bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of an Endothelin Antagonist on Hemodynamic Responses to Angiotensin II
Authors: Balakrishnan Suchitra M. , Wang Hui Di , Gopalakrishnan Venkat , Wilson Thomas W. , McNeill J. Robert
Published: June 2012

We determined changes in blood pressure, cardiac output, and total peripheral conductance evoked by intravenous infusions of angiotensin II (Ang II) in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) before and after pretreatment with bosentan, a nonselective endothelin antagonist. Blood pressure was recorded by radiotelemetry and cardiac output by ultrasonic transit-time flow probes. Bosentan per se failed to affect basal blood pressure and evoked only small changes in cardiac output and total peripheral conductance in both strains. The pressor effects of Ang II were exaggerated in SHR compared with WKY. Strikingly, bosentan pretreatment blunted the increases in blood pressure, the fall in cardiac output, and the decreases in conductance evoked by lower doses of Ang II but not higher doses of the peptide. This effect was observed in both rat strains but was more pronounced in SHR. These data suggest that endothelin contributes to the hemodynamic effects of Ang II in both SHR and WKY and that endothelin may contribute to the exaggerated pressor responsiveness of SHR to Ang II.
The Y Chromosome
Authors: Kreutz Reinhold , Stock Philippe , Struk Berthold , Lindpaintner Klaus
Published: June 2012

Previous studies have revealed conflicting evidence concerning a Y-chromosome effect on blood pressure (BP) in genetic crosses involving different strains of spontaneously hypertensive rats (SHR or SHRSP). We had previously found an ≈16 mm Hg difference in systolic BP (
P
<10
−7
) at baseline but not after dietary salt loading (
P
=.82) between F
2
males derived from an SHRSP
HD
grandfather and a Wistar-Kyoto (WKY
HD
-0) grandmother and F
2
males from a reciprocal cross (WKY
HD
-0 grandfather). When we examined F
2
animals from reciprocal crosses between SHRSP
HD
and a congenic strain, WKY
HD
-1, which carries a 6-centimorgan-long SHRSP
HD
-homologous genomic fragment on chromosome 10 that contains a quantitative trait locus linked to BP (
BP/SP-1a
), we found no significant differences either at baseline (
P
=.39) or after salt loading (
P
=.51) in the two reciprocal F
2
cohorts. To test the hypothesis that Y-chromosome–autosomal epistasis accounts for the discrepant Y-chromosome effects on BP, we analyzed the interaction between
BP/SP-1a
and reciprocal cross status on BP in the two crosses. In the F
2
(WKY
HD
-0×SHRSP
HD
) cross, no significant interaction was found for basal systolic BP (
P
=.89), arguing against a major influence of
BP/SP-1a
on the Y-chromosome effects on basal BP. However, a significant interaction between zygosity at the
BP/SP-1a
locus and reciprocal cross status for systolic BP after salt loading (
P
=.022) indicated that the
BP/SP-1a
–SHRSP
HD
allele exhibited a significant effect on BP after dietary excess salt only in males that inherited the SHRSP Y chromosome. These results support the relevance of a Y-chromosome effect on BP and suggest that a complex interplay of epistatic and ecogenetic interactions governs its effect on phenotype.
The Role of Genetic Polymorphisms of Angiotensin-Converting Enzyme in the Progression of Renal Diseases
Authors: McLaughlin Kevin J. , Harden Paul N. , Ueda Shinichiro , Boulton-Jones J. Michael , Connell John M.C. , Jardine Alan G.
Published: June 2012

The renin-angiotensin system is likely to be important in the progression of renal diseases because of its effect on tissue hemodynamics and glomerular cell function. Recent evidence from small studies has suggested a possible role for the genetic determinants of angiotensin converting enzyme activity in the rate of progression of renal failure. We studied the effect of the insertion/deletion
(I/D)
polymorphism of the angiotensin-converting enzyme gene on the rate of renal function deterioration in 822 patients with a variety of renal diseases. We found that the slope of the reciprocal serum creatinine–versus-time plot was steeper in patients homozygous for the deletion allele (
DD
) compared with those homozygous for the insertion allele (
II
) (
P
=.015). When patients with similar renal function at presentation (creatinine <200 μmol/L) were compared,
II
homozygotes had significantly improved renal survival (
P
=.039). Separate analyses of patients with glomerular diseases and tubulointerstitial diseases demonstrated an effect of this genotype in glomerular diseases only. These data provide further evidence of the possible role of the angiotensin-converting enzyme gene in the rate of progression of renal failure, although further studies are required to evaluate the role of this and other proposed candidate genes in renal diseases.
Chelerythrine Inhibits Na
+
-H
+
Exchange in Platelets From Spontaneously Hypertensive Rats
Authors: Gende Oscar A.
Published: June 2012

Hypertension has been associated with increased activity of the Na
+
-H
+
exchanger. To study the role played by protein kinase C in this process, we used chelerythrine, a potent and specific inhibitor of the kinase. After an acid load by ammonium chloride preincubation, platelets isolated from spontaneously hypertensive rats showed a faster and larger increase in intracellular pH than platelets from Wistar-Kyoto rats. The initial rate of intracellular pH recovery was 2.46±0.26 pH units per minute in spontaneously hypertensive rats and 1.74±0.19 in Wistar-Kyoto rats. For protein kinase C inhibition, platelets were incubated for 30 minutes with 10 μmol/L chelerythrine. This treatment induced a significant reduction in the recovery rate only in spontaneously hypertensive rat platelets, indicating that a pathway involving protein kinase C participates in the prestimulation of the exchanger in cells from this rat strain. Addition of chelerythrine reduced the baseline intracellular pH of platelets. No significant difference was found between the decrease of steady-state intracellular pH induced by chelerythrine in either rat strain. These findings indicate that this model of hypertension is characterized by increased Na
+
-H
+
activity mediated by protein kinase C stimulation.
Catecholamine Release Mediates Pressor Effects of Adrenomedullin-(15-22) in the Rat
Authors: Champion Hunter C. , Fry Rebecca C. , Murphy William A. , Coy David H. , Kadowitz Philip J.
Published: June 2012

Human adrenomedullin, a novel hypotensive peptide, contains a six-member ring structure similar to that found in calcitonin gene–related peptide and pancreatic amylin. Unlike the full-sequence peptide, human adrenomedullin-(15-22) [hADM-(15-22)], which contains the ring structure, increases systemic arterial pressure in the rat but not the cat. We undertook the present study to investigate the mechanism by which hADM-(15-22) increases systemic arterial pressure in the rat. Injection of hADM-(15-22) in doses of 10 to 300 nmol/kg IV increased systemic arterial pressure in a dose-dependent manner and was threefold less potent than norepinephrine when doses were compared on a nanomole basis. However, the ring structures of human calcitonin gene–related peptide and human amylin, human calcitonin gene–related peptide-(1-8) and human amylin-(1-8), respectively, had no significant effect on systemic arterial pressure in the rat. Pressor responses to hADM-(15-22) were reduced significantly after administration of phentolamine or reserpine. Responses to hADM-(15-22) were not altered by the angiotensin type 1 blocking agent DuP 753 or the endothelin-A/endothelin-B receptor blocking agent bosentan, and responses to hADM-(15-22) and the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) were reduced after bilateral adrenalectomy. Pressor responses to DMPP were reduced by hexamethonium, whereas the nicotinic blocking agent had no effect on the pressor response to hADM-(15-22). These data suggest that increases in systemic arterial pressure in response to hADM-(15-22) in the rat are mediated by the activation of α-adrenergic receptors by catecholamines released from the adrenal medulla. The present data suggest that hADM-(15-22) releases catecholamines from the adrenal medulla by a noncholinergic mechanism.
Influence of Lifestyle, Coping, and Job Stress on Blood Pressure in Men and Women
Authors: Lindquist Thalina L. , Beilin Lawrence J. , Knuiman Matthew W.
Published: June 2012

We designed this study to clarify the role of work stress on long-term blood pressure control and in particular to investigate whether perceived work stress directly affected resting blood pressure levels or whether there were indirect effects mediated by coping mechanisms and lifestyle. Men (n=337) and women (n=317) working in a government tax office completed questionnaires for assessment of work-related stress, coping strategies, and lifestyle. Seven resting blood pressure measurements were recorded serially on each of two occasions a week apart. Men had higher blood pressures (119.6/68.6 versus 110.9/65.6 mm Hg) than women; they used more “maladaptive” coping strategies, drank more alcohol, and ate less healthily but exercised more than women. There were no direct associations between measures of work stress and blood pressure. In univariate and regression analyses, both body mass index and lifestyle factors in the form of alcohol consumption, exercise, and diet were related to blood pressure in men and women. Various “adaptive” or “maladaptive” coping mechanisms were identified and independently related to both job stress and blood pressure levels. Women were more likely to use “healthier” or adaptive coping mechanisms than men. Thus, work stress per se had no direct effect on blood pressure, but the ways that individuals reported coping with stress were significantly related to blood pressure, with blood pressure elevation effects appearing to be mediated largely by dietary and drinking habits and physical inactivity. The results point to the need to target individual coping strategies and lifestyle as much as the working environment in workplace cardiovascular health promotion programs.
Nitric Oxide in Renal Cortex and Medulla
Authors: Zou Ai-Ping , Cowley Allen W.
Published: June 2012

This study examined the production of nitric oxide (NO) in the renal cortex and medulla through the use of an in vivo microdialysis technique. Oxyhemoglobin (OxyHb) at a concentration of 3 μmol/L was perfused through the dialysis system to trap tissue NO. Methemoglobin (MetHb), which was formed by NO oxidation of OxyHb in the dialysate, was spectrophotometrically assayed at 401 nm. Because the oxidation of OxyHb to produce MetHb is stoichiometric with NO, the production of NO can be determined by the rate of MetHb formation. We found that NO concentration was significantly higher (
P
<.05) in the medulla (57.1±5.57 nmol/L, n=10) than in the cortex (31.2±5.7 nmol/L, n=9). The minimal detectable NO level of this assay is ≈10 nmol/L. Intravenous infusion of
l
-arginine (3 mg/kg per minute) for 30 minutes produced a twofold to threefold increase in cortical and medullary NO; N
G
-nitro-
l
-arginine methyl ester (L-NAME) (10 μg/kg per minute) decreased NO by 33% in the renal cortex and by 46.5% in the renal medulla. We have also compared under the same conditions the degradation products of NO, nitrite, and nitrate in the renal cortex and medulla using in vivo microdialysis combined with microtiter plate colorimetry. Nitrite/nitrate concentration was significantly higher (
P
<.05) in the medulla (2.7±0.6 μmol/L, n=4) than in the cortex (2.1±0.2 μmol/L, n=4). Infusion of
l
-arginine increased cortical and medullary nitrite/nitrate by 65% and 39%, respectively. L-NAME reduced cortical and medullary nitrite/nitrate by 18% and 23%, respectively. The results indicate that the OxyHb-NO microdialysis trapping technique is a highly sensitive in situ method for detecting regional tissue NO concentration and changes in the NO synthase activity in the kidney. These studies have shown that NO concentration is higher in medullary tissue than in the cortex.
Aberrant Renal Vascular Morphology and Renin Expression in Mutant Mice Lacking Angiotensin-Converting Enzyme
Authors: Hilgers Karl F. , Reddi Vasantha , Krege John H. , Smithies Oliver , Gomez R. Ariel
Published: June 2012

To determine whether angiotensin-converting enzyme plays a role in the development and maintenance of normal renal architecture, the renal morphology of 10- to 12-month-old female mice homozygous for a disruption of the converting enzyme gene was compared with that of age-matched wild-type mice. Tubular obstruction, dilatation, and atrophy were present in all kidneys from the homozygous mutant mice but absent in wild types; two kidneys from 4 mutant mice but none from the wild types were hydronephrotic. The entire arterial vascular tree, microdissected from mice with no converting enzyme, was grossly distorted in comparison to the vasculature of wild-type mice; all intrarenal arterial vessels were widened and thickened, including the terminal (afferent) arterioles. In wild-type mice kidneys, renin-positive cells were detected exclusively in a juxtaglomerular localization. In contrast, abnormal distribution of renin immunostaining was observed in mice without converting enzyme; scattered renin-positive cells were seen along the arterial vessels, often in a perivascular localization, and interstitial reninpositive cells surrounded glomeruli. Kidney renin mRNA was increased more than 32-fold in the mutant mice compared with wild types. Northern blot analysis revealed that this increase included the accumulation of large amounts of smaller renin RNA transcripts. In summary, mice lacking the converting enzyme exhibit abnormal renal vessels and tubules. Renin synthesis is increased, accompanied by the presence of small renin mRNA species, and renin is present mainly in interstitial and perivascular cells. We conclude that angiotensin-converting enzyme is necessary to preserve normal kidney architecture and the normal pattern of renin expression.
The Link Among Nitric Oxide Synthase Activity, Endothelial Function, and Aortic and Ventricular Hypertrophy in Hypertension
Authors: Hayakawa Hiroshi , Raij Leopoldo
Published: June 2012

The adaptive changes that occur in the left ventricle (LV) and vessels in response to hypertension, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction, and extracellular matrix increase, do not depend solely on blood pressure elevation. These changes are, in fact, maladaptive since they are forerunners of cardiac failure, stroke, and renal failure. Nitric oxide, an endogenous vasodilator and inhibitor of vascular smooth muscle cell growth, is synthesized in the endothelium by constitutive nitric oxide synthase (cNOS). We investigated the relationships among LV and aortic cNOS activity (conversion of [
14
C] L-arginine to [
14
C] L-citrulline), with LV hypertrophy (LV weight/body weight), and (2) aortic hypertrophy (aortic weight/ length) in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for blood pressure (219±12 versus 211±7 mm Hg,
P
=NS) and age. Compared with their normotensive counterparts, aortic cNOS activity was increased 106% in SHR but reduced by 73% in DS rats. The correlation between blood pressure and aortic cNOS activity was positive (
r
=.74,
P
<.01) in SHR and negative (
r
=-.82,
P
<.01) in DS rats. LV cNOS activity was increased 73% in SHR compared with normotensive Wistar-Kyoto rats (
P
<.01). On the other hand, LV cNOS activity was not increased in hypertensive DS rats compared with normotensive DS rats. In SHR, aortic hypertrophy did not increase significantly and LV hypertrophy increased only 15%, whereas in hypertensive DS rats the aorta and LV hyper-trophied 36% and 88%, respectively (both
P
<.01). Moreover, in DS rats there was a negative correlation between cNOS activity and aortic hypertrophy (
r
=−.70,
P
<.01). In DS rats, antihyper-tensive therapy consisting of an angiotensin-converting enzyme inhibitor, perindopril, and a diuretic, indapamide, normalized blood pressure, aortic cNOS activity, and LV hypertrophy and reduced aortic hypertrophy. Our studies imply that upregulation of vascular cNOS activity has a protective cardiovascular homeostatic role in hypertension. Clinically, the variable end-organ disease observed in individuals with similar severity of hypertension may be explained, at least in part, by genetically conditioned differences in vascular cNOS activity in response to hypertension.
Asymmetrical Dimethylarginine, an Endogenous Nitric Oxide Synthase Inhibitor, in Experimental Hypertension
Authors: Matsuoka Hidehiro , Itoh Shingo , Kimoto Masumi , Kohno Keisuke , Tamai Osamu , Wada Yoshifumi , Yasukawa Hideo , Iwami Gensho , Okuda Seiya , Imaizumi Tsutomu
Published: June 2012

N
G
,
N
G
-dimethyl-
l
-arginine (ADMA) is an endogenously synthesized nitric oxide (NO) synthase inhibitor which has potent pressor/vasoconstrictor effects. Dimethylargininase metabolizes ADMA to
l
-citrulline and plays a key role in determining the in vivo levels of ADMA. To investigate the role of ADMA in the pathogenesis of hypertension, we measured 24-hour urinary excretion of ADMA (UADMA) and nitrate/nitrite (NOx) in Dahl salt-sensitive hypertensive rats and spontaneously hypertensive rats (SHR). In Dahl salt-resistant rats, high-salt diet (8% NaCl) did not increase blood pressure and increased urinary NOx (
P
<.01) without changes in UADMA compared with low-salt diet (0.3% NaCl). In contrast, in Dahl salt-sensitive rats, high-salt diet increased blood pressure (
P
<.01), did not change urinary NOx excretion, and increased UADMA (
P
<.01). There was a significant (
r
=.65,
P
<.01) correlation between UADMA and the level of blood pressure in Dahl salt-sensitive rats. Plasma levels of NOx and ADMA and renal dimethylargininase content were comparable among them. These results may suggest that in Dahl salt-resistant rats, blood pressure is kept constant during high-salt intake, possibly due to the compensatory increased production of NO, and that in Dahl salt-sensitive rats, high-salt intake increases the production of ADMA, attenuates the compensatory increases in NO, and increases blood pressure. These results also suggest that the systemic production of ADMA is not dependent on renal dimethylargininase. SHR had significantly greater urinary NOx excretion (
P
<.05) and smaller UADMA than Wistar-Kyoto rats (
P
<.05), and UADMA was inversely correlated with their mean arterial pressure (
r
=.64,
P
<.05). In conclusion, ADMA, independently of the renal dimethylargininase content, may play a role in the pathogenesis in Dahl salt-sensitive hypertensive rats but not in SHR.
Vascular Smooth Muscle Thromboxane A
2
Receptors Mediate Arachidonic Acid-Induced Sudden Death in Rabbits
Authors: Pfister Sandra L. , Kotulock Donna A. , Campbell William B.
Published: June 2012

We recently identified a subgroup of rabbits (called nonresponders) that were deficient in vascular thromboxane A
2
receptors. Thromboxane A
2
-mediated platelet aggregation was not different between responders and nonresponders. In the present study, we utilized these nonresponders as a model to study the relative contribution of the platelet and vascular thromboxane A
2
receptors to the observed hemodynamic responses associated with arachidonic acid-induced sudden death. Mean arterial pressure was slightly but not significantly lower in the nonresponders compared with the responders. However, nonresponders were protected from arachidonic acid-induced sudden death. While 100% of the responders died at the 2.0 mg dose of arachidonic acid, only 27% of nonresponders died at this same dose. Administration of the thromboxane A
2
mimetic
U46619
(5 μg/kg IV) decreased blood pressure by 41±6 mm Hg in responders but had no effect in the nonresponders. The affinity and density of thromboxane A
2
receptors in cultured aortic vascular smooth muscle cells obtained from both responders and nonresponders were assessed using radioligand binding. The
K
d
values were not different (4.4±1.0 versus 2.4±0.6 nmol/L, responder versus nonresponder). However, there was a significant decrease in the density of receptors from vascular smooth muscle cells of nonresponders (B
max
=397±59 versus 157±59 fmol/10
6
cells, responder versus nonresponder,
P
<.01).
U46619
produced a concentration-dependent increase in [
3
H]-thymidine incorporation into responder vascular smooth muscle cells but had no effect in the nonresponder cells. Using an anti-thromboxane A
2
receptor antibody, we compared the amount of receptor expressed in aortic tissue obtained from responders and nonresponders. Consistent with the results observed with [
3
H]-thymidine uptake and radioligand binding assays, the expression of thromboxane A
2
receptor protein was decreased in nonresponder compared with responder vascular tissue. Platelet thromboxane A
2
receptor expression was not different. These studies demonstrate that the vascular smooth muscle cells of nonresponder rabbits are deficient in the thromboxane A
2
receptor. Furthermore, the reduction in arachidonic acid-induced sudden death in nonresponders indicates that the vascular smooth muscle thromboxane A
2
receptor mediates this effect.
Intima-Media Thickness of the Carotid Artery in Hypertensive Subjects and Hypertrophic Cardiomyopathy Patients
Authors: Ohya Yusuke , Abe Isao , Fujii Koji , Kobayashi Kazuo , Onaka Uran , Fujishima Masatoshi
Published: June 2012

While hypertension is known to cause left ventricular and vascular hypertrophy, the relationship between alterations of vascular and cardiac structures in patients with hypertrophic cardiomyopathy has not been fully clarified. We measured intima-media thickness of carotid arteries by ultrasonography in patients with hypertrophic cardiomyopathy (n=16), normotensive subjects (n=358), and hypertensive subjects (n=386) in a cohort of 7940 male employees of a bus company. Our object was to determine whether vascular alteration occurs in hypertrophic cardiomyopathy similarly as in hypertension. Hypertrophic cardiomyopathy (wall thickness ≥ 15 mm; asymmetrical hypertrophy without hypertension) was screened with family history and electrocardiography followed by echocardiography. The intima-media thickness in patients with hypertrophic cardiomyopathy (mean, 0.61 mm) did not differ from that of normotensive subjects (0.60 mm) but was significantly less than that of hypertensive subjects with left ventricular hypertrophy (wall thickness ≥ 14 mm; n=22; 0.73 mm). In a scatterplot of intima-media thickness versus interventricular septal thickness, these two parameters were significantly correlated in normotensives and hypertensives. The patients with hypertrophic cardiomyopathy distributed outside the 95% confidence range of the normotensive and hypertensive subjects. In summary, the increase in intima-media thickness of the carotid artery paralleled left ventricular hypertrophy in normotensive and hypertensive subjects. Patients with hypertrophic cardiomyopathy had a normal intima-media thickness regardless of the hypertrophied left ventricle. Thus, information on intima-media thickness may be useful in differentiating hypertensive left ventricular hypertrophy from hypertrophic cardiomyopathy.
Bovine Aortic Endothelial Cells Contain an Angiotensin-(1–7) Receptor
Authors: Tallant E. Ann , Lu Xiaowei , Weiss Randi B. , Chappell Mark C. , Ferrario Carlos M.
Published: June 2012

Angiotensin-(1–7) is a novel peptide of the reninangiotensin system that counteracts the pressor and proliferative responses to angiotensin II. We now report that cultured bovine aortic endothelial cells contain a saturable, high-affinity [
125
I]angiotensin-(1–7) binding site with an affinity of 19.3±10.7 nmol/L and a density of 1351±710 fmol/mg protein. Angiotensin-(1–7) competed at a second lower-affinity site, with an IC
50
of 2.9 μmol/L. The high-affinity angiotensin II receptor antagonist sarcosine
1
-isoleucine
8
-angiotensin II blocked [
125
I]angiotensin-(1–7) binding to bovine aortic endothelial cells at both a high-(IC
50
=1.3 nmol/L) and a low-affinity (IC
50
=6.2 μmol/L) binding site. In contrast,
d
-alanine
7
-angiotensin-(1–7) completely blocked [
125
I]angiotensin-(1–7) binding, with an IC
50
of 19.8 nmol/L, suggesting that
d
-alanine
7
-angiotensin-(1–7) may selectively block responses to angiotensin-(1–7) in endothelial cells. Neither the AT
1
antagonist losartan nor the AT
2
antagonist PD 123319 exhibited significant competition for [
125
I]angiotensin-(1–7) binding to endothelial cells isolated from bovine aorta, in agreement with the absence of detectable mRNAs encoding typical angiotensin receptor subtypes 1 or 2 (AT
1
or AT
2
). Angiotensin II also competed for [
125
I]angiotensin-(1–7) binding to bovine aortic endothelial cells; however, the relative affinity was 13-fold lower than angiotensin-(1–7), suggesting a preference for angiotensin-(1–7) over angiotensin II. These results demonstrate that bovine aortic endothelial cells contain a unique non-AT
1
, non-AT
2
angiotensin receptor that preferentially binds angiotensin-(1–7).
G-Protein Function Is Reduced in Hypertension
Authors: Feldman Ross D. , Chorazyczewski Jozef
Published: June 2012

A functional impairment in vasodilator tone may be important in the pathogenesis and/or maintenance of elevated peripheral vascular resistance in hypertension. Previous studies of hypertensive subjects have demonstrated impaired β-adrenergic-mediated vasodilation paralleling a reduction in lymphocyte β-adrenergic-stimulated adenylyl cyclase activity. We have suggested that this impairment is related to a defect in G-protein function. To determine whether this defect alters the coupling between the G-protein complex and adenylyl cyclase, we performed [
3
H]forskolin binding studies in lymphocytes from hypertensive subjects, older normotensive subjects, and younger normotensive control subjects. Maximal specific [
3
H]forskolin binding was used as an index of adenylyl cyclase binding sites. Gpp(NH)p-, NaF/AlCl
3
-, and isoproterenol-stimulated binding were used as indices of G-protein/adenylyl cyclase coupling. In the absence of other stimulators, maximal [
3
H]forskolin binding was not significantly different among groups. However, both Gpp(NH)p- and isoproterenol-stimulated [
3
H]forskolin binding were significantly decreased in lymphocytes from hypertensive subjects. Overall, Gpp(NH)p- and isoproterenol-stimulated [
3
H]forskolin binding were significantly inversely correlated with blood pressure. No differences in NaF/AlCl
3
-stimulated [
3
H]forskolin binding were detected between groups. These studies indicate that G-protein/adenylyl cyclase coupling is impaired in lymphocytes from younger hypertensive subjects and may contribute to the blood pressure-related defect in β-adrenoceptor-stimulated adenylyl cyclase activity.
Effect of High Salt Intake in Mutant Mice Lacking Bradykinin-B
2
Receptors
Authors: Alfie Marcos E. , Sigmon David H. , Pomposiello Silvia I. , Carretero Oscar A.
Published: June 2012

Renal kinins release prostaglandins and nitric oxide via the B
2
receptor, promoting diuresis and natriuresis; hence, they may also contribute significantly to blood pressure regulation. We hypothesized that mutant mice lacking the gene encoding for the bradykinin-B
2
receptor (B
2
-KO) become hypertensive when placed on a long-term high-salt diet. To test this, B
2
-KO and control mice were placed on either a normal (0.2%) or high-Na
+
diet (3.15% in food plus 1% saline as drinking water) for 8 weeks. Systolic blood pressure was determined during weeks 6 and 8 by a computerized tail-cuff system. At the end of the 8-week period, mice were anesthetized for determination of mean blood pressure, renal blood flow, and renal vascular resistance. In B
2
-KO mice maintained on high Na
+
, systolic blood pressure was 15 mm Hg higher than in knockout animals on normal Na
+
(
P
<.01). In contrast, there was no difference in blood pressure in control mice fed either a normal or a high-Na
+
diet. Consistent with the systolic blood pressure data, direct mean arterial pressure revealed that B
2
-KO mice on high Na
+
were hypertensive (115±6 in B
2
-KO on high-Na
+
diet versus 79±2.8 in B
2
-KO on normal Na
+
,
P
<.0001); renal blood flow was reduced by 20% (
P
<.05) and renal vascular resistance was doubled (
P
<.0001) compared with B
2
-KO mice on normal Na
+
. In contrast, control mice on high Na
+
were normotensive and tended to have increased renal blood flow and decreased renal vascular resistance compared with control mice on a normal Na
+
diet. These findings indicate that kinins play an important role in preventing salt-sensitive hypertension; this may be achieved by maintaining renal blood flow under conditions of high salt intake.
Hypotension in Transgenic Mice Overexpressing Human Bradykinin B
2
Receptor
Authors: Wang Dan-zhao , Chao Lee , Chao Julie
Published: June 2012

Bradykinin binds to its receptor at target organs and exerts a wide spectrum of biological activities including vasodilation, smooth muscle contraction and relaxation, pain, and inflammation. To gain a better insight into the physiological function of this potent vasoactive peptide, we created transgenic mice that harbor the human bradykinin B
2
receptor transgene under the control of the Rous sarcoma virus 3′-LTR promoter (RSV-cHBKR). Expression of HBKR in these transgenic mice was identified in the aorta, brain, heart, lung, liver, kidney, uterus, and prostate gland by reverse transcription-polymerase chain reaction Southern blot analysis. Two transgenic mouse lines expressing the human B
2
receptor resulted in a significant reduction of blood pressure (84.2±0.6 mm Hg, n=28; 76.9±0.8 mm Hg, n=24;
P
<.001) compared with the control littermates (96.9±0.4 mm Hg, n=52). Administration of Hoe 140, a bradykinin B
2
receptor antagonist, restored the blood pressure of the transgenic mice to normal levels within 1 hour, and the effect diminished within 4 hours. The transgenic mice displayed enhanced blood pressure-lowering effect induced by a bolus intra-aortic injection of kinin and showed increased response in kinin-induced uterine smooth muscle contractility compared with control littermates. These studies show that overexpression of human bradykinin B
2
receptor causes a sustained reduction of blood pressure in transgenic mice. They also suggest that the B
2
receptor-mediated signal transduction pathway plays a role in blood pressure regulation.
Combined Effects of Hypertension and Hypercholesterolemia on Radial Artery Function
Authors: Giannattasio Cristina , Mangoni Arduino A. , Failla Monica , Stella Maria L. , Carugo Stefano , Bombelli Michele , Sega Roberto , Mancia Giuseppe
Published: June 2012

Compliance and distensibility of middle-sized conduit arteries are increased in hypertension and reduced in hypercholesterolemia. Despite their frequent association in the same individual, the combined effect of these two conditions on arterial mechanical properties is unknown. We studied four groups of age- and sex-matched subjects: 10 normotensive normocholesterolemic subjects, 10 mild hypertensive normocholesterolemic subjects, 10 mild hypercholesterolemic normotensive subjects, and 10 mild hypertensive and mild hypercholesterolemic subjects. We measured radial artery diameter by an echotracking device and beat-to-beat blood pressure from an ipsilateral finger. Compliance-pressure and distensibility-pressure curves were derived by Langewouters' formula. Between-group comparisons were made by calculating for both compliance and distensibility the integral of the area under the portion of the curve common to the four groups (“isobaric” compliance and distensibility). Blood pressure was similarly elevated in the two hypertensive groups, and serum cholesterol was similarly elevated in the two hypercholesterolemic groups. Compared with values in normotensive normocholesterolemic subjects, isobaric compliance and distensibility were greater in hypertensive normocholesterolemic (+38% and 47%, respectively) and smaller in normotensive hypercholesterolemic (−6% and −23%) subjects. However, when both hypertension and hypercholesterolemia were present, isobaric compliance and isobaric distensibility were significantly reduced (−26% and −18%,
P
<.05). Therefore, hypercholesterolemia reverses the effect of hypertension on arterial compliance and causes arterial stiffening, as when present alone.
Pressure-Overload Deinduction of Human α
2
Na,K-ATPase Gene Expression in Transgenic Rats
Authors: Ruiz-Opazo Nelson , Xiang Xie Hou , Herrera Victoria L.M.
Published: June 2012

The early and sustained deinduction of α
2
Na,K-ATPase gene expression in both cardiac left ventricle and aorta in various pressure-overload rat models and in hypertrophied human heart suggests a common transcriptional pressure response mechanism to pressure overload in both rats and humans. To test this hypothesis, we developed transgenic rat lines expressing the chloramphenicol acetyltransferase reporter gene regulated by the human α
2
Na,K-ATPase (−798 to +67) regulatory region, Hα
2
-CAT. Analysis of two homozygous transgenic rat lines revealed (1) parallel tissue-specific regulation of the Hα
2
-CAT transgene and rat α
2
Na,K-ATPase gene and (2) parallel load-induced deinduction of both cardiac and vascular (aortic) Hα
2
-CAT transgene and rat α
2
Na,K-ATPase gene expression in a 3-day model of induced pressure overload. Cardiac Hα
2
-CAT deinduction was detected at a systolic pressure greater than or equal to 150 mm Hg and correlated with the degree of systolic pressure elevation (
r
=.82,
P
<.0001). The data suggest a systolic pressure gradient–dependent coordinate pressure-overload transcriptional response mechanism in the heart and aorta, with one of its target genes being the α
2
Na,K-ATPase gene in both humans and rats.
α
1
-Adrenergic Receptor Antibodies in Patients With Primary Hypertension
Authors: Luther Hans-Peter , Homuth Volker , Wallukat Gerd
Published: June 2012

Autoimmune mechanisms have been proposed to play a role in the pathogenesis of primary (essential) hypertension. Autoantibodies against the α
1
-adrenergic receptor have been described in patients with malignant and secondary hypertension. To investigate the incidence of autoantibodies against the α
1
-adrenoceptor in patients with primary hypertension, we examined the immunoglobulin fractions of sera from 54 patients with primary hypertension and 26 normotensive control subjects for the presence of autoantibodies against the α
1
-adrenoceptor. Sera from 24 patients (44%) and 3 subjects (12%) were positive. An epitope analysis of 16 autoantibody-positive immunoglobulin fractions revealed that in two thirds of the cases, the antibodies were directed against the first extracellular loop of the α
1
-adrenoceptor and in one third, against the second. The autoantibodies had a positive chronotropic effect on isolated neonatal rat cardiomyocytes, an effect that was blocked by α
1
-adrenergic antagonists. Since the functional characteristics of the autoantibodies showed no desensitization phenomena, they may play a role in elevating peripheral vascular resistance and promoting cardiac hypertrophy in patients with primary hypertension.
Effect of African-American Race and Hypertensive Left Ventricular Hypertrophy on Coronary Vascular Reactivity and Endothelial Function
Authors: Houghton Jan L. , Smith Vivienne E. , Strogatz David S. , Henches Nancy L. , Breisblatt Warren M. , Carr Albert A.
Published: June 2012

Excess cardiovascular morbidity and mortality among African (black) Americans remains an important yet unexplained public health problem. One possible explanation proposes that intrinsic or acquired abnormalities in coronary vascular reactivity and endothelial function result in excess ischemia among black Americans. To examine this hypothesis, we subjected 80 individuals with normal coronary arteries to invasive testing of coronary artery and microvascular relaxation using intracoronary infusions of acetylcholine and adenosine, a Doppler tipped intracoronary guide wire, and quantitative coronary angiography. We measured the percent increase in coronary blood flow and epicardial diameter after graded infusion of intracoronary acetylcholine and in coronary blood flow after intracoronary adenosine in 31 normotensive subjects (10 black, 21 white) and 49 hypertensive subjects with left ventricular hypertrophy (25 black, 24 white). Categorical and multivariate analyses revealed that in response to intracoronary adenosine and acetylcholine, the depression in endothelium-independent and -dependent microvascular relaxation during peak agonist effect was largely related to the presence of chronic hypertension and left ventricular hypertrophy. Normotensive subjects demonstrated no intrinsic racial differences in conduit and resistance vessel vasoreactivity. In response to maximal infusion of acetylcholine, epicardial coronary arteries constricted similarly in black and white subjects with hypertensive left ventricular hypertrophy and dilated similarly in normotensive black and white subjects. Thus, our study shows that in a cohort of black and white subjects referred for coronary arteriography because of chest pain, African American race is not associated with excess intrinsic or acquired depression in coronary vascular relaxation during the peak effect of the endothelium-dependent and -independent agonists acetylcholine and adenosine, after adjustment for the presence of left ventricular hypertrophy.
Hypertension Causes Premature Aging of Endothelial Function in Humans
Authors: Taddei Stefano , Virdis Agostino , Mattei Paola , Ghiadoni Lorenzo , Fasolo Ciro Basile , Sudano Isabella , Salvetti Antonio
Published: June 2012

We designed the present study to evaluate whether in normotensive subjects and hypertensive patients aging causes endothelial dysfunction by a defect in the L-arginine–nitric oxide pathway or production of cyclooxygenase-dependent vasoconstrictors. In 43 normotensive subjects and 47 essential hypertensive patients, we evaluated forearm blood flow (strain-gauge plethysmography) modifications evoked by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, in the presence of saline,
l
-arginine (1 μmol/100 mL per minute), or indomethacin (50 μg/100 mL per minute), a cyclooxygenase inhibitor, and by sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. Vasodilation to acetylcholine was lower (
P
<.01) in essential hypertensive patients than normotensive control subjects, and in both groups, it declined with advancing age. In normotensive subjects older than 30 years,
l
-arginine potentiated the response to acetylcholine in parallel with increasing age, whereas indomethacin increased the vasodilation to acetylcholine only in the oldest group (>60 years). In younger hypertensive patients (<30 years),
l
-arginine but not indomethacin potentiated the response to acetylcholine. In adult patients (31 to 45 years),
l
-arginine still potentiated the vasodilation to acetylcholine, and indomethacin began to show some effect. In the oldest patients (46 to 60 and >60 years),
l
-arginine was no longer effective, and indomethacin exerted a potentiating action that was positively related to advancing age. In normotensive and hypertensive humans, similar mechanisms, including dysfunction of the nitric oxide pathway and production of cyclooxygenase-dependent vasoconstrictors, cause age-related impairment of endothelium-dependent vasodilation, and only their earlier appearance characterizes hypertensive disease. Thus, the endothelial dysfunction that occurs in hypertension seems to represent an accelerated form of dysfunction that occurs in aging.
Calcium Channel Blockers Blunt Postural Cutaneous Vasoconstriction in Hypertensive Patients
Authors: Iabichella Maria Letizia , Dell'Omo Giulia , Melillo Elio , Pedrinelli Roberto
Published: June 2012

The aim of this work was to test whether calcium channel blockers interfere with skin vasoconstrictor reflexes that minimize postural increases in capillary pressure and avoid fluid extravasation and eventually subcutaneous edema. Studies were conducted in 23 untreated mild to moderate essential hypertensives; drugs, either calcium channel blockers or not, were given for 2 weeks according to a crossover, sequence-randomized design. Skin blood flow was measured by laser Doppler flowmetry in two skin areas: (1) the dorsum of the foot, where arteriovenous anastomoses are poorly represented, and (2) the plantar surface of the great toe, where those anastomoses are predominant. Determinations were obtained both with the foot at heart level and with it placed passively 50 cm below the heart level; percent flow changes from the horizontal to the dependent position were the measure of postural vasoconstriction. Two dihydropyridine derivatives, amlodipine (10 mg UID) and nifedipine (60 mg UID), and verapamil (240 mg BID), a chemically unrelated compound, diminished to similar extents the postural fall in skin blood flow at the dorsum of the foot. Blockade of α
1
-adrenergic and AT-1 subtype angiotensin II receptors by doxazosin (4 mg UID) and losartan (50 mg UID), respectively, exerted no effect. Postural skin blood flow responses at the plantar surface of the great toe were unmodified during the pharmacological trials. Thus, calcium channel blockers of different chemical origins antagonized postural skin vasoconstriction at the dorsum of the foot. The data indicate altered postural capillary blood flow regulation, since arteriovenous anastomoses are anatomically absent at this site; the effect was independent of either α
1
-adrenoceptor or angiotensin II receptor antagonism. Interference with skin postural vasoconstrictor mechanisms may result in net filtration of fluid to the extravascular compartment. This mechanism might explain the as yet unknown pathogenesis of ankle edema during treatment with calcium antagonists.
Effects of Subfornical Organ Lesions on Sympathetic Nerve Responses to Insulin
Authors: Muntzel Martin S. , Thunhorst Robert L. , Johnson Alan Kim
Published: June 2012

Abstract
Although insulin exerts potent excitatory effects on the sympathetic nervous system, the mechanisms of insulin-induced activation remain unclear. To demonstrate a central nervous system site of sympathoexcitation, we recently found that destruction of tissues surrounding the anteroventral third ventricle region abolishes elevations in sympathetic nerve activity to intravenous insulin administration. Anteroventral third ventricle lesions may eliminate sympathoexcitation by destroying cell bodies in the lesioned area or by interrupting fibers of passage from the subfornical organ. To determine whether the lesions abolish sympathetic increases by disrupting efferent fibers from the subfornical organ, we measured lumbar sympathetic activity in anesthetized anteroventral third ventricle–lesioned (n=4) and subfornical organ–lesioned (n=12) rats before and during intravenous insulin at 0.13 U/h while maintaining euglycemia. Additional sham-lesioned rats received infusion of insulin (n=10) and the vehicle for insulin (n=10). Insulin administration in sham-lesioned rats elevated lumbar activity from 100% to 171±14% (±SE), whereas vehicle infusion did not alter sympathetic activity (100% to 113±11%). In anteroventral third ventricle–lesioned rats, insulin failed to increase sympathetic nerve activity (100% to 119±14%). Importantly, rats with subfornical organ lesions had increases in nerve activity that were indistinguishable from increases observed in insulin-infused sham-lesioned rats (100% to 163±21%). These findings indicate that whereas the anteroventral third ventricle region itself is crucial for sympathoexcitation to insulin, the subfornical organ and fibers originating from the subfornical organ traversing the anteroventral third ventricle area are not essential in mediating elevations in lumbar sympathetic nerve activity to hyperinsulinemia.
Nutrient Intake and Blood Pressure in the Dietary Intervention Study in Children
Authors: Simons-Morton Denise G. , Hunsberger Sally A. , Van Horn Linda , Barton Bruce A. , Robson Alan M. , McMahon Robert P. , Muhonen Linda E. , Kwiterovich Peter O. , Lasser Norman L. , Kimm Sue Y. S. , Greenlick Merwyn R.
Published: June 2012

Abstract
Delineating the role that diet plays in blood pressure levels in children is important for guiding dietary recommendations for the prevention of hypertension. The purpose of this study was to investigate relationships between dietary nutrients and blood pressure in children. Data were analyzed from 662 participants in the Dietary Intervention Study in Children who had elevated low-density lipoprotein cholesterol and were aged 8 to 11 years at baseline. Three 24-hour dietary recalls, systolic pressure, diastolic pressure, height, and weight were obtained at baseline, 1 year, and 3 years. Nutrients analyzed were the micronutrients calcium, magnesium, and potassium; the macronutrients protein, carbohydrates, total fat, saturated fat, polyunsaturated fat, and monounsaturated fat; dietary cholesterol; and total dietary fiber. Baseline and 3-year longitudinal relationships were examined through multivariate models on diastolic and systolic pressures separately, controlling for height, weight, sex, and total caloric intake. The following associations were found in longitudinal analyses: analyzing each nutrient separately, for systolic pressure, inverse associations with calcium (
P
<.05); magnesium, potassium, and protein (all
P
<.01); and fiber (
P
<.05), and direct associations with total fat and monounsaturated fat (both
P
<.05); for diastolic pressure, inverse associations with calcium (
P
<.01); magnesium and potassium (both
P
<.05); protein (
P
<.01); and carbohydrates and fiber (both
P
<.05), and direct associations with polyunsaturated fat (
P
<.01) and monounsaturated fat (
P
<.05). Analyzing all nutrients simultaneously, for systolic pressure, direct association with total fat (
P
<.01); for diastolic pressure, inverse associations with calcium (
P
<.01) and fiber (
P
<.05), and direct association with total and monounsaturated fats (both
P
<.05). Results from this sample of children with elevated low-density lipoprotein cholesterol indicate that dietary calcium, fiber, and fat may be important determinants of blood pressure level in children.
Relative Influence of Menopausal Status, Age, and Body Mass Index on Blood Pressure
Authors: Portaluppi Francesco , Pansini Francesco , Manfredini Roberto , Mollica Gioacchino
Published: June 2012

Abstract
The objective of this study was to assess the influence of menopausal status on blood pressure levels in a cross-sectional population study in the setting of a preventive health care program clinically conducted in Ferrara, Italy. The patients were 2397 healthy women 35 to 65 years old (489 in premenopause, 847 in perimenopause, 887 in spontaneous menopause, and 174 in surgical menopause); subgroups were also obtained with increasing duration of menopause (1 to >5 years) matched with premenopausal and perimenopausal women by chronological age at onset of menopause. Measurements of sphygmomanometric blood pressure, age, age at menopause, duration of menopause, and body mass index were made. Postmenopausal women had higher blood pressure than premenopausal and perimenopausal subjects. After adjustment for body mass index, the blood pressure changes with menopausal status were still significant, but not after correction by age. The increased risk of hypertension of postmenopausal women also lost statistical significance after adjustment for age and body mass index. At multivariate analysis, blood pressure showed no significant relation with the duration of menopause, whereas age was a significant covariant for systolic blood pressure, and body mass index for systolic and diastolic blood pressure. A transient initial rise in blood pressure and body mass index was detected in surgical but not in spontaneous menopause. Blood pressure rises after menopause appear to be due more to increased body mass index and aging than ovarian failure per se.