bluuebunny/crossref_metadata_2025 huggingface dataset:
Seasonal Change in 24-Hour Blood Pressure and Heart Rate Is Greater Among Smokers Than Nonsmokers
Authors: Kristal-Boneh Estela , Harari Gil , Green Manfred S.
Published: June 2012

Abstract
In general, blood pressure is higher in winter than in summer, and this factor may be partly responsible for the higher mortality from cardiovascular disease in winter. Cigarette smoking causes an acute pressor response that may interact with this cardiovascular response to cold exposure. We sought to determine whether the seasonal variation in blood pressure and heart rate differs between cigarette smokers and nonsmokers. We evaluated 24-hour ambulatory systolic blood pressure (SBP), ambulatory diastolic blood pressure (DBP), and ambulatory heart rate of 97 healthy men (73 nonsmokers and 24 smokers), 28 to 63 years of age, during the summer and winter, taking indoor temperatures into consideration. Smokers and nonsmokers both had higher daytime ambulatory SBPs and DBPs in winter than in summer (after adjustment for potential confounders). However, the winter increase seen in the smokers was significantly higher for mean daytime SBP (7.3 versus 2.7 mm Hg,
P
<.01), for mean daytime DBP (4.4 versus 3.1 mm Hg,
P
=.051), and for ambulatory heart rate (3.9 versus −1.7 beats/min,
P
<.001). The double product increased from summer to winter (daytime) by 10.53 for smokers and by only 0.11 for nonsmokers (
P
<.01). There was an independent interaction between season and smoking status that affected SBP (standardized β=0.66,
P
<.0001) and DBP (standardized β=0.32,
P
<.0001). Smokers have a greater seasonal variation in blood pressure and heart rate than nonsmokers and show a larger increase in the cardiovascular load in winter. Smoking apparently potentiates the cardiovascular response to various climatic conditions. Season should be taken into account in studies of blood pressure and in the diagnosis and treatment of hypertension, particularly among cigarette smokers.
11βOH-Progesterone Affects Vascular Glucocorticoid Metabolism and Contractile Response
Authors: Brem Andrew S. , Bina Robert B. , King Thomas , Morris David J.
Published: June 2012

Abstract
Vascular smooth muscle (VSM) contains a bidirectional isoform of 11β-hydroxysteroid dehydrogenase (11β-HSD), the enzyme that can metabolize endogenous glucocorticoids to their respective 11-dehydro derivatives. 11βOH-progesterone (11βOH-P), a compound that can be produced in vivo, is as potent or more potent than licorice derivatives in inhibiting renal and hepatic 11β-HSD. When studied in homogenates prepared from primary cultures of rat VSM, 11βOH-P and its derivative, 11-keto-progesterone (11-keto-P), proved to be potent, directionally specific inhibitors of vascular 11β-HSD. 11βOH-P selectively inhibited the forward dehydrogenase reaction (corticosterone→11-dehydrocorticosterone), whereas 11-keto-P selectively blocked the reverse oxidoreductase reaction. To test the physiological effects, vascular rings were prepared from rat aorta. Rings were incubated in culture media containing either a submaximal concentration of corticosterone (10 nmol/L), 11-dehydrocorticosterone (100 nmol/L), 11βOH-P (1 μmol/L), 11-keto-P (1 μmol/L), or a combination of glucocorticoid and inhibitor for 24 hours. After the 24-hour incubation, rings were briefly stimulated sequentially with phenylephrine (10 nmol/L to 1 μmol/L) and angiotensin II (1 μmol/L). The immediate contractile response in rings incubated with both corticosterone and 11βOH-P was greater than in rings previously incubated with either the corticosterone or 11βOH-P alone (eg, response to 100 nmol/L phenylephrine in milligrams of force, mean±SE: corticosterone, 728±56, n=9; 11βOH-P, 325±105, n=4; both, 1132±122, n=8; corticosterone versus both,
P
<.01). In contrast, the immediate contractile responses to phenylephrine and to angiotensin II were attenuated in rings exposed previously to both 11-dehydrocorticosterone and 11-keto-P. Thus, 11βOH-P and 11-keto-P (and possibly structurally similar compounds) alter the vascular effects of glucocorticoids and may play a role in glucocorticoid-induced hypertension.
Altered Balance Between Cell Replication and Apoptosis in Hearts and Kidneys of Newborn SHR
Authors: Moreau Pierre , Tea Bun-Seng , Dam Than-Vinh , Hamet Pavel
Published: June 2012

Abstract
Apoptosis is involved in neonatal remodeling of organs of the cardiovascular system. Since we previously reported hyperplasia of these organs at birth in several forms of genetic hypertension, the aim of this study was to determine whether alterations of the apoptotic process could explain our findings. The heart, aorta, and kidneys of newborn Wistar-Kyoto and spontaneously hypertensive rats were harvested 24 hours after an injection of [
3
H]thymidine. DNA was extracted to measure its specific activity (index of DNA synthesis) and DNA fragmentation as an estimation of apoptosis. All organs studied showed an increased weight to body weight ratio in spontaneously hypertensive rats. Twenty-four hours after birth, DNA synthesis in all organs of spontaneously hypertensive rats was comparable to that in normotensive rats. However, apoptosis was markedly decreased in the heart and kidneys of newborn spontaneously hypertensive rats compared with their normotensive controls. In the aorta, apoptosis was reduced, but not significantly. Calculation of a proliferation index (DNA synthesis/fragmentation) revealed a significant increase of heart proliferation, with a similar trend in the aorta and kidneys. In addition, we found a negative correlation between heart weight and DNA fragmentation. Although other factors may influence hyperplasia of the aorta, we propose that a reduction of apoptotic activity is responsible, at least in part, for heart and kidney hyperplasia in newborn spontaneously hypertensive rats.
Cold Pressor Test Raises Serum Concentrations of ICAM-1, VCAM-1, and E-Selectin in Normotensive and Hypertensive Patients
Authors: Buemi Michele , Allegra Alessandro , Aloisi Carmela , Corica Francesco , Alonci Andrea , Ruello Antonella , Montalto Gaetano , Frisina Nicola
Published: June 2012

Abstract
In patients with essential hypertension, elevated soluble E-selectin (sE-selectin) levels may indicate endothelial cell injury or activation. We therefore sought to ascertain whether arterial blood pressure increased by the cold pressor test can modify serum concentrations of sE-selectin and other soluble forms of adhesion molecules, such as soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), or the expression of any adhesion molecules in circulating monocytes and lymphocytes. Our findings show that levels of sE-selectin, sVCAM-1, and sICAM-1 are higher in patients with essential hypertension than in normotensive subjects (sICAM-1, 380±52 versus 262±96 ng/mL,
P
<.05; sVCAM-1, 720±52 versus 625±38 ng/mL,
P
<.05; and sE-selectin, 75±21 versus 61±22 ng/mL,
P
<.05). Furthermore, in normotensive and hypertensive patients, the cold pressor test caused an increase in serum concentrations of sICAM-1, sVCAM-1, and sE-selectin, but it did not cause changes in the expression of adhesion molecules in circulating monocytes and lymphocytes. High arterial blood pressure may therefore increase the production of serum adhesion molecules, probably through endothelial activation.
Decreased Vasodilator Response to Isoproterenol During Nitric Oxide Inhibition in Humans
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Quyyumi Arshed A. , Cannon Richard O. , Panza Julio A.
Published: June 2012

Abstract
The vasodilator effect of β-adrenergic agonists has traditionally been ascribed solely to a direct effect on vascular smooth muscle. Experimental studies, however, have suggested a role of endothelium-derived nitric oxide (NO) in β-adrenergic–mediated vasodilation. The purpose of this investigation was to determine whether NO contributes to the vasodilator effect of β-adrenergic stimulation in humans. We analyzed the forearm blood flow response to increasing doses of isoproterenol (50, 100, and 200 ng/min), a β-adrenoceptor agonist, during the concomitant infusion of saline or
N
G
-monomethyl-
l
-arginine (L-NMMA; 4 μmol/min), a blocker of NO synthesis, in 23 normal subjects (9 men and 14 women, aged 48±7 years). The effect of L-NMMA was also assessed during infusion of sodium nitroprusside (0.8, 1.6, and 3.2 μg/min), an exogenous NO donor. Drugs were infused into the brachial artery, and forearm blood flow was measured by plethysmography. The vasodilator effect of isoproterenol was significantly blunted during the administration of L-NMMA compared with saline (maximum flow, 7.7±4 versus 11.2±5 mL · min
−1
· dL
−1
, respectively;
P
<.001). In contrast, the vasodilator response to sodium nitroprusside was not significantly affected by the infusion of L-NMMA (maximum flow, 8.8±3.7 mL · min
−1
· dL
−1
during L-NMMA versus 8.9±3.2 mL · min
−1
· dL
−1
during saline;
P
=.25). These findings indicate that NO inhibition blunts the vasodilator effect of β-adrenergic agonists in the human forearm and suggest that an abnormal response to adrenergic stimulation may occur in conditions associated with impaired NO activity.
High Plasma Level of
N
-Acetyl-Seryl-Aspartyl-Lysyl-Proline
Authors: Azizi Michel , Ezan Eric , Nicolet Laurence , Grognet Jean-Marc , Ménard Joël
Published: June 2012

Abstract
The acute administration of the angiotensin-converting enzyme (ACE) inhibitor captopril to healthy subjects transiently increases 5.5-fold the plasma levels of a natural stem-cell regulator,
N
-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). The aim of this study was to measure plasma Ac-SDKP levels during chronic treatment with all types of ACE inhibitors and to assess its relevance as a marker of ACE inhibition. Plasma levels of Ac-SDKP were blindly determined in age- and sex-matched hypertensive patients either treated (ACEI group, n=27) or not (non-ACEI group, n=23) with an ACE inhibitor for more than 1 month. Geometric mean [range] of plasma Ac-SDKP levels were significantly higher in the ACEI group (3.78 [1.48 to 14.5] pmol/mL) than in the non-ACEI group, with no overlap between the groups (0.75 [0.36 to 1.22] pmol/mL,
P
<.0001). The measurement of Ac-SDKP in plasma discriminated all the patients of the ACEI group, whereas the simultaneous determination of either in vitro (using hippuryl-histidine-leucine as substrate) or in vivo (angiotensin II/angiotensin I ratio) ACE activity failed to identify nine and five cases, respectively. We conclude that Ac-SDKP accumulates in plasma during chronic ACE inhibitor treatment. The long-term consequences of Ac-SDKP accumulation are unknown. The reliability of plasma Ac-SDKP measurement makes it the best marker of chronic ACE inhibition, which can help to verify patients’ compliance to ACE inhibitor treatment.
Effect of Nitric Oxide on DNA Replication Induced by Angiotensin II in Rat Cardiac Fibroblasts
Authors: Takizawa Toshikazu , Gu Miaofen , Chobanian Aram V. , Brecher Peter
Published: June 2012

Abstract
Our previous in vivo studies (Hou et al.
J Clin Invest.
1995;96:2469-2477.) demonstrated that chronic inhibition of nitric oxide synthase led to an exaggerated response to relatively low doses of angiotensin II, resulting in a rapid and marked cardiac fibrosis. To examine further the importance of angiotensin II in inducing cardiac fibrosis and the possibility that nitric oxide serves as a modulator of the proliferative effects of angiotensin II, we used cultured rat cardiac fibroblasts to study the interrelationships between these substances. Angiotensin II induced a delayed DNA synthetic response in quiescent cells that occurred 30 hours after exposure to the hormone. The most pronounced effect of angiotensin II on thymidine uptake occurred 36 to 42 hours after the addition to cells. This response was inhibited in a dose-dependent manner by the addition of either
S
-nitroso-
N
-acetylpenicillamine or sodium nitroprusside, each a source of nitric oxide. The nitric oxide donor was most effective in reducing thymidine incorporation when added 12 hours after angiotensin II, whereas the metabolite
N
-acetylpenicillamine had no effect at any time. The inhibitory effect of
S
-nitroso-
N
-acetylpenicillamine was mimicked by 8-bromoguanosine 3′:5′-cyclic monophosphate but not by 8-bromoadenosine 3′:5′-cyclic monophosphate. Nitric oxide donors did not appear to inhibit the induction of c-
fos
,
Egr-1
, or other immediate-early genes in response to angiotensin II. The results suggest that nitric oxide affects the cell cycle following the transition into G
1
and modulates the proliferation of fibroblasts during cardiac fibrosis induced by angiotensin II.
Cardiac Myocyte Membrane Wounding in the Abruptly Pressure-Overloaded Rat Heart Under High Wall Stress
Authors: Fischer Thomas A. , McNeil Paul L. , Khakee Robert , Finn Peter , Kelly Ralph A. , Pfeffer Marc A. , Pfeffer Janice M.
Published: June 2012

Abstract
The potential role of transient sarcolemmal membrane wounding as a signal transduction event for cardiomyocyte hypertrophy was evaluated in rats with short-term pressure overload caused by banding of the proximal aorta. This procedure resulted in significant increases in left ventricular systolic (1.5-fold) and end-diastolic (2.6-fold) pressures and wall stresses that were associated with significant wall thinning and cavitary enlargement. Quantitative image analysis of frozen sections of the stressed ventricles obtained 60 minutes after banding demonstrated a 6- to 10-fold increase in cytosolic staining with a horseradish peroxidase–labeled anti-albumin antibody compared with sham-operated controls, indicating that an increase in transient sarcolemmal membrane permeability (wounding) is an early response to an abrupt increase in hemodynamic load in vivo. We conclude that an intense hemodynamic stress in vivo can result in histologically detectable cardiomyocyte wounding.
Monocyte Chemoattractant Protein-1 Expression in Aortic Tissues of Hypertensive Rats
Authors: Capers Quinn , Alexander R. Wayne , Lou Pingping , Hector De Leon  , Wilcox Josiah N. , Ishizaka Nobukazu , Howard Adam B. , Taylor W. Robert
Published: June 2012

Abstract
Monocyte chemoattractant protein-1 (MCP-1), a potent monocyte chemoattractant synthesized by vascular cells and monocytes, has been proposed to be an important mediator of inflammatory responses in the arterial vasculature. It was recently demonstrated that hypertension is associated with an inflammatory response in the arterial wall. To determine the effect of hypertension on arterial MCP-1 expression, we induced hypertension in Sprague-Dawley rats by infusing angiotensin II (0.75 mg · kg
−1
· d
−1
SC) for 7 days. Using Northern blot analysis, we detected a 3.6-fold increase in MCP-1 mRNA in the aortas of hypertensive rats. When we normalized blood pressure in angiotensin II–treated rats through oral administration of the nonspecific vasodilator hydralazine (15 mg · kg
−1
· d
−1
), aortic MCP-1 mRNA expression was significantly reduced. Similar results were obtained with a norepinephrine model of hypertension. Taken together, these data suggest that mechanical factors may be responsible in part for the upregulation of expression. Consistent with this interpretation, we found that cultured rat aortic vascular smooth muscle cells exposed to mechanical strain (20% peak deformation at 1 Hz) exhibited a marked increase in MCP-1 expression, suggesting the hemodynamic strain imparted onto arterial cells in hypertension is an important stimulus underlying this phenomenon. These results provide important insights into the in vivo regulation of MCP-1 and have potential implications for understanding the influence of hypertension on atherosclerosis.
Diagnosing Gestational Hypertension and Preeclampsia With the 24-Hour Mean of Blood Pressure
Authors: Hermida Ramón C. , Ayala Diana E.
Published: June 2012

Abstract
The use of ambulatory blood pressure monitoring has provided a method of blood pressure assessment that may compensate for some of the limitations of isolated measurements. Here we aim to examine prospectively the effectiveness of the commonly used 24-hour mean as a potential screening test for the identification of gestational hypertension and preeclampsia. We analyzed 503 blood pressure series from 71 healthy pregnant women and 256 series from 42 women who developed gestational hypertension or preeclampsia. Forty-eight-hour blood pressure monitoring was done once every 4 weeks after the first obstetric consultation. Sensitivity and specificity of the 24-hour mean of blood pressure were computed for each trimester of pregnancy by comparing distributions of values obtained for healthy and complicated pregnancies, without assuming an a priori threshold for diagnosing gestational hypertension on the basis of mean blood pressure. Sensitivity ranges from 31.8% for diastolic blood pressure in the second trimester to 84.1% for systolic blood pressure in the third trimester. However, specificity is as low as 6.9% for diastolic blood pressure in the first trimester. The positive predictive value does not reach 55% for any variable in any trimester. The higher relative risk was consistently obtained for systolic blood pressure (4.9 in the third trimester). Despite the highly statistically significant differences in blood pressure found between healthy and complicated pregnancies in all trimesters, the daily mean of blood pressure does not provide a proper and stable individualized test for diagnosing hypertensive complications in pregnancy. Other indexes obtained from the blood pressure series have been shown, however, to identify early in pregnancy those women who subsequently will develop gestational hypertension or preeclampsia, rendering ambulatory blood pressure monitoring a useful, but still costly, technique in pregnancy.
Patterns of Neuronal Activation During Development of Sodium Sensitive Hypertension in SHR
Authors: Budzikowski Adam S. , Vahid-Ansari Faranak , Robertson George S. , Leenen Frans H. H.
Published: June 2012

Abstract
The effects of regular (RNa) or high (HNa) sodium diet for 3, 7, and 14 days on Fra-like immunoreactivity (Fra-LI) in the brains of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were examined using an antibody that recognizes all known members of the Fos family (Fos, Fos-B, Fra-1, and Fra-2). Two weeks of HNa significantly exacerbated hypertension in SHR but had no effects in WKY. On RNa, compared with WKY, SHR showed higher Fra-LI in the median preoptic nucleus, supraoptic nucleus, both parts of the paraventricular nucleus, nucleus of the solitary tract, and central gray. Fra-LI in the subfornical organ did not differ between the two strains. On RNa, Fra-LI in the anterior hypothalamic area could be detected only in WKY. In osmoregulatory areas, HNa diet increased Fra-LI in both SHR and WKY to comparable extents, but in the median preoptic nucleus, Fra-LI was increased to a greater extent in SHR. HNa produced smaller increases in the subfornical organ of SHR compared with WKY. In both the parvocellular and magnocellular paraventricular nuclei, increases in Fra-LI by HNa were more pronounced in SHR than in WKY. In the anterior hypothalamic area, Fra-LI could no longer be detected in WKY on HNa, whereas it appeared in SHR. HNa increased Fra-LI in the NTS and central gray to similar levels in WKY and SHR. These results indicate that WKY and SHR differ in the pattern of neuronal activation accompanying maturation on RNa. HNa activates neurons in a number of brain areas, and the pattern of these changes also differs between WKY and SHR.
Effects of Continuous Infusion of Endothelin-1 in Pregnant Sheep
Authors: Greenberg Suzanne G. , Baker R. Scott , Yang DaSeng , Clark Kenneth E.
Published: June 2012

Abstract
Plasma concentration of endothelin-1, a potent vasoconstrictor produced by the vascular endothelium, has been observed to be significantly increased in a number of pathophysiological states, including preeclampsia. In the present study we have evaluated the effects of elevated plasma endothelin-1 in pregnant sheep by continuous exogenous endothelin-1 administration. Nine pregnant ewes (110±5 days’ gestation) were instrumented for measurements of maternal mean arterial pressure, renal blood flow, and uterine blood flow. After recovery, endothelin-1 was infused intravenously for 4 hours at a dose that was adjusted to raise mean arterial pressure by ≈20 mm Hg by the end of the first hour (range 5 to 20 ng/kg per minute). Mean arterial pressure, renal blood flow, uterine blood flow, urinary protein excretion, hematocrit, and plasma endothelin-1 concentration were measured hourly, and renal and uterine vascular resistances were calculated. Endothelin-1 produced significant increases (% change from baseline at t=4 hours) in mean arterial pressure (45±8%), renal vascular resistance (353±66%), and uterine vascular resistance (59±21%). Endothelin-1 also increased microvascular permeability both systemically and within the kidney, as suggested by marked increases in hematocrit (0.27±0.01 to 0.32±0.01) and urinary protein concentration (0.95±0.1 to 7.9±3.2 mg/mL per mg creatinine). There was a highly significant correlation (
P
<.0001) between plasma endothelin-1 and mean arterial pressure, renal vascular resistance, uterine vascular resistance, hematocrit, and urinary protein content in all sheep studied. In addition, plasma endothelin-1 corresponded well with the time course of the changes in cardiovascular parameters and urinary protein excretion observed. These results provide evidence to suggest that elevation of circulating endothelin-1 in pregnant sheep can produce cardiovascular and hemodynamic changes that in many ways resemble the human disease preeclampsia. This supports the hypothesis that endothelial cell damage and/or dysfunction that is associated with increased production of endothelin-1 could directly contribute to the progression of preeclampsia.
Integrins, Adhesion, and Cardiac Remodeling
Authors: Hsueh Willa A. , Law Ronald E. , Do Yung S.
Published: June 2012

Integrins are heterodimeric cell surface receptors that mediate a cell’s ability to perceive its environment, respond to changed in its environment, and alter its environment. When activated, these receptors form focal adhesions, which are areas of close attachment of the cells to extracellular matrix proteins in which colocalization of cytoskeletal proteins, intracellular signaling molecules, and growth factor receptors occurs. In cardiac fibroblasts, integrins mediate cell growth and adhesion. Growth factors such as angiotensin II regulate DNA synthesis, protooncogene expression, extracellular matrix production, adhesion, and other actions of cardiac fibroblasts, many of which require integrin activation. In addition to controlling growth factor and hemodynamic effects, regulation of integrin activity may be useful to affect cardiac fibrosis and the remodeling process.
Angiotensin II Stimulates Synthesis of Endothelial Nitric Oxide Synthase
Authors: Hennington Bettye S. , Zhang Huimin , Miller M. Todd , Granger Joey P. , Reckelhoff Jane F.
Published: June 2012

Previous studies have suggested that NO may play an important role in protecting the renal vessels from angiotensin II (ANGII)-mediated vasoconstriction. One possible mechanism for this interaction is that ANGII could stimulate NO production in the kidney by increasing endothelial NO synthase (NOS III). The present studies were performed in rats to determine whether acute or chronic elevations in ANGII are associated with enhanced renal NOS III mRNA or protein synthesis. In both acute and chronic studies captopril (20 μg/kg/min) was given IV to inhibit endogenous ANGII production. Acute suprarenal infusion of ANGII (8 ng/kg/min) for 110 minutes had no effect on arterial pressure but decreased GFR and renal plasma flow by 20% and 30%, respectively, and increased renal vascular resistance by 70%. Acute ANGII increased renal NOS III mRNA by 70% (as determined by ribonuclease protection assay), but had no effect on renal NOS III protein concentration (as detected by Western blot analyses). In contrast, chronic infusion of ANGII (5 ng/kg/min) for 10 days, increased arterial pressure by 30% and tended to reduce GFR and renal plasma flow. Chronic ANGII had no effect on renal NOS III mRNA levels, but increased NOS III protein by 90%. These data suggest that ANGII can stimulate NOS III synthesis and suggest that this may be one of the mechanisms whereby AngII may enhance NO production.
Distinct Endothelial Impairment in Coronary Microvessels from Hypertensive Dahl Rats
Authors: Gauthier-Rein Kathryn M. , Rusch Nancy J.
Published: June 2012

Hypertension has been linked to an impaired dilator function of the coronary microvascular endothelium in vivo. However, the profile and mechanism of this dysfunction remain obscure. Thus, this study compared diameter responses to acetylcholine (ACH), bradykinin (BKN), and substance P (SP) between coronary microvessels (i.d.=106±4 μm) dissected from left ventricles of normotensive and hypertensive Dahl rats (Dahl-NT and Dahl-HT, respectively). Vessels were cannulated and pressurized on glass pipettes at 80 mm Hg, and internal diameters were monitored by videomicroscopy. Coronary microvessels from Dahl-NT and Dahl-HT showed similar dilator responses to ACH (100 pmol/L to 10 μmol/L), with maximal diameter increases of 63±5 μm and 63±7 μm, respectively (n=31,17). However, only vessels from Dahl-NT showed dilator responses to SP (10 fmol/L to 1 nmol/L) and BKN (100 fmol/L to 10 nmol/L). All dilator responses persisted after N-nitro-
l
-arginine (10 μmol/L) or indomethacin (10 μmol/L), but were blunted after inhibition of cytochrome P450 by 10 μmol/L octadecynoic acid (n=6–8). These results suggest that: (1) coronary microvessels from Dahl-HT show a unique pattern of endothelial impairment, whereby ACH-induced relaxations persist at a time when dilator responses to SP and BKN are severely blunted, and (2) a cytochrome P450 product, rather than nitric oxide or prostacyclin, may partly mediate the vasodilator responses to ACH, SP and BKN.
AT
1
and AT
2
Receptor Blockade and Epinephrine Release During Insulin-Induced Hypoglycemia
Authors: Worck René H. , Frandsen Erik , Ibsen Hans , Petersen Jørgen Søberg
Published: June 2012

Angiotensin II facilitates epinephrine release during insulin-induced hypoglycemia, and this effect appears to be independent of type 1 angiotensin II (AT
1
) receptors in man. In the present study, we hypothesized that the action of angiotensin II on adrenomedullary epinephrine release is mediated by an AT
2
receptor-dependent mechanism. In conscious chronically instrumented rats, we measured plasma concentrations of catecholamines during acute insulin-induced hypoglycemia in groups of rats pretreated with the AT
1
receptor antagonist losartan (10 mg/kg IV), the AT
2
receptor antagonist PD123319 (30 mg/kg IV), combined losartan + PD123319, the converting enzyme inhibitor enalapril (1 mg/kg IV), or vehicle. In vehicle-treated rats, the area under the curve for changes in plasma epinephrine concentration [AUC(plasma epinephrine)] during insulin-induced hypoglycemia was 111±8 nmol×h/L (±SEM). Pretreatment with losartan alone did not affect AUC(plasma epinephrine) (113±17 nmol×h/L), while pretreatment with PD123319 tended to reduce the response (87±10 nmol×h/L;
P
=.08 versus vehicle). However, AUC(plasma epinephrine) was significantly reduced in rats that were pretreated with combined losartan + PD123319 (68±5 nmol×h/L;
P
<.001 versus vehicle) or enalapril: 86±10 nmol×h/L (
P
<.05 versus vehicle). Thus, combined treatment with losartan + PD 123319 proved more effective in attenuating the reflex increase in plasma epinephrine concentration during hypoglycemia than either of the two AT receptor antagonists given alone. We speculate that angiotensin II through binding to both receptor subtypes facilitates the sympathoadrenal reflex response by actions at several anatomical levels of the neural pathways involved in the sympathoadrenal reflex response elicited during insulin-induced hypoglycemia.
Chronic Leptin Infusion Increases Arterial Pressure
Authors: Shek Eugene W. , Brands Michael W. , Hall John E.
Published: June 2012

Plasma leptin concentration is increased in hypertensive obese humans, but whether leptin contributes to the increased arterial pressure in obesity is not known. In this study, we tested whether chronic increases in leptin, to levels comparable to those in obesity, could cause a sustained increase in arterial pressure and also the importance of central nervous system (CNS) versus systemic mechanisms. Five male Sprague-Dawley rats were implanted with chronic nonoccluding catheters in the abdominal aorta and both carotid arteries for CNS infusion, and five other rats were implanted with an abdominal aorta catheter and femoral vein catheter for intravenous (IV) infusion. After 7 days of control, leptin was infused into the carotid arteries or femoral vein at 0.1 μg/kg/min for 5 days and 1.0 μg/kg/min for 7 days, followed by a 7-day recovery period. The carotid artery and IV infusions of leptin at 1μg/kg/min significantly increased plasma leptin levels, from 1.2 ± 0.4 ng/mL to 91 ± 5 ng/mL and from 0.9 ± 0.1 ng/mL to 94 ± 9 ng/mL, respectively, but there was no significant increase in either group at the low dose. Food intake also did not change at the low dose but decreased by approximately 65% in the carotid group and 69% in the IV group after 7 days of the 1 μg/kg/min infusion. Mean arterial pressure (MAP) increased slightly at the low dose only in the carotid group, but this was not statistically significant. At the higher dose, however, MAP increased significantly from 86 ± 1 mm Hg to 94 ± 1 mm Hg in the carotid group and from 87 ± 1 mm Hg to 93 ± 1 mm Hg in the IV group. Heart rate also increased significantly in both groups at 1 μ/g/kg/min leptin infusion. Fasting blood glucose and insulin levels decreased significantly at 1 μg/kg/min in both the carotid artery group (−10.5% and −82.5%, respectively) and the IV group (−13.6% and −80.4%, respectively). All variables returned to control levels after leptin infusion was stopped. These results indicate that chronic increases in circulating leptin cause sustained increases in arterial pressure and heart rate and are consistent with a possible role for leptin in obesity hypertension.
Testosterone Exacerbates Hypertension and Reduces Pressure-Natriuresis in Male Spontaneously Hypertensive Rats
Authors: Reckelhoff Jane F. , Zhang Huimin , Granger Joey P.
Published: June 2012

Studies were performed in intact male and female, gonadectomized male and female, and gonadectomized female rats given testosterone for 5 weeks to investigate the role played by testosterone in altered blood pressure control and pressure-natriuresis in male SHR. Serum testosterone levels reached a peak at 12 weeks of age in intact male SHR. Systolic blood pressure, measured weekly from 5 to 20 weeks of age, was similar between groups until 12 weeks of age when blood pressure became higher in males (195±3 mm Hg) than in females (168±3 mm Hg) or males castrated at 4 weeks (173±4 mm Hg). At 17 to 19 weeks direct measurement of arterial pressure in anesthetized rats confirmed that mean arterial pressure was higher in male (182±1 mm Hg) than in female (159±2 mm Hg) and castrated male SHR (159±2 mm Hg). In addition, testosterone (5 mg in Silastic pellets, SC for 5 weeks) administered to ovariectomized (ovx+T) females caused arterial pressure to increase by mm11% (175±2 mm Hg), which was significantly higher than in intact female, castrated male, or untreated ovariectomized (ovx) female SHR (158±2 mm Hg). Acute pressure-natriuresis was blunted in male SHR compared with females, castrated males, or ovx females, in which this relationship was similar. Pressure-natriuresis was also blunted in ovx+T females as found in intact male SHR. These data support the hypothesis that male sex hormones contribute to the exacerbation of hypertension in SHR by reducing pressure-natriuresis.
Effects of AT
1
and AT
2
Angiotensin Receptor Antagonists in Angiotensin II-Infused Rats
Authors: Li Jin S. , Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Angiotensin II (Ang II) appears to exert its contractile and growth-promoting effects through the AT
1
receptor subtype, whereas the AT
2
subtype may have growth-inhibitory and proapoptotic properties. Recently, some data have challenged this emerging concept. To clarify the role of AT
1
and AT
2
receptors, we treated Wistar rats that were infused with Ang II (120 ng/kg/min subcutaneously by osmotic minipump), with the AT
1
antagonist losartan (10 mg/kg/d in the drinking water) and the AT
2
antagonist
PD123319
(30 mg/kg/d subcutaneously by osmotic minipump) for 21 days. At the end of the study, tail-cuff systolic blood pressure was 106±2.8 mm Hg in untreated rats and 108±2.0 mm Hg in rats infused with Ang II that received losartan, whereas it rose to 158±4.9 mm Hg in Ang II-infused rats and 158±3.0 mm Hg in rats infused with Ang II rats and
PD123319
(the two latter groups
P
<.01 versus the two other groups). Heart weight, and aorta cross-section/body weight ratio were higher in Ang II-infused rats than in controls and were significantly reduced in Ang II-infused rats that received losartan (
P
<.05). Wire-myograph-mounted coronary, renal, mesenteric, and femoral small arteries from Ang II-infused rats and Ang II-infused rats receiving
PD123319
had a greater media, media cross-section, and media/lumen ratio than vessels from untreated or Ang II-infused rats treated with losartan. These results support the concept that in Wistar normotensive rats infused for 3 weeks with angiotensin II, growth in the heart, aorta, and coronary, renal, mesenteric, and femoral small arteries is mediated by the AT
1
receptor; the results show little evidence of a role of AT
2
receptors in mediating angiotensin II effects in this experimental paradigm.
Trends in Hypertension Prevalence, Treatment, and Control In a Well-Defined Older Population
Authors: Barker William H. , Mullooly John P. , Linton Kathryn L. P.
Published: June 2012

To assess medical attention focused on hypertension (HBP) in the elderly, this study examines trends in HBP prevalence, treatment, and control status in a defined population of persons ≥65 years of age enrolled in a large HMO. Random samples of approximately 400 persons were drawn for the years 1967, 1974, 1981, and 1988. First recorded ambulatory pressures, available on over 90% of subjects in each period, were obtained from medical records. Prevalence of HBP (SBP ≥ 160 and/or DBP ≥95, and/or taking anti-HBP drugs) ranged between 44% to 53%. Proportion with HBP on treatment increased from 25% in 1967 to 60% in 1988 (
P
<.001); proportion on treatment and controlled (SBP<160, DBP<95) increased from 8% to 34% (
P
<.001). Mean population SBP declined from 155.2 in 1967 to 144.0 in 1988 (
P
<.001); mean DBP declined from 85.2 to 81.2 (
P
<.001). Proportion with isolated systolic hypertension (ISH) (SBP≥160, DBP<90) remained unchanged at 12% to 14%. Use of diuretics and adrenergic antagonist agents declined while use of beta blockers and newer classes of anti-HBP drugs increased significantly among treated hypertensives in the 1980s. These findings parallel HBP trends in younger adults from National Health Survey data though we find evidence of a substantial gap in addressing the problem in the elderly, who constitute the population at greatest risk of cardiovascular complications of HBP.
Blood Pressure Excess for the Early Identification of Gestational Hypertension and Preeclampsia
Authors: Hermida Ramón C. , Ayala Diana E. , Mojón Artemio , Fernández José R. , Silva Inés , Ucieda Rafael , Iglesias Manuel
Published: June 2012

Abstract
—We have examined prospectively whether the combined approach of establishing tolerance intervals for the circadian variability of blood pressure (BP) as a function of gestational age, and then determining the so-called hyperbaric index (area of BP excess above the upper limit of the tolerance interval) by comparison of any patient’s BP profile (obtained by ambulatory monitoring) with those intervals provides a high sensitivity test for the early detection of pregnant women who subsequently will develop gestational hypertension or preeclampsia. We analyzed 657 BP series from 92 women with uncomplicated pregnancies and 378 series from 60 women who developed gestational hypertension or preeclampsia. BP was sampled for about 48 hours once every 4 weeks after the first obstetric consultation. Circadian 90% tolerance limits were determined as a function of trimester of gestation from 497 series previously sampled from a reference group of 189 normotensive pregnant women. The hyperbaric index was then determined for each individual BP series in the validation sample. Sensitivity of this test for diagnosing gestational hypertension was 93% for women sampled during the first trimester of gestation and increased up to 99% in the third trimester. The positive and negative predictive values were above 96% in all trimesters. Despite the limitations of ambulatory monitoring, the approach presented here, now validated prospectively, represents a reproducible, noninvasive, and high sensitivity test for the very early identification of subsequent gestational hypertension and preeclampsia, on the average, 23 weeks before the clinical confirmation of the disease.
Candidate Genes in the Regulation of Na
+
Transport by Inner Medullary Collecting Duct Cells From Dahl Rats
Authors: Husted Russell F. , Rapp John P. , Stokes John B.
Published: June 2012

Abstract
—Recently, we reported that primary cultures of inner medullary collecting duct cells from Dahl salt-sensitive (S) rats absorb more Na
+
than do cells cultured from Dahl salt-resistant (R) rats. To begin to evaluate the molecular basis for this difference, we selected four candidate gene products that on the basis of their physiology and genetics could participate in regulation of Na
+
transport by these cells. During 24-hour exposure, inhibitors of the cytochrome P450 enzymes had no effect on Na
+
transport by either S or R monolayers. Twenty-four-hour exposure to
N
G
-monomethyl-
l
-arginine (0.5 mmol/L), a nonspecific inhibitor of NO synthase, also had no effect on Na
+
transport by either S or R monolayers. Neither atrial natriuretic peptide 1–28 (100 nmol/L) nor 8-Br-cyclic GMP (100 μmol/L) had any short-term effect on Na
+
transport by either S or R monolayers. 18-Hydroxy-11-deoxycorticosterone (100 nmol/L), an adrenocorticoid hormone that is produced in greater amounts in S rats, stimulated Na
+
transport by both S and R monolayers via the mineralocorticoid receptor; however, its effect was less potent than aldosterone. Congenic rats in which the R isoform of the 11β-hydroxylase gene was bred onto the S background had monolayers that transported Na
+
at a rate similar to the S rats. These results demonstrate that neither cytochrome P450 genes, NO synthase genes, the atrial natriuretic peptide receptor gene, nor the 11β-hydroxylase gene is a likely candidate to explain the difference in Na
+
transport between S and R inner medullary collecting duct monolayers in primary culture.
Diabetic Nephropathy Is Associated With AGT Polymorphism T235
Authors: Rogus John J. , Moczulski Dariusz , Freire Maria Beatriz S. , Yang Yadong , Warram James H. , Krolewski Andrzej S.
Published: June 2012

Abstract
—Diabetic nephropathy is a serious and frequent complication of insulin-dependent diabetes mellitus (IDDM) that has a strong genetic component. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specifically the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be introduced by unrecognized differences in the populations selected for cases and control subjects. In contrast, family-based approaches, such as the transmission/disequilibrium test, assess whether a particular variant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own control, thereby eliminating spurious results caused by mismatched population samples. To take advantage of this study design for further investigation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free patients with long-duration IDDM, and, very importantly, parents of all these individuals. We found that among males (but not females) the T allele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (
P
=.05). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal disease (
P
=.04). In conclusion, results obtained in our family-based study support a role of the angiotensinogen gene M235T polymorphism, and specifically the T allele, in the development of diabetic nephropathy in IDDM.
Maintenance of Baseline Angiotensin II Potentiates Insulin Hypertension in Rats
Authors: Keen Henry L. , Brands Michael W. , Smith Manis J. , Hall John E.
Published: June 2012

Abstract
—Chronic insulin infusion in rats increases mean arterial pressure (MAP) by a mechanism dependent on angiotensin II (Ang II). However, the fact that plasma renin activity (PRA) decreases with insulin infusion suggests that Ang II sensitivity is increased and that the parallel reduction in Ang II may partly counteract any hypertensive action of insulin. This study tested that hypothesis by clamping Ang II at baseline levels during chronic insulin infusion. Sprague-Dawley rats were instrumented with artery and vein catheters, and MAP was measured 24 hours per day. In seven angiotensin clamped rats (AC rats), renin–angiotensin II system activity was clamped at normal levels throughout the study by continuous intravenous infusion of the angiotensin-converting enzyme inhibitor benazepril at 5 mg/kg per day (which decreased MAP by 18±2 mm Hg) together with intravenous Ang II at 5 ng/kg per minute. Control MAP in AC rats after clamping averaged 99±1 mm Hg, which was not different from the 101±2 mm Hg measured before clamping Ang II levels. Control MAP in the 8 vehicle-infused rats averaged 105±2 mm Hg. A 7-day infusion of insulin (1.5 mU/kg per minute IV) plus glucose (20 mg/kg per minute IV) increased MAP in both groups of rats; however, the increase in MAP was significantly greater in AC rats (12±1 versus 5±1 mm Hg). This enhanced hypertensive response to insulin in AC rats was associated with a greater increase in renal vascular resistance (153±10% versus 119±6% of control) and a significant increase in renal formation of thromboxane (149±11% of control). Thus, decreased Ang II during insulin infusion limits the renal vasoconstrictor and hypertensive actions of insulin, and this may be caused, at least in part, by attenuation of renal thromboxane production.
Influence of Nitric Oxide in the Chronic Phase of Two-Kidney, One Clip Renovascular Hypertension
Authors: Sigmon David H. , Beierwaltes William H.
Published: June 2012

Abstract
—Chronic two-kidney, one clip (2K1C) renovascular hypertension is characterized by a largely angiotensin-independent elevated blood pressure (BP). We hypothesized that the long-term effect of hypertension would compromise endothelium-derived nitric oxide (NO) and diminish its influence in controlling renal perfusion. We determined the influence of endothelium-derived NO on renal hemodynamics and the angiotensin-NO interaction regulation of renal perfusion in rats with chronic 2K1C hypertension. Renal blood flow (RBF) was measured by radioactive microspheres in rats with either early-phase (4 weeks after clipping, n=7) or chronic-phase (13 to 16 weeks after clipping, n=7) 2K1C hypertension. The systemic and renal response to NO synthesis inhibition was determined with 10 mg/kg body wt
N
ω
-nitro-
l-
arginine methyl ester (L-NAME). In rats with early-phase 2K1C hypertension, BP was 149±3 mm Hg, which increased by 42±3 mm Hg with L-NAME (
P
<.001). L-NAME decreased RBF by 20% (
P
<.02) and 17% (
P
<.005) and increased renal vascular resistance (RVR) by 58% (
P
<.005) and 62% (
P
<.02) in the nonclipped and clipped kidneys, respectively. In rats with chronic 2K1C hypertension, BP was 166±3 mm Hg, and L-NAME increased this by 35±6 mm Hg (
P
<.001). In the nonclipped and clipped kidneys of chronic 2K1C hypertensive rats, L-NAME decreased RBF by 20% (
P
<.01) and 17% (
P
<.01) and increased RVR by 51% (
P
<.005) and 60% (
P
<.02), respectively. There were no differences in L-NAME–induced changes between early- and chronic-phase 2K1C hypertensive rats. Next, we treated seven chronic-phase 2K1C hypertensive rats with 10 mg/kg body wt losartan, which reduced BP by only 7.7% (
P
<.005). After losartan, L-NAME increased BP by 41±3 mm Hg (
P
<.001), decreased RBF to the nonclipped kidney by 44% (
P
<.05), and increased RVR by 110% (
P
<.005); the decrease in RBF was significantly greater compared with untreated chronic-phase controls (
P
<.05). In the clipped kidney, L-NAME decreased RBF by 26% (
P
<.05) and increased RVR by 76% (
P
<.05). Thus, angiotensin blockade did not attenuate the systemic or renal vasoconstriction to L-NAME. Our results suggest that in both early and chronic phases of 2K1C hypertension, NO contributes significant dilator tone to buffer the hypertension and maintains perfusion of both kidneys by counterbalancing angiotensin-independent vasoconstriction.
Regulatory Elements Required for Human Angiotensinogen Expression in HepG2 Cells Are Dispensable in Transgenic Mice
Authors: Yang Gongyu , Sigmund Curt D.
Published: June 2012

Abstract
—Previous researchers have identified two sequences present upstream (angiotensinogen gene–activating element [AGE2]) and downstream (d61–2) of the human angiotensinogen gene that act as cell-specific enhancers of transcription in transiently transfected HepG2 cells. To examine the importance of these two sequences in regulating tissue- and cell-specific expression of the gene in vivo, we generated transgenic mice containing the mutations in the context of a genomic transgene previously shown to exhibit appropriate tissue and cell specificity. The ability of these sequences to enhance transcription of a basal human angiotensinogen promoter was confirmed in transient transfection assays in HepG2 cells, and mutations within the AGE2 and d61–2 sequences abolished transactivation of the promoter. Tissue- and cell-specific expression was examined in three lines of transgenic mice carrying the d61–2 mutation, two lines of transgenic mice carrying the AGE2 mutation, and three founder transgenic mice carrying a double-mutant construct. Although the absolute levels of expression varied among lines, the pattern of tissue-specific expression was essentially unaltered by the mutations. In situ hybridization confirmed that the mutations were also dispensable for proximal tubule-specific expression within the kidney. Finally, a comparison of transgene expression with transgene copy number revealed a direct proportionality in liver (
R
=.77,
P
=.0014) and kidney (
R
=.76,
P
=.0024). These results clearly demonstrate that these sites, which strongly induce promoter activity in cells in culture, are not required for appropriate expression of the gene when present in a genomic construct in vivo.