bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Losartan on a Background of Hydrochlorothiazide in Patients With Hypertension
Authors: Soffer Beth A. , Wright Jackson T. , Pratt J. Howard , Wiens Brian , Goldberg Allan I. , Sweet Charles S.
Published: June 2012

Abstract
The purpose of this multicenter trial was to compare the antihypertensive efficacy and safety of losartan potassium (losartan), a selective angiotensin II receptor antagonist, when added to hydrochlorothiazide in hypertensive patients whose blood pressure was not adequately controlled by 25 mg hydrochlorothiazide monotherapy. After a 4-week monotherapy period of 25 mg hydrochlorothiazide, 304 patients with trough (22 to 26 hours postdose) sitting diastolic pressure between 93 and 120 mm Hg were maintained on 25 mg hydrochlorothiazide and randomized double-blind into treatment arms consisting of either 25, 50, or 100 mg losartan or placebo once daily for 12 weeks. The reductions in sitting diastolic pressure for patients treated with 25, 50, or 100 mg losartan concomitantly administered with 25 mg hydrochlorothiazide were significantly greater (
P
≤.05) than the reductions observed in the 25 mg hydrochlorothiazide plus placebo group beginning 1 week after randomization. The antihypertensive response in all groups was greater at week 3 than week 1, with some additional decrease in blood pressure in some groups at later times. Sitting systolic pressures were also significantly reduced in each group over time. Standing blood pressures at week 12 were similar to sitting blood pressures. A dose-response relationship to losartan was observed in this patient population. The percentages of the total drug-related clinical adverse experiences as assessed by the investigator were generally similar in the 25, 50, and 100 mg losartan plus 25 mg hydrochlorothiazide groups (10.3%, 24.4%, and 20.0%, respectively) compared with the placebo plus 25 mg hydrochlorothiazide group (24.7%). In addition, the anticipated hydrochlorothiazide-associated decrease in serum potassium and the increase in serum uric acid appeared to be somewhat blunted in the losartan plus hydrochlorothiazide groups relative to the hydrochlorothiazide plus placebo group. These results demonstrate that the addition of 25, 50, and 100 mg losartan to 25 mg hydrochlorothiazide produced a significant and dose-related reduction in blood pressure at trough after 12 weeks compared with the 25 mg hydrochlorothiazide plus placebo group. In addition, losartan given concomitantly with hydrochlorothiazide was generally well tolerated in this study.
Effects of Low and High Doses of Fosinopril on the Structure and Function of Resistance Arteries
Authors: Rizzoni Damiano , Castellano Maurizio , Porteri Enzo , Bettoni Giorgio , Muiesan Maria Lorenza , Cinelli Angelo , Rosei Enrico Agabiti
Published: June 2012

Abstract
It has been suggested that angiotensin-converting enzyme inhibitors may induce a significant regression of cardiovascular hypertrophy not only through blood pressure reduction but also as a possible consequence of growth factor inhibition. The aim of this study was to evaluate the effects of the angiotensin-converting enzyme inhibitor fosinopril, given either at a hypotensive high dose or a nonhypotensive low dose, on structural and functional alterations of mesenteric resistance arteries and on cardiac mass in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats. Fosinopril was administered in the drinking water from 6 to 12 weeks of age. Rats were killed at 12 weeks, and the ratio of heart weight to body weight was measured. Mesenteric arterioles were dissected and mounted on a micromyograph (Mulvany’s technique). Vascular morphology (media-lumen ratio, media thickness) and endothelial function (response to acetylcholine) were then assessed. During the 6 weeks of treatment, systolic pressure in SHR treated with high-dose fosinopril was significantly lower compared with that in untreated SHR, whereas no difference was observed with low-dose fosinopril. In SHR treated with both high-dose and low-dose fosinopril, a statistically significant reduction of vascular structural alterations, in terms of both media-lumen ratio and media thickness, was observed. The ratio of heart weight to body weight was reduced only in SHR treated with high-dose fosinopril. An improvement in the endothelium-dependent relaxation to acetylcholine was observed in SHR treated with high-dose fosinopril compared with untreated SHR, whereas in SHR treated with low-dose fosinopril no improvement in endothelial function was detected. In conclusion, low-dose fosinopril selectively prevented the structural but not functional vascular alterations in SHR, thus suggesting a possible interference of angiotensin-converting enzyme inhibitors with growth factors, at least in the peripheral vasculature.
Differing Mechanisms of Action of Angiotensin-Converting Enzyme Inhibition in Black and White Hypertensive Patients
Authors: Weir Matthew R. , Gray James M. , Paster Robert , Saunders Elijah
Published: June 2012

Abstract
The antihypertensive effect of the angiotensin-converting enzyme inhibitor trandolapril administered in doses of 1, 2, and 4 mg/d was compared in 207 white patients and 91 black patients with mild to moderate hypertension following a double-blind, randomized, placebo-controlled, parallel study design. Trandolapril is a prodrug that is rapidly hydrolyzed to its active diacid metabolite, trandolaprilat. After 6 weeks of double-blind treatment, trandolapril lowered baseline sitting diastolic pressure in both white and black patients. A comparison of the antihypertensive response of the two populations revealed that the black patients required between two and four times the dose of trandolapril to obtain a response similar to that observed in the white patients. A dose of 1 mg/d trandolapril resulted in a 6.1 mm Hg mean decrease in baseline sitting diastolic pressure for white patients; a similar response (−6.5 mm Hg) was observed in the black patients at 4 mg/d. In contrast to the population differences in blood pressure, the decreases in angiotensin-converting enzyme activity were similar for both populations. An evaluation of trandolaprilat levels revealed that there were no racial differences in the trandolaprilat concentrations required to achieve a given degree of angiotensin-converting enzyme inhibition. Therefore, it appears that the antihypertensive response of black patients is not completely explained by a reduction in angiotensin-converting enzyme activity. The lack of response at a lower dose but increasing response at a higher dose could reflect another vasodepressor activity of trandolapril or just be evidence of reduced sensitivity of high blood pressure in blacks to angiotensin-converting enzyme inhibition.
Nifedipine Prevents Renal Injury in Rats With Chronic Nitric Oxide Inhibition
Authors: Ribeiro Miriam Oliveira , Antunes Edson , Muscará Marcelo Nicolas , De Nucci Gilberto , Zatz Roberto
Published: June 2012

Abstract
Chronic nitric oxide inhibition promotes hypertension, renal dysfunction, and renal injury by unclear mechanisms. We examined the effects in this model of concomitant treatment with the calcium channel blocker nifedipine. Six adult male Munich-Wistar rats received 0.025% nifedipine in chow. Six untreated rats served as controls. Fifteen days later, renal function was evaluated in anesthetized rats before and after a bolus injection of the nitric oxide inhibitor
N
ω
-nitro-
l
-arginine methyl ester at 3 mg/kg IV. Renal vasoconstriction and systemic hypertension induced by the inhibitor were similar in untreated and nifedipine-treated rats. In a second protocol, eight rats received the nitric oxide inhibitor in their drinking water at 2.6 mmol/L. Eight additional rats also received nifedipine as above. At day 15, rats given the nitric oxide inhibitor exhibited systemic hypertension and renal vasoconstriction. Simultaneous nifedipine lowered blood pressure slightly without ameliorating renal hemodynamics. Tail-cuff pressure rose continuously in rats receiving the nitric oxide blocker, reaching 171±7 mm Hg at 30 days, but remained at 143±3 mm Hg in rats also given nifedipine. At this stage, rats treated with the nitric oxide inhibitor exhibited extremely variable plasma renin activity, tuft collapse in 10.1±2.2% of the glomeruli, and renal interstitial fibrosis. Simultaneous nifedipine treatment normalized the dispersion of plasma renin levels, while preventing renal morphological abnormalities. These results suggest that in the chronic nitric oxide inhibition model, sustained operation of voltage-sensitive calcium channels is not essential for renal vasoconstriction but contributes to systemic hypertension and plays a pivotal role in the development of renal structural injury.
Coronary Kinin Generation Mediates Nitric Oxide Release After Angiotensin Receptor Stimulation
Authors: Seyedi Nahid , Xu XiaoBin , Nasjletti Alberto , Hintze Thomas H.
Published: June 2012

Abstract
Our goal was to determine whether angiotensin II (Ang II) and its metabolic fragments release nitric oxide and the mechanisms by which this occurs in blood vessels from the canine heart. We incubated 20 mg of microvessels or large coronary arteries in phosphate-buffered saline for 20 minutes and measured nitrite release. Nitrite release increased from 27±2 up to 103±5, 145±17, 84±4, 107±16, and 54±4 pmol/mg (
P
<.05) in response to 10
−5
mol/L of Ang I, II, III, IV, and Ang-(1-7), respectively. The effects of all angiotensins were blocked by
N
ω
-nitro-
l
-arginine methyl ester (100 μmol/L), indicating that nitrite was a product of nitric oxide metabolism, and by Hoe 140 (10 μmol/L), a specific bradykinin B
2
receptor antagonist, indicating a potential role for local kinin formation. The protease inhibitors aprotinin (10 μmol/L) and soybean trypsin inhibitor, which block local kinin formation, inhibited nitrite release by all of the angiotensins. Angiotensin nonselective (saralasin), type 1–specific (losartan), and type 2–specific (PD 123319) receptor antagonists abolished the nitrite released in response to all the fragments. Angiotensin type 1 and type 2 and receptors mediate nitrite release after Ang I, II, III, and Ang-(1-7), whereas only type 2 receptors mediate nitrite release after Ang IV. Similar results were obtained in large coronary arteries. In summary, formation of nitrite from coronary microvessels and large arteries in the normal dog heart in response to angiotensin peptides is due to the activation of local kinin production in the coronary vessel wall.
Influence of Androgen on Tyrosine Hydroxylase mRNA in Adrenal Medulla of Spontaneously Hypertensive Rats
Authors: Kumai Toshio , Tanaka Masami , Watanabe Minoru , Nakura Hironori , Kobayashi Shinichi
Published: June 2012

Abstract
We investigated the effects of castration and testosterone propionate on tyrosine hydroxylase mRNA, its activity, and catecholamine synthesis in the adrenal medulla of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Four-week-old male rats were castrated. Testosterone propionate (500 μg per rat) was administered subcutaneously twice a week to castrated rats (between 14 and 25 weeks of age). Systolic pressure was measured at the age of 25 weeks, and rats were decapitated. The systolic pressure of castrated SHR was significantly lower than that of control and testosterone-replaced SHR. Epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and tyrosine hydroxylase mRNA in the adrenal medulla of castrated SHR were significantly lower than in control and testosterone-replaced SHR. Systolic pressure and epinephrine and norepinephrine levels, tyrosine hydroxylase activity, and tyrosine hydroxylase mRNA levels in the adrenal medulla of WKY showed no significant differences among the control, castrated, and testosterone-replaced groups. These results suggest that androgens contribute to the development and maintenance of hypertension in SHR via sustained enhancement of tyrosine hydroxylase synthesis in the adrenal medulla, leading to increased epinephrine and norepinephrine levels.
Effects of Hypertension on Viscoelasticity of Carotid and Femoral Arteries in Humans
Authors: Armentano Ricardo , Megnien Jean Louis , Simon Alain , Bellenfant Florence , Barra Juan , Levenson Jaime
Published: June 2012

Abstract
We compared the properties of common carotid and femoral arteries of 16 normotensive and 14 hypertensive men. Arterial pressure and diameter were recorded noninvasively in each vessel by tonometric and echotracking devices. The
x
-
y
composition of pressure and diameter waves provided the diameter-pressure hysteresis loop. The elastic diameter-pressure curve and wall viscosity index were deduced after hysteresis elimination. The compliance-pressure and distensibility-pressure curves were derived from the diameter-pressure curve, allowing the calculation of effective compliance and distensibility at the prevailing pressure of each subject and isobaric compliance and distensibility at the same standard pressure in all subjects. Systolic, diastolic, mean, and pulse pressures and diameters in each vessel were higher in the hypertensive than the normotensive group, except carotid pulse diameter, which did not differ. The carotid diameter-pressure, compliance-pressure, and distensibility-pressure curves did not differ between groups. In the carotid artery hypertensive patients had isobaric compliance and distensibility values similar to those of normotensive subjects, despite lower effective compliance (
P
<.05) and distensibility (
P
<.01). The femoral diameter-pressure curve was higher (
P
<.05) and the femoral compliance-pressure and distensibility-pressure curves were lower (
P
<.01) in the hypertensive than the normotensive group. Hypertensive patients had effective and isobaric femoral compliance and distensibility values lower than to those of normotensive subjects (
P
<.001). In both arteries, viscosity index was higher in the hypertensive than the normotensive group (
P
<.001). In hypertension, the pressure-independent alterations of geometric and elastic properties were distributed preferentially to the femoral artery, and the alteration of wall viscosity affected carotid and femoral sites in a uniform manner.
Nitric Oxide and Prostaglandins in the Prolonged Effects of Losartan and Ramipril in Hypertension
Authors: Cachofeiro Victoria , Maeso Rosaura , Rodrigo Elena , Navarro Josefa , Ruilope Luis M. , Lahera Vicente
Published: June 2012

Abstract
We investigated the role of endogenous nitric oxide, kinins, and prostaglandins in the vasodepressor and renal excretory effects of the angiotensin II receptor antagonist losartan and the angiotensin-converting enzyme inhibitor ramipril administered for 1 week to spontaneously hypertensive rats. To this end, either losartan (10 mg/kg per day) or ramipril (2.5 mg/kg per day) was administered in drinking water with or without simultaneous administration of (1) the nitric oxide synthesis inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 6 mg/kg per day), (2) the cyclooxygenase inhibitor indomethacin (5 mg/kg per day), (3) the bradykinin B
2
receptor antagonist Hoe 140 (0.5 mg/kg per day SC), or (4) L-NAME plus indomethacin. Both losartan and ramipril significantly reduced blood pressure as measured by the tail-cuff method. L-NAME increased blood pressure when administered solely or in combination with losartan. However, L-NAME attenuated the hypotensive effect of ramipril. Indomethacin did not affect blood pressure but it reduced the antihypertensive action of losartan and ramipril. Indomethacin administration did not potentiate the increase in blood pressure induced by L-NAME. However, the concurrent administration of both inhibitors almost totally blunted the vasodepressor action of ramipril. By contrast, losartan administration in the presence of L-NAME and indomethacin increased blood pressure to a level similar to that after losartan plus L-NAME. Hoe 140 did not modify either blood pressure or the hypotensive effects of losartan or ramipril. Increases in diuresis and water intake were observed during ramipril administration. Both effects were blunted only with the concurrent administration of L-NAME and indomethacin. None of the cotreatments were able to modify renal excretory function by themselves. These data suggest a contribution of endogenous nitric oxide and prostaglandins but not of kinins in the prolonged antihypertensive effect of both losartan and ramipril in the spontaneously hypertensive rat.
Physiological Influences on Continuous Finger and Simultaneous Intra-arterial Blood Pressure
Authors: Lal Saroj K. L. , Henderson Robyn J. , Cejnar Michael , Hart Michael G. , Hunyor Stephen N.
Published: June 2012

Abstract
Because of the clinical and experimental utility of continuous finger blood pressure measurements and the need for accuracy, we tested the performance of a new hydraulic device in 22 consecutive hypertensive subjects during physiological and pharmacological interventions. Ipsilateral brachial intra-arterial pressure was monitored during rest, Valsalva’s maneuver, static handgrip, and mental arithmetic and after sublingual glyceryl trinitrate. In excess of 40 000 blood pressure values were analyzed. Average bias (intra-arterial minus finger blood pressure) was 8.2±17.0 mm Hg (mean±SD,
P
=NS) for systolic and 2.8±10.4 mm Hg (
P
=NS) for diastolic pressure. Two-way ANOVA of biases with subject and task factors showed a subject effect (
P
<.001). Intersubject and intrasubject standard deviations of bias were 13.8 and 9.8 mm Hg systolic and 8.7 and 5.7 diastolic, respectively. Linear drift (millimeters of mercury per minute) of finger pressure was greater (
P
<.001) for systolic than diastolic pressure during static exercise and math and after glyceryl trinitrate. Coefficients of determination for blood pressure ranged from 0.4±0.3 to 0.8±0.3 during the tasks. We conclude that (1) noninvasive finger blood pressure faithfully follows intra-arterial changes but with clinically relevant offsets, (2) this technique is best suited for assessing pressure changes, (3) physiological and pharmacological interventions do not consistently affect finger pressure accuracy, (4) many reports of finger blood pressure measuring devices are based on direct readings obtained with inadequate system response characteristics, and (5) the tested instrument falls short of the standards requirements (bias ≤5±8 mm Hg) for devices that measure intermittently.
Structural Versus Functional Modulation of the Arterial Baroreflex
Authors: Chapleau Mark W. , Cunningham J. Thomas , Sullivan Margaret J. , Wachtel Ruth E. , Abboud François M.
Published: June 2012

Abstract
Structural changes in large arteries are often considered the predominant mechanism responsible for decreased baroreflex sensitivity and baroreceptor resetting in hypertension, atherosclerosis, and aging. Recent work has demonstrated that “functional” mechanisms, both at the level of the peripheral sensory endings and within the central nervous system, contribute significantly to altered baroreflex responses. We have conducted both reductive studies of mechanoelectrical transduction in cultured baroreceptor neurons and integrative studies with in vivo recordings of the activity of baroreceptor afferent fibers and efferent sympathetic nerves. Results suggest that the primary mechanism of mechanical activation of baroreceptor neurons involves opening of stretch-activated ion channels susceptible to blockade by gadolinium. Baroreceptor nerve activity is modulated by the activity of potassium channels and the sodium-potassium pump and by paracrine factors, including prostacyclin, oxygen free radicals, and factors released from aggregating platelets. Endothelial dysfunction and altered release of these paracrine factors contribute significantly to the decreased baroreceptor sensitivity in hypertension and atherosclerosis. The central mediation of the baroreflex depends on the pulse phasic pattern of afferent baroreceptor discharge. Baroreflex-mediated inhibition of sympathetic nerve activity is well maintained during pulse phasic afferent activity. Continuous, nonphasic baroreceptor discharge or a rapid (>1.5 Hz) pulse phasic discharge results in disinhibition of sympathetic activity. This disinhibition during continuous baroreceptor input is exaggerated with aging. Thus, a defect in central mediation of the baroreflex may be a major cause of the impaired baroreflex and sympathoexcitation in the elderly. In summary, functional neural mechanisms, in addition to structural vascular changes, contribute importantly to altered baroreflex responses in normal and pathophysiological states. Therefore, it may be possible to implement therapies that reverse functional changes and restore baroreflex sensitivity long before the reversal of structural vascular changes.
Is White Coat Hypertension Associated With Arterial Disease or Left Ventricular Hypertrophy?
Authors: Cavallini M. Chiara , Roman Mary J. , Pickering Thomas G. , Schwartz Joseph E. , Pini Riccardo , Devereux Richard B.
Published: June 2012

Abstract
Although white coat hypertension may be present in 20% or more of hypertensive individuals, its prognostic significance is unknown. We compared prognostically relevant measures of target-organ damage among 24 individuals with white coat hypertension and age- and sex-matched groups of sustained hypertensive and normotensive subjects classified by clinical and 24-hour ambulatory blood pressures. Left ventricular and carotid artery structure and function were evaluated by ultrasonography. Left ventricular mass index was similar in white coat hypertensive (82±17 g/m
2
) and normotensive (78±15 g/m
2
) subjects but was higher in sustained hypertensive subjects (97±19 g/m
2
,
P
<.02 and
P
<.002, respectively). Similarly, carotid artery intimal-medial thickness was greater in the sustained hypertensive group (0.98±0.21 mm) than in the white coat hypertensive (0.84±0.16 mm,
P
<.05) and normotensive (0.76±0.18 mm,
P
<.001) groups. The prevalence of discrete atherosclerotic plaques was higher in the sustained hypertensive group (58%) than in the white coat hypertensive (25%,
P
<.05) and normotensive (21%,
P
<.02) groups. Cardiac and carotid structure in individuals with white coat hypertension resemble findings in normotensive subjects and differ significantly from those in age- and sex-matched sustained hypertensive subjects. These findings suggest that white coat hypertension may be a benign condition for which pharmacological intervention may not be necessary, a hypothesis that needs to be tested in longitudinal studies with clinical end points.
Differential Modulation of Baroreceptor Sensitivity by Long-term Antihypertensive Treatment
Authors: Ichikawa Masashi , Suzuki Hiromichi , Kumagai Kazuhiro , Kumagai Hiroo , Ryuzaki Munekazu , Nishizawa Masahiko , Saruta Takao
Published: June 2012

Abstract
We investigated the effects of long-term oral treatment with four different classes of antihypertensive drugs (a thiazide diuretic [trichlormethiazide, 10 mg/kg per day]; a β-blocker [atenolol, 90 mg/kg per day]; a calcium channel antagonist [nicardipine, 150 mg/kg per day]; and an angiotensin-converting enzyme inhibitor [enalapril maleate, 10 mg/kg per day]) on aortic baroreceptor activity in spontaneously hypertensive rats with chronic hypertension (36 weeks of age). Treatment with each of the four drugs, given from 10 to 36 weeks of age, similarly decreased arterial pressure (171±2 to 144±1 mm Hg,
P
<.01) and similarly decreased the threshold pressure for baroreceptors (116±3 to 103±1 mm Hg,
P
<.05). The four antihypertensive drugs also potentiated the maximal gain of the pressure-activity relation in these rats (untreated, 1.08±0.05% maximum/mm Hg); however, nicardipine and enalapril (1.77±0.04% and 1.70±0.06% maximum/mm Hg, respectively) augmented the maximal gain to a greater extent
(P
<.05 to .01) than did trichlormethiazide or atenolol (1.49±0.05% and 1.42±0.02% maximum/mm Hg, respectively). When the initiation of treatment was delayed to 28 weeks of age, no differences were found in the effects on either threshold pressure (104±1 mm Hg) or maximal gain (1.36±0.03% maximum/mm Hg) for all four drugs. These findings suggest that in the treatment of chronic hypertension (1) baroreceptor resetting to a lower pressure level is similarly induced with the four drugs, and (2) baroreceptor sensitivity is augmented more by early and long-term treatment with calcium channel antagonists or angiotensin-converting enzyme inhibitors than by diuretics or β-blockers.
Effect of Captopril and Angiotensin II Receptor Blockade on Pressure Natriuresis in Transgenic TGR(mRen-2)27 Rats
Authors: Gross Volkmar , Lippoldt Andrea , Schneider Wolfgang , Luft Friedrich C.
Published: June 2012

Abstract
The pressure-natriuresis curve of transgenic rats harboring an extra mouse renin gene [TGR(mRen-2)27] is shifted rightward compared with controls; however, whether intrarenal angiotensin II effects are responsible for the rightward shift is unknown. To clarify this issue we infused the converting enzyme inhibitor captopril or the angiotensin II receptor blocker CV 11974 into transgenic and normotensive Sprague-Dawley Hannover control rats. We eliminated any other neural or endocrine regulatory differences between transgenic and control rats by renal denervation and infusion of vasopressin, aldosterone, corticosterone, and norepinephrine in sufficient quantities to occupy all receptors. Sodium excretion increased from 3.4±1.2 to 10.1±0.5 μmol/min per gram kidney weight in transgenic rats when renal perfusion pressure was increased from 158 to 201 mm Hg. Captopril (4 mg/kg) and CV 11974 (0.1 mg/kg) shifted the pressure-natriuresis curve of transgenic rats leftward, so that sodium excretion was threefold higher at similar renal perfusion pressures (150 to 160 mm Hg). Similarly, fractional sodium and water excretion curves were shifted leftward, so that values for transgenic and control rats were no longer different. Over the pressure range, renal blood flow in transgenic rats ranged from 3.1±0.7 to 4.4±0.5 mL/min per gram kidney weight and increased (
P
<.05) with both captopril and CV 11974 to ranges from 4.8±0.9 to 6.8±0.6 or from 4.5±0.7 to 6.9±1.0 mL/min per gram kidney weight, respectively. Glomerular filtration rate in transgenic rats, on the other hand, was not increased. Transgenic kidneys showed severe hypertension-induced nephrosclerosis. These results suggest that the hypertensive, rightward shift in the transgenic pressure-natriuresis curve is largely due to angiotensin II–dependent renal effects. Altered renal structure may also play a role in shifting the renal function curve rightward.
Postischemic Blood Flow Response in Hypercholesterolemic Patients
Authors: Hayoz Daniel , Weber Roger , Rutschmann Blaise , Darioli Roger , Burnier Michel , Waeber Bernard , Brunner Hans R.
Published: June 2012

Abstract
We undertook this cross-sectional study to compare the mechanical behavior and postischemic response of the radial artery of 15 newly diagnosed hypercholesterolemic patients with those of 15 age- and sex-matched normocholesterolemic control subjects and 21 hypercholesterolemic patients treated for 2 years with an 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 10 to 20 mg/d). At the time of the study total cholesterol levels were at 7.9±0.2, 4.9±0.2, and 6.0±0.3 mmol/L in the three groups, respectively (mean±SEM,
P
<.001). High-resolution, noninvasive echotracking for assessment of internal arterial diameter was combined with measurements of blood flow velocity by Doppler and blood pressure by photoplethysmography. Radial cross-sectional compliance and distensibility were similar in all groups. Forearm blood flow and flow-mediated dilation were measured after a 5-minute upper arm occlusion. Flow was calculated from the vessel diameter and blood flow velocity recorded simultaneously at the same site. Flow-mediated dilation after ischemia was not significantly different among the three groups. However, forearm blood flow increase was markedly blunted (
P
<.01) in untreated hypercholesterolemic patients (211%) compared with the normocholesterolemic control subjects (411%) and treated patients (365%). These findings suggest that the distensibility of the radial artery, a muscular conduit vessel usually devoid of atherosclerotic lesions, and its flow-mediated dilation are preserved in hypercholesterolemic patients. In contrast, forearm resistance vessels exhibit a markedly reduced postischemic blood flow response that may be restored by prolonged lipid-lowering intervention.
Noninvasive Pulse Wave Analysis for the Early Detection of Vascular Disease
Authors: Cohn Jay N. , Finkelstein Stanley , McVeigh Gary , Morgan Dennis , LeMay Lisa , Robinson Jennifer , Mock James
Published: June 2012

Abstract
A noninvasive technique has been developed and validated for calculating capacitive and oscillatory systemic arterial compliance with the use of pulse wave analysis and a modified Windkessel model. Application of the technique to subjects with hypertension, postmenopausal women with symptomatic coronary artery disease, and appropriate control subjects has confirmed a reduction of oscillatory compliance in the disease states and an increase in capacitive and oscillatory compliances in response to vasodilator drugs. This method should be useful in screening subjects for early evidence of vascular disease and in monitoring the response to therapy.
Sick Vessel Syndrome
Authors: Heistad Donald D. , Armstrong Mark L. , Baumbach Gary L. , Faraci Frank M.
Published: June 2012

Abstract
This review describes vascular changes in atherosclerotic and hypertensive vessels as well as effects of treatment. Changes in vascular structure in both atherosclerosis and hypertension are characterized by thickening of the vessel wall and vascular “remodeling.” Remodeling tends to preserve the size of the lumen in atherosclerotic vessels and results in a smaller lumen in hypertensive vessels. Changes in vascular function are characterized by preservation of smooth muscle relaxation, with the exception of activity of ATP-sensitive potassium channels, and dysfunction of endothelium. Regression of atherosclerosis, by treatment of hyperlipidemia, results in quite rapid removal of lipid from the vessel wall but with inconsistent improvement in maximal vasodilator capacity. In contrast, endothelial function improves during regression of atherosclerosis, and hyperresponsiveness to serotonin subsides rapidly. Effective treatment of hypertension produces regression of vascular hypertrophy, and some approaches (especially angiotensin-converting enzyme inhibitors) are effective in correcting vascular remodeling. Endothelium-dependent relaxation generally improves during antihypertensive treatment. Reduction in pulse pressure may be more important than reduction in mean arterial pressure in reversing the structural and functional abnormalities of hypertensive vessels.
Investigation of the Phenylethanolamine
N
-Methyltransferase Gene as a Candidate Gene for Hypertension
Authors: Koike George , Jacob Howard J. , Krieger Jose E. , Szpirer Claude , Hoehe Margret R. , Horiuchi Masatsugu , Dzau Victor J.
Published: June 2012

Abstract
Genetic mapping studies have located a gene,
Bp1
, that accounts for approximately 30% of the genetic variation in the stroke-prone spontaneously hypertensive rat (SHRSP) to a region on chromosome 10 containing the angiotensin-converting enzyme gene. In humans, the gene encoding phenylethanolamine
N
-methyltransferase (PNMT) was localized near the angiotensin-converting enzyme gene on human chromosome 17. Since most of human chromosome 17 is known to be homologous to rat chromosome 10 and PNMT is known to play a role in blood pressure homeostasis, we reasoned (1) that the rat gene encoding PNMT (
Pnmt
) may reside on chromosome 10 within the confidence interval containing
Bp1
and (2) that
Pnmt
is a good candidate gene for
Bp1.
With the use of a somatic cell hybrid panel and genetic mapping techniques,
Pnmt
mapped within the confidence interval that contains
Bp1
. To examine further this possibility of
Pnmt
as a candidate for
Bp1
, we cloned and characterized
Pnmt
s of the original parental strains, the Wistar-Kyoto rat and SHRSP from the Heidelberg colony. We did not identify any sequence differences between the Wistar-Kyoto rats and SHRSP in the primary structure, in 1077 bp of the 5′-flanking region, or in the 256-bp 3′-end region, making
Pnmt
an unlikely gene for the genetic basis of salt-loaded hypertension.
Renin mRNA, Quantified by Polymerase Chain Reaction, in Renal Hypertensive Rat Tissues
Authors: Lou Yi-kun , Liu Dennis T. , Whitworth Judith A. , Morris Brian J.
Published: June 2012

Abstract
To determine responses in renin gene expression in different tissues of two-kidney, one clip hypertensive Sprague-Dawley rats and the effect of NaCl loading, we developed a novel, highly sensitive quantitative polymerase chain reaction technique and measured renin mRNA at 19 and 40 days after clipping. Basal renin mRNA concentrations were 1575±127 fg/μg total RNA in kidney, 52±7 in hypothalamus, 7.9±0.7 in adrenal, and 4.7±0.5 in atria. In two-kidney, one clip rats, renin mRNA in the clipped kidney was increased 5.4-fold (
P
=.00001) and 2.3-fold (
P
=.001) on each respective day after clipping and in the unclipped kidney was decreased by 27% (
P
=.01) and 38% (
P
=.04). In adrenal, 3.9-fold (
P
=.004) and 1.7-fold (
P
=.02) increases were seen on days 19 and 40, respectively, and a decrease of 57% (
P
=.02) was found in a hypothalamic block at day 19 but not at day 40. The decrease in hypothalamus was abolished by 1% oral NaCl, which reduced renin mRNA by 37% in the clipped kidney and by 30% in the adrenal but did not lead to any change in the unclipped kidney or hypothalamus at day 40. Hypothalamic renin mRNA was also decreased by enalapril compared with increases of sixfold to ninefold in other tissues. In conclusion, we have quantified a decrease in hypothalamic renin mRNA in two-kidney, one clip rats 19 days after clipping that can be abolished by NaCl loading, whereas in the adrenal, renin mRNA was increased. Similar relative tissue-specific changes were also seen in enalapril-treated rats.
Cyclosporine Impairs Vasodilation Without Increased Sympathetic Activity in Humans
Authors: Stein C. Michael , He Huaibing , Pincus Theodore , Wood Alastair J.J.
Published: June 2012

Abstract
Hypertension and nephrotoxicity frequently complicate treatment with cyclosporine; two suggested mechanisms are increased sympathetic activity and altered vascular reactivity. It is difficult to assess these mechanisms in patients receiving cyclosporine after transplantation because of the accompanying major physiological alterations. Therefore, we studied 12 patients with rheumatoid arthritis twice—while they were taking and not taking cyclosporine. We measured vascular response in the dorsal hand vein using the linear variable differential transformer technique. Cyclosporine treatment significantly attenuated vasodilation induced by 60 ng/min isoproterenol (no cyclosporine, 19.8±3.5% versus cyclosporine, 7.9±2.2%;
P
=.02) and prostaglandin E
1
at 1000 pg/min (no cyclosporine, 72.6±10.2% versus cyclosporine, 45.6±9.0%) and 2000 pg/min (no cyclosporine, 100.8±14.7% versus cyclosporine, 68.6±8.0%; F=5.47,
P
=.047). However, neither vascular response to phenylephrine or nitroglycerin nor sympathetic activity assessed by measurement of norepinephrine spillover with a radioisotope dilution technique was affected by cyclosporine (no cyclosporine, 516.1±47.9 ng/min versus cyclosporine, 476.6±51.8 ng/min;
P
=.42). Cyclosporine impaired venodilation in response to two agonists that act through adenylate cyclase without altering α-agonist–induced venoconstriction or sympathetic activity. Therefore, in humans impaired vasodilation rather than sympathetic activation or enhanced vasoconstriction may be an important mechanism for the alterations of vascular tone that occur after long-term cyclosporine administration.
Effects of Chronic Estrogen Replacement Therapy on Beat-to-Beat Blood Pressure Dynamics in Healthy Postmenopausal Women
Authors: Lipsitz Lewis A. , Connelly Carolyn M. , Kelley-Gagnon Margaret , Kiely Dan K. , Morin Raymond J.
Published: June 2012

Abstract
Recent data showing gender differences in autonomic control of heart rate and acute estrogen effects on vasodilatation suggest that estrogen may influence autonomic regulation of heart rate and blood pressure. We aimed to determine the effect of postmenopausal estrogen replacement therapy on autonomic control of beat-to-beat heart rate and blood pressure dynamics. Subjects included 20 healthy postmenopausal women aged 60 to 75 years with normal exercise tolerance tests, 10 of whom were taking oral estrogen for 13±3 (±SEM) years. Six healthy premenopausal women were also studied. Continuous electrocardiographic and noninvasive radial artery blood pressure measurements and intermittent forearm blood flow recordings (by venous-occlusion plethysmography) were obtained before and after a 20-minute, 60° head-up tilt and a 420-kcal meal during periods of spontaneous and metronomic breathing (at 0.25 Hz). Low-frequency (0.01- to 0.15-Hz) and high-frequency (0.15- to 0.50-Hz) heart rate and blood pressure spectral powers were computed with a fast Fourier transform. Cardiovascular and heart rate spectral power responses to upright tilt and meal digestion were the same in postmenopausal estrogen users and nonusers. However, during spontaneous breathing the blood pressure spectral power responses to upright tilt and meal ingestion were significantly different between the two groups of women. The low-frequency systolic pressure power response to upright tilt was smaller in estrogen users than nonusers (
P
=.01). After meal ingestion nonusers had an early postprandial fall (20 to 30 minutes after the meal) and late rise (50 to 60 minutes) in low-frequency systolic and diastolic pressure powers, which were significantly attenuated in estrogen users (
P
<.02). Healthy premenopausal women had a response similar to that of postmenopausal estrogen users. Estrogen may attenuate the low-frequency vasomotor response to posture change and meal digestion in healthy postmenopausal women. This effect of estrogen may represent damping of vasomotor instability after menopause.
Autonomic Nervous Function in Non-dipper Essential Hypertensive Subjects
Authors: Kohara Katsuhiko , Nishida Wataru , Maguchi Motofumi , Hiwada Kunio
Published: June 2012

Abstract
Autonomic nervous function was evaluated by means of power spectral analysis of heart rate variability in hospitalized dipper (n=31) and non-dipper (n=31) essential hypertensive subjects. Twenty-four–hour blood pressure (BP) measurement was performed by the cuff-oscillometric method to evaluate the nocturnal decrease of BP. The non-dipper subjects were defined as those whose nocturnal decrease of systolic BP was <10% of daytime BP. Power spectral analysis of RR interval was performed from Holter ECG every 10 minutes by the maximum entropy method to obtain the low-frequency band (LFB, 0.04 to 0.15 Hz), which is an index of both parasympathetic and sympathetic nervous activities, and the high-frequency band (HFB, 0.15 to 0.4 Hz), which reflects parasympathetic nervous activity. LFB and HFB were averaged every hour to obtain hourly LFB and HFB values. Total LFB and total HFB were calculated as the mean values of 24 hourly averaged LFBs and HFBs. Both LFB and HFB were significantly lower in non-dipper hypertensives than in dipper subjects throughout the day. In dipper hypertensives, LFB showed a nocturnal decrease, whereas HFB was significantly increased during the nighttime. However, these diurnal changes in LFB and HFB were significantly blunted in non-dipper subjects. These findings indicate that non-dipper hypertensive subjects were characterized with a decreased physiological circadian fluctuation on autonomic functions compared with dipper subjects. This alteration in the autonomic nervous function may explain the non-dipper phenomenon in essential hypertension.
Contribution of Atrial Reservoir Function to Ventricular Filling in Hypertensive Patients
Authors: Nagano Reiko , Masuyama Tohru , Naka Masashi , Hori Masatsugu , Kamada Takenobu
Published: June 2012

Abstract
We designed this study to assess the importance of left atrial function as a contributor to mitral flow velocity pattern in hypertensive patients. In hypertensive patients the early diastolic flow velocity and ratio of early to late diastolic flow velocity in the mitral flow velocity pattern increase in association with sublingual administration of nifedipine. These changes have been interpreted as signs of improved left ventricular diastolic function; however, the mitral flow velocity pattern is also affected by various other factors. Thus, the nifedipine-induced changes may not necessarily indicate the improvement of left ventricular diastolic function. Transthoracic Doppler echocardiographic parameters of mitral and pulmonary venous flow velocity patterns and left ventricular M-mode echograms were obtained in 16 untreated hypertensive patients before and after sublingual administration of nifedipine (10 mg). Normal values of the parameters were determined in 50 age-matched healthy subjects. After nifedipine peak early diastolic mitral flow velocity increased beyond the normal value, although the peak increasing rate of left ventricular inner dimension, another index of left ventricular diastolic function, did not recover to the normal value. Peak systolic velocity in the pulmonary venous flow velocity pattern increased beyond the normal value, indicating improvement of the reservoir function of the left atrium during systole. Nifedipine-induced normalization of the mitral flow velocity pattern was associated with further abnormalities of the pulmonary venous flow velocity pattern, indicating enhanced left atrial reservoir function. Thus, nifedipine-induced normalization of the mitral flow velocity pattern should be explained not only by the normalization of left ventricular diastolic function but also by another adaptive alteration in left atrial reservoir function in hypertensive patients. Combined analysis of mitral and pulmonary venous flow velocity patterns may be useful in avoiding the misinterpretation of the mitral flow velocity pattern.
5-Hydroxytryptamine
2B
Receptor Mediates Contraction in the Mesenteric Artery of Mineralocorticoid Hypertensive Rats
Authors: Watts Stephanie W. , Gilbert Lisa , Webb R. Clinton
Published: June 2012

Abstract
Vascular responsiveness to 5-hydroxytryptamine (5-HT) is dramatically increased in hypertension. The hypothesis that augmented vasoconstriction to 5-HT in hypertension is due to a change in receptor subtype on vascular myocytes was tested. Mesenteric arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive (systolic blood pressure >180 mm Hg) and sham normotensive (systolic blood pressure <130 mm Hg) rats were mounted in isolated tissue baths for measurement of isometric contractile force. The receptor mediating contraction in isolated mesenteric arteries from sham and DOCA-salt hypertensive rats is a member of the 5-HT
2
family based on rank order of agonist potency (5-HT=α-methyl-5-HT [5-HT
2
receptor agonist]>tryptamine>5-hydroxykynuramine). 5-HT was approximately 10-fold more potent in contracting mesenteric arteries from DOCA-salt hypertensive rats compared with arteries from sham normotensive rats. The tryptophan metabolite kynuramine, which possesses significant contractile activity at the 5-HT
2B
receptor, contracted hypertensive arteries significantly (50% of 5-HT maximum) but not sham arteries. Ketanserin (5-HT
2A
antagonist) competitively inhibited contraction to 5-HT in arteries from normotensive rats (−log dissociation constant [mol/L]; p
K
B
=8.54) but not from hypertensive rats (p
K
B
>6.5). Moreover, contraction to kynuramine was not blocked by ketanserin. Thus, under normal conditions, 5-HT
2A
receptors mediate contraction to 5-HT. However, in DOCA-salt hypertension, ketanserin-insensitive 5-HT
2
receptors, possibly 5-HT
2B
receptors, mediate mesenteric arterial contraction to 5-HT.
Suboptimal Outcome of Management of Metabolic Cardiovascular Risk Factors in Hispanic Patients With Essential Hypertension
Authors: Laffer Cheryl L. , Elijovich Fernando
Published: June 2012

Abstract
We studied outcome of management of metabolic cardiovascular risk factors in 155 randomly chosen Hispanic hypertensive patients (mean age, 63±1 years; 79% female) screened for dyslipidemia. Hypertriglyceridemia (n=12) or high risk–adjusted low-density lipoprotein cholesterol (LDL-C) (n=89) was found in 65%. Triglycerides did not change (6.16±0.58 to 7.44±2.34 mmol/L;
P
=NS) over 2.2±0.5 years. Only 58 patients with high LDL-C were treated, and 8 had no follow-up lipid tests. In the other 50, LDL-C decreased by 10±3% (
P
<.001) over 2.8±0.2 years but attained goal in only 12. In a subset of 24 patients with extended follow-up (3.8±0.2 years), there was an initial marked decline in LDL-C, followed by a rebound to baseline levels. In 29 of 54 patients with normal LDL-C, lipid testing was markedly overused compared with recommendations. Obesity (n=94, 61%) did not improve in those with repeated data (+0.6±0.8 kg;
P
=NS; n=40) over 2.7±0.3 years. Forty-four of 63 patients with type II diabetes had repeated measurement of glycosylated hemoglobin, with no change (10.5±0.5% to 11.2±0.5%;
P
=NS) over 2.2±0.3 years. Ten-year risk of coronary events (Framingham cohort parametric regression) calculated for 61 patients with known untreated blood pressures (169±3/98±1 mm Hg) was 21.0±1.7%, with a skewed distribution reaching high values (66%) and attributable in large part (72%) to modifiable risk factors. With the use of the model, hypothetical correction of metabolic risk factors was more powerful than reduction of systolic blood pressure to 140 mm Hg (Δrisk, −8.3±0.9% versus −4.2±0.5%;
P
<.0001) and predicted a reduction in risk 25-fold larger than that actually sustained by the patient sample (−0.3±0.6%;
P
=NS). In summary, Hispanics with essential hypertension exhibit a multifactorial risk profile, with the potential (as yet unrealized) for large reduction in cardiovascular morbidity. Our studies make it apparent that in this population, adequate treatment of concomitant metabolic illnesses is equally as important as or even more important than management of blood pressure.
Autonomic Dysfunction in Short-term Experimental Diabetes
Authors: Maeda C.Y. , Fernandes T.G. , Timm H.B. , Irigoyen M.C.
Published: June 2012

Abstract
Previous data showed that diabetes induced by streptozotocin for 5 days causes changes in arterial pressure control and baroreflex regulation of heart rate in male Wistar rats. The impairment of baroreflex may be related to autonomic neuropathy as described by several investigators. The aim of this study was to identify autonomic changes in short-term experimental diabetes in rats (induced for 5 days with streptozotocin 65 mg IP). Intra-arterial blood pressure signals were obtained from 6 control group and 7 diabetic group rats and processed in a data acquisition system (
codas
, 1 kHz). Both vagal and sympathetic function were assessed through intravenous injections of methylatropine and propranolol. Streptozotocin induced hyperglycemia (18.9±1.8 versus 5.8±0.2 mmol/L) and reductions in mean arterial pressure (102±2 versus 117±3 mm Hg) and resting heart rate (298±14 versus 332±2 beats per minute). Sodium and potassium levels were not different between groups. The intrinsic heart rate was reduced in the diabetic group (302±10 versus 398±6 beats per minute). This group also exhibited depressed vagal and sympathetic tone (50% and 22%, respectively), reduction of vagal effect (42%), and no change in sympathetic effect. In conclusion, early autonomic dysfunction in short-term streptozotocin-induced diabetes seems to be related to changes in arterial pressure and baroreflex control.