bluuebunny/crossref_metadata_2025 huggingface dataset:
Glucagon Receptor Gene Mutation (Gly40Ser) in Human Essential Hypertension
Authors: Brand Eva , Bankir Lise , Plouin Pierre-François , Soubrier Florent
Published: June 2012

Abstract
—A missense mutation (Gly40Ser) in exon 2 of the glucagon receptor gene (
GCG-R
) was shown to reduce ligand affinity and impair cAMP response. We conducted a case-control study with a sample of 741 French hypertensive patients with moderate to severe hypertension and 412 normotensive control subjects, who were genotyped for this biallelic variant by use of hybridization with allele-specific oligonucleotides. The Gly40Ser polymorphism was not significantly associated with hypertension in the whole study population, although the frequency of 40Ser carriers in hypertensive subjects was double that in normotensive subjects (3.1% in hypertensives versus 1.5%;
P
=0.087). However, the separate analysis of both genders revealed that 40Ser allele carriers were significantly more frequent (
P
=0.035) among male patients (17/429; 4.0%) than among normotensive male controls (2/242; 0.8%), whereas no significant difference was observed in female subjects (6/312 in hypertensives and 4/170 in normotensives). Further studies are required to interpret the significance of this association.
Evidence for Linkage Between Essential Hypertension and a Putative Locus on Human Chromosome 17
Authors: Baima Jader , Nicolaou Michael , Schwartz Faina , DeStefano Anita L. , Manolis Athanasios , Gavras Irene , Laffer Cheryl , Elijovich Fernando , Farrer Lindsay , Baldwin Clinton T. , Gavras Haralambos
Published: June 2012

Abstract
—Several clinical and animal studies indicate that essential hypertension is inherited as a multifactorial trait with a significant genetic and environmental component. In the stroke-prone spontaneously hypertensive rat model, investigators have found evidence for linkage to blood pressure regulatory genes (quantitative trait loci) on rat chromosomes 2, 10, and X. In 1 human study of French and UK sib pairs, evidence for linkage has been reported to human chromosome 17q, the syntenic region of the rat chromosome 10 quantitative trait loci (QTL). Our study confirms this linkage (
P
=0.0005) and refines the location of the blood pressure QTL.
Attenuated In Vitro Coronary Arteriolar Vasorelaxation to Insulin-like Growth Factor I in Experimental Hypercholesterolemia
Authors: Hasdai David , Nielsen Michael F. , Rizza Robert A. , Holmes David R. , Richardson Darcy M. , Cohen Pinchas , Lerman Amir
Published: June 2012

Abstract
—Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10
−12
to 10
−7
mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10
−4
mol/L
N
G
-monomethyl-
l
-arginine (L-NMMA) or the potassium channel blocker 10
−2
mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5±1.0 versus 1.9±0.08 mmol/L;
P
<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (
P
=0.80) or IGF-1 (
P
=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79±6% versus 42±8%;
P
=0.01) but not insulin (43±6% versus 53±7%;
P
=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (
P
<0.001) and TEA (
P
=0.01), whereas only L-NMMA attenuated insulin (
P
<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (
P
<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.
Microvascular Responses to Ischemia/Reperfusion in Normotensive and Hypertensive Rats
Authors: Kurose Iwao , Wolf Robert , Cerwinka Wolfgang , Granger D. Neil
Published: June 2012

Abstract
—The objective of the present study was to determine whether long-term arterial hypertension renders the microvasculature more vulnerable to the deleterious inflammatory responses elicited by ischemia and reperfusion (I/R). Intravital fluorescence microscopy was used to monitor leukocyte adherence and emigration, platelet-leukocyte aggregation, and albumin extravasation in mesenteric postcapillary venules of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) after 10 minutes of ischemia and subsequent reperfusion. Significant and comparable increases in leukocyte adherence/emigration and the formation of platelet aggregates were elicited by I/R in both WKY and SHR. Albumin extravasation was enhanced after I/R in SHR, but not in WKY. Monoclonal antibodies directed against the adhesion glycoproteins CD18, P-selectin, or ICAM-1 showed similar patterns of protection against the I/R-induced inflammatory responses in WKY and SHR. The enhanced albumin extravasation noted in postischemic venules of SHR was prevented by immunoneutralization of either CD18 on leukocytes or ICAM-1 on endothelial cells. These results suggest that, whereas long-term arterial hypertension does not significantly modify the leukocyte and platelet recruitment normally elicited in venules by I/R, it does result in an exaggerated albumin leakage response, which is mediated by an interaction between β
2
(CD18) integrins on leukocytes and ICAM-1 on endothelial cells.
Prevention of Renal Damage by Angiotensin II Blockade, Accompanied by Increased Renal Hepatocyte Growth Factor in Experimental Hypertensive Rats
Authors: Matsumoto Keiko , Morishita Ryuichi , Moriguchi Atsushi , Tomita Naruya , Yo Yoshikage , Nishii Tadahiko , Matsumoto Kunio , Nakamura Toshikazu , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Abstract
—Hepatocyte growth factor (HGF) is a unique growth factor that has many protective functions against renal damage. Our previous study demonstrated that HGF stimulated the growth of endothelial and epithelial cells without the replication of mesangial cells. Moreover, angiotensin (Ang) II significantly decreased local HGF production in mesangial cells. Therefore, we examined the effects of Ang II blockade on renal HGF expression and renal damage in experimental hypertensive rats. An angiotensin-converting enzyme inhibitor (cilazapril; 10 mg · kg
−1
· d
−1
), an Ang II type 1 receptor antagonist (E-4177; 30 mg · kg
−1
· d
−1
), hydralazine (8 mg · kg
−1
· d
−1
), and vehicle were administered to 16-week-old stroke-prone spontaneously hypertensive rats (SHR-SP) for 3 weeks. Renal damage was evaluated with a computer analysis system, and renal HGF mRNA was measured by Northern blot analysis. Blood pressure of SHR-SP was significantly decreased by all drug treatments compared with vehicle. Moreover, cilazapril, E-4177, and hydralazine significantly decreased the thickening and necrosis of blood vessels compared with vehicle. Similarly, degeneration and necrosis of glomeruli were also markedly improved by cilazapril and E-4177 (
P
<0.01). We next examined the effects of Ang II blockade on renal HGF expression in SHR-SP. Renal HGF mRNA was markedly decreased in SHR-SP compared with Wistar-Kyoto rats, although Ang II blockade by cilazapril and E-4177 but not hydralazine significantly increased renal HGF mRNA in SHR-SP. Ang II blockade significantly increased renal HGF (a protective growth factor for tubular epithelial cells); thus, we examined tubular histological appearance. Degeneration and necrosis of tubules were significantly improved by cilazapril and E-4177 treatment (
P
<0.01). In addition, cell infiltration into the glomeruli and hemorrhage were also significantly reduced in SHR-SP treated with cilazapril or E-4177. The present data demonstrated the prevention of renal damage by Ang II blockade in SHR-SP, which was accompanied by a significant increase in renal HGF mRNA. Given the strong mitogenic activity and antiapoptotic actions of HGF on endothelial and epithelial cells, we believe that increased local HGF production by the blockade of Ang II may improve renal function in hypertension.
Altered Adrenal Sensitivity to Angiotensin II in Low-Renin Essential Hypertension
Authors: Fisher Naomi D. L. , Hurwitz Shelley , Ferri Claudio , Jeunemaitre Xavier , Hollenberg Norman K. , Williams Gordon H.
Published: June 2012

Abstract
—Low-renin essential hypertension (LREH) describes a widely recognized classification validated by clinical features, including salt-sensitive blood pressure and diuretic responsiveness. Classic physiological teaching has cited normal plasma aldosterone concentration despite suppressed renin as evidence for adrenal supersensitivity to angiotensin II (Ang II). We studied 94 patients with LREH, 242 normal-renin hypertensives, and 135 normal subjects as controls. Low-renin hypertensives did not differ significantly from the other groups in either basal or Ang II–stimulated aldosterone concentrations on a high-sodium diet. Stimulated with a low-sodium diet, LREH patients demonstrated the smallest rise in basal aldosterone secretion. Ang II responsiveness was also subnormal: the rise in aldosterone after Ang II infusion in LREH (613±39 pmol/L), although greater than in nonmodulators (180±17 pmol/L;
P
=0.001), was less than either the patients with intact modulation (940±53 pmol/L;
P
=0.001) or normotensives (804±50 pmol/L;
P
<0.05). Blacks with LREH demonstrated an even lower response than low-renin whites ((388±50 versus 610±47 pmol/L;
P
=0.0001). In contrast, the rise in systolic blood pressure with Ang II infusion on a low-salt diet was greatest among LREH patients (
P
=0.001). Patients with LREH and nonmodulators were equally salt-sensitive. These results indicate that the adrenal response in LREH is normal on a high-salt diet but becomes progressively more abnormal as sodium control mechanisms are stressed. The factors that mediate enhanced adrenal response to Ang II with sodium restriction may be defective, suggesting the existence of alternative physiological mechanisms for sodium homeostasis in the low-renin state.
In Vivo Evidence That Endogenous Dopamine Modulates Sympathetic Activity in Man
Authors: Mannelli Massimo , Ianni Lucia , Lazzeri Chiara , Castellani Walter , Pupilli Cinzia , La Villa Giorgio , Barletta Giuseppe , Serio Mario , Franchi Franco
Published: June 2012

Abstract
—Dopamine receptors type 2 (D2)-like receptor blockers cause an increase in the norepinephrine response to intense physical exercise. However, during intense physical exercise, D2-like antagonists also cause an increase in the epinephrine response, which itself might cause an increase in plasma norepinephrine through the activation of β2 presynaptic receptors. Therefore, we evaluated the effect of domperidone, a D2-like antagonist, on the norepinephrine response to physical exercise in 6 Addison patients (3 were adrenalectomized and 3 had adrenal tuberculosis). In these patients, the norepinephrine increase observed during exercise was significantly higher after the administration of domperidone than a placebo (F=4,328;
P
<0.001). Because peripheral plasma norepinephrine does not reflect the sympathetic tone to the heart accurately, we evaluated the effect of domperidone administration (20 mg orally) on the sympathovagal balance, which was measured by the ratio between the high- and low-frequency components of heart rate variability, in 9 normal volunteers in the supine and sitting positions. When compared with placebo, domperidone caused a significant increase in the low/high frequency ratio (
P
<0.05) in the sitting position without modifying basal and stimulated norepinephrine plasma levels or blood pressure. These data support a role for endogenous dopamine in modulating norepinephrine release by human sympathetic nerves in vivo.
Role of Angiotensin Receptor Subtypes in Mesenteric Vascular Proliferation and Hypertrophy
Authors: Cao Zemin , Dean Rachael , Wu Leonard , Casley David , Cooper Mark E.
Published: June 2012

Abstract
—The aim of this study was to explore the regulation of angiotensin receptors after chronic infusion with angiotensin II (Ang II) and to clarify the relative roles of the angiotensin type 1 (AT
1
) and type 2 (AT
2
) receptors in the mediation of Ang II–induced mesenteric vascular hypertrophy. In male Sprague-Dawley rats, Ang II infusion at a dose of 58.3 ng/min by subcutaneous osmotic minipumps for 14 days led to increased mesenteric weight and wall:lumen ratio of the vessels and proliferation of smooth muscle cells. These vascular changes were attenuated by either valsartan, an AT
1
receptor antagonist, at a dose of 30 mg · kg
−1
· d
−1
by gavage, or
PD123319
, an AT
2
receptor antagonist, at a dose of 830 ng/min by intraperitoneally implanted osmotic minipumps. Ang II infusion was associated with hypertension, which was prevented by valsartan, but not PD123319.
125
I-Sar
1
, Ile
8
Ang II binding to mesenteric vasculature was increased after Ang II infusion. Valsartan treatment was associated with reduced Ang II binding to both receptor subtypes, whereas
PD123319
was associated with reduced Ang II binding to only the AT
2
receptor subtype. These findings suggest that the trophic and proliferative effects of Ang II on the mesenteric vasculature are mediated by both AT
1
and AT
2
receptors.
Activation of the Na
+
-H
+
Exchanger Modulates Angiotensin II–Stimulated Na
+
-Dependent Mg
2+
Transport in Vascular Smooth Muscle Cells in Genetic Hypertension
Authors: Touyz Rhian M. , Schiffrin Ernesto L.
Published: June 2012

Abstract
—This study investigated the role of the Na
+
-H
+
exchanger (NHE) on angiotensin II (Ang II)–induced activation of Na
+
-dependent Mg
2+
transport in vascular smooth muscle cells (VSMCs) from Wistar-Kyoto rats (WKY; n=20) and spontaneously hypertensive rats (SHR; n=20). Intracellular free concentrations of Mg
2+
([Mg
2+
]
i
) and Na
+
([Na
+
]
i
) and intracellular pH (pH
i
) were measured with the specific fluorescent probes mag–fura 2-AM, SBFI-AM, and BCECF-AM, respectively. Na
+
dependency of Mg
2+
transport was assessed in Na
+
-free buffer, and the role of the NHE was determined with the highly selective NHE blocker 5-(
N
-methyl-
N
-isobutyl) amiloride (MIA). Basal [Mg
2+
]
i
was lower in SHR than WKY (0.59±0.01 versus 0.71±0.01 mmol/L,
P
<0.05). Basal pH
i
and [Na
+
]
i
were not different between the 2 groups. Ang II dose dependently increased [Na
+
]
i
and pH
i
and decreased [Mg
2+
]
i
. Responses were significantly greater (
P
<0.05) in SHR versus WKY ([Na
+
]
i
E
max
=37.5±1.1 versus 33.7±1.9 mmol/L; pH
i
E
max
=7.35±0.04 versus 7.20±0.01; [Mg
2+
]
i
E
min
=0.28±0.09 versus 0.53±0.02 mmol/L, SHR versus WKY). In Na
+
-free buffer, Ang II–elicited [Mg
2+
]
i
responses were inhibited. MIA (1 μmol/L) inhibited Ang II–stimulated responses in WKY and normalized responses in SHR ([Mg
2+
]
i
E
min
=0.49±0.02). Ang II–stimulated activation of NHE was significantly increased (
P
<0.05) in SHR (0.07±0.002 ΔpH
i
/s) compared with WKY (0.05±0.004 ΔpH
i
/s). These data demonstrate that in VSMCs [Mg
2+
]
i
regulation is Na
+
dependent, that activation of NHE modulates Na
+
-Mg
2+
transport, and that increased activity of NHE may play a role in altered Na
+
-dependent regulation of [Mg
2+
]
i
in SHR.
Effect of Angiotensin-(1-7) and Bradykinin in Patients With Heart Failure Treated With an ACE Inhibitor
Authors: Davie Andrew P. , McMurray John J. V.
Published: June 2012

Abstract
—Angiotensin-(1-7) is a product of angiotensin processing that has been proposed to have vasodepressor effects, both on its own and in combination with bradykinin, which may be pathophysiologically and therapeutically important. Despite this, there has been very little examination of its effects in humans and none in heart failure patients or in other patients treated with ACE inhibitors. We therefore sought to determine the effects of angiotensin-(1-7) in patients with heart failure treated with an ACE inhibitor, as well as any interaction with the effects of bradykinin. A locally active dose of angiotensin-(1-7), alone and in combination with bradykinin, was infused into the nondominant brachial artery while forearm blood flow was measured by venous occlusion plethysmography in 8 patients with heart failure treated with ACE inhibitors. Although bradykinin on its own caused profound vasodilation, there was no effect of angiotensin-(1 to 7) on its own or any effect of angiotensin-(1-7) on the response to bradykinin. We conclude that angiotensin-(1-7) is biologically inactive in the forearm circulation of patients with heart failure treated with an ACE inhibitor. The contrast between these findings and previously reported preclinical findings calls into question the relevance of angiotensin-(1-7) to the hemodynamic effects of ACE inhibitors.
Effect of Dietary Patterns on Ambulatory Blood Pressure
Authors: Moore Thomas J. , Vollmer William M. , Appel Lawrence J. , Sacks Frank M. , Svetkey Laura P. , Vogt Thomas M. , Conlin Paul R. , Simons-Morton Denise G. , Carter-Edwards Lori , Harsha David W.
Published: June 2012

Abstract
—We measured ambulatory blood pressure (ABP) in 354 participants in the Dietary Approaches to Stop Hypertension (DASH) Trial to determine the effect of dietary treatment on ABP (24-hour, day and night) and to assess participants’ acceptance of and compliance with the ABP monitoring (ABPM) technique. After a 3-week run-in period on a control “typical” American diet, subjects (diastolic blood pressure [BP], 80 to 95 mm Hg; systolic BP, <160 mm Hg; mean age, 45 years) were randomly assigned to 1 of 3 diets for an 8-week intervention period: a continuation of the control diet; a diet rich in fruits and vegetables; and a “combination” diet that emphasized fruits, vegetables, and low-fat dairy products. We measured ABP at the end of the run-in and intervention periods. Both the fruit/vegetable and combination diets lowered 24-hour ABP significantly compared with the control diet (
P
<0. 0001 for systolic and diastolic pressures on both diets: control diet, −0.2/+0.1 mm Hg; fruit/vegetable diet, −3.2/−1.9 mm Hg; combination diet, −4.6/−2.6 mm Hg). The combination diet lowered pressure during both day and night. Hypertensive subjects had a significantly greater response than normotensives to the combination diet (24-hour ABP, −10.1/−5.5 versus −2.3/−1.6 mm Hg, respectively). After correction for the control diet responses, the magnitude of BP lowering was not significantly different whether measured by ABPM or random-zero sphygmomanometry. Participant acceptance of ABPM was excellent: only 1 participant refused to wear the ABP monitor, and 7 subjects (2%) provided incomplete recordings. These results demonstrate that the DASH combination diet provides significant round-the-clock reduction in BP, especially in hypertensive participants.
The Nature of Intracrine Peptide Hormone Action
Authors: Re Richard
Published: June 2012

Abstract
—Current theory holds that peptide hormone action results from hormone binding to cell-surface receptors, with the generation of intracellular second messengers. However, a growing body of evidence suggests that intracellular peptide hormone, either internalized or synthesized in situ, can exert physiologically relevant effects. These effects are diverse and poorly understood. I propose that such intracrine action can serve to modulate cellular function over time and thereby play a role in biological memory of various sorts, in the maintenance of hormonal responsiveness, and in cellular differentiation.
Early Upregulation of Endothelial Adhesion Molecules in Obese Hypertensive Men
Authors: Ferri Claudio , Desideri Giovambattista , Valenti Marco , Bellini Cesare , Pasin Mehtap , Santucci Anna , Giancarlo De Mattia
Published: June 2012

Abstract
—Upregulation of endothelial adhesion molecules is the earliest step of atherogenesis. Whether obesity induces endothelial adhesin upregulation is unknown. To address this topic, circulating vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), E-selectin, and von Willebrand factor (vWF) concentrations were evaluated in 22 obese hypertensive (51.4±4.6 years [mean±SD age]), 19 obese normotensive (50.6±3.8 years), 18 nonobese hypertensive (52.3±3.9 years), and 16 nonobese normotensive (52.4±3.5 years) men without other risk factors or overt atherosclerosis. All measurements were repeated in the obese subgroups after weight loss induced by 12 weeks of caloric restriction. Basal circulating VCAM-1 levels were similar between the 2 obese groups but were higher (
P
<0.0001) than in the 2 nonobese groups. No differences were found between nonobese hypertensives and normotensives. Serum low density lipoprotein cholesterol was weakly correlated with plasma soluble VCAM-1 levels in pooled, obese subjects (
r
=0.362,
P
=0.02). Plasma soluble adhesin and vWF concentrations decreased significantly after weight loss in obese hypertensives (VCAM-1
P
=0.03, ICAM-1
P
=0.004, E-selectin
P
<0.0001, and vWF
P
=0.003) and normotensives (VCAM-1
P
=0.04, ICAM-1
P
=0.003, E-selectin
P
<0.0001, and vWF
P
<0.0001). Body mass index was correlated with plasma E-selectin concentrations at baseline and after weight loss in obese hypertensives (
r
=0.501,
P
=0.018 and
r
=0.466,
P
=0.03, respectively) and obese normotensives (
r
=0.523,
P
=0.021 and
r
=0.460,
P
=0.05, respectively). In conclusion, our data show that obesity per se induces early endothelial activation in hypertensive and normotensive men. Weight loss counteracted endothelial activation in both obese hypertensive and normotensive men.
Genome Scan for Blood Pressure Loci in Mice
Authors: Wright Fred A. , O’Connor Daniel T. , Roberts Elizabeth , Kutey Greg , Berry Charles C. , Yoneda Lisa U. , Timberlake David , Schlager Gunther
Published: June 2012

Abstract
—Hypertension is a complex trait of unknown cause in humans. Mice of the inbred strain BPH/2 serve as a rodent model of human hypertension and display elevated blood pressure compared with the hypotensive strain BPL/1. An F2 intercross of BPH/2 and BPL/1 and 2 backcrosses of BPL/1 with
Mus spretus
were used to perform interval linkage mapping for systolic blood pressure in a genome scan. Significant linkage was observed in the F2s on chromosome 10 (logarithm of the odds score [LOD]=4.9) and on chromosome 13 in the
M spretus
backcross (LOD=3.3), with additional suggestive LODs on chromosomes 2, 6, 8, and 18. In addition, several suggestive linkages were observed for phenotypes associated with human hypertension. Our study is the first reported genome-wide linkage scan for blood pressure genes in the mouse.
Aging, High Salt Intake, and Renal Dopaminergic Activity in Fischer 344 Rats
Authors: Vieira-Coelho Maria A. , Hussain Tahir , Kansra Vikram , Serrao Maria P. , Guimaraes Joao T. , Pestana Manuel , Soares-da-Silva Patricio , Lokhandwala Mustafa F.
Published: June 2012

Abstract
—The present study examined renal dopaminergic activity and its response to high salt (HS) intake in adult (6-month-old) and old (24-month-old) Fischer 344 rats. Daily urinary excretion of
l
-3,4-dihydroxyphenylalanine (
l
-DOPA), dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid was similar in adult and old rats; by contrast, daily urinary excretion of norepinephrine in old rats was almost twice that in adult animals. HS intake (1% NaCl) over a period of 24 hours resulted in a 2-fold increase in the urinary excretion of dopamine, DOPAC, and norepinephrine in adult animals but not in old animals. Norepinephrine and L-DOPA plasma levels did not change during HS intake and were similar in both groups of rats. The natriuretic response to an HS intake in old rats (from 4.7±0.4 to 10.7±2.0 nmol · kg
−1
· d
−1
; Δ=6.0±0.9 nmol · kg
−1
· d
−1
) was less than in adult rats (from 5.2±0.4 to 13.5±2.5 nmol · kg
−1
· d
−1
; Δ=8.3±0.8 nmol · kg
−1
· d
−1
). A diuretic response to HS intake was observed in adult rats (from 20.9±2.3 to 37.6±2.8 mL · kg
−1
· d
−1
) but not in old rats (from 37.7±5.7 to 42.3±6.0 mL · kg
−1
· d
−1
). Dopamine levels and dopamine/L-DOPA ratios in the renal cortex of old rats were greater than in adult rats. HS intake increased both dopamine levels and dopamine/L-DOPA ratios in the renal cortex of adult rats but not in old rats. Aromatic
l
-amino acid decarboxylase activity was higher in old rats than in adult rats; HS intake increased
l
-amino acid decarboxylase activity (nmol · mg protein
−1
· l5 min
−1
) in adult rats (from 67±1 to 93±1) but not in old rats (from 86±2 to 87±2). Dopamine inhibited Na
+
,K
+
-ATPase activity in proximal tubules obtained from adult rats, but it failed to exert such an inhibitory effect in old rats. It is concluded that renal dopaminergic tonus in old rats is higher than in adult rats but fails to respond to HS intake as observed in adult rats. This may be due in part to the inability of dopamine to inhibit Na
+
,K
+
-ATPase activity in old rats.
Adenovirus-Mediated Gene Delivery to Hypothalamic Magnocellular Neurons in Mice
Authors: Vasquez Elisardo C. , Beltz Terry G. , Meyrelles Silvana S. , Johnson Alan Kim
Published: June 2012

Abstract
—Vasopressin is synthesized by magnocellular neurons in supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei and released by their axon terminals in the neurohypophysis (NH). With its actions as an antidiuretic hormone and vasoactive agent, vasopressin plays a pivotal role in the control of body fluids and cardiovascular homeostasis. Because of its well-defined neurobiology and functional importance, the SON/PVN-NH system is ideal to establish methods for gene transfer of genetic material into specific pathways in the mouse central nervous system. In these studies, we compared the efficiency of transferring the gene lacZ, encoding for β
-
galactosidase (β-gal), versus a gene encoding for green fluorescent protein by using replication-deficient adenovirus (Ad) vectors in adult mice. Transfection with viral concentrations up to 2×10
7
plaque-forming units per coverslip of NH, PVN, and SON in dissociated, cultured cells caused efficient transfection without cytotoxicity. However, over an extended period of time, higher levels (50% to 75% of the cells) of β
-
gal expression were detected in comparison with green fluorescent protein (5% to 50% of the cells). With the use of a stereotaxic approach, the pituitary glands of mice were injected with Ad (4×10
6
plaque-forming units). In material from these animals, we were able to visualize the expression of the β
-
gal gene in the NH and in magnocellular neurons of both the PVN and SON. The results of these experiments indicate that Ad–Rous sarcoma virus promoter–β
-
gal is taken up by nerve terminals at the injection site (NH) and retrogradely transported to the soma of the neurons projecting to the NH. We conclude that the application of these experimental approaches will provide powerful tools for physiological studies and potential approaches to deliver therapeutic genes to treat diseases.
A
−6
G Variant of Angiotensinogen Gene and Aldosterone Levels in Hypertensives
Authors: Fardella Carlos , Zamorano Pamela , Mosso Lorena , Gómez Luis , Pinto Mauricio , Soto Julia , Oestreicher Eveline , Cortés Paola , Claverie Ximena , Montero Joaquín
Published: June 2012

Abstract
—Recently, a novel mutation in the promoter region of the angiotensinogen gene that involves the presence of an adenine instead of a guanine 6 bp upstream from the transcription initiation site (A
−6
G) has been shown to induce an increase in gene transcription. The aim of this study was to determine the prevalence of the A
−6
G mutation in essential hypertensive patients and to correlate it with aldosterone and renin activity levels. We studied 191 hypertensives. We measured levels of aldosterone (plasma and urinary) and plasma renin activity. We determined the variants A and G using a mutagenically separated polymerase chain reaction technique. In 191 hypertensives, the A variant was detected in 266 of 382 (69.6%) and the G variant in 116 of 382 alleles (30.4%). Plasma aldosterone was significantly higher in patients homozygous for AA than in those homozygous for GG (369±208 versus 246±142 pmol/L). Urinary aldosterone was significantly higher in homozygous AA than in AG or GG patients (62.4±39.4 versus 50.8±25.2 and 37.4±22.3 nmol/d, respectively). When the patients were grouped according to the presence or absence of the A allele, the aldosterone levels and the plasma aldosterone/plasma renin activity ratio were significantly higher in patients with the A allele. The presence of the A variant was associated with higher levels of aldosterone. These results suggest that the presence of the A variant could determine the appearance of arterial hypertension through higher transcription activity of the angiotensinogen gene and concomitant aldosterone production.
Modulation of Coronary Flow and Cardiomyocyte Size by Sensory Fibers
Authors: Zanesco Angelina , Costa Soraia K. P. , Riado Sonia R. , Nathan Luciana P. , de Oliveira Claudia F. , De Luca Iara M. S. , Antunes Edson , De Nucci Gilberto
Published: June 2012

Abstract
—Cardiac tissue is densely innervated by sensory neurons that are believed to play important modulatory roles in cardiac functions. In this study, pretreatment of neonate rats with capsaicin was performed. In adult rats, cardiomyocyte size and amount of fibrous tissue in left ventricles as well as in vitro coronary flow were evaluated. The chronotropic and inotropic responses to β-adrenoceptor agonists (norepinephrine and isoproterenol), muscarinic agonists (carbachol and pilocarpine), and calcitonin gene–related peptide (CGRP) were also investigated with the use of the isolated right atria preparation. Capsaicin pretreatment significantly (
P
<0.05) reduced both basal coronary flow (18% reduction) and cardiomyocyte size (34% reduction) without affecting the amount of fibrous tissues in the left ventricles. The positive inotropic and chronotropic effects in response to norepinephrine in the isolated rat heart did not significantly differ between control and capsaicin-treated rats. Similarly, the positive chronotropic effects in response to norepinephrine, isoproterenol, and CGRP as well as the negative chronotropic responses to carbachol and pilocarpine in the isolated right atria were not affected by capsaicin pretreatment. Our data are consistent with the suggestion that reductions of both basal coronary flow and cardiomyocyte size seen in hearts from capsaicin-pretreated rats may be consequences of CGRP depletion. The cardiomyocyte size reduction produced by capsaicin treatment may be related to a modulatory role of CGRP as a growth factor.
Long-Term Nitric Oxide Inhibition and Chronotropic Responses in Rat Isolated Right Atria
Authors: Riado Sonia R. , Zanesco Angelina , Barker Louis Allen , De Luca Iara M. S. , Antunes Edson , De Nucci Gilberto
Published: June 2012

Abstract
—The long-term administration of nitric oxide synthesis inhibitors induces arterial hypertension accompanied by left ventricular hypertrophy and myocardial ischemic lesions. Because the enhancement of sympathetic drive has been implicated in these phenomena, the current study was performed to determine the potency of β-adrenoceptor agonists and muscarinic agonists on the spontaneous rate of isolated right atria from rats given long-term treatment with the nitric oxide inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME). Atrial lesions induced by long-term treatment with L-NAME were also evaluated. Long-term L-NAME treatment caused a time-dependent, significant (
P
<0.05) increase in tail-cuff pressure compared with control animals. Our results showed that the potency of isoproterenol, norepinephrine, carbachol, and pilocarpine in isolated right atria from rats given long-term treatment with L-NAME for 7, 15, 30, and 60 days was not affected as compared with control animals. Addition of L-NAME in vitro (100 μmol/L) affected neither basal rate nor chronotropic response for isoproterenol and norepinephrine in rat heart. Stereological analysis of the right atria at 15 and 30 days revealed a significant increase on amount of fibrous tissues in L-NAME–treated groups (27±2.3% and 28±1.3% for 15 and 30 days, respectively;
P
<0.05) as compared with the control group (22±1.1%). Our results indicate that nitric oxide does not to interfere with β-adrenoceptor–mediated and muscarinic receptor–mediated chronotropic responses.
Effects of Amlodipine on Tubulointerstitial Lesions in Normotensive Hyperoxaluric Rats
Authors: Toblli Jorge Eduardo , Ferder León , Angerosa Margarita , Inserra Felipe
Published: June 2012

Abstract
—Although controversial, a number of reports have suggested that calcium antagonists can retard or prevent the progression of various renal diseases in experimental models. Nevertheless, there are few data related to tubulointerstitial changes in these studies. On the other hand, hyperoxaluria is a recognized cause of tubulointerstitial lesions, and this could contribute to the development of hypertension and chronic renal failure. The aim of the present study was to evaluate a possible beneficial effect of amlodipine, a 1,4-dihydropyridine class of calcium antagonist, in a model of primary tubulointerstitial lesion produced by hyperoxaluria. Two-month-old male Sprague-Dawley rats were separated into 4 groups for a 4-week period: G1 (control; tap water only); G2 (hyperoxaluric); G3 (hyperoxaluric plus amlodipine treatment); and G4 (amlodipine treatment). G2 and G3 rats were given 1% ethylene glycol (a precursor for oxalates) in drinking water, and G3 and G4 rats were given amlodipine 2 mg · kg
−1
· d
−1
by gavage. At the end of the study, we evaluated by semiquantitative scores (0 to 4) the different renal tubulointerstitial lesions, urinary albumin excretion, renal function by creatinine clearance, and blood pressure. Rats belonging to the hyperoxaluric group treated with amlodipine (G3) had fewer tubulointerstitial lesions, as follows: (1) inflammatory infiltrate score: 3.31±0.07 versus 0.23±0.12;
P
<0.05; (2) tubular atrophy score: 3.33±0.33 versus 0.50±0.22,
P
<0.05; (3) interstitial fibrosis score: 2.76±0.34 versus 0.31±0.16,
P
<0.05; (4) oxalate deposits score: 3.66±0.33 versus 0.09±0.08,
P
<0.05; (5) lower urinary albumin excretion (11.3±2 versus 27±4.5 mg/d,
P
<0.01); and (6) higher creatinine clearance (1.22±0.08 versus 1.13±0.08,
P
<0.01) compared with the hyperoxaluric group untreated with amlodipine (G2). On the other hand, there were no significant changes in blood pressure in any group. In view of these data, we suggest that amlodipine, probably by nonhemodynamic mechanisms of action, can provide an important benefit in the prevention of epithelial tubular cell injury and inflammatory response and therefore in the prevention of the progressive tubulointerstitial fibrosis caused by oxalates.
Influence of Female Sex Hormones on Endothelium-Derived Vasoconstrictor Prostanoid Generation in Microvessels of Spontaneously Hypertensive Rats
Authors: Dantas Ana Paula V. , Scivoletto Regina , Fortes Zuleica B. , Nigro Dorothy , Carvalho Maria Helena C.
Published: June 2012

Abstract
—Although female sex hormones may attenuate endothelial dysfunction in spontaneously hypertensive rats (SHR) by increasing endothelium-derived relaxing factors (EDRFs), the influence of ovarian hormones on the generation of endothelium-derived contracting factors (EDCFs) remains unknown. The aim of this study was to evaluate the effect of estrogen and progesterone on the generation of vasoconstrictor prostanoids and superoxide anion (O
2
−
) by microvessels from SHR. Vascular reactivity to norepinephrine (NE), acetylcholine (ACh), and sodium nitroprusside (SNP) were evaluated in the mesenteric arteriolar bed from estrous (OE) and ovariectomized (OVX) SHR. OVX-SHR were treated for 24 hours or 15 days with estradiol and for 15 days with estradiol+progesterone. The vascular reactivity was evaluated in the absence or presence of indomethacin (INDO, 10 μmol/L) and sodium diclofenac (DIC, 10 μmol/L), ridogrel (RID, 50 μmol/L), dazoxiben (DAZ, 10 μmol/L), or superoxide dismutase (SOD, 100 U/mL). Prostanoid levels in the arteriolar perfusate of mesenteries with or without endothelium were measured by enzyme immunoassay. An increased reactivity to NE and reduced sensitivity to ACh were observed in microvessels from OVX-SHR compared with OE-SHR. There were no differences in the responses to SNP. Treatments with estradiol and estradiol+progesterone similarly restored these altered responses. INDO, DIC, RID, and SOD also restored the NE and ACh responses in OVX-SHR. DAZ had no effect on the vascular reactivities. The release of PGF
2α
, but not of TXB
2
and 6-keto-PGF
1α
, was greater in OVX-SHR than in OE-SHR microvessels with endothelium when stimulated by NE. This response was normalized by hormonal treatments. Neither NE nor ACh stimulated prostanoid production by microvessels without endothelium. These results suggest that estrogen may protect female SHR against severe hypertension partly by decreasing the synthesis of EDCFs such as PGH
2
/PGF
2α
and O
2
−
.
Increased Acetylcholine-Induced Vasodilation in Pregnant Rats
Authors: Dantas Maria Fernanda Villela , Urban Marcia , Spray David , Catelli de Carvalho Maria Helena , Passaglia Rita de Cassia Aleixo Tostes
Published: June 2012

Abstract
—We have tested the hypothesis that increased gap junctional communication contributes to the augmented endothelium-dependent vasodilation in pregnancy. Contractile force and connexin43 expression were measured in aortic rings from nonpregnant and pregnant rats. Norepinephrine-constricted aortas from pregnant rats were more sensitive to acetylcholine, but not to sodium nitroprusside, compared with those from nonpregnant rats. Vessels from pregnant rats, constricted either with 45 mmol/L KCl or with norepinephrine+10
−4
mol/L
N
G
-monomethyl-
l
-arginine (L-NMMA), an inhibitor of nitric oxide synthase, also exhibited greater relaxation to acetylcholine. Heptanol, an uncoupler of gap junctional communication, inhibited acetylcholine responses in norepinephrine-constricted aortas from nonpregnant rats but greatly impaired acetylcholine relaxation in aortas from pregnant rats. Heptanol also inhibited in both groups acetylcholine responses in vessels constricted with KCl, only minimally affected acetylcholine relaxation in arteries constricted with norepinephrine+L-NMMA, and did not change sodium nitroprusside–induced relaxation. Tetraethylammonium chloride induced greater contractions in control aortas compared with aortas from pregnant rats. Increased connexin43 mRNA levels were found in the uterus and in the mesenteric, uterine, and thoracic aortic arteries, but not in the heart and brain, from pregnant rats. These results suggest that increased gap junctional communication, possibly due to increased gap junction protein expression, may facilitate the effects of endothelium-derived relaxing factors, contributing to the augmented endothelium-dependent relaxation in arteries from pregnant rats.
Defective Dopamine Receptor Function in Proximal Tubules of Obese Zucker Rats
Authors: Hussain Tahir , Beheray Sucheta A. , Lokhandwala Mustafa F.
Published: June 2012

Abstract
—Some of the pathophysiological consequences of obesity include insulin resistance, increased renal sodium reabsorption, and the development of hypertension. Dopamine promotes renal sodium excretion via activation of D
1
-like receptors present on the proximal tubules. Reduced dopamine-induced natriuresis and a defect in D
1
-like receptor function have been reported in the proximal tubules of hypertensive animals. The present study investigated D
1
-like dopamine receptors and associated G proteins as the initial signaling components in the proximal tubular basolateral membranes of obese Zucker and control lean Zucker rats. We found that the obese rats were hyperinsulinemic, hyperglycemic, and hypertensive compared with the lean rats. Dopamine produced concentration-dependent inhibition of Na,K-ATPase activity in the proximal tubules of lean rats, whereas the inhibitory effect of dopamine was reduced in obese rats. The D
1
-like receptors measured by [
3
H]SCH 23390 binding revealed an ≈45% decrease in
B
max
without a change in
K
d
in the basolateral membranes of obese rats compared with lean rats. Although we found an increase in G
q
/11α and no change in G
s
α in the basolateral membranes of obese rats, dopamine and SKF 38393 failed to stimulate G proteins as measured by [
35
S]GTPγS binding in obese rats, suggesting a receptor–G protein coupling defect. We conclude that decrease in D
1
-like dopamine receptor binding sites and diminished activation of G proteins, resulting perhaps from defective coupling, led to the reduced inhibition by dopamine of Na,K-ATPase activity in the proximal tubules of obese Zucker rats. Such a defect in renal dopamine receptor function may contribute to sodium retention and development of hypertension in obese rats.
Natriuretic Response to Increased Pressure Is Preserved With COX-2 Inhibitors
Authors: Gross Jennifer M. , Dwyer Jennifer E. , Knox Franklyn G.
Published: June 2012

Abstract
—Elevation of renal interstitial hydrostatic pressure (RIHP) by direct renal interstitial volume expansion increases sodium excretion. This natriuretic response is blunted by the nonspecific inhibition of the cyclooxygenase (COX) enzymes. The present study tested the hypothesis that the natriuretic response to increased RIHP during direct renal interstitial volume expansion is dependent on COX-1 but not COX-2. RIHP and fractional excretion of sodium (FE
Na
) were measured before and after direct renal interstitial volume expansion in control rats (n=7), rats infused with the COX-1 inhibitor piroxicam (n=6, 1.5 mg/kg), and rats infused with the COX-2 inhibitors NS-398 (n=5, 1.5 mg/kg) and meloxicam (n=6, 0.3 mg/kg). In control animals, direct renal interstitial volume expansion significantly increased RIHP (Δ2.3±0.5 mm Hg,
P
<0.05) and FE
Na
(Δ1.1±0.3%,
P
<0.05). Likewise, in animals infused with NS-398 or meloxicam, direct renal interstitial volume expansion significantly increased RIHP (Δ1.8±0.6 mm Hg,
P
<0.05, and Δ1.7±0.3 mm Hg,
P
<0.05) and FE
Na
(Δ1.5±0.4%,
P
<0.05, and Δ1.1±0.3%,
P
<0.05), respectively. In contrast, infusion of piroxicam significantly blunted the natriuretic response to direct renal interstitial volume expansion (ΔFE
Na
0.3±0.2%), even though RIHP was increased (Δ1.9±0.6 mm Hg,
P
<0.05). Infusion of piroxicam but not NS-398 or meloxicam blunted the natriuretic response to increased renal interstitial hydrostatic pressure, suggesting that the natriuretic response to increased blood pressure may be preserved during inhibition of COX-2.
Carvedilol and Lacidipine Prevent Cardiac Hypertrophy and Endothelin-1 Gene Overexpression After Aortic Banding
Authors: Massart Pierre-Emmanuel , Donckier Julian , Kyselovic Jan , Godfraind Théophile , Heyndrickx Guy R. , Wibo Maurice
Published: June 2012

Abstract
—Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%;
P
<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times;
P
<0.05) and skeletal α-actin (3.6 times;
P
<0.05), but the expression of cardiac α-actin was not modified. Oral administration of carvedilol at a dose of 30 mg · kg
−1
· d
−1
to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal α-actin gene expression. Carvedilol at a lower dose (7.5 mg · kg
−1
· d
−1
) and lacidipine 1 mg · kg
−1
· d
−1
had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (
P
<0.01) and preproendothelin-1 overexpression (
P
<0.05). Labetalol (60 mg · kg
−1
· d
−1
) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg · kg
−1
· d
−1
did not prevent myocardial overexpression of skeletal α-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.
Role of the Angiotensin Type 2 Receptor in the Regulation of Blood Pressure and Renal Function
Authors: Carey Robert M. , Wang Zhi-Qin , Siragy Helmy M.
Published: June 2012

Abstract
—The renin-angiotensin system is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Virtually all of the biological actions of the principle effector peptide angiotensin II (ANG II) have been attributed to an action at the type 1 (AT
1
) ANG receptor. Until recently, the functional role of the type 2 (AT
2
) receptor, if any, has been unknown, possibly because the AT
2
receptor has a low degree of expression compared with that of the AT
1
receptor. Evidence has now accumulated that the AT
2
receptor opposes functions mediated by the AT
1
receptor. Whereas the AT
1
receptor stimulates cell proliferation, the AT
2
receptor inhibits proliferation and promotes cell differentiation. These differences in growth responses have been ascribed to different cell signaling pathways in which the AT
1
receptor stimulates protein phosphorylation and the AT
2
receptor dephosphorylation. During the past 5 years, studies have demonstrated that the AT
2
receptor is responsible for vasodilation and natriuresis, thus opposing the vasoconstrictor and antinatriuretic effects of ANG II mediated through the AT
1
receptor. Work from our laboratory and others indicates that the AT
2
receptor stimulates vasodilation and natriuresis by an autocrine cascade including bradykinin, nitric oxide, and cyclic GMP. The AT
2
receptor also has been found to control vasodilator prostaglandins, which have a role in blood pressure regulation. The AT
2
receptor appears to play a counterregulatory protective role in the regulation of blood pressure and sodium excretion that opposes the AT
1
receptor.