bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-Intensity Exercise Training Attenuates Cardiac β-Adrenergic Tone During Exercise in Spontaneously Hypertensive Rats
Authors: Gava Nilo Sérgio , Véras-Silva Acácio Salvador , Negrão Carlos Eduardo , Krieger Eduardo Moacyr
Published: June 2012

Abstract
Acute and chronic exercise decrease peripheral sympathetic nerve activity, but the effect of exercise training of varying intensity on the sympathetic control of heart rate of spontaneously hypertensive rats has not yet been described. The effect of low and high intensities of exercise training on the vagal and sympathetic activities that control heart rate at rest and during dynamic exercise at 0.5, 0.8, and 1.0 mph for 4 minutes per stage was investigated in sedentary (SED, n=11), high-intensity (HT, n=12), and low-intensity exercise–trained (LT, n=13) spontaneously hypertensive rats. Exercise training was performed on a treadmill for 60 minutes, 5 days per week for 18 weeks, at 55% maximum oxygen consumption for the LT group and 85% for the HT group. Vagal and sympathetic activities were studied after administration of methylatropine (3 mg/kg) and propranolol (4 mg/kg), respectively. The LT group had a significantly lower heart rate (at 0.5, 0.8, 1.0 mph versus rest: 410±7, 426±7, 464±9, and 295±6 beats per minute [bpm], respectively) than the HT (440±6, 453±7, 474±5, and 315±4 bpm) and the SED (474±11, 500±11, 523±10, and 327±3 bpm) groups. Sympathetic effect (LT: 84±10, 88±12, 105±12, and 9±4; HT: 123±8, 125±7, 133±7, and 34±7; SED: 130±13, 143±12, 150±10, and 38±7 bpm) and sympathetic tonus (LT: 125±6, 121±5, 112±6, and 91±6; HT: 145±9, 136±6, 142±8, and 118±7; SED: 136±6, 129±6, 132±7, and 118±8 bpm) were significantly decreased by low-intensity exercise training. In conclusion, low- but not high-intensity exercise training causes resting bradycardia and attenuation of tachycardiac response during progressive dynamic exercise in spontaneously hypertensive rats. This effect can be attributed to a significantly decreased β-adrenergic tone that controls heart rate.
Adenosine A
1
Receptor mRNA in Microdissected Rat Nephron Segments
Authors: Yamaguchi Satoshi , Umemura Satoshi , Tamura Kouichi , Iwamoto Tamio , Nyui Nobuo , Ishigami Tomoaki , Ishii Masao
Published: June 2012

Abstract
Adenosine plays several roles in the kidney mediated by the specific receptors A
1
, A
2
, and possibly A
3
. We studied the localization of adenosine A
1
receptor mRNA in rat nephron segments using reverse transcription and polymerase chain reaction (RT-PCR). The nephron segments of male Sprague-Dawley rats (6 to 8 weeks old) were microdissected. Total RNA was prepared by the acid-guanidinium–phenol–chloroform method and used in the following RT-PCR assay. Because the PCR primers spanned no intron, samples reacted in the absence of RT were used as controls for amplification of genomic DNA. The PCR products were size-fractionated by electrophoresis, visualized with ethidium bromide staining, and confirmed by Southern blot analysis. PCR products were detected in all of the nephron segments examined. No signals were detected in samples reacted in the absence of RT. Strong signals were detected in glomeruli, medullary collecting duct, cortical thick ascending limb, and medullary thick ascending limb, while weak signals were found in proximal convoluted and straight tubules. Previously, the presence of A
1
receptors has been demonstrated in glomeruli, collecting duct, and thick ascending limb in the rat kidney by autoradiography and binding studies. In addition to these segments, we further detected A
1
receptor mRNA in proximal convoluted and straight tubules. Thus, A
1
receptor mRNA seems to be broadly expressed along the nephron.
Role of Anthropometric Indexes and Blood Pressure as Determinants of Left Ventricular Mass and Geometry in Adolescents
Authors: Brandão Andrea A. , Pozzan Roberto , Albanesi Filho Francisco M. , Brandão Ayrton P.
Published: June 2012

Abstract
To evaluate left ventricular structural changes and their relationship to blood pressure and anthropometric indexes, we examined by echocardiography 108 adolescents aged 13 to 19 years. Subjects were divided into three groups according to blood pressure tracking during three moments of observation: group 1 (n=27), ≥95th percentile; group 2 (n=37), ≤50th percentile; and group 3 (n=44), blood pressure not stable in the original percentile. Left ventricular mass index and the prevalence of altered left ventricular geometry were greater in group 1 (
P
<.05 and
P
<.02, respectively). Of all the anthropometric indexes, body surface area showed the best correlation with left ventricular mass (
P
<.00001). Left ventricular mass also correlated with systolic and diastolic pressures (
P
<.00001 and
P
<.003, respectively). Ventricular septal and posterior wall thicknesses and left ventricular diastolic diameter showed good correlations with body surface area (
P
<.00001). These variables also correlated with systolic pressure (
P
<.001). In a multiple regression model when body surface area was controlled, systolic pressure did not correlate significantly with left ventricular mass. In a similar model systolic pressure maintained a significant correlation with ventricular septal and posterior wall (
P
<.00001) thicknesses but not with left ventricular diastolic diameter (
P
>.05). We conclude that left ventricular structural changes can occur early after initial abnormalities of blood pressure. Considering that body surface area and systolic pressure were the best predictors of left ventricular alterations in adolescents, the usual way of correcting left ventricular mass by body surface area should be reviewed.
Malignant Hypertension Is Accompanied by Marked Alterations in Chylomicron Metabolism
Authors: Bernardes-Silva Helio , Toffoletto Odaly , Bortolotto Luiz A. , Latrilha Maria C.M. , Krieger Eduardo M. , Pileggi Fulvio , Maranhão Raul C.
Published: June 2012

Abstract
Malignant hypertension (MH) is a severe complication of untreated arterial hypertension that damages the vascular system. It is often accompanied by disturbances in lipid metabolism that could contribute to its pathophysiology. We examined chylomicron metabolism in MH patients using a triglyceride-rich emulsion known to mimic natural chylomicrons when injected into the bloodstream. The emulsion was labeled with [
3
H]triolein and [
14
C]cholesteryl oleate and injected intravenously into 15 normolipidemic MH patients aged 29 to 56 years (8 men) for comparison with 17 healthy control subjects. Consecutive plasma samples were taken at regular intervals during 1 hour for determination of the disappearance curves of the labels. The fractional clearance rate of the [
3
H]triolein emulsion in MH patients was twice as small as that of control subjects (0.061±0.012 and 0.141±0.074 min
−1
, respectively). On the other hand, [
14
C]cholesteryl oleate fractional clearance rate was not statistically different in MH patients and control subjects (0.032±0.004 and 0.056±0.014 min
−1
, respectively). These results indicate that in MH, lipolysis (measured by the fractional clearance rate of [
3
H]triolein) is pronouncedly diminished, whereas the removal of the remnant particles (measured by the fractional clearance rate of [
14
C]cholesteryl oleate) is not importantly affected. In conclusion, there is an alteration in the circulatory transport of dietary lipids that may be an important component in the vascular disease associated with MH.
The Egyptian National Hypertension Project (NHP)
Authors: Ashour Zeinab , Ibrahim M. Mohsen , Appel Lawrence J. , Ibrahim Amal Sami , Whelton Paul K.
Published: June 2012

Abstract
Hypertension and its complications appear to be increasingly common in Egypt. The National Hypertension Project (NHP) is a collaborative Egyptian-American effort with the following objectives: (1) to determine the prevalence of hypertension and blood pressure–related preclinical and clinical complications in Egyptian adults, (2) to identify environmental factors associated with high blood pressure, and (3) to build an infrastructure for research and education in cardiovascular disease prevention in Egypt. The NHP surveys were conducted in six of Egypt’s 26 governorates, representing distinct geographic regions. In each of these six governorates, a probability sample of 600 households was surveyed. NHP was conducted in two phases. In phase I a team of specially trained physicians conducted household surveys in which all adult residents (age ≥25 years) were screened for hypertension. In phase II hypertensive adults identified in phase I (ie, those with systolic pressure ≥140 mm Hg and/or diastolic pressure ≥90 mm Hg and/or those receiving antihypertensive drug therapy) along with a randomly selected sample of normotensive control subjects were asked to participate in a more extensive evaluation. This included a detailed history and clinical examination, an electrocardiogram, an echocardiogram, laboratory studies, and skin color reflectance (on a subsample). As the first systematic, national survey of hypertension and its complications in an Arab country, NHP should provide data of great interest to the scientific, provider, and public health communities.
Vasoactive Diadenosine Polyphosphates Promote Growth of Cultured Renal Mesangial Cells
Authors: Schulze-Lohoff Eckhard , Zanner Susann , Ogilvie Adaling , Sterzel Ralf Bernd
Published: June 2012

Abstract
Diadenosine polyphosphates (diadenosine triphosphate, Ap3A; diadenosine tetraphosphate, Ap4A; diadenosine pentaphosphate, Ap5A; diadenosine hexaphosphate, Ap6A) are potent vasoactive molecules stored and released by platelets. We examined whether these dinucleotides might contribute to the glomerular inflammatory response by stimulating the proliferation of mesangial cells. In cultured rat mesangial cells all four tested dinucleotides (10 to 100 μmol/L) significantly stimulated DNA synthesis as measured by [
3
H]thymidine uptake at 48 hours (x-fold increase compared with unstimulated control cells: Ap3A, 1.5; Ap4A, 1.8; Ap5A, 1.6; Ap6A, 1.6). In combination with the platelet products platelet-derived growth factor, epidermal growth factor, and serotonin, the dinucleotides synergistically increased DNA synthesis. Dinucleotides by themselves increased cell counts by 23% to 43% at day 2 and augmented mesangial cell growth induced by platelet-derived growth factor, epidermal growth factor, and serotonin. Furthermore, dinucleotides (100 μmol/L) rapidly induced a modest increase in expression of the early growth response gene Egr-1 at 30 minutes (x-fold increase over baseline control: Ap3A, 1.9; Ap4A, 2.8; Ap5A, 2.2; Ap6A, 2.1). We found that extracellular Ap4A was metabolized by mesangial cell ectoenzymes to mononucleotides and adenosine, which also have been shown to be mitogenic for mesangial cells. The combination of Ap4A with mononucleotides or adenosine failed to cause additive stimulation of DNA synthesis in mesangial cells. We conclude that diadenosine polyphosphates stimulate proliferation of cultured mesangial cells and augment mesangial cell growth induced by other mitogens released from platelets. Different molecular mechanisms may be involved in dinucleotide-induced mitogenesis of mesangial cells. Direct effects of dinucleotides on cultured mesangial cells appear to play a role because dinucleotides rapidly caused activation of Egr-1. On the other hand, independent or additional effects of the mitogenic metabolites ATP, ADP, AMP, and adenosine may contribute to dinucleotide-induced mesangial cell replication.
Chronic Inhibition of Nitric Oxide Synthesis Causes Coronary Microvascular Remodeling in Rats
Authors: Numaguchi Kohtaro , Egashira Kensuke , Takemoto Masao , Kadokami Toshiaki , Shimokawa Hiroaki , Sueishi Katsuo , Takeshita Akira
Published: June 2012

Abstract
The aim of the present study was to investigate the effects of long-term blockade of nitric oxide synthesis with the
l
-arginine analogue
N
ω
−nitro-
l
-arginine methyl ester (L-NAME) for 8 weeks on coronary vascular and myocardial structural changes. Four groups of Wistar-Kyoto rats were studied: those with no treatment, those treated with L-NAME 1 g/L (3.7 mmol/L in drinking water), those treated with L-NAME 0.1 g/L (0.37 mmol/L in drinking water), and those treated with L-NAME 1.0 g/L and hydralazine 120 mg/L (0.6 mmol/L in drinking water). After 8 weeks, the heart was excised, and the degrees of structural changes in coronary arteries (wall-to-lumen ratio and perivascular fibrosis), myocardial fibrosis, and myocyte size were quantified by an image analyzer. Chronic inhibition of nitric oxide synthesis increased arterial pressure compared with control animals. Chronic inhibition of nitric oxide synthesis caused significant microvascular remodeling (increased wall-to-lumen ratio and perivascular fibrosis). Cardiac hypertrophy was also observed after chronic inhibition of nitric oxide synthesis. Coadministration of hydralazine prevented arterial hypertension but did not affect microvascular remodeling and cardiac hypertrophy induced by the chronic inhibition of nitric oxide synthesis. In addition, chronic inhibition of nitric oxide synthesis caused scattered lesions of myocardial fibrosis, which was significantly attenuated by cotreatment with hydralazine. These results suggest that long-term blockade of nitric oxide synthesis caused coronary microvascular remodeling and cardiac hypertrophy in rats in vivo by a mechanism other than arterial hypertension. In contrast, arterial hypertension contributed to the development of myocardial fibrosis induced by long-term blockade of nitric oxide synthesis.
Gender Differences in Left Ventricular Growth
Authors: de Simone Giovanni , Devereux Richard B. , Daniels Stephen R. , Meyer Richard A.
Published: June 2012

Abstract
Because the number of human cardiac myocytes is determined in infancy, subsequent increases in left ventricular (LV) muscle mass reflect cellular enlargement (hypertrophy). To determine whether the greater LV mass in adult men than in women reflects sex differences that are present throughout development or disproportionate LV growth during puberty in men, we compared echocardiographic LV mass in 333 female and 278 male normal-weight, normotensive subjects from 4 months to 70 years of age. Only a small sex difference in LV mass (mean=6%) existed before age 12 years, whereas in all older-age strata LV mass in men was 25% to 38% greater than that in women (
P
<.02 to
P
<.0001). The divergence in LV mass between male and female adolescents closely paralleled differences in height and weight and was due to proportional increases in LV chamber dimension and wall thickness in males (with no sex difference in relative wall thickness). LV mass grew less rapidly from infancy through childhood than did body size, assessed by body weight or height
2.7
, yielding a reduction of LV mass/body size ratios up to puberty, which was followed by gradual increases during adulthood. Indexation of LV mass by body weight or height
2.7
but not by body surface area or height markedly reduced the sex differences in LV mass/body size ratios from puberty through the seventh decade of life. Thus, before puberty, LV mass is only modestly higher in boys than in girls. Most of the sex difference in adult LV mass follows differences in body size and is due to a greater “physiological” LV hypertrophy in men than in women.
Blunted Pressure Natriuresis in Ovariectomized Dahl-Iwai Salt-Sensitive Rats
Authors: Otsuka Keiichi , Suzuki H. , Sasaki T. , Ishii N. , Itoh H. , Saruta T.
Published: June 2012

Abstract
Our objective was to determine whether increased salt sensitivity after menopause precedes the development of overt hypertension. We investigated the effect of ovariectomy on pressure natriuresis in Dahl-Iwai salt-sensitive (DS) and salt-resistant (DR) rats by in vivo perfusion studies. Differences in the neural and hormonal backgrounds of the kidney were minimized by renal denervation and by holding plasma vasopressin, aldosterone, corticosterone, and norepinephrine levels constant by intravenous infusion. The pressure-natriuresis relationship was blunted in DS rats compared with DR rats (slope, 0.30 versus 0.63 μmol·min
−1
·g kidney wt
−1
·mm Hg
−1
,
P
<.01). The impaired pressure-natriuresis response of DS rats was further blunted by ovariectomy (from 0.30 to 0.14 μmol·min
−1
·g kidney wt
−1
·mm Hg
−1
,
P
<.05), and that of DR rats was not. The ovariectomized DS rats developed hypertension earlier than sham-operated DS rats by salt loading. These results show that ovariectomy enhances genetic salt sensitivity by blunting the pressure-natriuresis relationship, which precedes the development of overt hypertension in female DS rats.
Nitric Oxide and the Depressor Response to Angiotensin Blockade in Hypertension
Authors: Guan Hui , Cachofeiro Victoria , Pucci Michael L. , Kaminski Pawel M. , Wolin Michael S. , Nasjletti Alberto
Published: June 2012

Abstract
We investigated the contribution of nitric oxide to the short-term blood pressure reduction caused by interruption of the renin-angiotensin system in angiotensin-dependent hypertension. The blood pressure of rats made hypertensive by coarctation of the aorta between the renal arteries at their origin fell after administration of the angiotensin-converting enzyme inhibitor ramiprilat (2 mg/kg IV; −75±5 mm Hg) or the angiotensin II antagonist losartan (30 mg/kg IV; −79±6 mm Hg). But the antihypertensive effect of these agents was attenuated in rats pretreated with
N
G
-nitro-
l
-arginine methyl ester (10 mg/kg IV) to inhibit nitric oxide synthesis (ramiprilat, −23±7 mm Hg; losartan, −37±5 mm Hg). In rats made hypertensive by long-term infusion of angiotensin II (60 ng/min IV, 6 to 7 days), the vasodepressor response to discontinuation of the angiotensin II infusion also was attenuated by pretreatment with the nitric oxide synthesis inhibitor (−52±7 versus −31±7 mm Hg); this attenuation was not demonstrable in rats receiving sodium nitroprusside (1 μg·kg
−1
·min
−1
IV) to replace the loss of endogenous nitric oxide (−72±9 mm Hg). Pretreatment with
N
G
-nitro-
l
-arginine methyl ester did not interfere with the vasodepressor effect of sodium nitroprusside or prazosin in rats with aortic coarctation–induced hypertension or with the blood pressure reduction caused by discontinuation of an infusion of phenylephrine in rats made hypertensive by long-term administration of this drug. These data suggest a contribution of nitric oxide to the blood pressure reduction caused by interruption of the renin-angiotensin system in models of established angiotensin-dependent hypertension.
Indigo Carmine Inhibits Endothelium-Dependent and -Independent Vasodilation
Authors: Chang Kyoung S.K. , Zhong Min Z. , Davis Richard F.
Published: June 2012

Abstract
To investigate the potential mechanisms by which indigo carmine produces hypertension, we tested the hypothesis that indigo carmine inhibits endothelium-dependent vasodilation and determined the possible site of the inhibition (endothelium versus smooth muscle). Using isolated rat thoracic aortic rings that were precontracted with phenylephrine, we examined vasodilatory responses to acetylcholine, histamine, and Ca
2+
ionophore A23187 (in endothelium-intact rings) and sodium nitroprusside and isoproterenol (in endothelium-denuded rings) in the presence and absence of indigo carmine. In addition, the effects of methylene blue on the acetylcholine- and sodium nitroprusside–induced vasodilation were compared with those of indigo carmine. Indigo carmine (10
−6
, 10
−5
, and 10
−4
mol/L) significantly inhibited receptor- and non–receptor-mediated endothelium-dependent vasorelaxation. Indigo carmine (10
−4
mol/L) also inhibited endothelium-independent vasorelaxation induced by sodium nitroprusside (an activator of vascular smooth muscle soluble guanylyl cyclase), although to a lesser extent than vasodilation from acetylcholine, histamine, and Ca
2+
ionophore A23187. In contrast, indigo carmine (10
−4
mol/L) had no effect on the vasodilation induced by isoproterenol (an activator of adenylyl cyclase), indicating that indigo carmine selectively inhibits nitric oxide–mediated responses. Methylene blue, a known inhibitor of soluble guanylyl cyclase, inhibited both acetylcholine- and sodium nitroprusside–induced vasorelaxation. The inhibition was also greater in the acetylcholine- than the sodium nitroprusside–induced vasodilation. These results suggest that indigo carmine, like methylene blue, may inhibit endothelium-dependent relaxation by a mechanism that involves two levels. The major action of indigo carmine appears to be at the level of nitric oxide generation and/or release from the endothelial cell. In addition, indigo carmine appears to inhibit vascular smooth muscle guanylyl cyclase. Thus, indigo carmine may elevate blood pressure by interfering with these nitric oxide–mediated vasodilatory mechanisms.
Role of Transcriptional
cis
-Elements, Angiotensinogen Gene–Activating Elements, of Angiotensinogen Gene in Blood Pressure Regulation
Authors: Morishita Ryuichi , Higaki Jitsuo , Tomita Naruya , Aoki Motokuni , Moriguchi Atsushi , Tamura Kouichi , Murakami Kazuo , Kaneda Yasufumi , Ogihara Toshio
Published: June 2012

Abstract
Results of recent genetic studies suggest that the angiotensinogen gene is a possible determinant of hypertension. Using antisense technology, we demonstrated that generation of circulating angiotensinogen is a rate-limiting step in blood pressure regulation. In the present study, we examined how the angiotensinogen gene is regulated in vivo. The transcriptional
cis
-elements, angiotensinogen gene–activating elements (AGE) 2 and 3, have been reported to regulate angiotensinogen production in human hepatocytes in vitro. To determine the critical transcriptional regulator of angiotensinogen production in vivo, we used synthetic double-stranded oligodeoxynucleotides (ODN) as “decoy”
cis
-elements to block the binding of nuclear factors to promoter regions of the targeted gene, resulting in the inhibition of gene transactivation. Here we examined whether AGE 2 and AGE 3 in the promoter region of the angiotensinogen gene have a pivotal role in hepatic angiotensinogen production in vivo. Hepatic angiotensinogen mRNA was decreased by the transfection of AGE 2 but not mismatched decoy ODN. Transfection of decoy but not mismatched ODN against AGE 2 resulted in a transient decrease in blood pressure of spontaneously hypertensive rats (SHR), accompanied by a reduction in plasma angiotensinogen and angiotensin II levels. In contrast, transfection of AGE 3 decoy ODN had little effect on blood pressure. Overall, our results demonstrate that transfection of decoy ODN against AGE 2, but not against AGE 3, of the angiotensinogen gene resulted in a transient decrease in high blood pressure of SHR, suggesting that the transcriptional
cis
-element AGE 2, rather than AGE 3, has an important role in blood pressure regulation through the control of circulating angiotensinogen.
Polymorphisms of Renin-Angiotensin Genes Among Nigerians, Jamaicans, and African Americans
Authors: Rotimi Charles , Puras Angel , Cooper Richard , McFarlane-Anderson Norma , Forrester Terrence , Ogunbiyi Olufemi , Morrison Ryk Ward Linda
Published: June 2012

Abstract
Within the context of an international collaborative study of the evolution of hypertension in the black diaspora, we determined the allelic distribution of hypertension candidate genes for the renin-angiotensin system in three populations of African origin. The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) and the M235T and T174M variants of the angiotensinogen
(AGT)
gene were examined in individuals from Nigeria, Jamaica, and the United States. Large differences in the prevalence of hypertension were recorded in door-to-door surveys, ranging from 16% in Nigeria to 33% in the United States. The frequency of the
D
allele was similar in all groups (54%, 59%, and 63% in Nigeria, Jamaica, and the United States, respectively). The 235T allele of the
AGT
gene was found in 81% of US and Jamaican blacks and 91% of Nigerians; very little variation was seen for the T174M marker. Despite large differences in hypertension rates, genetic variation at the index loci among these groups was modest. Overall, the frequency of the
ACE

★

D allele was only slightly higher than that reported for European and Japanese populations, whereas the
AGT
235T allele was twice as common. Compared with blacks in the western hemisphere, Nigerians had a higher frequency of the 235T allele, which is consistent with 25% European admixture in Jamaica and the United States. The results indicate the potential for etiologic heterogeneity in genetic factors related to hypertension across ethnic groups while suggesting that environmental exposures most likely explain the gradient in risk in the comparison among black populations.
Influence of NaCl Concentration at the Macula Densa on Angiotensin II–Induced Constriction of the Afferent Arteriole
Authors: Ren YiLin , Carretero Oscar A. , Ito Sadayoshi
Published: June 2012

Abstract
The macula densa, a plaque of specialized tubular epithelial cells, monitors NaCl concentrations in tubular fluid and controls resistance of the glomerular afferent arteriole (AA). In vivo micropuncture studies suggest that there are significant interactions between angiotensin II (Ang II) and macula densa control of glomerular hemodynamics. We tested the hypothesis that Ang II causes stronger constriction of the AA when NaCl concentration at the macula densa is elevated. Rabbit AAs and the attached macula densa were simultaneously microperfused in vitro, and dose-response curves to Ang II were obtained when the macula densa was not perfused or was perfused with either low NaCl (Na
+
, 26 mEq/L; Cl
−
, 7 mEq/L) or high NaCl (Na
+
, 84 mEq/L; Cl
−
, 65 mEq/L). Ang II induced stronger constriction when the macula densa was perfused with high NaCl; the decrease in diameter at 100 pmol/L was 29±5.6% (n=7) compared with 2.1±1.2% (n=8) for the nonperfused macula densa or 6.1±4.2% (n=7) for low NaCl (
P
<.002). However, there was no such difference in the action of norepinephrine. Adding furosemide (10 μmol/L) to the macula densa perfusate abolished the difference in Ang II action between low and high NaCl at the macula densa. Since AA tone is higher when the NaCl concentration at the macula densa is elevated, we tested whether augmented Ang II action is due to higher AA tone. Preconstriction of the AA by 20% with norepinephrine had no effect on Ang II action. Thus, our results demonstrate that sensitivity of the AA to Ang II increases when NaCl concentration at the macula densa is elevated. Such modulation of Ang II action by macula densa NaCl concentration may be important in the control of glomerular hemodynamics.
Nitric Oxide Release From Kidneys of Hypertensive Rats Treated With Imidapril
Authors: Hirata Yasunobu , Hayakawa Hiroshi , Kakoki Masao , Tojo Akihiro , Suzuki Etsu , Kimura Kenjiro , Goto Atsuo , Kikuchi Kazuya , Nagano Tetsuo , Hirobe Masaaki , Omata Masao
Published: June 2012

Abstract
To examine whether endothelial dysfunction in hypertension is reversible or not, we studied the effects of imidapril, an angiotensin-converting enzyme inhibitor, on nitric oxide release in stroke-prone spontaneously hypertensive rats (SHR) and deoxycorticosterone acetate (DOCA)–salt hypertensive rats. After a 4-week treatment with imidapril (1 or 10 mg/d SC) or vehicle, acetylcholine-induced vasodilation and nitric oxide release in the isolated kidneys were determined. Nitric oxide release was measured by a chemiluminescence assay. Imidapril lowered blood pressure in stroke-prone SHR in a dose-dependent manner. Untreated stroke-prone SHR exhibited significantly attenuated responses to acetylcholine (10
−8
mol/L) of both renal perfusion pressure (stroke-prone SHR 42±4% versus Wistar-Kyoto rats [WKY] 58±4% [mean±SE],
P
<.01) and nitric oxide release (stroke-prone SHR +7.6±2.1 versus WKY +29.7±9.7 fmol/min per gram of kidney wt,
P
<.01). Imidapril at 10 mg/d significantly increased acetylcholine-induced renal vasodilation and nitric oxide release in stroke-prone SHR (renal perfusion pressure, 56±3%; nitric oxide release, +27.1±6.4 fmol/min per gram of kidney wt; both
P
<.01 versus stroke-prone SHR treated with vehicle). On the other hand, imidapril neither decreased blood pressure nor changed nitric oxide release induced by acetylcholine in DOCA–salt hypertensive rats. Staining for endothelial nitric oxide synthase and brain nitric oxide synthase was clearly detected in the kidneys of both stroke-prone SHR and WKY, whereas staining intensity was weaker in DOCA–salt hypertensive rats. Inducible nitric oxide synthase immunoreactivity was barely noticeable in any type of rat. Thus, imidapril restored endothelial damage by pressure-dependent mechanisms. Most of the nitric oxide detected in the perfusate seemed to be derived from constitutive nitric oxide synthase.
Increased Responsiveness and Decreased Expression of G Proteins in Deoxycorticosterone Hypertension
Authors: Kanagy Nancy L. , Webb R. Clinton
Published: June 2012

Abstract
Deoxycorticosterone-salt (DOCA-salt) hypertension is characterized by elevated vasoconstriction to agonists that stimulate G protein–mediated activation of phospholipase C. However, the mechanisms responsible for the augmented responsiveness are unknown. This study tested the hypothesis that this augmented vascular responsiveness is due to elevated content of Gα
q
, the G protein α-subunit that activates phospholipase C. Thoracic aortae from DOCA-salt hypertensive rats (systolic blood pressure 183±7 mm Hg) and normotensive controls (systolic blood pressure 115±2 mm Hg) were homogenized and G protein content determined. Western analysis revealed that Gα
i
content was decreased in DOCA compared with control rats (1364±196 versus 2343±188 densitometry units,
P
≤.05) with no differences observed for Gα
q
or Gα
s
. In addition, contractile responses in denuded femoral artery strips revealed a significant decrease in EC
50
values in DOCA arteries to all of the agonists examined: aluminum fluoride (DOCA=1.42, control=2.34 mmol/L), mastoparan (DOCA=0.51, control=35 μmol/L), phenylephrine (DOCA=0.08, control=0.53 μmol/L), and serotonin (DOCA=0.014, control=0.04 μmol/L, EC
20
values). Finally, arteries from DOCA rats contracted with aluminum fluoride had increased sensitivity to G protein antagonists but not to a phospholipase C inhibitor. The enhanced contractile responsiveness in the DOCA arteries may be mediated in part through decreased Gα
i
levels. However, it is not caused by increased concentrations of Gα
q
in the cell membrane or by increased phospholipase C sensitivity, and the increased constrictor response to G protein stimulators of phospholipase C appears to depend primarily on increased G protein sensitivity.
Vascular Smooth Muscle Polyploidy and Cardiac Hypertrophy in Genetic Hypertension
Authors: Dominiczak Anna F. , Devlin Alison M. , Lee Wai K. , Anderson Niall H. , Bohr David F. , Reid John L.
Published: June 2012

Abstract
We studied the mechanisms responsible for vascular and cardiac hypertrophy in hypertension (pressure load and humoral and genetic factors) in two experimental approaches: (1) We carried out a cosegregation analysis to correlate cardiac and vascular hypertrophy with subphenotypes of blood pressure in an F
2
generation of a cross between stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats; (2) we treated 8-week-old SHRSP with perindopril, an angiotensin-converting enzyme inhibitor; losartan, an angiotensin type 1 receptor antagonist; or perindopril combined with a nitric oxide synthase inhibitor to investigate the relative contributions of blood pressure and angiotensin II to the pathogenesis of cardiac hypertrophy and vascular smooth muscle polyploidy. Vascular smooth muscle polyploidy was measured with flow cytometry DNA analysis. Cardiac hypertrophy was assessed by measuring the ratios of heart weight to body weight and left ventricle+septum weight to body weight. Blood pressure was measured with radiotelemetry in the F
2
cosegregation experiment and with tail-cuff plethysmography in the pharmacological study. In the F
2
rats, the best predictor of smooth muscle polyploidy by ANCOVA was systolic pressure (F=29.28,
P
<.0001). The ratio of left ventricle+septum weight to body weight had four major predictors: the male progenitor of the cross, sex, pulse pressure, and change in systolic pressure during salt (F=43.67,
P
<.0001; F=16.37,
P
<.0001; F=8.41,
P
=.0022; and F=12.39,
P
=.0003, respectively). The ratio of heart weight to body weight had similar predictors. In the pharmacological study, treatment with losartan alone, perindopril alone, or perindopril in combination with
N
G
-nitro-
l
-arginine methyl ester prevented the development of smooth muscle polyploidy and cardiac hypertrophy. The prevention of cardiac hypertrophy was most marked in the SHRSP treated with perindopril plus
N
G
-nitro-
l
-arginine methyl ester, despite blood pressure being higher in this group than in the two other treatment groups. We conclude that vascular and cardiac hypertrophy in this form of hypertension are regulated by different variables. However, suppression of the action of angiotensin II lessens hypertrophy of both types of muscle.
20-HETE Requires Increased Vascular Tone to Constrict Rabbit Afferent Arterioles
Authors: Arima Shuji , Omata Ken , Ito Sadayoshi , Tsunoda Kazuo , Abe Keishi
Published: June 2012

Abstract
Renal production of 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450–dependent arachidonate metabolite, increases during development of hypertension in spontaneously hypertensive rats, and inhibition of its production prevents hypertension. Since 20-HETE is a potent vasoconstrictor, these findings suggest that 20-HETE may contribute to the development of hypertension by elevating renal vascular resistance. In this study we examined the direct action of 20-HETE on the afferent arteriole, a vascular segment crucial to the control of renal vascular resistance. Rabbit afferent arterioles were microperfused at 60 mm Hg in vitro, and 20-HETE was added to the lumen. Although 20-HETE (10
−10
to 10
−6
mol/L) had no effect on the diameter of nontreated afferent arterioles (n=6), it caused dose-dependent constriction when vascular tone was increased with norepinephrine (0.3 μmol/L); 20-HETE at 10
−6
mol/L decreased diameter by 43±4% (n=6,
P
<.001). This constriction was abolished by disrupting the endothelium (n=5). Moreover, pretreatment with the cyclooxygenase inhibitor indomethacin (50 μmol/L) or the thromboxane/endoperoxide receptor antagonist SQ29548 (1 μmol/L) significantly (
P
<.03) attenuated 20-HETE–induced constriction: 20-HETE at 10
−6
mol/L constricted norepinephrine-treated afferent arterioles by 28±3% (n=6) and 25±4% (n=5), respectively. These results demonstrate that an increase in afferent arteriolar tone is required for the vasoconstrictor action of 20-HETE, which is partly mediated by the endothelial cyclooxygenase pathway. Thus, increased production of 20-HETE in the kidney and increase in afferent arteriolar tone, both of which often precede the development of hypertension, may synergistically contribute to the development of hypertension by elevating renal vascular resistance.
Aging Progressively Impairs Endothelium-Dependent Vasodilation in Forearm Resistance Vessels of Humans
Authors: Gerhard Marie , Roddy Mary-Anne , Creager Shelly J. , Creager Mark A.
Published: June 2012

Abstract
Studies in experimental models suggest that endothelium-derived nitric oxide is reduced with aging, and this circumstance may be relevant to atherogenesis. The aim of this study was to determine whether increasing age resulted in altered endothelium-dependent vasodilation in the forearm resistance vessels of healthy humans. Forearm blood flow was measured in 119 healthy subjects, aged 19 to 69 years, by venous occlusion plethysmography. Brachial artery infusions of methacholine chloride (0.03 to 10.0 μg/min) were used to assess endothelium-dependent vasodilation and of sodium nitroprusside (0.03 to 10.0 μg/min) to assess endothelium-independent vasodilation. The slope of the dose–blood flow response relation was calculated in each subject for each drug. Univariate and multiple stepwise regression analyses were used to relate vascular reactivity to selected variables, including age, lipids, and blood pressure. Endothelium-dependent vasodilation was progressively impaired with increasing age, assessed as a reduction in slope from 2.25±0.16 to 0.34±0.11 (mL/100 mL tissue per minute)/(μg/min) (
P
<.001). The decline in endothelium-dependent vasodilation was already evident by the fourth decade (age 30 to 39 years). Endothelium-independent vasodilation did not change with age. Age, total cholesterol, and low-density lipoprotein cholesterol were univariate predictors of endothelium-dependent vasodilation. Age remained the most significant predictor of endothelium-dependent vasodilator responses by multiple stepwise regression analysis. From these observations, it can be concluded that endothelium-dependent vasodilation declines steadily with increasing age in healthy human subjects. Age is a strong univariate and multivariate predictor of endothelium-dependent vasodilation. This finding may be a marker for more widespread endothelial dysfunction.
Presynaptic Inhibition of Norepinephrine Release From Sympathetic Nerve Endings by Endogenous Adenosine
Authors: Rongen Gerard A. , Lenders Jacques W.M. , Lambrou Jorgo , Willemsen Jacques J. , Van Belle Herman , Thien Theo , Smits Paul
Published: June 2012

Abstract
ATP is coreleased with norepinephrine from sympathetic nerve endings and subsequently broken down to adenosine. In animal preparations, adenosine can inhibit norepinephrine release by stimulation of presynaptic receptors. We tested this feedback mechanism in humans by using a specific nucleoside transport inhibitor (draflazine) as a pharmacological tool to allow accumulation of endogenous adenosine in the synaptic cleft. In a dose-finding study on draflazine infusions into the brachial artery (n=10), we identified an optimal dose of 250 ng/min per deciliter of forearm tissue that induced considerable local nucleoside transport inhibition (approximately 40%) without systemic effects. In the main study, we investigated the effects of this draflazine dose on sympathetic-mediated norepinephrine spillover during lower body negative pressure (−25 mm Hg) by use of the [
3
H]norepinephrine isotope dilution technique (n=25). Lower body negative pressure induced a significant increase in total body norepinephrine spillover, forearm norepinephrine appearance rate, forearm vascular resistance, and heart rate. During draflazine infusion into the brachial artery, the responses to lower body negative pressure were preserved for all parameters, with the exception of the median increase in forearm norepinephrine appearance rate, which was reduced from 54% to 2% (
P
<.05). We conclude that accumulation of endogenous adenosine in the synaptic cleft during sympathetic stimulation can inhibit norepinephrine release from sympathetic nerve endings.
Abnormalities of Insulin Receptors in Spontaneously Hypertensive Rats
Authors: Sechi Leonardo A. , Griffin Chandi A. , Giacchetti Gilberta , Zingaro Laura , Catena Cristiana , Bartoli Ettore , Schambelan Morris
Published: June 2012

Abstract
Insulin resistance is present in some strains of rats with genetic hypertension. To determine whether this abnormality is present at the level of the insulin receptor, we compared insulin sensitivity, insulin receptor binding, and mRNA levels in tissues of 10-week-old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WKY) controls. Because we have previously demonstrated an inverse relationship between dietary sodium intake and renal insulin receptor density and mRNA levels in normal Sprague-Dawley rats, the two rat strains in the current experiment were fed either low salt (0.07% NaCl) or high salt (7.5% NaCl) chow until the SHR became hypertensive. Fasting plasma glucose and plasma insulin levels did not differ between SHR and WKY and were not affected by salt intake. When the rats were maintained on the low salt diet, the rate of glucose infusion required to maintain euglycemia during a hyperinsulinemic clamp was significantly lower in SHR than WKY. High salt diet decreased the rate of glucose utilization during the hyperinsulinemic clamp in WKY but not SHR. During the low salt diet, insulin infusion decreased sodium excretion in both WKY and SHR. When the rats were maintained on the high salt diet, the antinatriuretic response to insulin was blunted in WKY but not SHR. Both the density and mRNA levels of insulin receptor were comparable in the kidney of WKY and SHR, but only WKY had the previously demonstrated decrease in receptor number and mRNA levels when fed the high salt chow. Hepatic insulin receptor mRNA levels were significantly lower in SHR than WKY fed the low salt diet. High salt diet decreased significantly insulin receptor mRNA levels in the liver of WKY but not of SHR. Thus, SHR appear to have lost the feedback mechanism that normally limits insulin-induced sodium retention when extracellular volume is expanded. A decreased expression of insulin receptor in the liver of SHR provides a possible explanation for the insulin resistance and decreased insulin clearance present in this strain.
Changes in Left Ventricular Anatomy and Function in Hypertension and Primary Aldosteronism
Authors: Rossi Gian Paolo , Sacchetto Alfredo , Visentin Pieralberto , Canali Cristina , Graniero Gian Rocco , Palatini Paolo , Pessina Achille C.
Published: June 2012

Abstract
We investigated the effects on the heart of hypertension due to the excess of aldosterone and suppression of the renin-angiotensin system caused by primary aldosteronism with M-mode echocardiography and transmitral Doppler flow velocity measurements. We studied 34 consecutive patients with primary aldosteronism and 34 with essential hypertension individually matched for age, gender, race, body mass index, blood pressure values, and duration of hypertension. The groups were similar in age, body mass index, blood pressure, and duration of hypertension. However, lower serum potassium levels (3.5±0.6 versus 4.1±0.2 mmol/L,
P
<.0001) and plasma renin activity (0.53±0.45 versus 1.82±1.59 ng Ang I·mL
−1
·h
−1
,
P
<.0001) and higher plasma aldosterone levels (1107±774 versus 206±99 pmol/L,
P
<.0001), left ventricular wall thickness, and left ventricular mass index (112±4.7 versus 98±3.7 g/m
2
,
P
=.029) were found in patients with primary aldosteronism compared with those with essential hypertension. Similarly, the PQ interval was longer (173±20 versus 141±14 milliseconds,
P
<.001) in primary aldosteronism than in essential hypertension patients. Significantly more primary aldosteronism than essential hypertension patients had left ventricular hypertrophy or left ventricular concentric remodeling (50% versus 15%, χ
2
=11.97,
P
=.007). Both the E wave flow velocity integral (1063±65 versus 1323±78,
P
=.013) and the E/A integral ratio (0.91±0.05 versus 1.25±0.08,
P
<.001) were lower, and atrial contribution to left ventricular filling was higher (53.3±1.5% versus 45.5±1.3%,
P
<.001) in patients with primary aldosteronism compared with essential hypertension patients. After 1 year of follow-up, highly significant decreases of left ventricular wall thickness and mass were observed in patients treated with surgical excision of an aldosterone-producing tumor, but not in those treated with medical therapy. Thus, in patients with primary aldosteronism, the excess aldosterone with suppression of the renin-angiotensin system is associated with both increased left ventricular mass and significant changes of left ventricular diastolic filling. The former changes appear to be reversible on removal of the cause of excessive aldosterone production.
Cardiac and Vascular Structural Changes
Authors: Muiesan Maria Lorenza , Pasini GianFranco , Salvetti Massimo , Calebich Silvia , Zulli Roberto , Castellano Maurizio , Rizzoni Damiano , Bettoni Giorgio , Cinelli Angelo , Porteri Enzo , Corsetti Vittorio , Agabiti-Rosei Enrico
Published: June 2012

Abstract
The aims of this study were to determine the prevalence of structural changes in the carotid arteries and heart and the correlation between these changes and the commonly recognized cardiovascular risk factors in the general population. Structural changes in the carotid arteries were defined as the intima-media thickness of the artery measured by B-mode ultrasound. Changes in the heart were defined as left ventricular mass index (LVMI) measured by echocardiography. LVMI values greater than 134 g/m
2
in men and greater than 110 g/m
2
in women were considered abnormal, indicating the presence of left ventricular hypertrophy. Blood pressure (BP) was measured in the clinic setting with a mercury sphygmomanometer and by 24-hour noninvasive ambulatory monitoring. Hypertension was defined as a sustained systolic BP greater than or equal to 160 mm Hg and/or diastolic BP increase greater than or equal to 95 mm Hg. The study population consisted of 225 subjects (107 women and 118 men) 48 to 64 years old. Prevalence of intima-media thickening (intima-media thickness >1 mm) was 11% in normotensive subjects and 44% in hypertensive subjects. The presence of plaque (wall thickening with either mineralization or focal protrusion in the lumen at least 50% greater than the surrounding wall, usually >2 mm) was observed in 35% of normotensive subjects and 44% of hypertensive subjects. The prevalence of left ventricular hypertrophy was 13% in normotensive subjects and 19% in hypertensive subjects. Intima-media thickness in the common and bifurcation segments of carotid arteries correlated well with LVMI (
r
=.20 and
r
=.19, respectively;
P
<.01). Intima-media thickness and LVMI were both positively related to 24-hour monitored BP (
P
<.01). However, in the multivariate analysis, body mass index (
P
=.027), sex (
P
<.001), and 24-hour mean BP (
P
=.025) were the most significant determinants of LVMI, whereas carotid artery intima-media thickness was found to be associated best with age (
P
<.001), cigarette smoking (
P
=.009), serum cholesterol (
P
=.025), serum glucose (
P
=.038), and nighttime systolic BP (
P
=.006). Logistic regression analysis confirmed the association between the presence of plaque and age (
P
<.001), nighttime systolic BP (
P
<.05), and cigarette smoking (
P
<.05); a negative association between plaque and the decrease in mean systolic BP from daytime to nighttime was also observed (
P
<.001). In conclusion, in a general population of unselected middle-aged subjects, carotid wall thickness and LVMI were associated with each other and related to 24-hour BP levels although the major determinants of carotid wall and cardiac structure were different.