bluuebunny/crossref_metadata_2025 huggingface dataset:
Antihypertensive Therapy Prevents Endothelial Dysfunction in Chronic Nitric Oxide Deficiency
Authors: Takase Hiroyuki , Moreau Pierre , Küng Christoph F. , Nava Eduardo , Lüscher Thomas F.
Published: June 2012

Abstract
The objective of this study was to examine the effects of long-term antihypertensive therapy on blood pressure and vascular responses of resistance arteries during prolonged inhibition of nitric oxide synthesis. Four groups of 6-week-old Wistar-Kyoto rats were treated with either placebo as controls or
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) alone or in combination with verapamil or with trandolapril. Drugs were given orally for 6 weeks or short-term in vitro to vessels obtained from untreated rats. Endothelium-dependent and -independent relaxations as well as contractions were studied in isolated perfused mesenteric and renal arteries with an arteriograph. Kidney nitric oxide synthase activity was also evaluated. Verapamil and trandolapril prevented the increase in systolic blood pressure and the blunted acetylcholine-induced relaxations that occurred with L-NAME treatment without improving the nitric oxide synthase activity. Both antihypertensive regimens also normalized sensitivity to sodium nitroprusside, which was enhanced by L-NAME. In contrast, short-term in vitro preincubation with verapamil or trandolaprilat in the presence of L-NAME did not improve the impaired relaxations to acetylcholine. Long-term but not short-term therapy with a calcium antagonist or angiotensin-converting enzyme inhibitor improved the blunted endothelium-dependent relaxations in nitric oxide–deficient hypertension. These findings strongly suggest that the role of other vasodilator systems, which normally do not regulate vascular tone, is enhanced with long-term but not short-term treatment with these drugs. These observations emphasize the potential importance of these treatments in the management of hypertension in which nitric oxide production is diminished.
Plasma of Preeclamptic Women Stimulates and Then Inhibits Endothelial Prostacyclin
Authors: Baker Philip N. , Davidge Sandra T. , Barankiewicz Jerzy , Roberts James M.
Published: June 2012

Abstract
We propose that the dichotomy between the in vivo reduction in intravascular prostacyclin production that occurs in preeclampsia and the in vitro stimulatory effect of plasma from preeclamptic patients on endothelial cell prostacyclin production is due to differential effects of chronic versus acute exposure to the plasma. We studied the acute versus chronic effects of 2% plasma from healthy pregnant and preeclamptic subjects by measuring endothelial prostacyclin production at different time periods after exposure to plasma. To determine whether such effects were specific to prostacyclin, we also measured prostaglandin E
2
production. To determine whether chronic changes in prostacyclin production resulted from altered cellular responsiveness, we stimulated cells that had been exposed to plasma for 72 hours with arachidonic acid and measured prostaglandin production. Preliminary characterization of the plasma factor or factors responsible for alterations in prostaglandin production was performed. After 24 hours cells exposed to plasma from preeclamptic women produced more prostacyclin and prostaglandin E
2
than cells exposed to plasma from healthy pregnant women. In contrast, after 72 hours exposure to plasma from preeclamptic women resulted in less endothelial cell prostacyclin production than exposure to plasma from healthy pregnant women, but there were no such differences in prostaglandin E
2
production. Cells that had been exposed to plasma from preeclamptic women for 72 hours produced less prostacyclin but the same quantity of prostaglandin E
2
after stimulation with arachidonic acid than cells exposed to plasma from healthy pregnant women. The plasma factor or factors responsible for altered prostacyclin production were sensitive to heat, acid, and proteases. In contrast to acute exposure, chronic exposure to plasma from preeclamptic women alters endothelial cells to result in decreased prostacyclin production, an observation consistent with in vivo findings.
Paracrine Systems in the Cardioprotective Effect of Angiotensin-Converting Enzyme Inhibitors on Myocardial Ischemia/Reperfusion Injury in Rats
Authors: Liu Yun-He , Yang Xiao-Ping , Sharov Victor G. , Sigmon David H. , Sabbah Hani N. , Carretero Oscar A.
Published: June 2012

Abstract
After transient episodes of ischemia, benefits of thrombolytic or angioplastic therapy may be limited by reperfusion injury. Angiotensin-converting enzyme inhibitors protect the heart against ischemia/reperfusion injury, an effect mediated by kinins. We examined whether the protective effect of the angiotensin-converting enzyme inhibitor ramiprilat on myocardial ischemia/reperfusion is due to kinin stimulation of prostaglandin and/or nitric oxide release. The left anterior descending coronary artery of Lewis inbred rats was occluded for 30 minutes, followed by 120 minutes of reperfusion. Immediately before reperfusion rats were treated with vehicle, ramiprilat, or the angiotensin II type 1 receptor antagonist losartan. We tested whether pretreatment with the kinin receptor antagonist Hoe 140, the nitric oxide synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester, or the cyclooxygenase inhibitor indomethacin blocked the effect of ramiprilat on infarct size and reperfusion arrhythmias. In controls, infarct size as a percentage of the area at risk was 79±3%; ramiprilat reduced this to 49±4% (
P
<.001), but losartan had little effect (74±6%,
P
=NS). Pretreatment with Hoe 140,
N
G
-nitro-
l
-arginine methyl ester, or indomethacin abolished the beneficial effect of ramiprilat. Compared with the 30-minute ischemia/120-minute reperfusion group, nonreperfused hearts with 30 minutes of ischemia had significantly smaller infarct size as a percentage of the area at risk, whereas in the 150-minute ischemia group it was significantly larger. This suggests that reperfusion caused a significant part of the myocardial injury, but it also suggests that compared with prolonged ischemia, reperfusion salvaged some of the myocardium. Ventricular arrhythmias mirrored the changes in infarct size. Thus, angiotensin-converting enzyme inhibitors protect the myocardium against ischemia/reperfusion injury and arrhythmias; these beneficial effects are mediated primarily by a kinin–prostaglandin–nitric oxide pathway, not inhibition of angiotensin II formation.
Does the Renin-Angiotensin System Determine the Renal and Systemic Hemodynamic Response to Sodium in Patients With Essential Hypertension?
Authors: van Paassen Pieter , de Zeeuw Dick , Navis Gerjan , de Jong Paul E.
Published: June 2012

Abstract
Many patients with essential hypertension respond to a high dietary sodium intake with a rise in blood pressure. Experimental evidence suggests that the renal hemodynamic response to sodium determines, at least partially, this rise in blood pressure. Our aim was to clarify the role of the renin-angiotensin system in the renal and systemic adaptation to a change in dietary sodium. We studied changes in mean arterial pressure (MAP) (millimeters of mercury), effective renal plasma flow (ERPF), body weight, and immunoreactive renin in 17 patients with essential hypertension and 15 normotensive control subjects, randomly crossing over between a 3-week sodium-restricted (50 mmol/24 h) and a sodium-replete (200 mmol/24 h) diet period. In addition, the effects of renin inhibition by remikiren (600 mg, single oral dose) were studied during the high sodium period. In normotensive control subjects, high sodium intake had no effect on MAP or body weight, whereas ERPF increased (490±19 to 535±21 mL/min,
P
<.05) and immunoreactive renin decreased (32±6 to 14±1 pg/mL). In hypertensive subjects, high sodium intake induced a heterogeneous response of MAP (median change, 2.6 mm Hg; range, −4.7 to +21.2;
P
=NS) and ERPF (median change, 21 mL/min; range, −33 to +98;
P
=NS). Body weight increased from 81.3±1.9 to 82.5±2.0 kg (
P
<.05), and immunoreactive renin decreased from 18±3 to 10±1 pg/mL (
P
<.05). Interestingly, the patients with a distinct rise in MAP showed a blunted ERPF response to high sodium intake (
r
=−.70,
P
<.01) and an increase in body weight (
r
=.76,
P
<.001). Moreover, the increase of ERPF was more pronounced in patients with a larger fall in immunoreactive renin (
r
=.77,
P
<.001). After administration of remikiren, a heterogeneous response in ERPF was observed: the patients with the blunted ERPF response to high sodium intake showed the largest ERPF rise (
r
=.70,
P
<.01). The remikiren-induced rise in ERPF correlated (
r
=.68,
P
<.01) with the fall in MAP (114±2 to 110±2 mm Hg). In conclusion, in patients with essential hypertension a rise in blood pressure in response to high sodium intake appears to partially be the result of insufficient renal vasodilation. This seems to be due to an inadequate (intrarenal?) renin-angiotensin system response to increased sodium intake.
Sympathetic Nerve Activity and Insulin in Obese Normotensive and Hypertensive Men
Authors: Gudbjörnsdóttir Soffia , Lönnroth Peter , Sverrisdóttir Yrsa Bergmann , Wallin B. Gunnar , Elam Mikael
Published: June 2012

Abstract
The relationship between resting levels of muscle sympathetic nerve activity (MSA) and blood pressure is a matter of controversy. Body weight has recently been identified as an independent determinant of muscle sympathetic discharge, which may have influenced previous studies focused on MSA and mechanisms of hypertension. In the present study, we measured resting MSA and plasma insulin levels in 18 obese (body mass index, 32±4 kg/m
2
) (mean±SD), middle-aged (52±6 years), hypertensive (155±11/97±8 mm Hg) subjects and 16 age- and body mass index–matched normotensive control subjects. In the postabsorptive state, resting MSA was similar in the hypertensive and normotensive groups (43±4 versus 39±3 bursts per minute, 69±5 versus 64±5 bursts per 100 heart beats,
P
=NS) (mean±SEM) and did not correlate with either systolic or diastolic blood pressure. Weak but significant positive correlations were found between resting MSA and both fasting insulin levels (
P
<.05) and body mass index (
P
=.05) in hypertensive but not normotensive subjects. There was a strong positive correlation between fasting insulin and body mass index in both normotensive subjects and the entire study group (
P
<.005). Fasting insulin and body mass index correlated with diastolic blood pressure (
P
<.05) in the entire study group. In conclusion, a relationship between fasting insulin, body mass index, and blood pressure was confirmed, whereas only a weak correlation was found between MSA and fasting insulin in hypertensive but not normotensive subjects. The fact that MSA was similar in the two groups argues strongly against augmented MSA being important for the maintenance of hypertension, at least in middle-aged, obese men.
Metabolic and Hemodynamic Effects of a Graded Intracoronary Insulin Infusion in Normal and Fat Anesthetized Dogs
Authors: Rocchini Albert P. , Wilson Robert F. , Marker Paul , Cervenka Tereza
Published: June 2012

Abstract
This study evaluated both cardiac hemodynamic and metabolic effects of a graded intracoronary artery infusion of insulin in four normal and five obese anesthetized dogs. Dogs were anesthetized with isoflurane, a catheter was advanced under fluoroscopic guidance into the coronary sinus and great cardiac vein, and a 20-MHz 3F coronary Doppler catheter was advanced into either the mid left anterior descending or circumflex coronary artery. A graded intracoronary insulin infusion was administered (starting at 0.3 mU/min and doubling every 40 minutes until a maximum dose of 2.4 mU/min was achieved). Coronary glucose extraction, coronary blood flow velocity, and coronary artery size were measured at each infusion rate. An intracoronary artery infusion of insulin stimulated myocardial glucose uptake in normal dogs. However, in high-fat–fed dogs, weight gain was associated with a reduction in the ability of insulin to promote glucose uptake by cardiac muscle and a rightward shift in the dose-response curve. In normal dogs, an intracoronary insulin infusion resulted in an increase in coronary blood flow and coronary vasodilation (with insulin coronary vascular resistance index decreases to 0.72±0.06,
P
<.01), whereas with weight gain the vasodilator response to insulin was lost. The loss of coronary artery vasodilation to local hyperinsulinemia in fat-fed dogs is consistent with other reports in obese or hypertensive humans that document an impairment in the action of insulin to increase skeletal muscle blood flow.
Effects of Lisinopril on the Structure of Renal Arterioles
Authors: Notoya Mitsuru , Nakamura Masuhisa , Mizojiri Kenji
Published: June 2012

Abstract
We investigated the effect of long-term administration of the angiotensin-converting enzyme inhibitor lisinopril on renal arterioles in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) using a morphometric method and vascular cast technique. Rats were treated with lisinopril beginning at 4 weeks of age. At 15 weeks of age, the kidney vessels were fixed when maximally relaxed. Resin was perfused into the right kidney to make a cast of the renal vasculature. The opposite kidney was used for the morphometric study to evaluate structural changes of the vascular wall. The vascular cast study demonstrated a significant reduction in the lumen diameter of the afferent but not the efferent arterioles in SHR compared with those in WKY. In lisinopril-treated rats, the afferent arteriolar lumen diameters were significantly larger than those of the respective control groups in both strains. However, treatment did not affect the lumen diameter of efferent arterioles in either strain. The morphometric study revealed that the cross-sectional area of afferent arteriolar media was significantly smaller in SHR than WKY, suggesting that the impaired growth of the afferent arteriolar media was involved in the narrowed afferent arteriolar lumen in SHR. The presence of significantly smaller media-lumen ratio, greater media cross-sectional area, and larger internal as well as external diameters of the afferent arterioles in treated SHR than in untreated rats suggested that lisinopril treatment normalizes the structure of the afferent arterioles in SHR by vascular reverse remodeling and by inducing media growth.
Importance of Nitric Oxide and Prostaglandins in the Control of Rat Renal Papillary Blood Flow
Authors: Ortíz M. Clara , Atucha Noemí M. , Lahera Vicente , Vargas Félix , Quesada Tomás , García-Estañ Joaquín
Published: June 2012

Abstract
The role of nitric oxide and prostaglandins in the control of rat renal papillary blood flow has been studied in anesthetized Munich-Wistar rats by use of laser Doppler flowmeter. Acute administration of
N
ω
-nitro-
l
-arginine methyl ester (L-NAME) 10 mg/kg IV (n=8) increased mean arterial pressure by 27.8±3.6%, decreased papillary blood flow by 39.4±3.8%, and decreased renal blood flow by 47.4±1.9%. The subsequent administration of indomethacin (7.5 mg/kg IV) further decreased papillary blood flow (35.2±2.5%) without significant changes in mean arterial pressure or renal blood flow. In a second group (n=6), administration of indomethacin before L-NAME decreased papillary blood flow by 39.6±2.1% without significantly altering mean arterial pressure or renal blood flow. The subsequent injection of L-NAME further decreased papillary blood flow (32.9±1.8%) and renal blood flow (49.8±6.6%) while increasing mean arterial pressure to a level not significantly different from that found in the first group. Autoregulation studies showed that L-NAME but not indomethacin reduced the renal perfusion pressure–renal blood flow relationship without altering autoregulation. However, both nitric oxide and prostaglandins importantly affected the renal perfusion pressure–papillary blood flow relationship because L-NAME and indomethacin significantly decreased this relationship in an additive fashion. Although both drugs reduced the sensitivity of the pressure–papillary flow relationship, only L-NAME affected autoregulation so that papillary blood flow was autoregulated at higher renal perfusion pressures. Thus, the present results indicate that both nitric oxide and prostaglandins control a similar percentage of rat renal papillary blood flow, but nitric oxide seems to be more important than prostaglandins as a mediator of the pressure–blood flow relationship. In contrast, only nitric oxide modifies the renal blood flow level, although it does not disturb whole-kidney blood flow autoregulation.
Type 1 Angiotensin II Receptor Subtypes in Kidney of Normal and Salt-Sensitive Hypertensive Rats
Authors: Bouby Nadine , Bankir Lise , Llorens-Cortes Catherine
Published: June 2012

Abstract
We studied the localization and regulation of the two type 1 angiotensin II receptor subtypes AT
1A
and AT
1B
in different renal zones of the rat kidney by a reverse transcription–polymerase chain reaction amplification method. The yield of the reaction was quantified with an internal standard that was a 63-bp deleted mutant cRNA of the AT
1A
receptor. In kidneys of male Sprague-Dawley rats (n=4), the levels of AT
1A
and AT
1B
receptor mRNAs were highest in the inner stripe of the outer medulla, lowest in the inner medulla, and intermediate in the cortex and outer stripe of the outer medulla. Results (mean±SE) expressed in 10
5
molecules per microgram total RNA were for cortex, outer stripe, inner stripe, and inner medulla, respectively, 171±15, 152±27, 322±10, and 73±3 for AT
1A
, and 35±9, 26±1, 71±10, and 53±11 for AT
1B
. In Sabra rats sensitive (n=6) or resistant (n=6) to salt-induced hypertension and maintained on a normal salt diet, the percentage and level of each receptor subtype mRNA in cortex and outer stripe were similar in the two strains and comparable to those observed in Sprague-Dawley rats. However, AT
1A
of the inner stripe was significantly decreased in salt-resistant compared with salt-sensitive rats (166±28 and 318±58 10
5
molecules per microgram total RNA, respectively). These modifications were organ specific because no difference in the level of the receptor mRNAs was observed in the liver of the two Sabra rat strains, whereas a twofold increase in AT
1A
mRNA level but not in AT
1B
mRNA level was apparent in adrenal and in one renal zone, the inner stripe of the outer medulla, of hypertension-prone Sabra rats.
Renin Is Expressed in Rat Macrophage/Monocyte Cells
Authors: Iwai Naoharu , Inagami Tadashi , Ohmichi Nobuyuki , Kinoshita Masahiko
Published: June 2012

Abstract
The cardiac renin-angiotensin system has been suggested to be involved in various pathological conditions, including hypertrophy and remodeling. However, direct evidence that the renin synthesized in situ is really involved in the putative angiotensin II generation is still lacking because of the relatively low abundance of renin mRNA in cardiac tissues. We evaluated renin mRNA expression levels in the ventricles under various pathological conditions and found that renin gene expression was markedly increased in the ventricles of isoproterenol-treated rats. Renin mRNA expression levels in the ventricles of rats that had been injected with isoproterenol (150 mg/kg SC) were transiently and markedly increased to 6-, 90-, and 4-fold compared with control expression levels at 24, 72, and 120 hours, respectively, after isoproterenol administration. Immunohistochemical analysis revealed that some of the OX-42–positive macrophage/monocyte cells had a reninlike immunoreactivity. An in vitro experiment indicated that rat peritoneal macrophage/monocyte cells expressed renin mRNA in abundance. The present study confirmed that a subpopulation of macrophage/monocyte cells could express renin. Macrophage/monocyte cells may be a source of tissue renin in some pathological conditions.
Regulation of Angiotensin II Type 2 Receptor Gene by the Protein Kinase C–Calcium Pathway
Authors: Kijima Kazuhisa , Matsubara Hiroaki , Murasawa Satoshi , Maruyama Katsuya , Ohkubo Naohiko , Mori Yasukiyo , Inada Mitsuo
Published: June 2012

Abstract
In the present study, rat angiotensin II type 2 (AT
2
) receptor expression was upregulated in confluence-arrested PC12 cells compared with expression in proliferating cells. Treatment with cycloheximide inhibited the increase in mRNA levels in confluent cells. The state of growth arrest by serum deprivation was associated with increased expression of the AT
2
receptor, which was markedly suppressed by exposure to the active phorbol ester 12-
O
-tetradecanoylphorbol 13-acetate and the calcium ionophore A23187. Similar inhibitions were also observed in myocytes isolated from neonatal rat heart. The change in AT
2
mRNA levels by serum deprivation was due to the increase in the gene transcription rate. The effect of 12-
O
-tetradecanoylphorbol 13-acetate was mediated through decreases in gene transcription and mRNA stability, whereas A23187 affected mRNA stability. Vasoactive substances with the protein kinase C–calcium pathway, such as norepinephrine and angiotensin II, also downregulated the AT
2
mRNA level in myocytes. These findings indicate that the expression of AT
2
receptor in PC12 cells is regulated in a growth state–dependent manner, which is involved in confluence-induced new protein synthesis, thus providing a means by which cells can modulate their responsiveness to external angiotensin II stimulus. The activation of protein kinase C or calcium mobilization modifies this regulatory mechanism, suggesting that neurotransmitters or vasoactive substances with the protein kinase C–calcium pathway at least in part affect neuronal activity or blood pressure control by downregulating AT
2
receptor expression.
Acute Saline Infusion Decreases Norepinephrine Release in the Anterior Hypothalamic Area
Authors: Peng Ning , Meng Qing C. , Oparil Suzanne , Wyss J. Michael
Published: June 2012

Abstract
Ingestion of a high NaCl diet elevates arterial pressure in spontaneously hypertensive rats, at least in part, by reducing the release of norepinephrine in the anterior hypothalamic area. The mechanism by which dietary NaCl excess alters anterior hypothalamic area norepinephrine release is unknown. Plasma Na
+
is slightly elevated after ingestion of a meal; therefore, in the present study we tested the hypothesis that a small increase in plasma Na
+
could reduce the release of norepinephrine in the anterior hypothalamic area and elevate arterial pressure. Male spontaneously hypertensive rats were randomized to be fed a diet containing either 1% (basal) or 8% (high) NaCl at age 7 weeks and were maintained on the diets for 2 weeks. Age-matched normotensive Wistar-Kyoto rats received a basal NaCl diet only. All rats were instrumented with a push/pull cannula, and 5 days later, the baseline release of 3-methoxy-4-hydroxyphenyl glycol (the major metabolite of norepinephrine in brain) was measured in awake, freely moving rats. Rats were then challenged with an intravenous infusion (75 μL/min) of hypertonic (2.7%) saline for 20 minutes. In spontaneously hypertensive rats fed a basal NaCl diet, the hypertonic saline infusion elevated mean arterial pressure by 12% and reduced the concentration of the norepinephrine metabolite in the anterior hypothalamic area by 19%; these alterations persisted after termination of the hypertonic saline infusion. Spontaneously hypertensive rats maintained on the high NaCl diet showed greatly reduced arterial pressure and norepinephrine metabolite responses. In normotensive control rats compared with the hypertensive rats fed the basal NaCl diet, the hypertonic saline had considerably less effects on arterial pressure and norepinephrine metabolite levels in the anterior hypothalamic area, and the responses were significantly shorter. Thus, a small elevation in plasma Na
+
can reduce the release of norepinephrine in the anterior hypothalamic area. This response is greatly exaggerated in spontaneously hypertensive rats fed a basal (but not a high) NaCl diet, suggesting that a postprandial rise in NaCl could initiate the fall in norepinephrine and thereby contribute to the rise in arterial pressure in spontaneously hypertensive rats ingesting a high NaCl diet.
Hypotensive Response to Losartan in Normal Rats
Authors: Collister John P. , Hornfeldt Barbara J. , Osborn John W.
Published: June 2012

Abstract
We have reported that the angiotensin II (Ang II) AT
1
receptor antagonist losartan markedly lowers arterial pressure in sodium-replete, normotensive rats. We hypothesized that this action of losartan was mediated by its blocking the effects of endogenous Ang II. To test this hypothesis, rats were instrumented with arterial and venous catheters for measurement of arterial pressure and infusion of losartan, respectively. After 3 days of control measurements, losartan was infused for 10 days (10 mg·kg
−1
·d
−1
) in rats on a normal daily sodium intake (NNa; approximately 2 mmol/d, n=6) and rats on a high daily sodium intake (HNa; approximately 15 mmol/d, n=7) to suppress endogenous Ang II. Although basal plasma renin activity was markedly suppressed in HNa rats (0.9±0.4 ng Ang I·mL
−1
·h
−1
) compared with NNa rats (4.0±0.3 ng Ang I·mL
−1
·h
−1
), control arterial pressure was not different between NNa (113±4 mm Hg) and HNa (113±2 mm Hg) rats. Losartan decreased arterial pressure from control levels in NNa rats on the first day of infusion (−12±2 mm Hg) but had no effect on arterial pressure in HNa rats (+4±4 mm Hg). Furthermore, by day 10 of losartan infusion, arterial pressure had decreased further from control levels in NNa rats (−32±2 mm Hg) but remained unchanged compared with control in HNa rats (+5±6 mm Hg). A second study was conducted to test the hypothesis that the area postrema, a circumventricular organ proposed to mediate the long-term neurogenic pressor activity of Ang II, is a site of action for losartan. After 3 control days, losartan was administered for 10 days to area postrema–lesioned rats (APx; n=11) or sham-lesioned rats (n=10) consuming an NNa diet. Control arterial pressure was similar in sham (95±3 mm Hg) and APx (96±2 mm Hg) rats. Basal plasma renin activity was not different between groups (sham, 4.1±1.5 versus APx, 5.3±1.6 ng Ang I·mL
−1
·h
−1
). On day 1 of losartan treatment, arterial pressure decreased to a significantly lower level in sham (80±2 mm Hg) compared with APx (90±3 mm Hg) rats. This trend continued through day 4 of losartan infusion, in which arterial pressure in sham rats (72±2 mm Hg) was significantly lower than in APx rats (83±4 mm Hg). However, during the remainder of the losartan infusion, there were no significant differences between groups with the exception of day 8 (sham, 72±2 mm Hg; APx, 84±2 mm Hg). Taken together, these results support the hypothesis that the hypotensive actions of losartan in sodium-replete, normotensive rats are due to blockade of the physiological effects of endogenous Ang II. Furthermore, an intact area postrema is essential for full expression of the hypotensive actions of losartan in normal rats.
Renal Accumulation of Circulating Angiotensin II in Angiotensin II–Infused Rats
Authors: Zou Li-Xian , Hymel Anka , Imig John D. , Navar L. Gabriel
Published: June 2012

Abstract
Previous studies have demonstrated that low-dose angiotensin II (Ang II) infusion for 14 days mimics two-kidney, one clip Goldblatt hypertension and increases intrarenal Ang II levels. The objective of the present study was to determine whether the augmented intrarenal Ang II is due to intrarenal accumulation of the infused Ang II and/or to an increase in intrarenal formation of endogenous Ang II. Male Sprague-Dawley rats were uninephrectomized and divided into three groups: control (n=6), those infused with [Ile
5
]Ang II (endogenous form) (n=6), and those infused with [Val
5
]Ang II (n=8). [Ile
5
]Ang II or [Val
5
]Ang II was infused at 40 ng/min via an osmotic minipump implanted subcutaneously. By day 12, systolic blood pressure increased significantly in both [Val
5
]Ang II–infused rats (197±7 mm Hg) and [Ile
5
]Ang II–infused rats (173±3 mm Hg). Blood and kidney samples were harvested, subjected to high-performance liquid chromatography to separate [Val
5
]Ang II from [Ile
5
]Ang II, and then measured by radioimmunoassay. Plasma renin activity was markedly suppressed in both [Ile
5
]Ang II– and [Val
5
]Ang II–infused rats. Plasma Ang II levels were elevated in rats infused with both [Ile
5
]Ang II (121±24 fmol/mL) and [Val
5
]Ang II (119±14 fmol/mL) compared with controls (69±15 fmol/mL). Both [Ile
5
]Ang II– and [Val
5
]Ang II–infused rats exhibited an enhancement of total intrarenal Ang II. Only [Ile
5
]Ang II (358±53 fmol/g) was detected in the kidneys of rats infused with [Ile
5
]Ang II. In [Val
5
]Ang II–infused rats, a significant portion of total renal Ang II (371±57 fmol/g) was in the form of [Val
5
]Ang II (256±44 fmol/g). Renal [Ile
5
]Ang II levels were maintained in the [Val
5
]Ang II–infused rats (116±15 fmol/g) compared with control rats (116±11 fmol/g) despite marked suppression of renin release. These results support the hypothesis that infused circulating Ang II is bound to receptor or taken up intrarenally in a manner that protects against degradation.
Interaction of Adrenomedullin and Platelet-Derived Growth Factor on Rat Mesangial Cell Production of Endothelin
Authors: Kohno Masakazu , Yasunari Kenichi , Yokokawa Koji , Horio Takeshi , Ikeda Miwako , Kano Hiroaki , Minami Mieko , Hanehira Takao , Yoshikawa Junichi
Published: June 2012

Abstract
Adrenomedullin has recently been isolated from human pheochromocytoma. We designed the present study to examine the effect of adrenomedullin on the production of the vasoconstrictive and growth-promoting peptide endothelin-1 (ET-1) after stimulation with platelet-derived growth factor (PDGF) in cultured rat glomerular mesangial cells. PDGF stimulated ET-1 production in a concentration-dependent manner. Rat adrenomedullin inhibited this stimulated ET-1 production in a concentration-dependent manner between 10
−7
and 10
−8
mol/L. Rat adrenomedullin also increased the cellular level of cAMP in a concentration-dependent manner between 10
−7
and 10
−8
mol/L. Human adrenomedullin was less effective than rat adrenomedullin with respect to inhibiting ET-1 production and increasing cAMP levels. The addition of 8-bromo-cAMP (10
−3
and 10
−4
mol/L) reduced PDGF-induced ET-1 production. Furthermore, forskolin (10
−4
and 10
−5
mol/L), an activator of adenylate cyclase, reduced PDGF-induced ET-1 production. In contrast, the basal production of ET-1 was not significantly altered by rat and human adrenomedullin. These results indicate that adrenomedullin inhibits PDGF-induced ET-1 production in cultured rat mesangial cells, probably through a cAMP-dependent process.
Expression of the Subtype 1A Dopamine Receptor in the Rat Heart
Authors: Ozono Ryoji , O’Connell Damian P. , Vaughan Carl , Botkin Suzanne J. , Walk Scott F. , Felder Robin A. , Carey Robert M.
Published: June 2012

Abstract
The subtype 1A dopamine receptor (D
1A
) has recently been detected in the rat kidney. In the present study using light microscopic immunohistochemistry, electron microscopic immunocytochemistry, and in situ amplification of mRNA, we demonstrate the D
1A
receptor in Sprague-Dawley and Wistar-Kyoto rat hearts. For immunohistochemistry and immunocytochemistry, anti-peptide polyclonal antibodies were directed toward amino acid sequences of the third extracellular and intracellular domains of the native receptor. Selectivity was validated by recognition of the D
1A
receptor expressed in stably transfected LTK
−
cells. D
1A
receptor mRNA was detected with a novel transcription-based isothermal in situ amplification system as well as with reverse transcription–polymerase chain reaction. D
1A
receptor protein was distributed throughout the atrium and ventricular myocardium. Preimmune and preabsorption controls were negative. Electron microscopic immunocytochemistry using the protein A gold method demonstrated the D
1A
receptor along the cellular membranes of coronary smooth muscle cells and ventricular myocytes and in the myosin thick filaments and M-lines. D
1A
receptor mRNA was present in coronary vessels and myocardium in amplified but not in unamplified sections. Western blot analysis showed specific D
1A
bands in transfected LTK
−
cells and the atrium but not in nontransfected LTK
−
cells and the ventricle. The selective D1-like receptor agonist
SKF38393
stimulated adenylyl cyclase in ventricular myocardial plasma membranes in a dose-related fashion, and the response was abolished by the selective D1-like receptor antagonist
SCH23390
. These results demonstrate that the D
1A
receptor gene and protein are expressed in normal rat heart. The physiological and pathophysiological roles and predominant cell signaling mechanism or mechanisms of this receptor remain to be determined.
Myocardial Contractility Is Modulated by Angiotensin II via Nitric Oxide
Authors: Llambí H. Gómez , Manni F. , Padula P. La , Carretero O.A. , Taquini C.M.
Published: June 2012

Abstract
We hypothesized that in cardiac muscles, angiotensin II partially inhibits the contractile response to β-agonists. We studied the contractile response of isolated rat left ventricular papillary muscles to isoproterenol and the effect of angiotensin II on this response. We also investigated whether the effect of angiotensin II is mediated by bradykinin, prostaglandins, nitric oxide, and/or cGMP. Contractility of isolated papillary muscles was recorded with a force transducer, and rest tension, maximal developed tension (DT), maximal rate of rise in developed tension [T
(+)
], and maximal velocity of relaxation [T
(−
)
] were measured (1) under basal conditions, (2) after pretreatment with various drugs, and (3) after cumulative doses of isoproterenol. Pretreatment groups included (1) vehicle (controls); (2) angiotensin II; (3) angiotensin II and
N
ω
-nitro-
l
-arginine, an inhibitor of nitric oxide release; (4)
l
-arginine, the substrate for nitric oxide synthase; (5)
l
-arginine and
N
ω
-nitro-
l
-arginine; (6) 8-bromo-cGMP, analogous to the second messenger of nitric oxide; (7) angiotensin II and icatibant (Hoe 140), a bradykinin B
2
antagonist; and (8) angiotensin II and indomethacin, a cyclooxygenase inhibitor. There were no differences in contractile parameters before and after any of the pretreatments. Isoproterenol increased DT, T
(+)
, and T
(−
)
, and these effects were attenuated by angiotensin II,
l
-arginine, and 8-bromo-cGMP. The effects of angiotensin II and
l
-arginine were blocked by inhibition of nitric oxide release with
N
ω
-nitro-
l
-arginine. Neither the bradykinin B
2
antagonist nor the cyclooxygenase inhibitor altered the effects of angiotensin II. We concluded that angiotensin II partially inhibits the contractile response of cardiac papillary muscles to isoproterenol. This effect is likely mediated by nitric oxide release, perhaps acting via cGMP. Kinins and prostaglandins do not appear to participate in the inhibitory effect of angiotensin II. Attenuation of the contractile effect of isoproterenol by angiotensin II may help explain why cardiac function improves in heart failure after blockade of the renin-angiotensin system.
Hyperinsulinemia and Left Ventricular Geometry in a Work-Site Population in Japan
Authors: Ohya Yusuke , Abe Isao , Fujii Koji , Ohmori Susumu , Onaka Uran , Kobayashi Kazuo , Fujishima Masatoshi
Published: June 2012

Abstract
The present study was designed to test whether hyperglycemia or hyperinsulinemia influences left ventricular mass and geometry. An echocardiogram and 75-g oral glucose tolerance test were performed in 210 normotensive and 180 mildly to moderately hypertensive male workers in a bus company who were free from cardiac diseases and were not taking medication for hypertension and diabetes mellitus. When we divided subjects into four groups according to the left ventricular geometric pattern using left ventricular mass index of 110 g/m
2
and relative wall thickness (ratio of 2× posterior wall thickness to end-diastolic left ventricular diameter) of 0.44, body mass index and systolic blood pressure were higher in those with concentric hypertrophy and eccentric hypertrophy. In addition, hemoglobin A
Ic
level and the sum of fasting and 2-hour postload serum glucose levels were higher in subjects with concentric hypertrophy. In subjects without diabetes mellitus (n=336), 2-hour postload serum insulin level and the sum of fasting and 2-hour postload serum insulin levels tended to be higher in those with concentric hypertrophy and concentric remodeling. In multiple regression analysis, the sum of glucose levels (or hemoglobin A
1c
level) in all subjects and the sum of insulin (or 2-hour postload insulin) levels in subjects without diabetes mellitus significantly correlated with relative wall thickness independent of age, systolic blood pressure, and body mass index. Neither glucose nor insulin levels correlated with left ventricular mass index. Our results suggest that hyperglycemia and hyperinsulinemia may promote concentric changes in the left ventricle in normotensive and mildly to moderately hypertensive men.
cAMP Signaling Inhibits Dihydropyridine-Sensitive Ca
2+
Influx in Vascular Smooth Muscle Cells
Authors: Orlov Sergei N. , Tremblay Johanne , Hamet Pavel
Published: June 2012

Abstract
This study examines the role of the cAMP signaling pathway in the regulation of
45
Ca influx in cultured vascular smooth muscle cells from the rat aorta. K
+
o
-induced depolarization of smooth muscle cells increased the rate of
45
Ca uptake by twofold to threefold. This effect was completely abolished by the dihydropyridine derivatives nifedipine and nicardipine, with a
K
i
of 3 and 10 nmol/L, respectively. Activators of cAMP signaling (isoproterenol, forskolin, cholera toxin) increased cAMP content by 50- to 100-fold and decreased voltage-dependent
45
Ca uptake by 50% to 70%. Neither the dihydropyridines nor the cAMP activators affected basal
45
Ca influx. Direct addition of the protein kinase inhibitor H-89 to the incubation medium in the 1- to 10-μmol/L range did not alter basal
45
Ca uptake but completely abolished voltage-dependent Ca
2+
transport. Preincubation of cells for 1 hour with 10 μmol/L H-89 did not modify basal and depolarization-induced
45
Ca uptake in H-89–free medium but prevented forskolin-induced inhibition of voltage-dependent Ca
2+
influx. The addition of cytoskeleton-active compounds reduced voltage-dependent Ca
2+
transport and completely abolished its regulation by cAMP. Activation of cAMP signaling decreased the volume of smooth muscle cells by 12% to 15%. The same cell volume diminution in hyperosmotic medium did not alter voltage-dependent
45
Ca uptake. Thus, data obtained in this study show that in contrast to cardiac and skeletal myocytes, in vascular smooth muscle cells,
45
Ca influx, putatively due to L-type channels, is inhibited by cAMP. This regulatory pathway appears to be mediated via protein kinase A activation and cytoskeleton reorganization.
Reduced Pulmonary Artery Vasoconstriction to Methacholine in Cholesterol-Fed Rabbits
Authors: Pfister Sandra L. , Campbell William B.
Published: June 2012

Abstract
Alterations in vascular tone are well documented in hypercholesterolemia, yet little is known about the role of dietary cholesterol in endothelium-dependent contractions of pulmonary arteries. Methacholine and arachidonic acid cause endothelium-dependent contractions in normal rabbit pulmonary artery that are mediated by thromboxane A
2
. We tested the effect of these agonists on pulmonary arteries from rabbits fed standard rabbit chow or chow supplemented with 2% cholesterol for 2 weeks. Arachidonic acid–induced contractions did not differ in the groups. However, methacholine-induced contractions were significantly depressed in cholesterol-fed rabbits. Vascular thromboxane A
2
production was similar in normal and cholesterol-fed rabbits. Pretreatment with the nitric oxide synthase inhibitor nitro-
l
-arginine had no effect on contractions observed with methacholine in normal rabbits but enhanced methacholine-induced contractions in cholesterol-fed rabbits. In norepinephrine-precontracted vessels, methacholine caused a small relaxation response in normal rabbits. In contrast, in cholesterol-fed rabbits, methacholine produced enhanced relaxations, suggesting that cholesterol feeding augments relaxations and decreases contractions by increasing nitric oxide. However, nitric oxide synthase activity in pulmonary arteries from cholesterol-fed and normal rabbits was not different between the two groups. In an additional experiment, the calcium-dependent potassium channel blocker charybdotoxin had little effect on methacholine-induced contractions in cholesterol-fed rabbits. In summary, the present study demonstrates that hypercholesterolemia alters pulmonary artery vascular contractions and relaxations to methacholine. This effect is not mediated by a decreased production of thromboxane A
2
or by an increased production of nitric oxide. Although the mechanism mediating the altered vascular responses is still unknown, the results from this study clearly indicate that the regulation of vascular tone is different in normal and hypercholesterolemic vessels.
Contributions of Vascular Tone and Structure to Elastic Properties of a Medium-Sized Artery
Authors: Weber Roger , Stergiopulos Nikos , Brunner Hans R. , Hayoz Daniel
Published: June 2012

Abstract
Isobaric compliance and distensibility of the radial artery were recently reported to be normal or slightly increased in untreated hypertensive patients. However, these findings provide no information on the intrinsic mechanical properties of the wall material. To address this question, we determined intima-media wall thickness, wall-to-lumen ratio, and incremental elastic modulus in the radial artery of 25 untreated hypertensive patients with blood pressure of 150±14/103±6 mm Hg (mean±SD) and 25 matched control subjects with blood pressure of 118±9/79±6 mm Hg. High-resolution echo-tracking for assessment of internal diameter and intima-media wall thickness was combined with measurements of blood flow velocity by Doppler and blood pressure by photoplethysmography. In addition, isobaric compliance and distensibility and incremental elastic modulus were measured at peak diameter during reactive hyperemia after a 5-minute brachial occlusion. No significant difference was found between the two groups for isobaric compliance or distensibility at baseline or during hyperemia. However, incremental elastic modulus at 100 mm Hg tended to be lower in hypertensive patients than control subjects (1.9±1.1 versus 2.5±1.2 mm Hg·10
4
,
P
=.1) in resting conditions. Hypertensive patients and control subjects had similar internal diameters (2.47±0.32 versus 2.41±0.35 μm), but intima-media wall thickness and wall-to-lumen ratio were significantly increased in hypertensive patients compared with control subjects (0.268±0.032 versus 0.236±0.025 mm [
P
≤.01] and 0.220±0.038 versus 0.195±0.028 [
P
≤.05], respectively). Peak hyperemic blood flow response (hypertensive patients versus control subjects: 349% versus 360% increase from baseline) and reactive hyperemic dilation (7.2% versus 7.9%) were similar in amplitude and duration in the two groups. These results suggest that wall thickening is an adaptive process that reduces wall tension in hypertensive patients while preserving a normal mechanical behavior of the radial artery. This is most likely accomplished by modification of the incremental elastic modulus of wall components rather than by a change in vascular tone.
Tumor Necrosis Factor Activates Angiotensinogen Gene Expression by the Rel A Transactivator
Authors: Brasier Allan R. , Li Junyi , Wimbish Kenneth A.
Published: June 2012

Abstract
Angiotensinogen encodes the only known precursor of angiotensin II, a critical regulator of the cardiovascular system. Transcriptional control of angiotensinogen in hepatocytes is an important regulator of circulating angiotensinogen concentrations. Angiotensinogen transcription is increased by the inflammatory cytokine tumor necrosis factor (TNF)-α by a nuclear factor–κB–like protein binding to an inducible enhancer called the acute-phase response element. By gel mobility shift assays, we observe two specific acute-phase response element–binding complexes, C1 and C2. The abundance of C2 is not changed by TNF treatment. In contrast, C1 is faintly detected in untreated cells, and its abundance increases by fivefold after stimulation. We identify the nuclear factor–κB subunits in these complexes using subunit-specific antibodies in the gel mobility “supershift” assay. The transcriptionally inert nuclear factor–κB DNA-binding subunit NF-κB1 is present in both control and stimulated hepatocyte nuclei. Its abundance changes weakly upon TNF stimulation. In contrast, the potent transactivating protein Rel A is not found in unstimulated hepatocyte nuclei and is recruited by TNF-α into the C1 DNA-binding complex. Overexpression of Rel A results in acute-phase response element transcription. Cotransfection of a chimeric GAL4–Rel A protein with GAL4 DNA-binding sites is a strategy that allows for selective study of Rel A. The GAL4:Rel A chimera is a TNF-α–inducible transactivator. Deletion of the amino-terminal 254 amino acids of Rel A produces a constitutive activator (that is no longer TNF-α inducible). The cytokine induction of Rel A, then, is mediated through its amino-terminal 254 amino acids. We conclude that Rel A:NF-κB1 is a crucial cytokine-inducible transcription factor complex regulating angiotensinogen gene synthesis in hepatocytes and may be involved in controlling the activity of the renin-angiotensin system.
Differing Metabolism and Bioactivity of Atrial and Brain Natriuretic Peptides in Essential Hypertension
Authors: Pidgeon Grant B. , Richards A. Mark , Nicholls M. Gary , Espiner Eric A. , Yandle Tim G. , Frampton Chris
Published: June 2012

Abstract
Plasma concentrations of both atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are elevated in severe hypertension, acute myocardial infarction, and heart failure. In the current study of individuals with essential hypertension, we have documented the hemodynamic, hormonal, and endocrine effects of infusions of these two peptides given alone or in combination in equimolar doses calculated to induce increments in plasma peptides to concentrations (30 to 60 pmol/L) observed in these disease states. The metabolic clearance rate of ANP (4.56±0.62 L/min) was greater than that for BNP (3.4±0.23 L/min,
P
<.001). Infusions of each cardiac hormone impaired the clearance of coinfused peptide. All peptide infusions enhanced natriuresis (17% to 70% above preinfusion levels versus placebo, 6%;
P
<.001), lowered blood pressure (10 to 18 mm Hg fall in mean arterial pressure below placebo levels;
P
<.001), increased hematocrit, suppressed the renin-angiotensin-aldosterone system, and enhanced plasma norepinephrine concentrations. The natriuretic and blood pressure–lowering effects of BNP were twofold to threefold those of ANP. In contrast, ANP-induced increments in plasma and urinary second messenger (cGMP) levels were greater than those for BNP. Both peptides suppressed the renin-angiotensin-aldosterone system (approximately one-third fall in renin activity and plasma aldosterone) and enhanced plasma norepinephrine concentrations (+30%) to a similar degree. Increments in plasma ANP and BNP that occur simultaneously in cardiovascular disease states appear capable of causing hemodynamic, endocrine, and renal effects that would tend to ameliorate conditions such as hypertension or heart failure.