bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiovascular Changes by Long-term Inhibition of the Renin-Angiotensin System in Aging
Authors: Inserra Felipe , Romano Luis , Ercole Liliana , de Cavanagh Elena M.V. , Ferder León
Published: June 2012

Abstract
We studied four groups of 20 female mice to evaluate the long-term effect of an angiotensin-converting enzyme on myocardium and vessels during the natural process of aging. Three groups received enalapril in water from weaning to 24 months of age (group A, 20 mg/L; group B, 10 mg/L; group C, 5 mg/L); group D served as a control. Animals surviving after 24 months were killed, and morphometric studies were performed. Total corporal weight was higher in animals receiving enalapril. Cardiac weight relative to total body weight was lower in the treated groups than in the control group. Cardiac morphometric studies showed lower myocardiosclerosis in animals receiving angiotensin-converting enzyme inhibitor (groups A through D, respectively, 0.9±0.6%, 1.1±0.2%, 1.03±0.1%, and 9.5±4.3%;
P
<.01, groups A, B, and C versus D). The number of mitochondria per myocardiocyte was higher in the groups receiving enalapril (A through D, respectively, 85±7, 85±6, 83±8, and 58±8;
P
<.01, groups A, B, and C versus D). At the vascular level, vessel diameters were not significantly different between the groups receiving angiotensin-converting enzyme inhibitor and the control group, whereas differences were seen in arterial tunica media thickness (wall-lumen ratio) (groups A through D, respectively, aorta: 0.13±0.02, 0.11±0.02, 0.12±0.01, 2.81±0.35; intrapulmonary: 0.9±0.43, 0.6±0.41, 0.8±0.46, 1.9±0.51; intracerebral: 2.18±0.46, 2.29±0.45, 2.46±0.43, 3.30±0.41; intrarenal: 2.28±0.46, 2.73±0.48, 2.70±0.51, 3.23±0.41; intracariaciac: 2.27±0.44, 2.59±0.41, 2.80±0.43, 3.68±0.47;
P
<.001, groups A, B, and C versus D). No significant differences in blood pressure were found among the groups. We conclude that cardiovascular changes in aging may be altered by angiotensin-converting enzyme inhibitors.
Effect of Antihypertensive Treatment on Small Arteries of Patients With Previously Untreated Essential Hypertension
Authors: Thybo Niels K. , Stephens Nicola , Cooper Anne , Aalkjaer Christian , Heagerty Anthony M. , Mulvany Michael J.
Published: June 2012

Abstract
In a double-blind randomized trial, the effects of treatment with an angiotensin-converting enzyme (ACE) inhibitor (perindopril) and a β-blocker (atenolol) on small artery structure were compared in previously untreated essential hypertensive patients. Subjects (diastolic blood pressure ≥100 and ≤120 mm Hg) were randomly assigned to treatment for 12 months with either perindopril (n=13, 4 to 8 mg/d) or atenolol (n=12, 50 to 100 mg/d); the dosage was adjusted upward and in some cases combined (n=5, perindopril; n=2, atenolol) with thiazide diuretic to achieve target blood pressure (diastolic blood pressure below 90 mm Hg). Before and at the end of treatment, gluteal biopsies were taken under local anesthetic; from these biopsies, two small arteries were dissected and mounted on a myograph for morphometry. The reduction in blood pressure with atenolol (drop in mean blood pressure 28.4±1.8 mm Hg) was greater than with perindopril (20.6±1.8 mm Hg,
P
<.05). Perindopril treatment caused an increase in small artery diameter (231±14 to 274±13 μm,
P
<.05) and a reduction in the ratio of media thickness to lumen diameter (7.94±0.65% to 5.96±0.42%,
P
<.05), whereas atenolol had no effect (246±14 to 231±13 μm and 7.14±0.47% to 6.79±0.45%, respectively). The change in small artery morphology caused by perindopril was not accompanied by any change in media cross-sectional area, suggesting that the change was due to “remodeling.” The results support the possibility that treatment with ACE inhibitors causes a greater normalization of the structure of the resistance vasculature in essential hypertensive patients than treatment with β-blockers.
Endothelin-1 in Rat Periaqueductal Gray Area Induces Hypertension Via Glutamatergic Receptors
Authors: D’Amico Michele , Berrino Liberato , Maione Sabatino , Filippelli Amelia , Pizzirusso Anna , Vitagliano Saverio , Rossi Francesco
Published: June 2012

Abstract
We investigated the possible relationship between endothelin-1 injection into the dorsolateral periaqueductal gray area and the glutamatergic system in the control of cardiovascular function. Endothelin-1 was injected into the dorsolateral periaqueductal gray area of freely moving rats at doses ranging from 0.1 to 10 pmol. Endothelin-1 increased arterial blood pressure (from 7.0±1.6 to 55.0±4.1 mm Hg, mean±SEM) in a dose-dependent manner and induced characteristic behavioral changes such as longitudinal rolling of the body (barrel-rolling).
dl
-2-Amino-5-phosphonovaleric acid and (5
R
,10
S
)-(+)-5-methyl-10,11-dihydro-5
H
-dibenzo[
d
-α]cyclohepten-5,10-imine hydrogen maleate, both selective
N
-methyl-
d
-aspartate excitatory amino acid receptor antagonists, but not 6-cyano-7-nitroquinoxaline-2,3-dione, a non–
N
-methyl-
d
-aspartate excitatory amino acid receptor antagonist, significantly decreased endothelin-1–induced cardiovascular and behavioral changes (
P
<.01). Prazosin and propranolol, adrenergic blocking agents, and reserpine, a depletor of catecholamine stores, also prevented these effects. We propose that the glutamatergic system may exert, via
N
-methyl-
d
-aspartate receptors, a significant influence on endothelin-1–induced cardiovascular and behavioral effects after its injection into the periaqueductal area.
Brain Kallikrein-Kinin System Abnormalities in Spontaneously Hypertensive Rats
Authors: Khan Imran M. , Miller Donald H. , Strickland Judy , Margolius Harry S. , Privitera Philip J.
Published: June 2012

Abstract
The objective of the present study was to determine whether the brain kallikrein-kinin system differs between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and if so, whether any detected differences occur before the development of hypertension in SHR. We measured cerebrospinal fluid levels of various components of the system in adult and young prehypertensive SHR and WKY. Cerebrospinal fluid kinin concentration and appearance rate were higher in SHR. Cerebrospinal fluid active kallikrein level and kininogenase activity were also higher in adult SHR. In addition, cerebrospinal fluid kinin concentration and appearance rate were higher in prehypertensive, 5- to 6-week-old SHR compared with age-matched WKY. However, no differences in cerebrospinal fluid kallikrein or kininogenase activity were observed between the two strains of young rats. Cerebrospinal fluid kinin concentration was higher in young versus adult rats of the same strain. In WKY, cerebrospinal fluid kallikrein also decreased with age although cerebrospinal fluid kallikrein concentration did not decrease in young and adult SHR. Together, these data suggest that there is a hyperactive kallikrein-kinin system in the brain of SHR that may contribute to the hypertensive state in this animal model.
Expression of Angiotensin-Converting Enzyme in Renovascular Hypertensive Rat Kidney
Authors: Mai Monika , Hilgers Karl F. , Wagner Jürgen , Mann Johannes F. E. , Geiger Helmut
Published: June 2012

Abstract
We hypothesized that the gene expression of angiotensinogen, angiotensin-converting enzyme, and angiotensin II type 1 receptor, in addition to renin, is increased in kidneys after renal artery stenosis. Two-kidney, one clip renovascular hypertension was initiated in Sprague-Dawley rats by clipping of the left renal artery; control rats were sham operated. Blood pressure was not changed for the first 2 days after clipping but was elevated on day 4 (mean arterial pressure, 104±4 versus 87±2 mm Hg in sham-operated control rats,
P
<.002) and increased further during the next 24 days. Rats were killed 2, 4, 7, 14, and 28 days after clipping or sham operation, and poly(A)
+
-purified renal cortical RNA was analyzed by Northern blotting. Autoradiographs were quantitated by densitometry and normalized for the expression of a housekeeping gene. Renin expression was increased in the clipped kidney (by 149% on day 2) and decreased in the nonclipped kidney (by 82% on day 2), compared with kidneys of control rats. Expression of the angiotensin-converting enzyme was increased in clipped kidneys from the first day after clipping (158%) and throughout the experiment (66% on day 28), but was unchanged or slightly decreased in nonclipped kidneys. Angiotensinogen mRNA showed little change. Angiotensin II type 1 receptor expression was decreased in nonclipped kidneys but unchanged during the first 7 days in clipped kidneys. Our results show that components of the renin-angiotensin system other than renin are also differentially expressed in clipped kidneys. Increased expression of the angiotensin-converting enzyme in poststenotic kidneys occurs very early in the development of renovascular hypertension and may contribute to increased intrarenal angiotensin II formation.
cGMP Upregulates Nitric Oxide Synthase Expression in Vascular Smooth Muscle Cells
Authors: Inoue Takuo , Fukuo Keisuke , Nakahashi Takeshi , Hata Shigeki , Morimoto Shigeto , Ogihara Toshio
Published: June 2012

Abstract
8-Bromo-guanosine 3′:5′-cyclic monophosphate (8-Br-cGMP), an analogue of cyclic guanosine monophosphate (cGMP), induced a time- and dose-dependent enhancement of interleukin-1–induced nitric oxide production in vascular smooth muscle cells. Human atrial natriuretic polypeptide, which stimulates cGMP accumulation in vascular smooth muscle cells, also enhanced interleukin-1–induced nitric oxide release at a concentration of 100 nmol/L. In contrast, coincubation with 10 μmol/L methylene blue, an inhibitor of soluble guanylate cyclase, inhibited interleukin-1–induced nitric oxide release from vascular smooth muscle cells. Furthermore, coincubation with 8-Br-cGMP also enhanced the interleukin-1–induced increase in inducible nitric oxide synthase messenger RNA in vascular smooth muscle cells. However, the enhancement of nitric oxide production induced by 8-Br-cGMP was significantly prevented by coincubation with neutralizing antibody against tumor necrosis factor–α. Furthermore, 8-Br-cGMP enhanced the interleukin-1–induced increase in tumor necrosis factor–α messenger RNA level in vascular smooth muscle cells. These findings indicate that cGMP may upregulate inducible nitric oxide synthase gene expression through the stimulation of tumor necrosis factor–α production in vascular smooth muscle cells. Thus, there may be a positive feedback mechanism between nitric oxide and the cGMP system in vascular smooth muscle cells.
Endothelin-1 Enhances Nitric Oxide–Induced Cytotoxicity in Vascular Smooth Muscle
Authors: Nakahashi Takeshi , Fukuo Keisuke , Inoue Takuo , Morimoto Shigeto , Hata Shigeki , Yano Mitsuo , Ogihara Toshio
Published: June 2012

Abstract
Prolonged incubation with 1 nmol/L interleukin-1 induced high levels of nitric oxide release and cytotoxicity in vascular smooth muscle cells.
N
G
-Monomethyl-
l
-arginine, an inhibitor of nitric oxide synthesis, inhibited interleukin-1–induced cytotoxicity at a concentration of 3 mmol/L. Furthermore, prolonged incubation with 0.1 mmol/L sodium nitroprusside, a nitric oxide donor, also induced cytotoxicity. On the other hand, endothelin-1 at concentrations from 10
−10
to 10
−7
mol/L induced a concentration-dependent enhancement of cytotoxicity induced by interleukin-1. However, endothelin-1 did not affect interleukin-1–induced nitric oxide production. Coculture study of vascular smooth muscle cells and endothelial cells without direct cell contact revealed that incubation for 72 hours with interleukin-1 induced high levels of nitric oxide release from cocultured vascular smooth muscle cells to the same degree as release from vascular smooth muscle cells alone. However, interleukin-1–induced cytotoxicity was more enhanced in cocultured vascular smooth muscle cells than in vascular smooth muscle cells alone. Furthermore, coincubation with 20 nmol/L BQ-485, an antagonist of one type of endothelin receptor (ET
A
), prevented the enhancement of interleukin-1–induced cytotoxicity in cocultured vascular smooth muscle cells. These findings suggest that endothelin-1 secreted from endothelial cells may enhance nitric oxide–induced cytotoxicity by means of the ET
A
receptor in vascular smooth muscle cells.
Influence of Endothelium on Cultured Vascular Smooth Muscle Cell Proliferation
Authors: Peiró Concepción , Redondo Juliana , Rodríguez-Martínez M. Angeles , Angulo Javier , Marín Jesús , Sánchez-Ferrer Carlos F.
Published: June 2012

Abstract
The endothelium exerts a large influence on the underlying vascular smooth muscle, not only by the release of both contracting and relaxing factors but also by its ability to synthesize a large number of molecules that influence vascular smooth muscle growth. In addition to well-characterized growth promoters or growth inhibitors, some endothelium-derived factors, originally described as vasoactive compounds, seem to possess growth-regulatory properties. The vasoconstrictor endothelin-1 elicited a dose-dependent increase of cultured vascular smooth muscle cell DNA synthesis with a maximal effect of 57±14% over basal levels, whereas vasodilators such as prostacyclin, sodium nitroprusside, and 8-bromoguanosine 3′:5′-cyclic monophosphate reduced DNA synthesis by 19±5%, 22±2%, and 31±3%, respectively. Medium conditioned by cultured bovine aortic endothelial cells markedly stimulated both DNA synthesis and proliferation of smooth muscle cells. When medium was conditioned in the presence of the endothelin-converting enzyme inhibitor phosphoramidon, the mitogenic effect was significantly reduced, thus indicating a role for endothelin in the stimulation of smooth muscle cell growth by endothelial cells. However, when both cell types were maintained in a coculture system, a 13±2% decrease of DNA synthesis was observed in smooth muscle cultures. The addition of the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine methyl ester, the cyclooxygenase inhibitor indomethacin, or both during the coculture period did not revert the antiproliferative effect of endothelial cells in coculture, thereby indicating it is not likely due to these unstable endothelium-derived vasorelaxant molecules.
Angiotensin-(1-7) and Nitric Oxide Interaction in Renovascular Hypertension
Authors: Nakamoto Hidetomo , Ferrario Carlos M. , Fuller Stanley B. , Robaczewski David L. , Winicov Eric , Dean Richard H.
Published: June 2012

Abstract
New studies suggest that vasodilator systems may play an important role in restraining the rise in peripheral vascular resistance associated with the evolution of arterial hypertension. We characterized in conscious dogs the hemodynamic and hormonal effects of 4 weeks of feeding either the nitric oxide synthase inhibitor
N
ω
-nitro-
l
-arginine (3 mg · kg
−1
· d
−1
) or the nitric oxide precursor
l
-arginine (0.3 mg · kg
−1
· d
−1
) during the evolution of two-kidney, one clip hypertension. Inhibition of nitric oxide production elicited a form of hypertension more severe than that produced in placebo-fed two-kidney, one clip dogs. The higher levels of blood pressure were accompanied by lower levels of plasma renin activity and lower angiotensin II concentrations. During the chronic phase of renovascular hypertension, the fall in blood pressure produced by acute systemic injections of lisinopril or losartan was significantly reduced in dogs given the nitric oxide inhibitor. In contrast, chronic administration of
l
-arginine had no effect on the magnitude of hypertension or on the increases in renin activity and hyperangiotensinemia associated with the evolution of renal hypertension. Likewise, the fall in blood pressure produced by pharmacological blockade of angiotensin II was not different from that recorded in untreated renal hypertensive dogs. The vasodilator component of the blood pressure response due to intravenous injections of angiotensin-(1-7) (1 to 100 nmol/kg) was augmented in both untreated and
l
-arginine–treated two-kidney, one clip hypertensive dogs, but was significantly attenuated in hypertensive dogs fed the nitric oxide synthase inhibitor. These experiments demonstrated an important contribution of nitric oxide in modulating the increased activity of the peripheral renin-angiotensin system during the evolution of renovascular hypertension. Furthermore, our data show that the evolution of this form of experimental renal hypertension is accompanied by a magnification of the vasodilator actions of angiotensin-(1-7). Activation of endothelium-derived relaxing factors and angiotensin-(1-7) mechanisms may act in synergy to buffer the increase in vascular resistance produced by chronic renal ischemia.
Effects of Kinin Blockade on the Blood Pressure of Salt-Loaded Pregnant Rats
Authors: Madeddu Paolo , Parpaglia Paolo Pinna , Demontis Maria Piera , Varoni Maria Vittoria , Fattaccio Maria Caterina , Anania Vittorio , Glorioso Nicola
Published: June 2012

Abstract
We evaluated whether chronic inhibition of bradykinin B
2
receptors by the long-acting antagonist
d
-Arg,[Hyp
3
,Thi
5
,
d
-Tic
7
,Oic
8
]-bradykinin (Hoe 140) affects blood pressure of salt-loaded pregnant rats. Pairs of rats fed a high sodium diet (0.84 mmol sodium per gram chow) were mated at 14 weeks of age. Infusion of vehicle or Hoe 140 (300 nmol/d per kilogram body weight) was performed throughout each dam’s pregnancy by use of an Alzet osmotic pump implanted in the abdominal cavity. In both groups, no significant change in systolic pressure (tail-cuff plethysmography) or renal blood flow (Doppler flowmeter) was observed from that in the unmated state to that at midterm pregnancy. In the control group, systolic pressure decreased at the 21st day of pregnancy (from 126±2 to 97±2 mm Hg,
P
<.01), and renal blood flow increased (from 6.1±0.1 to 7.5±0.2 kHz,
P
<.01). These changes were nullified by the administration of Hoe 140 (systolic pressure changing from 124±2 to 118±4 mm Hg,
P
=NS; renal blood flow changing from 6.3±0.2 to 6.2±0.1 kHz,
P
=NS). In the group given Hoe 140, placental weight was greater (0.50±0.01 versus 0.43±0.01 g in controls,
P
<.01) and the fetal/placental weight ratio was reduced (4.53±0.09 versus 5.31±0.17 in controls,
P
<.01). A separate set of experiments was performed in the progeny of vehicle- and antagonist-treated dams to evaluate the effect of early postnatal administration of Hoe 140 combined with high sodium intake on survival rate. In the offspring of vehicle-treated rats, survival rate was reduced by chronic postnatal administration of Hoe 140 (at 70 days, 34% versus 62% in controls given vehicle). An earlier and more pronounced fall in survival rate was observed in the offspring of Hoe 140–treated rats maintained on antagonist or vehicle treatment during the postnatal period (0% and 18%, respectively, at 70 days). These results indicate that the kallikrein-kinin system plays a role in the regulation of blood pressure in pregnant rats exposed to a high sodium diet. The mechanism responsible for the increased early mortality in the progeny of Hoe 140–treated rats remains unknown. The possibility that it is related to blockade of kinin receptors may suggest a protective effect of endogenous kinins against the deleterious consequences of a dietary excess of sodium.
Different Effects of Fosinopril and Atenolol on Wave Reflections in Hypertensive Patients
Authors: Chen Chen-Huan , Ting Chih-Tai , Lin Shing-Jong , Hsu Tsui-Lieh , Yin Frank C. P. , Siu Cynthia O. , Chou Pesus , Wang Shih-Pu , Chang Mau-Song
Published: June 2012

Abstract
We conducted this study to compare the effects of fosinopril versus atenolol on peripheral blood pressure, central arterial wave reflection, and left ventricular mass in a group of patients with essential hypertension. We conducted a double-blind, randomized trial of fosinopril and atenolol in 79 hypertensive patients (52 men, 27 women; mean age, 45.8±8.5 years; range, 30 to 68 years). Carotid pressure waveforms were recorded noninvasively by applanation tonometry with a Millar micromanometer-tipped probe. The extent of wave reflection was estimated by the augmentation index defined as the ratio of the amplitude of pressure wave above its systolic shoulder to the pulse pressure. The augmentation index, left ventricular mass index by two-dimensional echocardiography, and 24-hour ambulatory blood pressures were determined before and after 8 weeks of daily treatment with fosinopril (10 to 20 mg) or atenolol (50 to 100 mg) with or without diuretics and compared with those values in 79 normotensive control subjects. After 8 weeks of treatment, both drugs lowered 24-hour ambulatory peripheral systolic and diastolic pressures into the normal range to a similar extent (fosinopril, −18/−13 mm Hg; atenolol, −23/−17 mm Hg, both
P
=NS). On the other hand, whereas the elevated augmentation index in hypertensive patients compared with normotensive subjects (16±11% versus 10±8%) was completely normalized by fosinopril (−9.3±9.8%,
P
≤.002), it was lowered by atenolol (−4.8±8.9%,
P
<.002) but to a significantly smaller extent (fosinopril versus atenolol effect,
P
=.04). Neither drug affected the slightly elevated left ventricular mass index (fosinopril, 93±13 gm/m
2
; atenolol, 98±20 gm/m
2
) compared with normotensive subjects (86±13 gm/m
2
). At the doses used, fosinopril and atenolol reduced peripheral blood pressure similarly but had different effects on central systolic wave reflections, implying a greater effect of fosinopril than atenolol in reducing central blood pressure than is apparent from measurements of peripheral pressure. Left ventricular mass was only slightly elevated in these mild hypertensive patients and was not altered after 8 weeks of treatment.
Cerebral ATP-Sensitive Potassium Channels During Acute Reduction of Carotid Blood Flow
Authors: Nishimura Masato , Takahashi Hakuo , Nanbu Akira , Sakamoto Masatoshi , Nakanishi Tadashi , Yoshimura Manabu
Published: June 2012

Abstract
The ATP-sensitive potassium channels (K
ATP
) are activated either by a decrease in intracellular ATP content or by a lowering of the ATP-ADP ratio such as during stroke. We studied the role of cerebral K
ATP
on arterial pressure during acute reduction of cerebral blood flow in 12-week-old male Wistar rats anesthetized with urethane by recording arterial pressure and heart rate continuously. After bilateral ligation of the common carotid arteries, glibenclamide, a specific blocker of K
ATP
, was injected intracerebroventricularly into the cerebral lateral ventricle. Glibenclamide elicited a sustained vasopressor response in a dose-dependent manner in rats with bilateral carotid artery ligation (10 nmol, +15±2 mm Hg; 1 nmol, +5±1 mm Hg,
P
<.01 versus vehicle), but hemodynamic alterations were barely recorded with glibenclamide in sham-operated control rats. The abdominal sympathetic discharge was not increased significantly enough to explain the pressor mechanism. Similarly, pretreatments with intravenous injections of bunazosin, an α
1
-adrenoceptor antagonist, did not affect the pressor response of intracerebroventricular glibenclamide. To investigate the vasopressor mechanism further, we measured plasma and pituitary concentrations of arginine vasopressin and determined the effects of vasopressin receptor antagonists. The intracerebroventricular injections of glibenclamide significantly increased the plasma concentration of vasopressin (
P
<.05) and significantly decreased the pituitary concentration of vasopressin (
P
<.05) in rats with bilateral carotid artery ligation. Intravenous pretreatment with the vasopressin V
1
receptor antagonist OPC-21268 abolished the vasopressor response to intracerebroventricular glibenclamide (+16±2 versus +1±1 mm Hg,
P
<.01). These findings indicate that K
ATP
in the brain may inhibit an excess rise in arterial pressure in part by decreasing the release of vasopressin from the pituitary during bilateral carotid artery ligation.
Na
+
-H
+
Antiporter Phenotype, Abundance, and Phosphorylation of Immortalized Lymphoblasts From Humans With Hypertension
Authors: Ng Leong L. , Sweeney Frank P. , Siczkowski Martin , Davies Joan E. , Quinn Paulene A. , Krolewski Bozena , Krolewski Andrzej S.
Published: June 2012

Abstract
Previous studies have demonstrated an elevated Na
+
-H
+
exchanger activity in various cell types from patients with essential hypertension. The phenotype of an increased maximal transport capacity is preserved in Epstein-Barr virus immortalized lymphoblasts from hypertensive patients. The mechanisms underlying this abnormality are unclear. In this study, we used lymphoblasts from hypertensive patients and normotensive control subjects with and without a family history of hypertension to determine (1) Na
+
-H
+
exchanger activity using fluorometry with the pH indicator 2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein, (2) Na
+
-H
+
exchanger isoform 1 abundance with specific polyclonal antibodies, and (3) Na
+
-H
+
exchanger phosphorylation by immunoprecipitation of the
32
P-labeled transporter. Na
+
-H
+
exchanger activity (in millimoles per liter per minute) measured when pH
i
was clamped at 6.0 was significantly higher in cells from hypertensive patients (18.8±0.6,
P
<.001) and those subjects with a family history of hypertension (16.4±0.6,
P
<.001) compared with normotensive control subjects (12.9±0.6). Exchanger abundance was identical in all three groups of subjects, indicating that increased activity in the hypertensive group was due to an elevated turnover number of the exchanger. Na
+
-H
+
exchanger phosphorylation in quiescent cells was significantly elevated in cells from hypertensive patients (1.58±0.16,
P
<.001) compared with control subjects (1.00±0.07), and cells from normotensive subjects with a hypertensive family history showed intermediate values (1.23±0.14). Identical changes in Na
+
-H
+
exchanger function and phosphorylation have been demonstrated in vascular smooth muscle cells from spontaneously hypertensive rats. Our findings suggest that the elevated Na
+
-H
+
exchanger activity in cells from human hypertensive patients is not associated with an increased exchanger abundance but may be related to increased exchanger phosphorylation.
Detection and Positional Cloning of Blood Pressure Quantitative Trait Loci: Is It Possible?
Authors: Rapp John P. , Deng Alan Y.
Published: June 2012

Abstract
Identification of the quantitative trait loci that influence blood pressure and cause genetic hypertension is a major challenge. Several genetically hypertensive rat strains exist and can be used to locate by linkage analysis broad chromosomal regions containing blood pressure quantitative trait loci. Such broad chromosomal regions, and then narrower subregions, can be moved among strains (ie, production of congenic strains and congenic substrains) to identify small chromosomal regions containing the blood pressure quantitative trait loci. However, ultimate positional cloning of the quantitative trait loci presents a major difficulty because the genetic variants involved are likely to result in subtle changes in function rather than the blatant loss of function characteristic of all mendelian disease genes discovered so far by positional cloning.
Potassium Negatively Regulates Angiotensin II Type 1 Receptor Expression in Human Adrenocortical H295R Cells
Authors: Bird Ian M. , Word R. Ann , Clyne Colin , Mason J. Ian , Rainey William E.
Published: June 2012

Abstract
We have previously shown that the human adrenocortical H295R cell line expresses the type 1 angiotensin II receptor (AT
1
-R) and that expression of this receptor is downregulated at the level of mRNA by forskolin or dibutyryl-cAMP as well as by angiotensin II (Ang II). In this study we examine the effects of K
+
on both AT
1
-R mRNA and receptors, as monitored through
125
I–Ang II binding in the presence of PD 123319. After treatment with a maximal stimulatory steroidogenic dose of K
+
(14 mmol/L), H295R cells showed an increase in cytosolic free Ca
2+
from 113 to 212 nmol/L. Unlike the effects of Ang II, this increase could be abolished by pretreatment with the Ca
2+
channel antagonist nifedipine (1 μmol/L). AT
1
-R mRNA levels also fell in response to elevated extracellular K
+
in a dose-dependent (
K
d
, 9 mmol/L; maximal fall in message at 12 mmol/L) and time-dependent (maximum 50% at 12 hours) manner. The change in AT
1
-R mRNA level was less rapid than that in response to activation of phosphoinositidase C by Ang II or adenylyl cyclase by forskolin or by dibutyryl-cAMP. Unlike the action of Ang II but similar to the action of forskolin or dibutyryl-cAMP, the action of K
+
was sustained. Changes in mRNA level in response to treatment with K
+
, Ang II, or dibutyryl-cAMP were also paralleled by changes in
125
I–Ang II binding in each case. The mechanism of action of K
+
on AT
1
-R mRNA also appears to be mediated through the opening of voltage-sensitive channels on the plasma membrane because the drop in AT
1
-R mRNA was similarly abolished by the Ca
2+
channel blocker nifedipine. In conclusion, our findings show that AT
1
-R mRNA levels can be controlled through a Ca
2+
-dependent signaling pathway, as well as through phosphoinositidase C or adenylyl cyclase signaling pathways, and that these changes in mRNA level underlie a corresponding change in receptor protein at the cell surface.
Pulmonary and Renal Neutral Endopeptidase EC 3.4.24.11 in Rats With Experimental Heart Failure
Authors: Abassi Zaid A. , Kotob Shaban , Golomb Eliahu , Pieruzzi Federico , Keiser Harry R.
Published: June 2012

Abstract
Congestive heart failure is characterized by avid sodium retention and a blunted renal response to exogenous and endogenous atrial natriuretic peptide. Inhibition of neutral endopeptidase EC
3.4.24.11
, the main enzyme that degrades natriuretic peptides, produces a natriuretic response in different models of congestive heart failure. This raises the possibility that an increase in either the expression or activity of neutral endopeptidase is responsible for these phenomena. In the present study, we examined (1) the renal effects of SQ-28,603, a neutral endopeptidase inhibitor, in rats with moderate and severe congestive heart failure induced by an aortocaval fistula compared with sham controls, and (2) neutral endopeptidase expression and activity in the lungs and kidneys of these rats. Infusion of SQ-28,603 (40 mg/kg IV) induced a significant natriuretic response in normal rats and rats with moderate congestive heart failure. This response was blunted in rats with severe congestive heart failure. Surprisingly, renal neutral endopeptidase mRNA levels, assessed by quantitative reverse transcriptase–polymerase chain reaction; protein levels, assessed by Western blotting; and activity, assessed by gelatin gels, were comparable in all groups. Pulmonary neutral endopeptidase mRNA levels decreased by 45% in rats with severe congestive heart failure but not in rats with mild congestive heart failure. In addition, pulmonary neutral endopeptidase immunoreactivity levels and activity were significantly decreased in congestive heart failure in correlation with the severity of the disorder. We conclude that an increase in neutral endopeptidase expression or activity does not occur in rats with congestive heart failure, and therefore, an upregulation of neutral endopeptidase is unlikely to account for the blunted natriuretic response to the atrial natriuretic peptide and the positive sodium balance in congestive heart failure.
Modulation of Cardiac Autonomic Control in Humans by Angiotensin II
Authors: Townend Jonathan N. , Al-Ani Muzahim , West John N. , Littler William A. , Coote John H.
Published: June 2012

Abstract
Angiotensin II (Ang II) exerts an inhibitory action on vagal activity in animals and may also facilitate sympathetic activity. The object of this study was to compare autonomic activity resulting from equivalent steady-state baroreflex activation during intravenous Ang II infusion with that resulting from a control infusion of phenylephrine. Eight healthy subjects aged 22 to 34 years were studied in a single-blind, randomized, prospective crossover study. Autonomic activity was determined by computer analysis of RR interval variability in the time and frequency domains. Despite equal experimental hypertension with Ang II and phenylephrine infusion, at peak infusion rates the mean RR interval was significantly shorter with Ang II (983±179 milliseconds; mean±SD) than with phenylephrine (1265±187 milliseconds,
P
<.01). The variability of RR intervals was not significantly different, but the variability (median interquartile difference) of RR interval successive differences was significantly lower with Ang II (66 milliseconds) than with phenylephrine (104 milliseconds,
P
<.02). Power spectral analysis revealed the power of the 0.25-Hz component in normalized units to be significantly smaller during Ang II infusion (20.5±12.7 U) than during phenylephrine (38.2±14.7 U,
P
<.05), whereas the power of the 0.1-Hz component was significantly greater during Ang II infusion (67.8±17.1 U) than phenylephrine (38.8±20.3 U,
P
<.05). Measures of vagal modulation of heart rate were significantly attenuated, and sympathetic modulation appeared to be increased during Ang II infusion compared with control phenylephrine infusions. These observations may underlie reports of increased vagal activity during angiotensin-converting enzyme inhibitor therapy.
Transient Decrease in High Blood Pressure by In Vivo Transfer of Antisense Oligodeoxynucleotides Against Rat Angiotensinogen
Authors: Tomita Naruya , Morishita Ryuichi , Higaki Jitsuo , Aoki Motokuni , Nakamura Yoshio , Mikami Hiroshi , Fukamizu Akiyoshi , Murakami Kazuo , Kaneda Yasufumi , Ogihara Toshio
Published: June 2012

Abstract
The renin-angiotensin system plays an important role in blood pressure regulation. Angiotensinogen, which is mainly produced in the liver, is a unique component of the renin-angiotensin system, because angiotensinogen is only known as a substrate for angiotensin I generation. It is unclear whether circulating angiotensinogen is a rate-limiting step in blood pressure regulation. Recent findings of genetic studies and analyses suggest that the angiotensinogen gene may be a candidate as a determinant of hypertension. To test the hypothesis that angiotensinogen may modulate blood pressure, we transfected antisense oligonucleotides against rat angiotensinogen into the rat liver via the portal vein using liposomes that contain viral agglutinins to promote fusion with target cells, a technique that has been reported to be highly efficient. Transfection of antisense oligonucleotides resulted in a transient decrease in plasma angiotensinogen levels in spontaneously hypertensive rats from day 1 to day 7 after the injection, consistent with the reduction of hepatic angiotensinogen mRNA. Plasma angiotensin II concentration was also decreased in rats transfected with antisense oligonucleotides. Moreover, a transient decrease in blood pressure from day 1 to day 4 was observed, whereas transfection of sense and scrambled oligonucleotides did not result in any changes in plasma angiotensinogen level, blood pressure, or angiotensinogen mRNA level. Overall, our results demonstrate that transfection of antisense oligonucleotides against rat angiotensinogen resulted in a transient decrease in the high blood pressure of spontaneously hypertensive rats, accompanied by a decrease in angiotensinogen and angiotensin II levels. These findings suggest that angiotensin production may be directly proportional to circulating angiotensinogen concentration and also raise the possibility that angiotensinogen may be a potential target for antihypertensive drugs.
Endothelial Stimulation of Sodium Pump in Cultured Vascular Smooth Muscle
Authors: Redondo Juliana , Peiró Concepción , Rodríguez-Mañas Leocadio , Salaices Mercedes , Marín Jesús , Sánchez-Ferrer Carlos F.
Published: June 2012

Abstract
We studied vascular sodium pump activity and its regulation by vasoactive agents and endothelium in cultured aortic vascular smooth muscle cells from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Baseline sodium pump activity (ouabain-inhibitable
86
Rb
+
uptake) was similar in cells from both rat strains. Angiotensin II and endothelin-1 increased ouabain-inhibitable
86
Rb
+
uptake more in SHR than WKY cells, whereas no effects were obtained with sodium nitroprusside, 8-bromo-cGMP, or iloprost. We examined the influence of endothelium on vascular sodium pump activity either by coculturing smooth muscle and endothelial cells or by using conditioned medium. Both coculture for 24 hours with endothelial cells and treatment with conditioned medium increased smooth muscle cell sodium pump activity, this effect being higher in SHR cells. These results suggest that the endothelium may modulate sodium pump activity in the underlying smooth muscle by releasing a diffusible compound, which is more active on SHR smooth muscle. The conditioned medium obtained in the presence of inhibitors of angiotensin-converting enzyme, endothelin-1–converting enzyme, cyclooxygenase, lipoxygenase, and nitric oxide synthase had no effect on the ability of conditioned medium to increase sodium pump activity, suggesting that angiotensin II, endothelin-1, eicosanoids, and nitric oxide are not involved in this stimulatory effect. The nature of the possible endothelial factor involved is still unknown, but it possesses a molecular weight between 25 and 50 kD, is heat stable, and is sensitive to trypsin treatment. We propose it could be a growth factor.
Pressor Effects of Portal Venous Oleate Infusion
Authors: Grekin Roger J. , Vollmer Alan P. , Sider Richard S.
Published: June 2012

Abstract
Increased visceral fat accumulation is a strong predictor of arterial hypertension. In this study, we explored the hypothesis that increased hepatic portal venous free fatty acid delivery results in increased blood pressure. Such an effect might explain the link between visceral obesity and hypertension. In nine conscious, instrumented rats, we studied the effects of 1-hour infusions of sodium oleate solution into the portal and femoral veins and infusions of sodium caprylate solution into the portal vein on 3 separate days. Basal blood pressure was not significantly different on the 3 study days. Mean arterial pressure increased 29±4 mm Hg during portal oleate infusion and 13±2 mm Hg during femoral oleate infusion (both significant increases over basal,
P
<.001). Mean arterial pressure did not change during portal caprylate infusion. The increase during portal oleate infusion was greater than that during femoral oleate infusion (
P
=.028). Heart rate rose during all three infusions; the increase was greatest during portal oleate infusion (334±4 to 412±2 beats per minute). During portal venous oleate infusion in five rats, plasma norepinephrine rose from 2.17±0.34 to 3.58±0.50 nmol/L, epinephrine rose from 0.79±0.28 to 1.84±0.44 nmol/L, and corticosterone rose from 147±55 to 1130±289 nmol/L. Three rats given portal venous oleate infusions for 1 week had increased blood pressure compared with baseline (mean increase, 16±4 mm Hg). These studies indicate that increases in portal venous fatty acid concentrations have significant pressor effects, perhaps mediated by increased sympathetic tone. Chronic increases in portal venous fatty acid levels may be responsible for the hypertension that accompanies visceral obesity.
Chromogranin A in Human Hypertension
Authors: Takiyyuddin Marwan A. , Parmer Robert J. , Kailasam Mala T. , Cervenka Justine H. , Kennedy Brian , Ziegler Michael G. , Lin Ming-Cheng , Li Jing , Grim Clarence E. , Wright Fred A. , O’Connor Daniel T.
Published: June 2012

Abstract
Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F
15,18
=2.93,
P
=.016) genetic variance (ς
2
g
), and its broad-sense heritability was high (
h
2
B
=0.983). Plasma chromogranin A was increased in essential hypertension (99.9±6.7 versus 62.8±4.7 ng/mL,
P
<.001) but was influenced little by genetic risk for (family history of) hypertension (in normotensive or hypertensive subjects), by race, or by several antihypertensive therapies (angiotensin-converting enzyme inhibitor, diuretic, or β-adrenergic antagonist). In normotensive subjects at genetic risk for essential hypertension, neither basal nor sympathoadrenal stress-evoked chromogranin A differed from values found in subjects not at risk. In established essential hypertension, plasma chromogranin A responses to adrenal medullary (insulin-evoked hypoglycemia) or sympathetic neuronal (dynamic exercise) activation were exaggerated, whereas responses to sympathoadrenal suppression (ganglionic blockade) were diminished, suggesting increased vesicular stores of chromogranin A and an adrenergic origin of the augmented chromogranin A expression in this disorder. We conclude that plasma chromogranin A displays substantial heritability and is increased in established essential hypertension. Its elevation in established hypertension is associated with evidence of increased vesicular stores of the protein and with adrenergic hyperactivity but is influenced little by customary antihypertensive therapies. However, the chromogranin A elevation is not evident early in the course of genetic hypertension.
Cardiovascular and Respiratory Effects of Endothelin in the Ventrolateral Medulla of the Normotensive Rat
Authors: Mosqueda-Garcia Rogelio , Yates Kendell , O’Leary Jim , Inagami Tadashi
Published: June 2012

Abstract
We studied the relevance of the ventrolateral medulla for the cardiovascular and respiratory effects of endothelin-1 in urethane-anesthetized rats. Microinjection of endothelin-1 into the rostral ventrolateral medulla (RVLM) evoked pressor and bradycardic effects followed by sustained decreases in blood pressure, bradycardia, and respiratory depression. These effects were inhibited by endothelin-A receptor antagonists (BQ-123 and BQ-610) but not by endothelin-B antagonists. In the caudal ventrolateral medulla (CVLM) endothelin-1 decreased blood pressure, renal sympathetic nerve activity, respiratory frequency, and phrenic nerve activity, whereas heart rate increased. Pretreatment with BQ-123 in the CVLM increased respiratory frequency by 15±6 breaths per minute and prevented the effects of intra-CVLM administration of endothelin-1. In separate experiments, the intracisternal administration of endothelin-1 (20 pmol) to rats pretreated with saline in both the RVLM and CVLM resulted in a hypotensive and bradycardic phase that was followed by hypertension (50±15 mm Hg), bradycardia, and 100% mortality. In a separate group, pretreatment with BQ-123 in the RVLM and CVLM completely inhibited the hypotensive phase and reduced by 83% the subsequent rise in blood pressure evoked by endothelin-1. Cardiorespiratory arrest was prevented in all the rats in this group. Selective endothelin receptor blockade in the RVLM attenuated the hypertensive period of intracisternal administration of endothelin-1 and prevented mortality by 33%, whereas in the CVLM the endothelin receptor antagonist inhibited the initial hypotension and reduced mortality by 25%. Our results support the concept that in the ventral medulla, endothelin-1 can modulate cardiovascular and respiratory function.
Effect of Regional and Systemic Changes in Vasomotor Tone on Finger Pressure Amplification
Authors: Bos Willem Jan W. , van den Meiracker Anton H. , Wesseling Karel H. , Schalekamp Maarten A.D.H.
Published: June 2012

Abstract
Pulse wave amplification, which leads to increased peripheral systolic pressures, is observed during vasoconstriction after head-up tilt and during exercise. This may influence finger pressure measurements with the Finapres. To distinguish between changes in regional vascular tone and changes in systemic hemodynamics as a cause of pulse wave amplification, we measured finger pressure, intra-arterial brachial artery pressure, heart rate, and left ventricular ejection time during high-dose intravenous and low-dose intra-arterial infusions of phenylephrine and sodium nitroprusside in eight subjects. Forearm blood flow was measured by means of venous occlusion plethysmography. Intravenous phenylephrine at the highest dose caused an increase in mean brachial artery pressure of 24±3 mm Hg, a decrease in heart rate of 10±11 beats per minute, and an increase in ejection time of 23±9 milliseconds (all
P
<.01), whereas pulse wave amplification was reduced. Finapres underestimated the rise in systolic brachial artery pressure of 41±9 mm Hg by 11±12 mm Hg (
P
<.01). Forearm blood flow did not change. Intravenous nitroprusside caused a decrease in mean brachial artery pressure of 23±9 mm Hg, an increase in heart rate of 18±11 beats per minute, and a decrease in ejection time of 36±31 milliseconds (all
P
<.01), whereas pulse wave amplification increased. Finapres underestimated the fall in systolic brachial artery pressure of 30±13 mm Hg by 9±10 mm Hg (
P
<.05). Forearm blood flow did not change. During regional infusion of phenylephrine and nitroprusside forearm flow halved and doubled, respectively. Blood pressure levels and pulse wave amplification were not affected. One subject performed dynamic exercise, which caused an increase in blood pressure and heart rate and a decrease in ejection time. As previously observed during bicycle exercise and contrary to the results with phenylephrine, the rise in systolic brachial artery pressure was overestimated with Finapres because of increased pulse wave amplification. We conclude that changes in regional vascular tone are not the main determinant of pulse wave amplification between the brachial and finger arteries. Changes in systemic hemodynamics, in particular changes in heart rate or ejection time, rather than changes in blood pressure level appear to be most important.
Aortic Wall Properties in Normotensive and Hypertensive Rats of Various Ages In Vivo
Authors: van Gorp Ad W. , van Ingen Schenau Dorette S. , Hoeks Arnold P.G. , Boudier Harry A.J. Struijker , Reneman Robert S. , De Mey Jo G.R.
Published: June 2012

Abstract
The distensibility of the arterial system, which is partly determined by arterial wall structure, smooth muscle tone, and actual pressure level, decreases with aging and hypertension. Our aim was to compare aortic wall properties in 3- and 6-month-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) at comparable blood pressures in vivo. During ketamine/xylazine anesthesia in rats we performed ultrasound arterial wall tracking and invasive pressure measurements to determine, at the level of the thoracic aorta, diastolic pressure, diastolic lumen area, changes in pressure and lumen area during the cardiac cycle, and indexes of compliance and distensibility. These observations were combined with histological measurements for determination of media cross-sectional area and thickness and the incremental elastic modulus under conditions as expected in situ. Anesthesia abolished the difference in diastolic pressure between SHR and WKY. Between 3 and 6 months of age in WKY, diastolic area and incremental elastic modulus increased significantly, distensibility decreased, and all other recorded variables were not modified. Between 3 and 6 months of age in SHR, diastolic area and incremental elastic modulus increased, distensibility of the aortic wall decreased, and all other mechanical and structural properties did not change significantly. At both ages, diastolic area and compliance were significantly smaller in SHR than WKY. The other mechanical and structural properties measured or calculated at comparable pressure did not differ between strains. Differences between the aorta of 3- and 6-month-old rats and between strains observed in vivo at comparable pressures can largely be attributed to differences in lumen caliber. These may represent the first findings concerning remodeling of the aorta in intact rats.