During Chronic Treatment With Angiotensin-Converting Enzyme Inhibition
Authors: Turkstra Erika , Braam Branko , Koomans Hein A.
Published: June 2012

Abstract
—Acute inhibition of angiotensin II formation by angiotensin-converting enzyme inhibition (ACE-I) attenuates tubuloglomerular feedback (TGF) responsiveness. This has been proposed to facilitate sodium excretion, which contributes to the antihypertensive effects of ACE-I. However, in previous experiments in spontaneously hypertensive Fawn-hooded rats, TGF responses were normal during chronic ACE-I treatment. In the present study, we investigated TGF responsiveness during chronic ACE-I treatment in normotensive rats and the involvement of changes in nitric oxide or angiotensin II activity. Maximum TGF responses were assessed in control Sprague-Dawley rats and in rats acutely (acute ACE-I, 3 μg/min IV) and chronically (chronic ACE-I, 100 mg/L PO 2 to 3 weeks+acute 3 μg/min enalaprilat IV) treated with ACE-I. In all groups, TGF responses were also assessed during late proximal tubular perfusion with 1 mmol/L nitro-
l
-arginine. In a last group, the chronic ACE-I treatment was combined with acute ACE-I and high doses of intrarenal losartan (acute 3 μg/min enalaprilat IV+50 mg/kg losartan). The maximum TGF responses in acutely treated ACE-I rats were strongly attenuated (0.7±0.4 mm Hg versus 6.5±0.8 mm Hg in control rats,
P
<0.05). Mean arterial pressure was lower in the chronically treated ACE-I group (107±5 mm Hg versus 126±5 mm Hg in control rats,
P
<0.05); however, TGF responses were normal (6.4±0.9 mm Hg). Intraluminal nitro-
l
-arginine infusion did not influence TGF responses during acute ACE-I (2.3±0.4 mm Hg) but enhanced TGF responses during chronic ACE-I to the same extent as in control rats (14.5±2.3 versus 16.7±1.9 mm Hg, NS). In the rats chronically treated with ACE-I with superimposed acute infusion of losartan or chronically treated with losartan, TGF responses were significantly attenuated (1.8±0.8 mm Hg and 2.6±0.8 mm Hg, respectively;
P
<0.05 versus chronic ACE-I and control). Prolonged administration with ACE-I is associated with normal TGF responses. This phenomenon appears to be mediated by AT1 receptors, because acute treatment with losartan in rats chronically treated with ACE-I and chronic treatment with losartan lead to strong attenuation of TGF responses.
Brachial Vascular Reactivity in Blacks
Authors: Perregaux Daniel , Chaudhuri Ajay , Rao Suresh , Airen Anshul , Wilson Michael , Sung Bong-Hee , Dandona Paresh
Published: June 2012

Abstract
—Endothelial function was studied ultrasonographically in a healthy subset of African Americans (blacks) because they have an increased risk of hypertension and vascular disease. Twenty-four healthy black and 28 well-matched white subjects were investigated. Ischemia was induced by inflating a cuff over the forearm to 40 mm Hg higher than systolic pressure for 5 minutes. Brachial artery diameter and blood flow velocity were measured at baseline and at 15, 45, and 60 seconds after deflation by use of an Acuson 128XP10 ultrasonograph with a 7.5 MHz transducer. Mean postischemic dilatation, an index of endothelial function, was 1.76±0.56% in blacks and 8.79±1.22% in whites (
P
<0.001). Median postischemic vasodilatation in black men [0% (0% to 2.86%)] was not significantly different to that in black women [0.82% (0% to 3.14%)], whereas white women [11.48% (8.70% to 14.29%)] dilated significantly more than white men [4.20% (2.13% to 5.56%)] (
P
<0.05). Both groups dilated significantly over baseline diameter to sublingual nitroglycerin administration 18.7±2.5% (blacks) and 20.2±3.2% (whites;
P
=NS). Mean hyperemic responses did not differ significantly between the 2 subject groups, nor did they differ between men and women of both ethnic groups. We conclude that endothelium-dependent vasodilatation is significantly impaired in healthy, young blacks compared with whites and that gender differences are not seen in blacks with regard to this phenomenon. An impairment in endothelium-dependent NO generation may be a contributing factor to future hypertension and vascular disease in healthy blacks.
Effects of Spinal Section and of Positive-Feedback Excitatory Reflex on Sympathetic and Heart Rate Variability
Authors: Montano Nicola , Cogliati Chiara , da Silva Valdo Jose Dias , Gnecchi-Ruscone Tomaso , Massimini Marcello , Porta Alberto , Malliani Alberto
Published: June 2012

Abstract
—The sympathetic outflow appears to be capable of displaying a rhythmicity synchronous with cardiovascular Mayer’s waves even after spinal section. To test the hypothesis that spinal sympathetic low frequency (LF) oscillation can be enhanced during sympathetic excitation, we recorded cardiac sympathetic nerve activity (SNA), R-R interval, arterial pressure, and ventilation in 9 unanesthetized decerebrate-vagotomized cats before and after C1 spinal section. LF and high frequency (HF) components were detected in the variability of SNA, R-R interval, and systolic arterial pressure both before and after spinal section. In this latter condition, a significant coherence between LF
SNA
and LF
R-R
was present in 5 animals, whereas HF
SNA
and HF
R-R
were correlated in 4 animals. During an excitatory sympathetic spinal reflex elicited by aortic constriction, the efferent sympathetic firing was markedly enhanced (from 7±2 to 33±7 spikes/s); concomitantly, the powers of both LF
SNA
and HF
SNA
were also increased. Coherence between LF
SNA
and LF
R-R
became significant in all cases, whereas HF
SNA
and HF
R-R
became correlated in 6 animals. In 3 animals, the reflex sympathetic excitation was no longer elicitable after interrupting a vast contingent of sympathetic afferents by means of thoracic dorsal root section. We report for the first time that LF and HF oscillations are detectable in SNA, R-R interval, and systolic arterial pressure variabilities of decerebrate-vagotomized spinal cats and that an excitatory spinal reflex is capable of increasing the power of both SNA spectral components.
Decreased Cardiopulmonary Baroreflex Sensitivity in Chagas’ Heart Disease
Authors: Consolim-Colombo Fernanda Marciano , Filho Jose Augusto Barreto , Lopes Heno Ferreira , Sobrinho Carlos Roberto Rodrigues , Otto Maria Estafânia , Riccio Grazia Maria Guerra , Mady Charles , Krieger Eduardo Moacyr
Published: June 2012

Abstract
—No study has been performed on reflexes originating from receptors in the heart that might be involved in the pathological lesions of Chagas’ heart disease. Our study was undertaken to analyze the role of cardiopulmonary reflex on cardiovascular control in Chagas’ disease. We studied 14 patients with Chagas’ disease without heart failure and 12 healthy matched volunteers. Central venous pressure, arterial blood pressure, heart rate, forearm blood flow, and forearm vascular resistance were recorded during deactivation of cardiopulmonary receptors. By reducing central venous pressure by applying −10 and −15 mm Hg of negative pressure to the lower body, we observed (a) a similar decrease of central venous pressure in both groups; (b) a marked increase in forearm vascular resistance in the control group but a blunted increase in the Chagas’ group; and (c) no significant changes in blood pressure and heart rate. To analyze cardiopulmonary and arterial receptors, we applied −40 mm Hg of lower-body negative pressure. As a consequence, (a) central venous pressure decreased similarly in both groups; (b) blood pressure was maintained in the control group, whereas in patients with Chagas’ disease, a decrease in systolic and mean arterial pressure occurred; (c) heart rate increased in both groups; and (d) forearm vascular resistance increased significantly and similarly in both groups. Unloading of receptors with low levels of lower-body negative pressure did not increase forearm vascular resistance in patients with Chagas’ disease, which suggests that the reflex mediated by cardiopulmonary receptors is impaired in patients with Chagas’ disease without heart failure. Overall control of circulation appears to be compromised because patients did not maintain blood pressure under high levels of lower-body negative pressure.
Cognitive Performance in Hypertensive and Normotensive Older Subjects
Authors: Harrington Frances , Saxby Brian K. , McKeith Ian G. , Wesnes Keith , Ford Gary A.
Published: June 2012

Abstract
—Longitudinal studies suggest that hypertension in midlife is associated with cognitive impairment in later life. Cross-sectional studies are difficult to interpret because blood pressure can change with onset of dementia and the inclusion of subjects on treatment and with hypertensive end-organ damage can make analysis difficult. We examined cognitive performance in hypertensive and normotensive subjects without dementia or stroke ≥70 years of age. Cognitive performance was determined with the use of a computerized assessment battery in 107 untreated hypertensives (55 women, age 76±4 years, blood pressure, 164±9/89±7; range, 138 to 179/68 to 99 mm Hg) and 116 normotensives (51 female, age 76±4 years, 131±10/74±7; 108 to 149/60 to 89 mm Hg). Older subjects with hypertension were significantly slower in all tests (reaction time, milliseconds; simple, 346±100 versus 318±56,
P
<0.05; memory scanning, 867±243 versus 789±159,
P
<0.01; immediate word recognition, 947±261 versus 886±192,
P
<0.05; and delayed word recognition, 937±230 versus 856±184,
P
<0.05; picture recognition, 952±184 versus 894±137,
P
<0.01; spatial memory, 1390±439 versus 1258±394,
P
<0.01; excepting choice reaction time, 510±75 versus 498±72,
P
=0.08). Accuracy was also impaired in tests of number vigilance, 99.2±2.5% versus 99.9±0.9,
P
<0.01; delayed word recognition, 83.5±16 versus 87.9±9.8,
P
<0.01; and spatial memory 64±32 versus 79±20,
P
<0.001. Hypertension in older subjects is associated with impaired cognition in a broad range of areas in the absence of clinically evident target organ damage.
Nervous Kidney
Authors: DiBona Gerald F.
Published: June 2012

Abstract
—Increases in renal sympathetic nerve activity regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. Because increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between the renal sympathetic nerves and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, for example, the direct (by specific innervation) and indirect (by angiotensin II) contributions of increased renal sympathetic nerve activity to the regulation of renal function. The effects of increased renal sympathetic nerve activity on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with ACE inhibitors or angiotensin II–type AT
1
-receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated after renal denervation. These interactions can also be extrarenal, for example, in the central nervous system, wherein renal sympathetic nerve activity and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, whose permeable blood-brain barrier permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II–type AT
1
-receptor antagonists into the ventricular system or microinjected into the rostral ventrolateral medulla are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (eg, congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin-angiotensin system and renal sympathetic nerve activity are involved in influencing the neural control of renal function.
Increased Vascular Adrenergic Vasoconstriction and Decreased Vasodilation in Blacks
Authors: Stein C. Michael , Lang Chim C. , Singh Iqbal , He Huai B. , Wood Alastair J. J.
Published: June 2012

Abstract
—Blood pressure reactivity is enhanced in young black subjects through mechanisms that are poorly understood. We compared α-adrenergic–mediated vasoconstrictor and β-adrenergic vasodilator sensitivity and their relation to sympathetic activity in blacks and whites. Ten healthy black (age, 29.9±2.4 years) and 10 white (age, 28.3±1.9 years) men were studied. Forearm blood flow was measured with strain-gauge plethysmography after the intrabrachial artery administration of phenylephrine (1.25 to 20 μg/min) and isoproterenol (60 and 400 ng/min) after application of lower-body negative pressure and after a cold pressor test. Forearm and systemic norepinephrine spillover were measured with a radioisotope dilution technique. α-Adrenergic vasoconstriction was markedly increased (ANOVA
P
=0.008) and β-adrenergic vasodilation decreased (ANOVA
P
=0.02) in blacks. Phenylephrine (10 μg/min) decreased forearm blood flow by 58.0±2.5% in blacks but only by 26.6±6.0% in whites (
P
<0.001). Vasoconstrictor response to endogenous norepinephrine, stimulated by a cold pressor test, resulted in a higher forearm vascular resistance in blacks than in whites (107.3±13 versus 64.8±13 mm Hg · mL
−
1
· 100 mL
−
1
,
P
=0.03). There were no significant ethnic differences in basal or stimulated forearm or systemic norepinephrine spillover. Increased vasoconstrictor and decreased vasodilator responses in blacks were not correlated. Increased sympathetically mediated vascular tone caused by enhanced vasoconstriction and attenuated vasodilation, effects that would be additive, and not increased sympathetic activity could enhance vascular reactivity and may play a role in the pathogenesis of hypertension in blacks.
Effect of Antioxidant Therapy on Blood Pressure and NO Synthase Expression in Hypertensive Rats
Authors: Vaziri Nosratola D. , Ni Zhenmin , Oveisi Fariba , Trnavsky-Hobbs Debra L.
Published: June 2012

Abstract
—Earlier studies have demonstrated evidence for increased reactive oxygen species, enhanced NO synthase (NOS) expression, and elevated NO production in spontaneously hypertensive rats (SHR). Given the negative-feedback regulation of NOS by NO, we hypothesized that enhanced NO inactivation by ROS may contribute to compensatory upregulation of NOS in SHR. The present study was designed to test this hypothesis. Eight-week-old male SHR and Wistar-Kyoto rats were treated for 3 weeks with either a placebo or the potent antioxidant, lazaroid (desmethyltirilazad, 10 mg · kg
−
1
· d
−
1
, by gastric gavage). Tail arterial blood pressure, urinary excretion of NO metabolites (ie, nitrate and nitrite), and immunodetectable NOS isotype proteins in the vascular, renal, cardiac, and cerebral tissues were measured. The placebo-treated SHR group showed a marked elevation of blood pressure and a significant upregulation of aorta, kidney, and cardiac tissue endothelial and inducible NOS (eNOS and iNOS, respectively) proteins and of brain and renal tissue neuronal NOS. Lazaroid therapy ameliorated hypertension and mitigated the upregulation of eNOS and iNOS in vascular, renal, and cardiac tissues but had limited effect on the expression of renal and brain neuronal NOS. In contrast, lazaroid therapy had no effect on blood pressure, urinary nitrate and nitrite excretion, or tissue NOS isotype expressions in the Wistar-Kyoto group. These findings support the role of oxidative stress in the genesis and/or maintenance of hypertension and compensatory upregulation of the expression of eNOS and iNOS in SHR.
Role of Cyclooxygenase-2–Derived Metabolites and NO in Renal Response to Bradykinin
Authors: Rodríguez Francisca , Llinás María T. , Moreno Carol , Salazar F. Javier
Published: June 2012

Abstract
—It has been reported that bradykinin (BK) can induce or activate both cyclooxygenase (COX) isoforms and that the renal effects of BK seem to be mediated by prostaglandins and NO. The first objective of this study was to evaluate the relative contribution of both COX isoforms in mediating the renal response to BK in anesthetized dogs. The second objective was to examine whether COX-2 inhibition potentiates the renal effects induced by NO reduction during BK administration. Intrarenal BK infusion (8 ng · kg
−1
· min
−1
, n=6) elicited a significant increment in renal blood flow, sodium excretion, urine volume, and the fractional excretion of lithium. COX-2 inhibition (nimesulide, 5 μg · kg
−1
· min
−1
, n=6) reduced the renal vasodilatation but did not significantly modify the natriuresis or diuresis secondary to BK. Administration of a nonspecific isozyme COX inhibitor (meclofenamate, 5 μg · kg
−1
· min
−1
; n=6) did not induce greater effects than those produced by nimesulide. NO synthesis reduction (
N
G
-nitro-
l
-arginine methyl ester [L-NAME], 3 μg · kg
−1
· min
−1
) prevented the renal vasodilatation and the increment in the fractional excretion of lithium induced by BK but did not affect the natriuretic or diuretic response. Simultaneous nimesulide infusion did not modify the renal effects of L-NAME during BK infusion (n=6). Finally, inhibition of both COX isoforms with meclofenamate, in dogs treated with L-NAME (n=6), completely prevented the vasodilator and excretory actions of BK. The results of this study suggest that (1) NO and prostanoids dependent on COX-2 seem to be involved in the renal vasodilatation induced by BK, and (2) there is an interaction between NO and COX-1–derived metabolites in mediating the natriuretic and diuretic response to BK.
Vascular Effects of Progesterone
Authors: Barbagallo Mario , Dominguez Ligia J. , Licata Giuseppe , Shan Jie , Bing Li , Karpinski Edward , Pang Peter K. T. , Resnick Lawrence M.
Published: June 2012

Abstract
—Vascular actions of progesterone have been reported, independently of estrogen, affecting both blood pressure and other aspects of the cardiovascular system. To study possible mechanisms underlying these effects, we examined the effects of P in vivo in intact rats and in vitro in isolated artery and vascular smooth muscle cell preparations. In anesthetized Sprague-Dawley rats
,
bolus intravenous injections of P (100 μg/kg) significantly decreased pressor responses to norepinephrine (0.3 μg/kg). In vitro, progesterone (10
−8
to 10
−5
mmol/L) produced a significant, dose-dependent relaxation of isolated helical strips, both of rat tail artery precontracted with KCl (60 mmol/L) or arginine vasopressin (3 nmol/L), and of rat aorta precontracted with KCl (60 mmol/L) or norepinephrine (0.1 μmol/L). In isolated vascular smooth muscle cells, progesterone (5×10
−
7
mol/L) reversibly inhibited KCl (30 mmol/L) -induced elevation of cytosolic-free calcium by 64.1±5.5% (
P
<0.05), and in whole-cell patch-clamp experiments, progesterone (5×10
−6
mol/L) reversibly and significantly blunted L-type calcium channel inward current, decreasing peak inward current to 65.7±4.3% of the control value (
P
<0.05). Our results provide evidence that progesterone is a vasoactive hormone, inhibiting agonist-induced vasoconstriction. The data further suggest that progesterone effects on vascular tissue may, at least in part, be mediated by modulation of the L-type calcium channel current activity and, consequently, of cytosolic-free calcium content.
Pharmacodynamic Contribution to the Vasodilator Effect of Chronic AT
1
Receptor Blockade in SHR
Authors: Paull Jeremy R. A. , Li Xiao C. , Sampey Donella B. , Widdop Robert E.
Published: June 2012

Abstract
—The present study investigated the pharmacodynamic contribution of AT
1
receptor blockade to the regional hemodynamic effects of long-term treatment with the AT
1
receptor antagonist candesartan cilexetil in adult spontaneously hypertensive rats (SHR). Blood pressure and Doppler flowmetry measurements were made during and after withdrawal of candesartan cilexetil, representing times of maximal and negligible blockade of AT
1
receptor–mediated vasoconstriction. There was marked renal, mesenteric, and hindquarter vasodilation in SHR treated for 4 weeks with candesartan cilexetil (2 mg/kg per day in drinking water, n=8) compared with vehicle (n=8). Blood pressure increased after withdrawal of candesartan cilexetil but was still reduced after 6 days, whereas regional flows and conductances did not reduce significantly compared with the last day of treatment. There was more prolonged inhibition of angiotensin (Ang) I–induced than Ang II–induced pressor responses after withdrawal of candesartan cilexetil, but these returned to control levels before blood pressure reached fully hypertensive levels. The renal and mesenteric vasoconstrictor effects of exogenously administered Ang I and Ang II returned to control levels just 2 days after withdrawal of candesartan cilexetil. Therefore, sustained inhibition of tonic Ang-mediated vasoconstriction caused by blockade of the AT
1
receptor is not the only factor contributing to the hemodynamic profile after long-term administration of candesartan cilexetil. In addition, compared with the vehicle group, blood pressures at maximum vasoconstriction and maximum vasodilation (an indirect measure of vascular hypertrophy) were significantly reduced in candesartan cilexetil–treated SHR on the last day of treatment, as was mesenteric media wall-to-lumen ratio in a separate group of similarly treated SHR. Collectively, these findings indicate that Ang-mediated vasoconstriction rapidly normalizes on withdrawal of AT
1
receptor blockade and that regression of vascular hypertrophy is important in determining blood pressure and hemodynamic status in candesartan cilexetil–treated SHR at this time.
Effect of Lead on Nitric Oxide Synthase Expression in Coronary Endothelial Cells
Authors: Vaziri Nosratola D. , Ding Yaoxian
Published: June 2012

Chronic exposure to low levels of lead causes hypertension (HTN) in humans and animals. We have previously shown that increased reactive oxygen species (ROS) leads to enhanced NO inactivation, depressed NO bioavailability, and compensatory upregulation of NO synthases (NOSs) in rats with lead-induced HTN. We have further demonstrated increased ROS generation with lead exposure in cultured endothelial cells. In the present study, we tested the effect of lead (medium containing lead acetate, 1 ppm) alone and with either the superoxide dismutase–mimetic agent tempol or a potent antioxidant lazaroid compound (both at 10
−8
and 10
−7
mol/L) on endothelial NOS expression and NO production in cultured human coronary endothelial cells. Lead-treated cells showed a significant upregulation of endothelial NOS (eNOS) protein abundance (
P
<0.002) and a significant increase in the production of NO metabolites (NO
2
−
+NO
3
−
=NOx,
P
<0.01). Cotreatment with either tempol or lazaroid abrogated the lead-induced upregulation of eNOS protein and NO
x
production. In contrast, tempol and lazaroid had no effect on either eNOS protein expression or NO
x
production in the control cells. Thus, lead exposure upregulated eNOS expression in vitro, simulating the results of our previous in vivo studies. This phenomenon points to a direct as opposed to an indirect (eg, HTN-mediated) effect of lead on NO metabolism. The reversal of lead effect by lazaroid and the cell-permeable superoxide dismutase–mimetic agent tempol suggests that lead exposure increases generation and/or reduces dismutation of superoxide, which in turn promotes oxidative stress, enhances NO inactivation, and elicits a compensatory upregulation of eNOS whose expression is negatively regulated by NO.
Nifedipine Increases Endothelial Nitric Oxide Bioavailability by Antioxidative Mechanisms
Authors: Berkels Reinhard , Egink Guido , Marsen Tobias A. , Bartels Henning , Roesen Renate , Klaus Wolfgang
Published: June 2012

Short-term treatment of the endothelium with dihydropyridine calcium antagonists resulted in an increased release in NO that is not due to a modulation of L-type calcium channels, because macrovascular endothelial cells do not express this channel. We investigated whether long-term (48 hours) treatment of porcine endothelial cell cultures with the dihydropyridine calcium antagonist nifedipine resulted in a similar enhanced NO liberation. Regarding to the underlying mechanism, we examined whether (1) nifedipine changed the mRNA and protein levels of the constitutive endothelial NO synthase (NOS) in endothelial cell cultures or (2) nifedipine exerts an NO protective effect via its antioxidative properties, as revealed in a cell culture model and with native endothelium from porcine coronary arteries. Nifedipine induced a significant time- and concentration-dependent increase (132±47%, 1 μmol/L, 40 minutes’ incubation) in the basal NO liberation (oxyhemoglobin assay). This increased NO release was not due to elevated NOS (type III) mRNA (Northern blot analysis) and protein (Western blot analysis) levels. However, nifedipine (both short- and long-term treatment) significantly reduced the basal and glucose (20 and 30 mmol/L)-stimulated formation of reactive oxygen species (lucigenin assay) of endothelial cell cultures and native cells. We conclude that the calcium antagonist nifedipine enhances the bioavailability of endothelial NO without significantly altering the NOS (type III) mRNA and protein expression, possibly via an antioxidative protection. This increased NO availability may cause part of the vasodilation and might contribute to the antithrombotic, antiproliferative, and antiatherosclerotic effects of dihydropyridine calcium antagonists.
Association Analysis of β
2
-Adrenergic Receptor Polymorphisms With Hypertension in Japanese
Authors: Kato Norihiro , Sugiyama Takao , Morita Hiroyuki , Kurihara Hiroki , Sato Tomohide , Yamori Yukio , Yazaki Yoshio
Published: June 2012

Significant evidence has been provided for the pathophysiological involvement of the β
2
-adrenergic receptor (
ADRB2
) in hypertension. Among
ADRB2
polymorphisms identified to date, 2 amino acid substitutions, Arg16Gly and Gln27Glu, and a promoter variant, T-47C, are considered functionally important. In particular, Arg16Gly was shown to be associated with hypertension in black and white subjects. To investigate the relevance of
ADRB2
polymorphisms to hypertension, we undertook an extensive association study in a Japanese population. An association was tested in 2 ways. First, a case-control study was conducted in 842 hypertensive and 633 normotensive subjects. In addition to the overall comparison between case and control groups, each was stratified by body mass index and compared with an independent panel of 525 diabetic subjects. Second, ANOVA and multivariate analyses were performed to test the significance of an association between
ADRB2
genotype and the level of blood pressure within the entire population except for 395 subjects who had been under treatment for hypertension. Although no significant association was observed for Arg16Gly and T-47C, 2 analytical methods indicated a marginal association (
P
=0.01 to 0.04) between the Glu27 variant and lower blood pressure levels. Given such a normotensive propensity, the odds ratio for Glu27 versus Gln27 allele frequencies was estimated to be 0.74, with a wide confidence interval (95% CI, 0.55 to 0.99) reflecting the low Glu27-allele frequency (6% to 8%) in Japanese. There were no apparent confounding influences of obesity and diabetes on the postulated association. Our data suggest that 3
ADRB2
polymorphisms tested are unlikely to confer principal genetic susceptibility for hypertension in the Japanese population. However, further investigation is warranted to clarify the relevance of
ADRB2
polymorphisms to blood pressure regulation.
Exclusion of the ACE D/I Gene Polymorphism as a Determinant of Endothelial Dysfunction
Authors: Rossi Gian Paolo , Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Albertin Giovanna , Favilla Stefania , Sudano Isabella , Pessina Achille C. , Salvetti Antonio
Published: June 2012

A deletion/insertion (D/I) polymorphism within the ACE gene may increase the risk of cardiovascular events through still unknown mechanisms. The latter may involve increased angiotensin II–induced NO breakdown and/or reduced agonist-mediated NO release. We therefore investigated whether the D allele of the ACE gene affects endothelium-dependent vasodilatation in mild-to-moderate primary hypertensive patients and healthy normotensive subjects. We compared in a cross-sectional study the forearm blood flow response of the 3 D/I genotypes with 5 incrementally increasing doses of the endothelium-dependent vasodilator acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg · 100 mL
−1
· min
−1
) in 142 subjects: 103 mild-to-moderate uncomplicated primary hypertensives (49.3±9.1 years old, 152±11/99±5 mm Hg) and 39 normotensives (44.6±15.3 years old, 122±12/78±6 mm Hg). We also assessed the endothelium-independent vasodilatation in the forearm, as blood flow response to 3 incrementally increasing doses of sodium nitroprusside (1, 2, and 4 μg · 100 mL
−1
· min
−1
). The overall genotype distribution was II, n=10; ID, n=70; and DD, n=62. It did not differ significantly between primary hypertensives and normotensives. A significant blunting of endothelium-dependent vasodilatation in primary hypertensive patients compared with normotensive subjects (
P
<0.001) was found. No effect of the DI genotype on endothelium-dependent and -independent vasodilatation was detected. Thus, these results obtained in a relatively large population do not support the contention that the D allele is associated with a blunting of either stimulated endothelial NO or donated NO responses in both mild-to-moderate primary hypertensive patients and normotensive subjects.
Left Ventricle and Arteries
Authors: Cohn Jay N.
Published: June 2012

The observation in the 1970s that the performance of the dysfunctional left ventricle was under the influence of aortic impedance led us to exploration of the role of the renin-angiotensin system and other hormonal systems in the progression of heart failure. The apparent efficacy of vasodilator drugs led to the first randomized, controlled trial in heart failure that demonstrated that all impedance-lowering drugs did not exert the same long-term benefit. Differences on the structural remodeling process in the myocardium and arterial vasculature were shown to account for the differential long-term response. We now recognize that the remodeling process in the left ventricle may be inhibited by nitrates, converting enzyme inhibitors, and β-blockers, and this growth process leads to adverse outcomes. The impedance load on the left ventricle is influenced by vascular remodeling that also may be inhibited by drugs such as converting enzyme inhibitors. Thus, progression of cardiovascular disease is largely a consequence of structural changes that are hormonally mediated and may be inhibited by drug therapy.
The Future of Hypertension Therapy: Sense, Antisense, or Nonsense?
Authors: Pachori Alok S. , Huentelman Matthew J. , Francis Sharon C. , Gelband Craig H. , Katovich Michael J. , Raizada Mohan K.
Published: June 2012

Hypertension is a debilitating disease with significant socioeconomic and emotional impact. Despite recent success in the development of traditional pharmacotherapy for the management of hypertension, the incidence of this disease is on the rise and has reached epidemic proportions by all estimates. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau, and novel approaches for the treatment and control of hypertension must be explored. We have begun to investigate the possibility of treating and/or curing hypertension by using genetic means. In this review, we will provide evidence in favor of targeting of the renin-angiotensin system by antisense gene therapy as an effective strategy for the lifelong prevention of hypertension in the spontaneously hypertensive rat model. In addition, we will discuss the properties of an ideal vector for the systemic delivery of genes and the potential experimental hurdles that must be overcome to take this innovative approach to the next level of evaluation.