bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Perindopril and Amlodipine in Cyclosporine-Treated Renal Allograft Recipients
Authors: Sennesael Jacques , Lamote Jan , Violet Isabelle , Tasse Sophie , Verbeelen Dierik
Published: June 2012

Abstract
The objective of this study was to compare the antihypertensive efficacy and influence on renal function of perindopril and amlodipine in cyclosporine-treated renal allograft recipients with mild to moderate hypertension. We conducted a randomized, double-blind, double-dummy crossover trial in ambulatory patients. Four phases were conducted: 2 weeks on placebo, 8 weeks of maintenance (perindopril or amlodipine), and 2 weeks of washout between treatment periods. Ten hypertensive patients with stable renal allograft function transplanted more than 6 months previously and receiving cyclosporine as part of their immunosuppressive regimen were studied. The patients were allocated to perindopril (2 or 4 mg/d) and amlodipine (5 mg/d) in a random sequence. If office diastolic pressure was greater than or equal to 90 mm Hg after 4 weeks, the dosage was doubled and continued for another 4 weeks. The main outcome measures were office and 24-hour ambulatory blood pressure changes after 8 weeks of active treatment and treatment and time effect on glomerular filtration rate and effective renal plasma flow. Perindopril and amlodipine were equally effective in lowering office blood pressure and similarly efficacious for the 24-hour period of the day. Neither drug affected glomerular filtration rate or effective renal plasma flow. Both agents demonstrated equivalent capacity (time×treatment,
P
=.955) to reverse renal vascular resistance (amlodipine from 0.35±0.02 to 0.30±0.02 mm Hg/mL per minute per 1.73 m
2
; perindopril from 0.36±0.03 to 0.32±0.01) (time effect of all treatments together,
P
=.043). After amlodipine, hemoglobin was higher (148±5 versus 135±5 g/L,
P
=.002) and serum uric acid was lower (351±17 versus 398±24 μmol/L,
P
=.001) compared with perindopril.
Assessment of Arterial Distensibility by Automatic Pulse Wave Velocity Measurement
Authors: Asmar Roland , Benetos Athanase , Topouchian Jirar , Laurent Pierre , Pannier Bruno , Brisac Anne-Marie , Target Ralph , Levy Bernard I.
Published: June 2012

Abstract
Pulse wave velocity is widely used as an index of arterial distensibility. The aim of this study was to evaluate the accuracy of a new automatic device to measure it and then to analyze the major determinants of pulse wave velocity by application of this device in a large population. We evaluated the accuracy of on-line and computerized measurement of pulse wave velocity using an algorithm based on the time-shifted and repeated linear correlation calculation between the initial rise in pressure waveforms compared with the reference method (manual calculation) in 56 subjects. The results, analyzed according to the recommendations of Bland and Altman, showed a mean difference of −0.20±0.45 m/s for the mean carotid-femoral pulse wave velocity values (reference method, 11.05±2.58 m/s; automatic device, 10.85±2.44 m/s). The inter-reproducibility and intrareproducibility of measurements by each method were analyzed with the use of the repeatability coefficient according to the British Standards Institution. The interobserver repeatability coefficient was 0.947 for the manual method and 0.890 for the automatic, and intraobserver repeatability coefficients were 0.938 and 0.935, respectively. We evaluated the major determinants of the carotid-femoral pulse wave velocity measured by the automatic method in a separate study performed in 418 subjects of both sexes without any cardiovascular treatment or complication (18 to 77 years of age; 98 to 222 mm Hg systolic and 62 to 130 mm Hg diastolic pressure). Multiple regression analysis between pulse wave velocity and clinical parameters (age, sex, weight, height, smoking, arterial blood pressure, heart rate) and biological plasma parameters (total cholesterol, high-density lipoprotein cholesterol, glycemia) showed that pulse wave velocity correlated positively and independently with age and systolic pressure (
r
2
=.47;
P
<.001) according to the equation Pulse Wave Velocity=0.07 Systolic Pressure (mm Hg)+0.09 Age (y)−4.3 (m/s). Similar results were obtained in the normotensive and hypertensive subgroups when analyzed separately. Pulse wave velocity can be easily and automatically determined. Its measurement is accurate and highly reproducible, and its major determinants are well established. It is of great interest to evaluate in large populations the therapeutic and epidemiological applications of an arterial parameter as evaluated by aortic pulse wave velocity.
Atrial Natriuretic Peptide in Chronically Hypertensive Dogs
Authors: Seymour Andrea A. , Asaad Magdi M. , Sheldon Jeffrey H. , Smith Patricia L. , Rogers W. Lynn
Published: June 2012

Abstract
We determined the renal and depressor activities of 10, 50, and 100 pmol/kg per minute IV of human atrial natriuretic peptide-(99-126) in conscious one-kidney, one clip dogs with chronic hypertension and modest renal dysfunction, as indicated by mild proteinuria. Atrial natriuretic peptide increased fractional sodium excretion by 0.009±0.002, 0.042±0.005, and 0.049±0.007, respectively; urinary excretion of atrial natriuretic peptide by −0.4±0.8, 3.3±1.4, and 15.8±7.4 fmol/min; and cGMP excretion by 0.65±0.06, 1.65±0.08, and 4.88±0.85 nmol/min in one-kidney shams. The changes in fractional sodium excretion were significantly attenuated in the hypertensive dogs (0.005±0.002, 0.018±0.003, and 0.022±0.004, respectively) despite exaggerated increases in atrial natriuretic peptide excretion (3.3±1.6, 22.0±5.0, and 46.6±10.8 fmol/min) and cGMP excretion (0.96±0.47, 4.51±1.27, and 7.06±1.38 nmol/min). The slope of the line relating urinary atrial natriuretic peptide to cGMP was significantly suppressed in the hypertensive dogs, suggesting a downregulation of the guanylate cyclase–linked receptors. The slope of the relationship between cGMP excretion and the natriuretic response was also depressed in the hypertensive dogs, indicating possible impairment of cGMP signal transduction. The differences between sham and hypertensive dogs were diminished when urinary levels of atrial natriuretic peptide were maximized by prior treatment with SQ 28603, an inhibitor of neutral endopeptidase EC
3.4.24.11
. Atrial natriuretic peptide caused comparable decreases in mean arterial pressure and increases in glomerular filtration rate in sham and hypertensive dogs, suggesting similar vascular reactivity. In conclusion, dogs with chronic one-kidney, one clip hypertension and mild proteinuria were hyporesponsive to the renal activity of atrial natriuretic peptide, presumably because of renal receptor downregulation and possible defects in cGMP signal transduction.
Endothelial AT
1
–Mediated Release of Nitric Oxide Decreases Angiotensin II Contractions in Rat Carotid Artery
Authors: Boulanger Chantal M. , Caputo Lidia , Lévy Bernard I.
Published: June 2012

Abstract
The purpose of this study was to examine whether angiotensin II (Ang II) stimulates the release of endothelium-derived nitric oxide, which then impairs the contractions of vascular smooth muscle caused by the peptide, and to determine the receptor subtypes mediating these responses. Experiments were performed on isolated rings of rat carotid artery either incubated in the presence of phosphodiesterase inhibitor for the measurement of intracellular levels of cGMP or suspended in organ chambers for recording of changes in isometric force. Ang II (10
−7
mol/L) caused a twofold increase in intracellular cGMP level in preparations with but not in those without endothelium. The presence of endothelium impaired the contractions evoked by the peptide and caused approximately 50% inhibition of the maximal response to Ang II (3×10
−8
mol/L); pD
2
values for Ang II were 8.9±0.1 and 9.6±0.2 in rings with and without endothelium, respectively. In rings with endothelium the contractions to Ang II were augmented by nitro-
l
-arginine (an inhibitor of nitric oxide synthase) but not indomethacin (an inhibitor of cyclooxygenase), to reach a response comparable to that of preparations without endothelium. In rings without endothelium losartan (a preferential angiotensin type 1 receptor antagonist) displayed competitive antagonism toward Ang II (pA
2
=9.5); PD 123319 (a preferential angiotensin type 2 receptor antagonist; up to 10
−7
mol/L) did not affect the response to the peptide. Losartan (3×10
−9
mol/L) but not PD 123319 (10
−7
mol/L) impaired the endothelium-dependent component of the response to the peptide. These results suggest that in the rat carotid artery stimulation of an Ang II type 1 receptor causes the release of nitric oxide, which in turn inhibits the contractions to Ang II also mediated by type 1 receptors.
Prostacyclin Synthesis Elicited by Endothelin-1 in Rat Aorta Is Mediated by an ET
A
Receptor via Influx of Calcium and Is Independent of Protein Kinase C
Authors: Wright Harold M. , Malik Kafait U.
Published: June 2012

Abstract
The purpose of this study was to characterize the receptor(s) and second messenger systems involved in prostacyclin (prostaglandin [PG] I
2
) synthesis elicited by endothelin (ET)-1 in the rat aorta. PGI
2
synthesis, measured as immunoreactive 6-keto-PGF
1α
, was assessed in aortic rings exposed to endothelin receptor agonists in the presence and absence of selective ET
A
and ET
B
receptor antagonists. ET-1, which has equal affinity for both endothelin receptor subtypes, and ET-3, a preferential ET
B
receptor agonist, enhanced 6-keto-PGF
1α
synthesis in a time- and concentration-dependent manner. ET-1 was more potent than ET-3 in increasing 6-keto-PGF
1α
synthesis. Moreover, the selective ET
B
receptor agonists IRL-1620 and sarafotoxin S6c did not significantly increase 6-keto-PGF
1α
synthesis. Furthermore, ET-1–induced 6-keto-PGF
1α
synthesis was attenuated by an ET
A
receptor antagonist, BQ-123, in a dose-dependent manner but not by an ET
B
receptor antagonist, BQ-788. Depletion of extracellular Ca
2+
or addition of Ca
2+
channel blockers (nifedipine, verapamil, SK&F 96365) attenuated ET-1–mediated 6-keto-PGF
1α
synthesis, while a Ca
2+
channel agonist,
S
(−)-Bay K 8644, potentiated this effect of ET-1. Selective protein kinase C inhibitors (bisindolylmaleimide I, calphostin C) did not alter ET-1–induced 6-keto-PGF
1α
synthesis. These data suggest that PGI
2
synthesis elicited by ET-1 in the rat aorta is mediated primarily through influx of extracellular Ca
2+
via activation of an ET
A
receptor and is independent of protein kinase C.
Insulin Effect on Renal Sodium Reabsorption in Adolescent Offspring of Essential Hypertensive Parents
Authors: Grunfeld B. , Gimenez M. , Balzaretti M. , Rabinovich L. , Romo M. , Simsolo R.
Published: June 2012

Abstract
We previously showed that children and adolescent offspring of patients with essential hypertension have an increased proximal renal sodium reabsorption as measured by lithium fractional excretion. Insulin has been shown to have antinatriuretic properties and to be increased (hyperinsulinemia) in essential hypertension. The aim of this study was to evaluate the role of insulin on the increased proximal renal sodium reabsorption previously reported. Lithium and sodium fractional excretions were measured 3 hours before and 3 hours after an intravenous glucose tolerance test in 20 normotensive adolescents with a family history of essential hypertension (F+, 14.8±0.5 years) and 10 normotensive control subjects without a family history of hypertension (F−, 15.2±0.9 years). Results are mean±SEM. Lithium fractional excretion before glucose loading was 16.1±1.8% in F+ versus 23.5±2.0% in F− (
P
<.02) and after glucose loading was 14.7±1.3% in F+ versus 20.9±1.7% in F− (
P
=NS). Lithium fractional excretion did not change after intravenous glucose loading in either group. The insulin area under the curve was 2815±499 in F+ versus 2290±418 μU/mL per hour in F− (
P
=NS). There was no correlation between lithium fractional excretion and insulin area under the curve. Fractional excretion of sodium before glucose loading was 0.99±0.1% in F+ versus 0.99±0.1% in F− (
P
=NS) and after glucose loading was 0.77±0.1 in F+ versus 0.85+0.1% in F− (
P
<.01 versus values before loading in both groups). In summary lithium fractional excretion did not change after the intravenous glucose loading, and no correlation was found with insulin levels. Thus, insulin does not appear to be involved in the decreased lithium fractional excretion in F+. However, sodium fractional excretion diminished significantly after the intravenous glucose loading. Therefore, our findings in physiological conditions in humans show that one possible role of insulin in the development of hypertension is through an antinatriuretic effect distal to the proximal tubule.
Thyrotropin-Releasing Hormone Hyperactivity in the Preoptic Area of Spontaneously Hypertensive Rats
Authors: Garcia S.I. , Dabsys S.M. , Martinez V.N. , Delorenzi A. , Santajuliana D. , Nahmod V.E. , Finkielman S. , Pirola C.J.
Published: June 2012

Abstract
Thyrotropin-releasing hormone (TRH) plays an important role in central cardiovascular regulation through the activation of different neurotransmitter systems at distinct extrahypothalamic sites. To study possible alterations in the TRH system in the hypertensive state, we measured TRH concentration in cerebrospinal fluid and TRH content of the preoptic area in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) by radioimmunoassay. In addition, we also measured the density of the TRH receptor in this area by a rapid filtration technique using [
3
H]methyl-TRH. We found a significant increase in both the TRH content (634±61 versus 350±26 pg/mg protein, SHR versus WKY;
P
<.01, n=5) and density of TRH receptors without changes in affinity (
B
max
, 5.0±0.1 versus 3.3±0.1 fmol/mg protein,
P
<.01, n=4). An increase in TRH concentration was also found in the cerebrospinal fluid of SHR (30±3 versus 21±2 pg/mL,
P
<.01, n=5), suggesting increased TRH release in the central nervous system. Northern blot analysis indicated a threefold augmented abundance of TRH precursor mRNA in the preoptic area of SHR. A polyclonal antibody raised against TRH injected peripherally or intracerebroventricularly lowered arterial blood pressure in SHR but not in WKY. In addition, long-term treatment with enalapril (5 mg/kg twice daily), which was effective in inhibiting serum angiotensin-converting enzyme activity by more than 50%, decreased arterial blood pressure and preoptic area TRH content of SHR, whereas another vasodilator, diltiazem (10 mg/kg every 8 hours), failed to produce a similar change. These results point out an activation of the TRH system, with increased production of TRH and an upregulation of its receptors in this genetic model of hypertension.
Changes of Renal Sympathetic Activity in Acute and Chronic Conscious Sinoaortic Denervated Rats
Authors: Irigoyen Maria Claudia , Moreira Edson Dias , Ida Fumio , Pires Mara , Cestari Idágene Aparecida , Krieger Eduardo Moacyr
Published: June 2012

Abstract
The arterial pressure level attained in sinoaortic denervated rats depends on the net effect of eliminating excitatory and inhibitory influences (chemoreceptor and baroreceptor elimination, respectively). After sinoaortic denervation is completed, the hypertension usually observed within the first few days is followed by normotension at the chronic stages. In this work renal sympathetic nerve activity was measured in conscious, unrestrained rats 6 hours (acute) and 20 days (chronic) after sinoaortic denervation. Increased arterial pressure (154±10 versus 114±3 mm Hg in controls) and renal sympathetic nerve activity (32±5 versus 13±2 bars per cycle in controls) with no changes in heart rate (404±17 vs 380±26 beats per minute) were observed in rats with acute sinoaortic denervation. In rats with chronic sinoaortic denervation, arterial pressure (119±8 mm Hg) and renal sympathetic nerve activity (13±6 bars per cycle) returned to control levels. Bradycardiac and tachycardiac responses to changes in blood pressure were reduced to 88% and 89%, respectively, in rats with acute sinoaortic denervation and 76% and 74%, respectively, in rats with chronic sinoaortic denervation. The reflex control of renal sympathetic nerve activity after acute and chronic sinoaortic denervation showed an impairment of sympathoinhibition (0.13±0.02 and 0.25±0.1 bars per cycle, respectively, versus 0.9±0.17 bars per cycle in controls). Sympathoexcitatory responses also were impaired in rats with acute and chronic sinoaortic denervation (0.08±0.03 and 0.37±0.1 bars per cycle, respectively, compared with 0.98±0.2 bars per cycle in controls). The variability of mean arterial pressure expressed by standard deviation was higher in rats with acute and chronic sinoaortic denervation (13±2 and 15±2 mm Hg, respectively) than in controls (6±3 mm Hg). The variability coefficient of renal sympathetic nerve activity was lower 6 hours (0.22±0.07) but normal 20 days after sinoaortic denervation (0.88±0.24 versus 0.77±0.06 in controls). We conclude that (1) acute sinoaortic denervation increases arterial pressure and renal sympathetic nerve activity and reduces renal sympathetic variability, (2) blood pressure and renal sympathetic activity return to normal levels in rats after chronic sinoaortic denervation, and (3) increased variability and impairment of the baroreflexes persisted in the chronic phase of sinoaortic denervation.
Calcium Channel Blockers as Inhibitors of Angiotensin I–Converting Enzyme
Authors: Casarini Dulce E. , Carmona Adriana K. , Plavnik Frida L. , Zanella Maria T. , Juliano Luiz , Ribeiro Artur B.
Published: June 2012

Abstract
Using ion-exchange chromatography of dialyzed human urine from healthy and hypertensive patients, we detected two peaks of angiotensin I–converting enzyme (ACE) activity on hippuryl-His-Leu eluted at ionic strengths of 0.7 (F1 peak) and 1.25 (F2 peak) mS. These hydrolytic activities decreased gradually in the urine of patients submitted to isradipine treatment, F2 and F1 disappearing after 12 and 24 hours, respectively. By Western blot analysis, the urine fractions corresponding to both peaks from healthy and untreated patients presenting ACE activity and from treated patients (24 hours) without this activity were recognized by an ACE-specific antibody. These results indicated that ACE was present but inhibited in the urine of isradipine-treated patients. In vitro assays with ACE isolated from human urine and guinea pig plasma demonstrated that the enzyme is inhibited by isradipine and other commercially available calcium channel blockers, such as felodipine, nifedipine, and verapamil. A noncompetitive inhibition was observed with all calcium channel blockers studied. In conclusion, these results suggest that besides the primary effect on calcium channels, the more commonly used calcium channel blockers are also ACE inhibitors. The development of efficient calcium channel blockers with higher ACE inhibitory activity could result in interesting bifunctional antihypertensive drugs.
Angiotensin-(1-7) Potentiates the Hypotensive Effect of Bradykinin in Conscious Rats
Authors: Paula Renata D. , Lima Celso V. , Khosla Mahesh C. , Santos Robson A.S.
Published: June 2012

Abstract
Treatment with angiotensin-converting enzyme inhibitors increases the angiotensin-(1-7) [Ang-(1-7)] and bradykinin concentrations in plasma and tissue. In this study we evaluated the interaction between these peptides by determining the effect of Ang-(1-7) on the hypotensive action of bradykinin in conscious rats. Administration of Ang-(1-7) (5 nmol) did not change mean arterial pressure or heart rate. However, the hypotensive effect of bradykinin, produced by an intravenous or intra-arterial route, was potentiated by Ang-(1-7) in a dose-dependent manner. The Ang-(1-7) doses necessary to transform the effect of a single dose of bradykinin into that produced by a double dose (potentiating unit) were 2 nmol IV and 5 nmol IA. The Ang-(1-7) dose used did not change either the pressor effect of Ang II or the hypotensive effect of sodium nitroprusside. The bradykinin-potentiating Ang-(1-7) activity was significantly attenuated by pretreatment with indomethacin (5 mg/kg IM, n=4). In an additional group the bradykinin-potentiating activity of Ang-(1-7) was evaluated 30 minutes after treatment with the angiotensin-converting enzyme inhibitor enalaprilat (10 mg/kg IV, n=9). Under this condition the bradykinin-potentiating activity of Ang-(1-7) was substantially increased, resulting in a potentiating unit of approximately 0.2 nmol IV. Pretreatment with indomethacin (5 mg/kg IM, n=7) also attenuated the bradykinin-potentiating activity of Ang-(1-7) in enalaprilat-treated rats. These results show that Ang-(1-7) is a bradykinin-potentiating peptide in vivo. Furthermore, the data obtained with indomethacin suggest that prostaglandins participate in the mechanism of the bradykinin potentiation by Ang-(1-7). More importantly, these data suggest that the interaction between Ang-(1-7) and bradykinin can contribute to the pharmacological effects of angiotensin-converting enzyme inhibitors.
Comparison of Candoxatril and Atrial Natriuretic Factor in Healthy Men
Authors: Ando Shin-ichi , Rahman Mohammed A. , Butler Gary C. , Senn Beverley L. , Floras John S.
Published: June 2012

Abstract
The purpose of these experiments was to compare the effects of endopeptidase inhibition with oral candoxatril on systemic and forearm hemodynamics and muscle sympathetic nerve activity with responses to a low-dose atrial natriuretic factor infusion. Eleven healthy men received at random on three separate days either intravenous saline, atrial natriuretic factor (1.6 pmol/kg per minute) plus saline, or oral candoxatril (200 mg) plus saline. Measurements were made at baseline and 30, 60, and 90 minutes after interventions. Atrial natriuretic factor lowered diastolic pressure (
P
<.01), central venous pressure (
P
<.001), forearm blood flow (
P
<.05), and forearm vascular compliance (
P
<.05) but had no effect on systolic pressure, heart rate or its variability, stroke volume, sympathetic nerve activity, plasma norepinephrine, or endothelin-1. Plasma epinephrine increased (
P
<.01). Candoxatril lowered central venous pressure (
P
<.001) and increased systolic pressure (from 116±6 to 120±7 mm Hg;
P
<.05), endothelin (from 4.6±1.1 to 6.8±3.2 pmol/L;
P
<.02), and epinephrine (
P
<.05), without affecting any other variables. Candoxatril and atrial natriuretic factor lowered central venous pressure in healthy men without causing a reflex increase in sympathetic nerve activity or norepinephrine, yet epinephrine rose. This suggests that both interventions may specifically inhibit sympathetic nerve traffic to muscle at physiological plasma atrial natriuretic factor concentrations. However, whereas the peptide lowered blood pressure, candoxatril increased systolic pressure. These contrasting hemodynamic responses may be related to differences in plasma atrial natriuretic peptide concentration and to altered endothelin metabolism by candoxatril.
Evaluation of the Technique Used by Health-Care Workers for Taking Blood Pressure
Authors: Villegas Iván , Arias Isabel C. , Botero Adriana , Escobar Alejandro
Published: June 2012

Abstract
The precise guidelines recommended by the American Heart Association for blood pressure measurement are commonly overlooked by health-care workers, who generally take blood pressure in an arbitrary way. To validate this observation we designed a descriptive and observational study to be carried out in a major hospital. One hundred and seventy-two health-care workers divided into four groups (63 general practitioners, 25 clinical and 25 surgical specialists, and 59 nurses) were evaluated in a two-part test. In the first part (practical), the examinee had to follow all the steps recommended by the American Heart Association to get a passing score. In the second part (theoretical, which came second to avoid influencing the practical), the examinee had to answer correctly 7 of 10 questions based on the American Heart Association’s guidelines to obtain a passing score. The highest accepted variation in systolic and diastolic pressures between examinee and observer was ±4 mm Hg. None of the examinees followed the American Heart Association’s recommendations. Sixty-three percent of systolic and 53% of diastolic readings were out of range. Surgical specialists obtained the best practical results (48% systolic and 64% diastolic within range), and nurses obtained the lowest values (29% and 39%, respectively;
P
=.03 versus surgical specialists). These two groups showed deficiencies in the theoretical test (nurses, 10% correct answers and surgical specialists, 16%). Clinical specialists obtained the best results on the theoretical test (60% correct;
P
<.05 versus the other groups) but were deficient in the practical test (32% systolic and 60% diastolic within range). In conclusion, on practical and theoretical bases health-care workers took blood pressure inaccurately and incorrectly.
Aortic Stiffness and Left Ventricular Mass in a Rat Model of Isolated Systolic Hypertension
Authors: Tatchum-Talom Rabelais , Niederhoffer Nathalie , Amin Fatiha , Makki Touria , Tankosic Pierre , Atkinson Jeffrey
Published: June 2012

Abstract
We tested whether cardiac mass can be related to decreased aortic stiffness in an original rat model of isolated systolic hypertension. Increased aortic stiffness was produced by calcium overload of elastic arteries after vitamin D
3
plus nicotine treatment. Half of the animals were chronically treated with the angiotensin-converting enzyme inhibitor perindopril (1 mg/kg per day PO). Rats were pithed, and lower body vascular resistance was measured. Blood pressure was then increased by phenylephrine infusion, and carotidofemoral pulse wave velocity was measured. This value together with those for thoracic aorta internal diameter and medial thickness (determined after in situ fixation and histomorphometry) were used to calculate elastic modulus. Vitamin D
3
plus nicotine treatment produced parallel increases in cardiac mass and elastic modulus, with a significant correlation between the two. There was no significant change in resistance. Treatment with perindopril reversed the changes in cardiac mass and elastic modulus but had no effect on resistance after calcium overload of the elastic arteries. In this model of isolated systolic hypertension, we showed that cardiac mass is related to arterial elasticity.
Cloning, Characterization, and Genetic Mapping of the Rat Type 2 Angiotensin II Receptor Gene
Authors: Koike George , Winer Eric S. , Horiuchi Masatsugu , Brown Donna M. , Szpirer Claude , Dzau Victor J. , Jacob Howard J.
Published: June 2012

Abstract
The renin-angiotensin system plays an important role in blood pressure homeostasis, but the contribution of the type 2 angiotensin II receptor (AT
2
R) is still unclear. The reports that the AT
2
R gene has been mapped to the X chromosome in human and rat and the previous report of a gene,
Bp3,
on the X chromosome responsible for an increase in blood pressure have suggested that the rat AT
2
R gene
(Agtr2)
could be this gene. To elucidate whether
Agtr2
is
Bp3, Agtr2
was cloned. A simple sequence repeat in the 3′-flanking region of this gene was identified and used as a genetic marker to map
Agtr2
to the X chromosome at 18.1 cM distal to the androgen receptor locus. This map position is outside the confidence interval reported for
Bp3,
demonstrating that
Agtr2
cannot be
Bp3
. However, these data will enhance the research into the AT
2
R biology as well as the study of the X chromosome.
Hypertensive Urgencies and Emergencies
Authors: Zampaglione Bruno , Pascale Claudio , Marchisio Marco , Cavallo-Perin Paolo
Published: June 2012

Abstract
The prevalence and clinical picture of hypertensive urgencies and emergencies in an emergency department are poorly known. The aim of the present study was to evaluate the prevalence of hypertensive crises (urgencies and emergencies) in an emergency department during 12 months of observation and the frequency of end-organ damage with related clinical pictures during the first 24 hours after presentation. Hypertensive crises (76% urgencies, 24% emergencies) represented more than one fourth of all medical urgencies-emergencies. The most frequent signs of presentation were headache (22%), epistaxis (17%), faintness, and psychomotor agitation (10%) in hypertensive urgencies and chest pain (27%), dyspnea (22%), and neurological deficit (21%) in hypertensive emergencies. Types of end-organ damage associated with hypertensive emergencies included cerebral infarction (24%), acute pulmonary edema (23%), and hypertensive encephalopathy (16%) as well as cerebral hemorrhage, which accounted for only 4.5%. Age (67±16 versus 60±14 years [mean±SD],
P
<.001) and diastolic blood pressure (130±15 versus 126±10 mm Hg,
P
<.002) were higher in hypertensive emergencies than urgencies. Hypertension that was unknown at presentation was present in 8% of hypertensive emergencies and 28% of hypertensive urgencies. In conclusion hypertensive urgencies and emergencies are common events in the emergency department and differ in their clinical patterns of presentation. Cerebral infarction and acute pulmonary edema are the most frequent types of end-organ damage in hypertensive emergencies.
Polymorphism of the Glycogen Synthase Gene in Hypertensive and Normotensive Subjects
Authors: Schalin-Jäntti Camilla , Nikula-Ijäs Pirjo , Huang Xudong , Lehto Markku , Knudsen Petteri , Syvänne Mikko , Lehtovirta Mikko T. , Tikkanen Tuula , Tikkanen Ilkka , Groop Leif C.
Published: June 2012

Abstract
Hypertension and non–insulin-dependent diabetes mellitus (NIDDM) are characterized by a strong genetic component and impaired ability to store glucose as glycogen in skeletal muscle. Impaired insulin activation and altered genetic control of muscle glycogen synthase, the rate-limiting enzyme for glucose storage in skeletal muscle, could provide an explanation for this insulin resistance. We examined whether there is an association between the glycogen synthase gene (
Xba
I polymorphism) and hypertension in 304 nondiabetic subjects. We examined glucose tolerance with an oral glucose tolerance test and glucose storage in skeletal muscle with the euglycemic insulin clamp technique in combination with indirect calorimetry. The
Xba
I A
2
allele of the glycogen synthase gene was enriched in subjects with hypertension and a family history of NIDDM (48%) compared with normotensive subjects without a family history of NIDDM (6%,
P
<.0001). The presence of the A
2
versus the A
1
allele was associated with decreased rates of insulin-stimulated glucose storage in hypertensive subjects (11.2±2.3 versus 16.9±2.6 μmol/kg lean body mass per minute,
P
=.029) but not in normotensive subjects (28.0±4.6 versus 29.6±3.7 μmol/kg lean body mass per minute). In conclusion,
Xba
I polymorphism of the glycogen synthase gene identifies a subgroup of hypertensive subjects with a family history of NIDDM. The data suggest that a locus in the glycogen synthase gene region on chromosome 19 may serve as a “thrifty gene,” increasing susceptibility for insulin resistance when exposed to other environmental or genetic factors.
Angiotensin II and Angiotensin-(1-7) Effects on Free Cytosolic Sodium, Intracellular pH, and the Na
+
-H
+
Antiporter in Vascular Smooth Muscle
Authors: Ye Minghao , Flores Guillermo , Batlle Daniel
Published: June 2012

Abstract
The aim of the present study was to define the effects of angiotensin II (Ang II) and Ang-(1-7) on free cytosolic Na
+
(Na
+
i
), intracellular pH (pH
i
), and the Na
+
-H
+
antiporter in cultured vascular smooth muscle cells from rat aorta. Cells were loaded with either BCECF-AM or SBFI-AM for measurement of pH
i
and Na
+
i
, respectively. Ang II (10
−6
mol/L) caused a rapid rise in Na
+
i
followed by a progressive increase that peaked at about 10 minutes (from 11±1.5 to 16±1.5 mmol/L,
P
<.001), whereas Ang-(1-7) (10
−6
mol/L) did not affect Na
+
i
significantly (from 11.5±1.1 to 11.8±0.07 mmol/L). The effect of Ang II on Na
+
i
was concentration dependent (ΔNa
+
i
, 5.1±0.9, 3.8±0.6, 1.6±0.6, and 0.14±0.18 mmol/L with decreasing concentrations of 10
−6
, 10
−7
, 10
−8
, and 10
−9
mol/L, respectively). Ang II caused a brief acidification followed by an increase in pH
i
(from 7.34±0.03 to 7.43±0.03 after 10 minutes,
P
<.005), and Ang-(1-7) had no significant effect on pH
i
(from 7.23±0.03 to 7.23±0.03). To investigate whether pH
i
and Na
+
i
changes induced by Ang II were due to cell Na
+
entry via stimulation of the Na
+
-H
+
antiporter, we pretreated cells with EIPA (25 μmol/L) or ouabain (2.0 mmol/L). Ang II in the presence of ouabain caused a greater increase than that seen with ouabain alone (ΔNa
+
i
, 13±1.5 versus 6.3±1.2 mmol/L,
P
<.0025). EIPA by itself decreased Na
+
i
and pH
i
. After EIPA, Ang II failed to increase both Na
+
i
and pH
i
, demonstrating that the Na
+
-H
+
antiporter is responsible for the rises in Na
+
i
and pH
i
during stimulation with Ang II. To further characterize the mechanism of Ang II action, we exposed cells to an Ang II type 1 receptor antagonist (L-158,809, 10
−6
mol/L) or two different type 2 receptor antagonists (PD 123177 and CGP 421112A, 10
−6
mol/L). L-158,809 completely blocked the rise in pH
i
caused by Ang II, whereas PD 123177 and CGP 421112A did not. We conclude that Ang II increases both Na
+
i
and pH
i
, and both effects are mediated by stimulation of the Na
+
-H
+
antiporter. Ang-(1-7), by contrast, has no significant effect on Na
+
i
, pH
i
, or the Na
+
-H
+
antiporter. Stimulation of this antiporter by Ang II is exerted through the type 1 receptor.
Chronic Kinin Blockade and Effect of Ramipril in Renal Adaptation to Sodium Restriction
Authors: Jover Bernard , Hérizi Abderraouf , Mimran Albert
Published: June 2012

Abstract
The contribution of endogenous kinins to impairment in renal adaptation to a 6-day period of dietary sodium withdrawal associated with treatment with ramipril (5 mg/kg per day) and losartan (30 mg/kg per day) was evaluated by use of concomitant chronic administration of the bradykinin B
2
-receptor antagonist Hoe 140 (150 or 300 μg/kg per day via subcutaneous osmotic pump). A similar level of higher cumulative sodium excretion was observed in ramipril- and losartan-treated rats compared with untreated animals, and the effect of ramipril was not affected by Hoe 140. Similarly, the fall in arterial pressure and the renal vasodilatation associated with ramipril and losartan were not modified by Hoe 140. Glomerular filtration rate (785±73 μL/min per g KW in untreated sodium-depleted rats) decreased to a larger extent in ramipril-treated rats compared with losartan-treated rats (371±78 and 550±55 μL/min per g KW, respectively). Hoe 140 markedly prevented the alteration in glomerular filtration rate associated with ramipril, thus resulting in a final glomerular filtration rate (543±41 μL/min per g KW) similar to that observed with losartan. These findings demonstrate that despite a lack of influence on arterial pressure and sodium balance, accumulation of kinins markedly contributes to deterioration of the glomerular filtration rate induced by ramipril in sodium-depleted rats.
Kinin-Mediated Antihypertensive Effect of Captopril in Deoxycorticosterone Acetate–Salt Hypertension
Authors: Chen Ke , Zhang Xuewei , Dunham Earl W. , Zimmerman Ben G.
Published: June 2012

Abstract
On the basis of evidence suggesting the activation of the kallikrein-kinin system in steroid-induced hypertension, we considered the possibility that the angiotensin-converting enzyme inhibitor captopril would lower the arterial blood pressure in deoxycorticosterone acetate (DOCA)–salt hypertensive rats through kininase II inhibition. In conscious DOCA-salt hypertensive rats with intact kidneys (n=6) or uninephrectomized rats (n=5), the short-term administration of captopril (8 mg/kg IV) decreased mean blood pressure from 141±3 to 118±3 mm Hg (
P
<.05) and from 176±12 to 158±15 mm Hg (
P
<.05), respectively. The maximal effect of captopril was manifested between 40 and 50 minutes after its administration, and blood pressure remained depressed for at least 2 hours. The bradykinin B
2
receptor antagonist Hoe 140 (500 μg/kg IV) abolished the antihypertensive effect of captopril in the DOCA-salt hypertensive rats, indicating kinin involvement. Losartan, an angiotensin type 1 receptor antagonist, had no effect on blood pressure in another group of DOCA-salt hypertensive rats (n=9) and did not significantly change the response to captopril. No effect of the angiotensin-converting enzyme inhibitor was seen in normotensive control rats (n=5), indicating the absence of a nonspecific hypotensive action of the drug. Plasma renin activity was lower in the DOCA-salt hypertensive rats (0.7±0.2 ng angiotensin I/mL per hour, n=4) than in normotensive control rats (8.8±1.7, n=4). The involvement of kinins in the antihypertensive effect of captopril in DOCA-salt hypertension supports the contention that the kallikrein-kinin system contributes to blood pressure regulation in this hypertension model.
Medullary Neurons Activated by Angiotensin II in the Conscious Rabbit
Authors: Hirooka Yoshitaka , Head Geoffrey A. , Potts Patrick D. , Godwin Shirley J. , Bendle Robert D. , Dampney Roger A.L.
Published: June 2012

Abstract
Previous studies have shown that angiotensin II (Ang II) can activate cardiovascular neurons within the medulla oblongata via an action on specific receptors. The purpose of this study was to determine the distribution of neurons within the medulla activated by infusion of Ang II into the fourth ventricle of conscious rabbits, using the expression of Fos, the protein product of the immediate early gene c-
fos
as a marker of neuronal activation. Experiments were done in both intact and barodenervated animals. In comparison with a control group infused with Ringer’s solution alone, in both intact and barodenervated animals, fourth ventricular infusion of Ang II (4 to 8 pmol/min) induced a significant increase in the number of Fos-positive neurons in the nucleus of the solitary tract and in the rostral, intermediate, and caudal parts of the ventrolateral medulla. Double-labeling for Fos and tyrosine hydroxylase immunoreactivity showed that 50% to 75% of Fos-positive cells in the rostral, intermediate, and caudal ventrolateral medulla and 30% to 40% of Fos-positive cells in the nucleus of the solitary tract were also positive for tyrosine hydroxylase in both intact and barodenervated animals. The distribution of Fos-positive neurons corresponded very closely to the location of Ang II receptor binding sites as previously determined in the rabbit. The results indicate that medullary neurons activated by Ang II are located in discrete regions within the nucleus of the solitary tract and ventrolateral medulla and include, in all of these regions, both catecholamine and noncatecholamine neurons.
Genetic and Biochemical Factors Associated With Variation in Blood Pressure in a Genetic Isolate
Authors: Hegele Robert A. , Brunt J. Howard , Connelly Philip W.
Published: June 2012

Abstract
We previously found an association between blood pressure and genetic variation of angiotensinogen in Canadian Hutterites. We hypothesized that variation in other candidate genes would also be associated with variation in blood pressure. We included genotypes of 12 candidate genes, along with clinical features and biochemical variables as covariates in an association analysis. We found that sex and body mass were significantly associated with variation in both systolic and diastolic blood pressures. We found that genotypes of
APOB
codon 4154 and
AGT
codon 174 were significantly associated with variation in systolic blood pressure. We found that genotypes of
APOB
codon 4154,
AGT
codon 174, and
F7
codon 353 were significantly associated with variation in diastolic blood pressure. We found a significant association between age and variation in systolic but not diastolic blood pressure. We found a significant association between plasma apo B concentration and variation in diastolic but not systolic blood pressure. The association of genomic variation with resting blood pressure is consistent with the existence of important structural elements within or proximal to some genes in lipoprotein metabolism, the renin-angiotensin system, and the coagulation cascade. The association between plasma apo B concentration and diastolic blood pressure suggests that these traits may share some determinants.
Exercise Blood Pressure Predicts Mortality From Myocardial Infarction
Authors: Mundal Reidar , Kjeldsen Sverre E. , Sandvik Leiv , Erikssen Gunnar , Thaulow Erik , Erikssen Jan
Published: June 2012

Abstract
Apparently healthy men (n=1999, 40 to 59 years old) were investigated from 1972 through 1975 to determine whether systolic blood pressure during bicycle ergometer exercise predicts morbidity and mortality from myocardial infarction beyond that of casual blood pressure taken after 5 minutes of supine rest. During a follow-up of 31 984 patient-years (average, 16 years), 235 subjects had myocardial infarctions, of which 143 were nonfatal and 92 were fatal. Exercise blood pressure was more strongly related than casual blood pressure to both morbidity and mortality from myocardial infarction. Among 520 men with casual systolic blood pressure ≥140 mm Hg, 304 increased their systolic blood pressure to ≥200 mm Hg during 6 minutes of exercise at an initial workload of 600 kpm/min. These 304 men had an excessive risk of myocardial infarction (18.8% versus 9.5% among the 1294 men with casual blood pressure <140 mm Hg and exercise blood pressure <200 mm Hg;
P
<.001). As many as 58% of those with myocardial infarction in this group died, compared with 33% (range, 26% to 35%) for all other groups (
P
=.0011), including those with casual blood pressure ≥140 mm Hg and exercise blood pressure <200 mm Hg. Thus, exercise blood pressure is a stronger predictor than casual blood pressure of morbidity and mortality from myocardial infarction, and an early rise in systolic blood pressure during exercise adds prognostic information about mortality from myocardial infarction among otherwise healthy middle-aged men with mildly elevated casual blood pressure. We suggest that blood pressure taken during standardized exercise testing may distinguish between severe and less severe hypertension.
Acute Baroreflex Resetting
Authors: Drummond Heather A. , Seagard Jeanne L.
Published: June 2012

Abstract
This study evaluated acute resetting of carotid baroreflex control of arterial blood pressure and renal or thoracic sympathetic nerve activity in thiopental-anesthetized mongrel dogs with the use of a vascularly isolated carotid sinus preparation, the experimental model used previously to characterize acute resetting in carotid baroreceptor afferent fibers. Carotid baroreceptors were conditioned with a pulsatile pressure for 20 minutes at three pressure ranges: low (50 to 75 mm Hg), mid (100 to 125), or high (150 to 175). Blood pressure and nerve activity were recorded in response to slow ramp increases in sinus pressure; nonlinear regression and best-fit analyses were used for determination of curve fit parameters of the blood pressure and nerve activity versus sinus pressure response curves. Carotid sinus pressure thresholds for blood pressure and renal nerve activity responses at all conditioning pressures were significantly different; however, only the pressure threshold for thoracic nerve activity at the low conditioning pressure was significantly different from the responses at other conditioning pressures. Average renal activity resetting (0.506±0.072) was significantly greater than blood pressure resetting (0.335±0.046) in the same dogs, and thoracic activity (0.200±0.057) was not different from blood pressure resetting (0.194±0.031) in the same dogs. In a previous investigation, our laboratory has demonstrated that type 1 carotid baroreceptors acutely reset at a value of about 0.15. These results indicate that (1) renal and thoracic nerve activities and blood pressure acutely reset to a greater degree than type 1 carotid baroreceptors and that (2) renal activity acutely resets to a greater degree than blood pressure and thoracic nerve activity.
Salt Sensitivity of Blood Pressure in Humans
Authors: Weinberger Myron H.
Published: June 2012

Abstract
A variety of different techniques have been used for the assessment of the blood pressure response to changes in salt and water balance in humans. These have generally been found to be reproducible and to yield congruent results. This review surveys the characteristics of subjects identified as salt sensitive and salt resistant by different investigators from demographic and physiological perspectives.
Strategies for Studying Cardiovascular Phenotypes in Genetically Manipulated Mice
Authors: Becker K. David , Gottshall Kim R. , Chien Kenneth R.
Published: June 2012

Abstract
Unraveling the pathogenesis of complex cardiovascular diseases, such as hypertension, requires the development of in vivo animal model systems. Although large-animal models have long served as the gold standard, recent advances in transgenic and gene-targeting approaches, mouse genetics, and microsurgical technology are initiating a revolution that has led to the unexpected coupling of in vivo molecular physiology with genetically engineered mice. This article discusses the design of strategies to study complex cardiovascular phenotypes in genetically modified mice, including both transgenic and gene-targeted animals. At this time, a number of strategies are used to address specific molecular or physiological questions, and examples are briefly highlighted. In addition, a number of potential problems in the generation and use of transgenic mice in the study of cardiovascular biology are presented.
Permanent Inhibition of Angiotensinogen Synthesis by Antisense RNA Expression
Authors: Schinke Martina , Böhm Manfred , Bricca Giampiero , Ganten Detlev , Bader Michael
Published: June 2012

Abstract
The renin-angiotensin system plays a pivotal role in blood pressure regulation. Recent molecular biological findings led to the new concept that in addition to the classic endocrine system, local tissue systems may also play an important role in cardiovascular diseases such as hypertension. In particular, the brain renin-angiotensin system was shown to influence the central control of blood pressure and is thought to contribute to the hypertensive phenotype of genetically hypertensive rat models. To identify the physiological role of these local systems, we established an antisense strategy to downregulate the expression of the precursor hormone angiotensinogen (AOGEN) in cell culture, which can also be used to establish transgenic rat lines. Plasmids encoding an RNA sequence complementary to the rat AOGEN mRNA under control of different viral and tissue-specific promoters were constructed and transfected into an AOGEN-expressing cell line. A competitive reverse transcription–polymerase chain reaction method was established for the quantification of AOGEN mRNA. Depending on the level of antisense RNA, the expression of the AOGEN gene was reduced down to 22% of control levels. Furthermore, the secretion of AOGEN protein was totally abolished. These results clearly demonstrate that the antisense constructs used are functional in reducing the AOGEN gene expression in vivo and can be used for the production of transgenic rats.