bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Stroke on Medical Resource Use and Costs in Acute Myocardial Infarction
Authors: Tung Chen Y. , Granger Christopher B. , Sloan Michael A. , Topol Eric J. , Knight J. David , Weaver W. Douglas , Mahaffey Kenneth W. , White Harvey , Clapp-Channing Nancy , Simoons Maarten L. , Gore Joel M. , Califf Robert M. , Mark Daniel B.
Published: June 2012

Background
—Stroke occurs concurrently with myocardial infarction (MI) in ≈30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States.

Methods and Results
—Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non–bypass surgery–related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301,
P
<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282,
P
<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were $15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non–hemorrhagic stroke patients (53% versus 15%,
P
<0.001), which was associated with ≈$7200 lower mean baseline hospitalization cost. At discharge, hemorrhagic stroke patients were more likely to be disabled (68% versus 46%,
P
=0.002).

Conclusions
—In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs.
PDGFβ Receptor Blockade Inhibits Intimal Hyperplasia in the Baboon
Authors: Hart Charles E. , Kraiss Larry W. , Vergel Selina , Gilbertson Debra , Kenagy Richard , Kirkman Thomas , Crandall David L. , Tickle Simon , Finney Helene , Yarranton Geoff , Clowes Alexander W.
Published: June 2012

Background
—We have evaluated the use of a mouse/human chimeric anti–platelet-derived growth factor-β receptor antibody in combination with heparin to inhibit intimal hyperplasia in the saphenous artery of the baboon after balloon angioplasty.

Methods and Results
—The study evaluated lesion development in sequential injuries made 28 days apart. Each animal received control treatment after the first injury and antibody/heparin therapy after the second injury to the contralateral artery. The antibody was administered by bolus intravenous injections (10 mg/kg) on study days 1, 4, 8, 15, and 22 and heparin coadministered by continuous intravenous infusion at a dose of 0.13 mg/kg per hour. Morphometric analysis of tissue sections showed a 53% decrease in intimal area after antibody/heparin treatment (
P
=0.005), corresponding to a 40% decrease in the intima-to-media ratio (
P
=0.005). Smooth muscle cell proliferation in the injured wall, measured at both 4 and 29 days after balloon injury, were similar in the control and antibody/heparin-treated animals.

Conclusions
—These data suggest that platelet-derived growth factor plays a key role in the development of intimal lesions at sites of acute vascular injury in the nonhuman primate.
Coronary Revascularization in Diabetic Patients
Authors: Detre Katherine M. , Guo Ping , Holubkov Richard , Califf Robert M. , Sopko George , Bach Richard , Brooks Maria Mori , Bourassa Martial G. , Shemin Richard J. , Rosen Allan D. , Krone Ronald J. , Frye Robert L. , Feit Frederick
Published: June 2012

Background
—Patients with treated diabetes in the randomized-trial segment of the Bypass Angioplasty Revascularization Investigation (BARI) who were randomized to initial revascularization with PTCA had significantly worse 5-year survival than patients assigned to CABG. This treatment difference was not seen among diabetic patients eligible for BARI who opted to select their mode of revascularization. We hypothesized that differences in patient characteristics, assessed and unmeasured, together with the treatment selection in the registry, at least partially account for this discrepancy.

Methods and Results
—Among diabetics taking insulin or oral hypoglycemic drugs at entry, angiographic and clinical presentations were comparable between randomized and registry patients. However, more registry patients were white, and registry diabetics tended to be more educated and more physically active and to report better quality of life. Procedural characteristics and in-hospital complications were comparable. The 5-year all-cause mortality rate was 34.5% in randomized diabetic patients assigned to PTCA versus 19.4% in CABG patients (
P
=0.0024; relative risk [RR]=1.87); corresponding cardiac mortality rates were 23.4% and 8.2%, respectively (
P
=0.0002; RR=3.10). The CABG benefit was more apparent among patients requiring insulin. In the registry, all-cause mortality was 14.4% for PTCA versus 14.9% for CABG (
P
=0.86, RR=1.10), with corresponding cardiac mortality rates of 7.5% and 6.0%, respectively (
P
=0.73; RR=1.07). These RRs in the registry increased to 1.29 and 1.41, respectively, after adjustment for all known differences between treatment groups.

Conclusions
—BARI registry results are not inconsistent with the finding in the randomized trial that initial CABG is associated with better long-term survival than PTCA in treated diabetic patients with multivessel coronary disease suitable for either surgical or catheter-based revascularization.
Skeletal Muscle Mitochondrial DNA Injury in Patients With Unilateral Peripheral Arterial Disease
Authors: Bhat Hari K. , Hiatt William R. , Hoppel Charles L. , Brass Eric P.
Published: June 2012

Background
—Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977–base pair (bp) mtDNA deletion mutation.

Methods and Results
—The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients.

Conclusions
—The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.
Validation of a New Noncontact Catheter System for Electroanatomic Mapping of Left Ventricular Endocardium
Authors: Gornick Charles C. , Adler Stuart W. , Pederson Brian , Hauck John , Budd Jeffrey , Schweitzer Jeff
Published: June 2012

Background
—Improvements in cardiac mapping are required to advance our understanding and treatment of arrhythmias. This study validated a new noncontact multielectrode array catheter and accompanying analysis system to provide electroanatomic mapping of the entire left ventricular (LV) endocardium during a single beat.

Methods and Results
—A 9F 64-electrode balloon array catheter with an inflated size of 1.8×4.6 cm was used to simultaneously record electrical potentials generated by the heart and locate a standard electrophysiology (EP) catheter within the same chamber. By use of the recorded location of the EP-catheter tip, LV geometry was determined. Array potentials served as inputs to a high-order boundary-element method to produce 3360 potential points on the endocardial surface translatable into electrograms or color-coded activation maps. Three methods of validation were used: (1) driven electrodes in an in vitro tank were located; (2) waveforms generated from the array catheter were compared with catheter contact waveforms in canine LV; and (3) sites of local LV endocardial activation were located and marked with radiofrequency lesions. Tank testing located a driven electrode to within 2.33±0.44 mm. Correlation of timing and morphology of computed versus contact electrograms was 0.966. Radiofrequency lesions marked 17 endocardial pacing sites to within 4.0±3.2 mm.

Conclusions
—This new system provides anatomically accurate endocardial isopotential mapping during a single cardiac cycle. The locator component enabled placement of a separate EP catheter to any site within the mapped chamber.
Elevated Levels of C-Reactive Protein at Discharge in Patients With Unstable Angina Predict Recurrent Instability
Authors: Biasucci Luigi M. , Liuzzo Giovanna , Grillo Rita L. , Caligiuri Giuseppina , Rebuzzi Antonio G. , Buffon Antonino , Summaria Francesco , Ginnetti Francesca , Fadda Giovanni , Maseri Attilio
Published: June 2012

Background
—In a group of patients admitted for unstable angina, we investigated whether C-reactive protein (CRP) plasma levels remain elevated at discharge and whether persistent elevation is associated with recurrence of instability.

Methods and Results
—We measured plasma levels of CRP, serum amyloid A protein (SAA), fibrinogen, total cholesterol, and
Helicobacter
pylori
and
Chlamydia
pneumoniae
antibody titers in 53 patients admitted to our coronary care unit for Braunwald class IIIB unstable angina. Blood samples were taken on admission, at discharge, and after 3 months. Patients were followed for 1 year. At discharge, CRP was elevated (>3 mg/L) in 49% of patients; of these, 42% had elevated levels on admission and at 3 months. Only 15% of patients with discharge levels of CRP <3 mg/L but 69% of those with elevated CRP (
P
<0.001) were readmitted because of recurrence of instability or new myocardial infarction. New phases of instability occurred in 13% of patients in the lower tertile of CRP (≤2.5 mg/L), in 42% of those in the intermediate tertile (2.6 to 8.6 mg/L), and in 67% of those in the upper tertile (≥8.7 mg/L,
P
<0.001). The prognostic value of SAA was similar to that of CRP; that of fibrinogen was not significant.
Chlamydia
pneumoniae
but not
Helicobacter
pylori
antibody titers significantly correlated with CRP plasma levels.

Conclusions
—In unstable angina, CRP may remain elevated for at ≥3 months after the waning of symptoms and is associated with recurrent instability. Elevation of acute-phase reactants in unstable angina could represent a hallmark of subclinical persistent instability or of susceptibility to recurrent instability and, at least in some patients, could be related to chronic
Chlamydia
pneumoniae
infection.
Enteroviral RNA Replication in the Myocardium of Patients With Left Ventricular Dysfunction and Clinically Suspected Myocarditis
Authors: Pauschinger Matthias , Doerner Andrea , Kuehl Uwe , Schwimmbeck Peter L. , Poller Wolfgang , Kandolf Reinhard , Schultheiss Heinz-Peter
Published: June 2012

Background
—Previous studies dealing with the detection of enteroviral RNA in human endomyocardial biopsies have not differentiated between latent persistence of the enteroviral genome and active viral replication. Enteroviruses that are considered important factors for the development of myocarditis have a single-strand RNA genome of positive polarity that is transcribed by a virus-encoded RNA polymerase into a minus-strand mRNA during active viral replication. The synthesis of multiple copies of minus-strand enteroviral RNA therefore occurs only at sites of active viral replication but not in tissues with mere persistence of the viral genome.

Methods and Results
—We investigated enteroviral RNA replication versus enteroviral RNA persistence in endomyocardial biopsies of 45 patients with left ventricular dysfunction and clinically suspected myocarditis. Using reverse-transcriptase polymerase chain reaction in conjunction with Southern blot hybridization, we established a highly sensitive assay to specifically detect plus-strand versus minus-strand enteroviral RNA in the biopsies. Plus-strand enteroviral RNA was detected in endomyocardial biopsies of 18 (40%) of 45 patients, whereas minus-strand RNA as an indication of active enteroviral RNA replication was detected in only 10 (56%) of these 18 plus-strand–positive patients. Enteroviral RNA was not found in biopsies of the control group (n=26).

Conclusions
—These data demonstrate that a significant fraction of patients with left ventricular dysfunction and clinically suspected myocarditis had active enteroviral RNA replication in their myocardium (22%). Differentiation between patients with active viral replication and latent viral persistence should be particularly important in future studies evaluating different therapeutic strategies. In addition, molecular genetic detection of enteroviral genome and differentiation between replicating versus persistent viruses is possible in a single endomyocardial biopsy.
Microvascular Function Relates to Insulin Sensitivity and Blood Pressure in Normal Subjects
Authors: Serné Erik H. , Stehouwer Coen D. A. , ter Maaten Jan C. , ter Wee Piet M. , Rauwerda Jan A. , Donker Ab J. M. , Gans Reinold O. B.
Published: June 2012

Background
—A strong but presently unexplained inverse association between blood pressure and insulin sensitivity has been reported. Microvascular vasodilator capacity may be a common antecedent linking insulin sensitivity to blood pressure. To test this hypothesis, we studied 18 normotensive and glucose-tolerant subjects showing a wide range in insulin sensitivity as assessed with the hyperinsulinemic, euglycemic clamp technique.

Methods and Results
—Blood pressure was measured by 24-hour ambulatory blood pressure monitoring. Videomicroscopy was used to measure skin capillary density and capillary recruitment after arterial occlusion. Skin blood flow responses after iontophoresis of acetylcholine and sodium nitroprusside were evaluated by laser Doppler flowmetry. Insulin sensitivity correlated with 24-hour systolic blood pressure (24-hour SBP;
r
=−0.50,
P
<0.05). Capillary recruitment and acetylcholine-mediated vasodilatation were strongly and positively related to insulin sensitivity (
r
=0.84,
P
<0.001;
r
=0.78,
P
<0.001, respectively), and capillary recruitment was inversely related to 24-hour SBP (
r
=−0.53,
P
<0.05). Waist-to-hip ratio showed strong associations with insulin sensitivity, blood pressure, and the measures of microvascular function but did not confound the associations between these variables. Subsequent regression analysis showed that the association between insulin sensitivity and blood pressure was not independent of the estimates of microvascular function, and part of the variation in both blood pressure (
R
2
=38%) and insulin sensitivity (
R
2
=71%) could be explained by microvascular function.

Conclusions
—Insulin sensitivity and blood pressure are associated well within the physiological range. Microvascular function strongly relates to both, consistent with a central role in linking these variables.
High-Resolution Intravascular Magnetic Resonance Imaging
Authors: Zimmermann-Paul Gesine G. , Quick Harald H. , Vogt Peter , von Schulthess Gustav K. , Kling Dorothee , Debatin Jörg F.
Published: June 2012

Background
—The individual makeup of atherosclerotic plaque has been identified as a dominant prognostic factor. With the use of an intravascular magnetic resonance (MR) catheter coil, we evaluated the effectiveness of high-resolution MR in the study of the development of atherosclerotic lesions in heritable hyperlipidemic rabbits.

Methods and Results
—Sixteen hyperlipidemic rabbits were investigated at the ages of 6, 12, 24, and 36 months. The aorta was studied with digital subtraction angiography and high-resolution MR with the use of a surface coil and an intravascular coil that consisted of a single-loop copper wire integrated in a 5F balloon catheter. Images were correlated with histological sections regarding wall thickness, plaque area, and plaque components. Digital subtraction angiography revealed no abnormalities in the 6- and 12-month-old rabbits and only mild stenoses in the 24- and 36-month-old rabbits. High-resolution imaging with surface coils resulted in an in-plane resolution of 234×468 μm. Delineation of the vessel wall was not possible in younger rabbits and correlated only poorly with microscopic measurements in the 36-month-old rabbits. Intravascular images achieved an in-plane resolution of 117×156 μm. Increasing thickness of the aortic wall and plaque area was observed with increasing age. In the 24- and 36-month-old animals, calcification could be differentiated from fibrous and fatty tissue on the basis of the T2-fast spin echo images, as confirmed by histological correlation.

Conclusions
—Atherosclerotic evolution of hyperlipidemic rabbits can be monitored with high-resolution intravascular MR imaging. Image quality is sufficient to determine wall thickness and plaque area and to differentiate plaque components.
Oxidized Low-Density Lipoprotein Regulates Matrix Metalloproteinase-9 and Its Tissue Inhibitor in Human Monocyte-Derived Macrophages
Authors: Xu Xiao-Ping , Meisel Simcha R. , Ong John M. , Kaul Sanjay , Cercek Bojan , Rajavashisth Tripathi B. , Sharifi Behrooz , Shah Prediman K.
Published: June 2012

Background
—Macrophages in human atherosclerotic plaques produce a family of matrix metalloproteinases (MMPs), which may influence vascular remodeling and plaque disruption. Because oxidized LDL (ox-LDL) is implicated in many proatherogenic events, we hypothesized that ox-LDL would regulate expression of MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in monocyte-derived macrophages.

Methods and Results
—Mononuclear cells were isolated from normal human subjects with Ficoll-Paque density gradient centrifugation, and adherent cells were allowed to differentiate into macrophages during 7 days of culture in plastic dishes. On day 7, by use of serum-free medium, the macrophages were incubated with various concentrations of native LDL (n-LDL) and copper-oxidized LDL. Exposure to ox-LDL (10 to 50 μg/mL) increased MMP-9 mRNA expression as analyzed by Northern blot, protein expression as measured by ELISA and Western blot, and gelatinolytic activity as determined by zymography. The increase in MMP-9 expression was associated with increased nuclear binding of transcription factor NF-κB and AP-1 complex on electromobility shift assay. In contrast, ox-LDL (10 to 50 μg/mL) decreased TIMP-1 expression. Ox-LDL–induced increase in MMP-9 expression was abrogated by HDL (100 μg/mL). n-LDL had no significant effect on MMP-9 or TIMP-1 expression.

Conclusions
—These data demonstrate that unlike n-LDL, ox-LDL upregulates MMP-9 expression while reducing TIMP-1 expression in monocyte-derived macrophages. Furthermore, HDL abrogates ox-LDL–induced MMP-9 expression. Thus, ox-LDL may contribute to macrophage-mediated matrix breakdown in the atherosclerotic plaques, thereby predisposing them to plaque disruption and/or vascular remodeling.
Acute Saline Infusion Reduces Alveolar-Capillary Membrane Conductance and Increases Airflow Obstruction in Patients With Left Ventricular Dysfunction
Authors: Puri Sundeep , Dutka David P. , Baker B. Leigh , Hughes J. Michael B. , Cleland J. G. F.
Published: June 2012

Background
—Impaired alveolar-capillary membrane conductance is the major cause for the reduction in pulmonary diffusing capacity for carbon monoxide (D
lco
) in heart failure. Whether this reduction is fixed, reflecting pulmonary microvascular damage, or is variable is unknown. The aim of this study was to assess whether D
lco
and its subdivisions, alveolar-capillary membrane conductance (D
m
) and pulmonary capillary blood volume (Vc), were sensitive to changes in intravascular volume. In addition, we examined the effects of volume loading on airflow rates.

Methods and Results
—Ten patients with left ventricular dysfunction (LVD) and 8 healthy volunteers were studied. D
m
and Vc were determined by the Roughton and Forster method. The forced expiratory volume in 1 second (FEV
1
), vital capacity, and peak expiratory flow rates (PEFR) were also recorded. In patients with LVD, infusion of 10 mL · kg
−1
body wt of 0.9% saline acutely reduced D
m
(12.0±3.3 versus 10.4±3.5 mmol · min
−1
· kPa
−1
,
P
<0.005), FEV
1
(2.3±0.4 versus 2.1±0.4 L,
P
<0.0005), and PEFR (446±55 versus 414±56 L · min
−1
,
P
<0.005). All pulmonary function tests had returned to baseline values 24 hours later. In normal subjects, saline infusion had no measurable effect on lung function.

Conclusions
—Acute intravascular volume expansion impairs alveolar-capillary membrane function and increases airflow obstruction in patients with LVD but not in normal subjects. Thus, the abnormalities of pulmonary diffusion in heart failure, which were believed to be fixed, also have a variable component that could be amenable to therapeutic intervention.
Regression of Atherosclerosis
Authors: Wang Bing-Yin , Ho Hoai-Ky V. , Lin Patrick S. , Schwarzacher Severin P. , Pollman Matthew J. , Gibbons Gary H. , Tsao Philip S. , Cooke John P.
Published: June 2012

Background
—We have recently found that administration of
l
-arginine to hypercholesterolemic rabbits induces regression of preexisting lesions. Others have previously shown that activation of the
l
-arginine/nitric oxide (NO) synthase pathway can induce apoptosis of vascular cells in vitro. Accordingly, the current study was designed to determine if dietary supplementation of
l
-arginine induces apoptosis of intimal lesions and if this effect is mediated through the NO synthase pathway.

Methods and Results
—Male New Zealand White rabbits were fed a 0.5% cholesterol diet for 10 weeks and subsequently placed on 2.5%
l
-arginine HCl in the drinking water, and the cholesterol diet was continued for 2 weeks, at which time the aortas were harvested for histological studies.
l
-Arginine treatment increased the number of apoptotic cells (largely macrophages) in the intimal lesions by 3-fold (11.9±3.9 vs 3.9±1.4 apoptotic cells/mm
2
,
P
<0.01). In subsequent studies, aortas were harvested for ex vivo studies. Aortic segments were incubated in cell culture medium for 4 to 24 hours with modulators of the NO synthase pathway. The tissues were then collected for histological studies and the conditioned medium collected for measurement of nitrogen oxides by chemiluminescence. Addition of sodium nitroprusside (10
−5
mol/L) to the medium caused a time-dependent increase in apoptosis of vascular cells (largely macrophages) in the intimal lesion.
l
-Arginine (10
−3
mol/L) had an identical effect on apoptosis, which was associated with an increase in nitrogen oxides released into the medium. These effects were not mimicked by
d
-arginine, and they were antagonized by the NO synthase inhibitor
l
-nitro-arginine (10
−4
mol/L). The effect of
l
-arginine was not influenced by an antagonist of cGMP-dependent protein kinase, nor was the effect mimicked by the agonist of protein kinase G or 8-BR cGMP.

Conclusions
—These results indicate that supplemental
l
-arginine induces apoptosis of macrophages in intimal lesions by its metabolism to NO, which acts through a cGMP-independent pathway. These studies are consistent with our previous observation that supplementation of dietary arginine induces regression of atheroma in this animal model. These studies provide a rationale for further investigation of the therapeutic potential of manipulating the NO synthase pathway in atherosclerosis.
Cardiovascular response to mental stress in normal adolescents with hypertensive parents. Hemodynamics and mental stress in adolescents.
Authors: Falkner B , Onesti G , Angelakos E T , Fernandes M , Langman C
Published: June 2012

The hemodynamic response to mental stress (mental arithmetic) was studied in adolscents with varying risk factors for essential hypertension (EH), One group (genetic) consisted of normotensive well adolescents who had at least one parentnt with EH. Another group (labile) consisted of adolescents with labile hypertension each of whom also had at least one pare with EH. The control population consisted of normotensive adolescents with a negative family history of EH. Subjects with labile hypertension demonstrated a sustained increase in systolic and diastolic pressure and heart rate during stress. This response was significantly different than the control population (P less than THE CONTROL POPULATION (P LESS THAN 0.001). The stress response of the normotensive genetic population was qualitatively similar to the group with labile hypertension and significantly different than the controls in diastolic pressure and heart rate (p less than 0.001, less than 0.02). Post-stress plasma catecholamines were higher in the labile hypertensive and genetic groups than in the control group. These findings demonstrate increased central nervous system mediated adrenergic activity and cardiovascular response in labile hypertension and also in some normotensive subjects with a genetic risk for hypertension.
Separation of dog brain renin-like activity from acid protease activity.
Authors: Osman M Y , Smeby R R , Sen S
Published: June 2012

A renin-like enzyme and acid protease (cathepsin) from whole and saline-pefused dog brains were separated by CM-cellulose chromatography with a linear NaCl gradient. Plasma renin and cathepsin were also separated using the same system. During the separation steps (in all the above cases) the specific activity of the brain renin-like enzyme was increased, while the specific activity of the brain cathepsin was decreased. Approximately a 70-fold increase in the specific activity of brain renin-like enzyme and a sixfold decrease in brain cathepsin specific activity was obtained from saline-perfused brain. The separation made it possible to study the pH optimum of the brain renin-like enzyme and acid protease. The brain renin-like enzyme showed optimal activity in the range of pH 6-7. Immunologically, the renin-like enzyme was distinctly different from dog kidney renin.
Prolongation of the saralasin responsive state of two-kidney, one clip Goldblatt hypertension in the rat by the orally administered converting enzyme inhibitor captopril (SQ14,225).
Authors: Weed W C , Vaughan E D , Peach M J
Published: June 2012

Two-kidney, one clip Goldblatt rats were treated with oral converting enzyme inhibitor captopril (SQ14,225) 6 mg/kg/day for 3 weeks after they had developed hypertension. Before treatment, systolic blood pressure rose from 143 to 202 mm Hg (p less than 0.05). Tail vein infusions of saralasin 10 microgram/kg/min in conscious rats reduced systolic blood pressure from 202 to 121 mm Hg (p less than 0.05) at 8 weeks after clipping the renal artery and before treatment with captopril. Chronic treatment with captopril for 3 additional weeks lowered blood pressure to 173 mm Hg (p less than 0.05). When saralasin infusion was repeated during treatment with captopril, blood pressure fell from 173 to 159 mm Hg (p less than 0.05). Blood pressure rose to 197 mm Hg within 4 days after captopril was discontinued and saralasin infusion 3 weeks after captopril (15 weeks after clipping the renal artery) again resulted in a dramatic fall in blood pressure from 197 to 142 mm Hg (p less than 0.05). Goldblatt rats who had not received captopril showed no blood pressure response to saralasin infusion at 12 weeks after renal artery clipping. The present study demonstrates that partial inhibition of the renin-angiotensin system with captopril results in a delay in the natural evolution of clip hypertension retarding the appearance of hypertension that is resistant to acute saralasin infusion.
Alterations in the responses of the sympathetic nervous system and renin in borderline hypertension.
Authors: Robertson D , Shand D G , Hollifield J W , Nies A S , Frölich J C , Oates J A
Published: June 2012

We investigated the effect of stimuli activate the sympathetic nervous system on plasma catecholamines, renin activity, urinary metanephrine and normetanephrine, and various hemodynamic parameters in normal subjects (NIs) and borderline hypertensive (BH) subjects. No differences were observed in sympathetic nervous system activity or renin activity when the subjects were in the resting state on a 150 mEq sodium diet. However, the BH group exhibited greater responses in terms of plasma catecholamines and plasma renin activity in response to sodium deprivation and treadmill exercise. Although hemodynamic differences in the cold pressor test and handgrip exercise did not emerge, the radio of atrial size decrement to venous tone increment during the Valsalva maneuver was significantly reduced in the BH group. The investigations suggest that in the basal state, BH subjects have appropriate levels of activation of the sympathetic and renin systems for a normal level of pressure but that perturbations of pressure and volume factors lead to unmasking of abnormalities in regulation of both systems. The data are also consistent with the suggestion that venous compliance is reduced in these patients.
Increased resistance and impaired maximal vasodilation in normotensive vascular beds of rats with coarctation hypertension.
Authors: Bell D R , Overbeck H W
Published: June 2012

To study the resistance of normotensive vascular beds in coarctation hypertension, we measured perfusion pressures of pump-perfused (blood), innervated, isolated hindlimbs of 12 rats (Group A) with 4 weeks of hypertension due to partial contriction of the abdominal aorta above the renal arteries, and of three control groups: 11 normotensive rats (Group B) with aorta sham-constricted, nine normotensive rats (Group C) with slight (5%) hindquarters atrophy due to partial constriction of the abdominal aorta below the renal arteries, and six rats with two-kidney, one clip Goldblatt hypertension (Group D). After aortic constriction, measured femoral arterial pressures in Group A rats remained normotensive. In hypertensive rats of Groups A and D, compared to normotensive Group B or C rats, hindlimb pressure-flow curves were displaced toward the pressure axis (p < 0.05). Compared to normotensive rats, drop in hindlimb resistance after acute local nerve section was increased in rats with coarctation hypertension. Residual resistance after maximal vasodilation with intraarterial sodium nitroprusside remained elevated in hypertensive rats of Groups A and D (p < 0.05), as compared to normotensive Group B or C rats; compared to Group B rats, this residual resistance in the coarcted rats of Group A was increased by 9%. Thus, in normotensive vascular beds of rats with chronic hypertension caused by aortic coarctation, resistance is elevated. The neurogenic component contributes to this high resistance, and structural vascular changes, indicated by impaired maximal vasodilation, may also contribute to the elevated resistance. It is most unlikely that these resistance changes are attributable to elevated hindlimb intravascular pressures.
Evidence against acetone-soluble renin inhibitors in normal human plasma.
Authors: Druilhet R E , Overturf M L , Hinshaw R A , Kirkendall W M
Published: June 2012

The presence of acetone-soluble renin inhibitors in normal plasma has been proposed to explain the variation of plasma reactivity (PRR) in samples from normotensive and hypertensive subjects. In our experience, acetone extraction decreased PRR in relation to unextracted control values, an observation which is not consistent with the circulating lipid-renin inhibitor hypothesis. Exposure to acetone at -40 degrees C for 1 minute invariably denatured some endogenous angiotensinogen. The PRR in extracted and unextracted plasma was positively correlated with the concentration of available angiotensinogen, r = 0.955 (p < 0.05), and r = 0.964 (p < 0.01), respectively, but the addition of exogenous substrate did not uniformly increase PRR in acetone-treated plasma above control values. These data argue against the use of acetone extraction to demonstrate the existence of circulating lipid-renin inhibitors. Acetone removed 14% to 25% of the normal plasma lipids and although the extract contained most of the major lipid classes, neutral lipids were the most abundant (73% by weight). The presence of acetone-soluble phospholipids appeared to increase angiotensin I formation in the partially purified renin-angiotensinogen system, but phospholipids interfered with the radioimmunoassay and resulted in an overestimation of angiotensin I. Plasma neutral lipids decreased in vitro renin activity by 13% (p < 0.025) but this degree of inhibition suggests that lipid-renin interactions may have minimal in vivo physiological significance. In contrast to previous reports, we found the correlation between PRR and endogenous angiotensinogen in normotensive and hypertensive plasmas to be statistically significant (r = 0.643, p < 0.01). Inactivated human angiotensinogen was also shown to be an inhibitor of renin in vitro. This effect could have possibly influenced PRR values that were determined by others in the presence of inactivated angiotensinogen.
Independence of the central nervous and the peripheral renin-angiotensin systems in the dog.
Authors: Nicholls M G
Published: June 2012

What regulates the activity of the central nervous renin-angiotensin system is not known. To define whether control of this central system is linked to that in the periphery, simultaneous blood and cerebrospinal fluid (CSF) samples for measurement of immunoreactive angiotensin II were drawn from anesthetized dogs during hemorrhage, furosemide-induced volume depletion, insulin-hypoglycemia, beta-adrenergic blockade and saline infusion. Despite vigorous increments or decrements in plasma innunoreactive angiotensin II, CSF levels remained stable. Since immunoreactive angiotensin II in dog CSF is claimed to be mainly the heptapeptide des-Asp1-angiotensin II (angiotensin III), the possibility that the level of this peptide within CSF simply reflects plasma concentrations was assessed by infusing angiotensin III (2.5 and 25 ng/kg/min intravenously, each for 60 minutes) and monitoring plasma and CSF peptide levels. Whereas plasma immunoreactive angiotensin II levels increased appropriately across the infusions, no change in CSF levels was observed. These studies indicate the angiotensin III does not cross the blood-CSF barrier, at least in the short term.
Relation between blood pressure and renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium in 574 ambulatory subjects.
Authors: Walker W G , Whelton P K , Saito H , Russell R P , Hermann J
Published: June 2012

Five hundred and seventy-four ambulatory subjects with blood pressures ranging from 94/58 to 250/145 mm Hg were studied on their usual dietary and sodium intake. Renin, renin substrate, angiotensin II, aldosterone and urinary sodium and potassium were compared with blood pressure to access the contribution of these variables to the blood pressure variance. Our analyses revealed that renin substrate was highly and positively correlated with diastolic blood pressure (r = +0.39; p < 0.00001) but all other components of the renin-aldosterone system exhibited a significant negative correlation with blood pressure. A highly significant relationship between potassium, the renin-aldosterone system and blood pressure was found but no such relationship could be demonstrated for sodium. Subjects with higher blood pressures had lower urinary potassium concentrations and lower potassium/creatine ratios. These findings raised the possibility of a significant pathogenetic relationship between potassium and high blood pressure. Multiple linear regression reveals that influences of the renin-angiotensin-aldosterone system can only account for less than 20% of the variance exhibited by the blood pressure in these subjects.
Hemodynamic and antihypertensive effects of captopril, an orally active angiotensin converting enzyme inhibitor.
Authors: Sullivan J M , Ginsburg B A , Ratts T E , Johnson J G , Barton B R , Kraus D H , McKinstry D N , Muirhead E E
Published: June 2012

Captopril inhibits angiotensin II formation and bradykinin degradation in vivo. Eleven patients with essential hypertension (EH) and four patients with renovascular hypertension (RVH) were treated with captopril for periods ranging from 3 days to 12 months. All patients had a diastolic blood pressure (DBP) over 95 mm Hg after receiving a placebo for 3 days. Captopril given in ascending doses (10-1000 mg/day) caused normalization of blood pressure in all but three patients, one with severe RVH whose pressure fell 11%, one patient with severe EH, whose pressure fell 27%, and one with EH whose blood pressure fell 8.5%. The average control DBP in patients with EH was 113.7 +/- 5.5 (SE) mm Hg and fell to 89.9 +/- 3.6 mm Hg (p less than 0.001), while DBP in patients with RVH fell from 110.7 +/- 7.6 mm Hg to 94.5 +/- 8.2 (p less than 0.005). All patients were studied in balance on a 100 mEq sodium (Na) diet. Plasma renin activity (PRA) versus 24-hour urinary Na excretion increased sevenfold during therapy while converting enzyme activity fell by about one half. The magnitude of the blood pressure response was not related to control PRA. Cardiac output was estimated by echocardiography during placebo administration and during maintenance therapy with captopril. A significant change was not observed. Total peripheral resistance fell an average of 18.9% (p less than 0.05) in 11 of the 13 patients in whom the measurement could be made. It is concluded that captopril effectively lowers blood pressure in patients with EH or RHV by reducing total peripheral resistance.
Evidence for enhanced sodium transport in the tail artery of the spontaneously hypertensive rat.
Authors: Friedman S M
Published: June 2012

Transmembrane Na+ and K+ gradients in the rat tail artery were dissipated by overnight incubation in K-free PSS at 10 degrees C and then allowed to recover in normal physiologic salt solution (PSS) at 37 degrees C. The active extrusion of Na+ and uptake of K+ during the recovery period was monitored with Na+ and K+ selective glass electrodes. Passive exchanges were differentiated by re-admitting K+ at 3 degrees C, or in the presence of 1 mM ouabain at both 3 degrees C and 37 degrees C. Active exchange was switched on by an abrupt transfer of the tissue from 3 degrees C to 37 degrees C. Active exchange, measured in perfused, superfused, or sequentially incubated arteries, was distinctly enhanced in young (16-, 20- and 26-week-old) spontaneously hypertensive rats (SHR) of the Okamoto strain compared with age-matched Wistar-Kyoto normotensive (WKY) controls. No such difference was observed in rats with hypertension of 7 or 12 weeks' duration and equal severity induced by unilateral constriction of the renal artery. Steady-state Nai and Ki were measured after washing the tissues for 45 minutes at 3 degrees C in lithium-substituted medium to exchange extracellular sodium with lithium. Cell sodium in these tissues was further partitioned into a free component proportional to [Na]0 and an independent, constrained component. Cell potassium was found to be distinctly elevated in 2- and 4-month-old SHR, while free cell sodium remained normal, despite increased cell permeability demonstrable in a significant exchange of lithium for cell potassium and sodium even at 3 degrees C.
Renal phospholipase C and diglyceride lipase activity in spontaneously hypertensive rats.
Authors: Kawaguchi H , Okamoto H , Saito H , Yasuda H
Published: June 2012

Phospholipase C activity and diglyceride lipase activity were studied in the renal cortex and medulla of 10- and 40-week-old stroke-prone spontaneously hypertensive rats (SHRSP) and age-matched normotensive Wistar-Kyoto rats (WKY). Enhanced phospholipase C activity was found in the cortical and medullary cytosol of kidney from SHRSP, and microsomal diglyceride lipase in SHRSP also increased. In SHRSP, phospholipase C and diglyceride lipase activities increased with age, but this increase was not evident in WKY. Phospholipase C had high substrate specificity for phosphatidylinositol in renal cytosol of both WKY and SHRSP. The increased activities were accompanied by prostaglandin E2 synthesis in renal medullary microsomes of 10-week-old SHRSP and were also present in the kidney of 40-week-old SHRSP. Total phospholipid and arachidonic acid contents in kidney were markedly high in the medulla of 10-week-old SHRSP, but these lipids were decreased in 40-week-old SHRSP. These results suggest that phospholipids and arachidonic acid in SHRSP may be genetically high and that the activated phospholipase C and diglyceride lipase hydrolyze phospholipids, providing arachidonic acid for prostaglandin synthesis, which results in a decrease of phospholipids and arachidonic acid in the kidney of 40-week-old SHRSP. These studies demonstrate that a phosphatidylinositol-specific phospholipase C-prostaglandin synthetic system may play an important role in the course of hypertension in SHRSP.
Papillary collecting tubule responsiveness to atrial natriuretic factor in Dahl rats.
Authors: Appel R G , Dunn M J
Published: June 2012

There is evidence that atrial natriuretic factor (ANF) has an action in the inner medullary collecting duct. In addition, the prehypertensive Dahl salt-sensitive (S) rat has an intrinsic tendency toward less natriuresis than the Dahl salt-resistant (R) rat has when challenged with ANF. To test the hypothesis that renal papillary collecting tubule cells from prehypertensive S rats might be genetically less responsive to ANF, S and R cells were grown in culture and studied for responsiveness to ANF by measurement of cyclic nucleotide responses. There was a concentration-dependent effect of ANF on renal papillary collecting tubule cell synthesis of intracellular cyclic guanosine 3',5'-monophosphate (cGMP) in both strains. However, the S cells were hyporesponsive compared with the R cells (p less than 0.002, by analysis of variance). Likewise, in response to Na nitroprusside, the S cells were hyporesponsive compared with the R cells as measured by intracellular cGMP accumulation (p less than 0.03, by analysis of variance). Arginine vasopressin stimulated intracellular cAMP equally in both strains. Also, ANF equally enhanced intracellular cGMP in glomerular mesangial cells from S and R rats, indicating possible specificity of the reduced responsiveness to ANF to the distal nephron of S rats. Plasma ANF levels had a slight tendency to be higher in prehypertensive S rats than in R rats (p = 0.088, by t test). These results suggest that the papillary collecting duct of Dahl S and R rats may differ in guanylate cyclase activity. This difference may partially explain the impaired natriuretic responses of S rats and could represent a factor contributing to the development of salt-sensitive hypertension.
Biological variability in Wistar-Kyoto rats. Implications for research with the spontaneously hypertensive rat.
Authors: Kurtz T W , Morris R C
Published: June 2012

The spontaneously hypertensive rat (SHR) initially bred in Kyoto is the most widely studied animal model of essential hypertension. As controls for the SHR, most workers have used normotensive descendants of Wistar rats from the colony in Kyoto from which the SHR strain was derived (Wistar-Kyoto rats, WKY). But the presumption that WKY are serviceable controls for SHR rests on the tacit assumption that all WKY constitute a single inbred strain. It appears, however, that whereas the National Institutes of Health distributed breeding stocks of SHR after they had been fully inbred (i.e., after 20 generations of brother-sister mating), the breeding stocks of WKY were distributed before they had been fully inbred. Accordingly, the biological variability of WKY may be greater than that of SHR. To investigate this possibility, we obtained SHR and WKY from two of the largest commercial suppliers in the United States and systematically measured the growth rate and blood pressure of these rats under identical physical and metabolic conditions. We found that WKY from one source differed from those of the other in both growth rate and blood pressure. In contrast, the SHR from the two suppliers were not different with respect to either growth rate or blood pressure. Because the National Institutes of Health may have distributed breeding stocks of WKY as early as the F6 generation, it is possible that rats currently designated as WKY do not constitute a single inbred strain. Thus, interpretation of studies employing "the Wistar-Kyoto rat strain" as a control for the SHR may be much more problematic than has previously been recognized.
The inhibitory role of 12- and 15-lipoxygenase products on renin release.
Authors: Antonipillai I , Nadler J L , Robin E C , Horton R
Published: June 2012

Release of arachidonic acid from membrane phospholipids is a limiting step in the synthesis of both cyclooxygenase products and lipoxygenase products. The direct effects of prostacyclin and some lipoxygenase products on renin release were studied using rat renal cortical slices. Prostacyclin, at concentrations of 10(-5) M, stimulated renin secretion, but this effect was short-lived. Leukotrienes or their precursor, 5-hydroperoxyeicosatetraenoic acid, did not affect basal renin release. In contrast, 10(-9) M 12-hydroperoxyeicosatetraenoic acid and 10(-8) M 12-hydroxyeicosatetraenoic acid were potent inhibitors of renin secretion. Similarly, 15-hydroperoxyeicosatetraenoic acid and its hydroxy derivative, 15-hydroxyeicosatetraenoic acid, at somewhat higher molar concentrations (10(-6) M) also reduced basal renin. These studies confirm prostacyclin as a potential renin secretagogue; however, its action in vitro is transient, probably because of its rapid degradation. Our studies provide new evidence that products of the 12-lipoxygenase and 15-lipoxygenase pathways, reported to be present in renal vascular tissue, are potent inhibitors of renin secretion and much more active on a molar basis on renin secretion than is prostacyclin. These studies suggest the potential presence of a dual system of stimulation and suppression that may regulate renin secretion in normal and clinical states.