bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic Association of 11β-Hydroxysteroid Dehydrogenase Type 2 (HSD11B2) Flanking Microsatellites With Essential Hypertension in Blacks
Authors: Watson Bracie , Bergman Suzanne M. , Myracle Angela , Callen David F. , Acton Ronald T. , Warnock David G.
Published: June 2012

11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2) specifically modulates access of the mineralocorticoid aldosterone to the kidney mineralocorticoid type 1 receptors in a physiological environment in which there is a molar excess of cortisol. Cortisol and aldosterone have similar affinities for mineralocorticoid receptors. Mechanistically, 11β-HSD2 converts cortisol to cortisone. The other known isoform, 11β-HSD1, not only catalyzes the cortisol to cortisone reaction but also the reverse reaction, making it unlikely to play an important role in modulating the access of aldosterone to mineralocorticoid receptors. Mutations in the HSD11B2 gene (both exonic and intronic) have been demonstrated to cause reduced activity of this enzyme in the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disorder. We hypothesized that this locus is also involved in the etiology of essential hypertension. To test this locus and flanking chromosomal regions for allelic association and genetic linkage to essential hypertension, it is necessary to have informative genetic markers. To this end, we have refined the localization of 11β-HSD2 to 16q22.1. We genotyped subjects using the nearest flanking microsatellites (D16S301 and D16S496). We conducted an association study using black subjects with hypertensive end-stage renal disease, black normotensive control subjects, and black and white individuals from the general population. We used χ
2
analysis and Fisher's exact test to test for association with these candidate gene markers. No significant association was found between D16S301 and hypertension. However, a positive association with hypertension was found at the D16S496 microsatellite locus (χ
2
=6.98,
df
=1,
P
≤.008). Our data suggest that HSD11B2 is associated with hypertension in our black subjects with hypertensive end-stage renal disease. The 16q22.1 chromosome region potentially harbors a candidate gene for essential hypertension. Confirmation of our findings in another independently ascertained group of hypertensive subjects will provide a basis for proceeding with sib-pair linkage analyses.
Cardiac Transplantation, Perindopril, and Left Ventricular Hypertrophy in Spontaneously Hypertensive Rats
Authors: Harrap Stephen B. , O'Sullivan Joseph B.
Published: June 2012

Angiotensin-converting enzyme inhibitors reduce blood pressure and cardiac mass but may also have a direct effect on myocardial growth. To test this hypothesis, we studied the effects of perindopril on the weight of transplanted hearts in which the left ventricle does not pump blood. Hearts were transplanted between littermate 10-week-old male spontaneously hypertensive rats, and recipients were treated for 2 weeks with vehicle (n=10), perindopril (3 mg/kg per day) (n=9), perindopril (3 mg/kg per day) plus the selective bradykinin B
2
receptor antagonist Hoe 140 (500 μg/kg per day) (n=13), or angiotensin II (200 ng/kg per minute) (n=12). Perindopril reduced blood pressure and native left ventricular weight and also caused a significant decrease in the weight of the transplanted left ventricle compared with controls. Hoe 140 did not significantly alter blood pressure or native left ventricular weight of perindopril-treated rats but caused a significant increase in the weight of the transplanted left ventricle compared with rats treated with perindopril alone. Angiotensin treatment resulted in a significant increase in blood pressure and native left ventricular weight but no significant change in the weight of the transplanted left ventricle. Blood pressure and left ventricular weight for native but not for transplanted hearts were positively correlated. Therefore, in the absence of mechanical load, the weight of the left ventricle of spontaneously hypertensive rats responds little to angiotensin II but can be reduced by angiotensin-converting enzyme inhibition. The effect of perindopril on transplanted hearts of spontaneously hypertensive rats appears to depend on bradykinin.
Racial Differences in Plasma Endothelin-1 Concentrations in Individuals With Essential Hypertension
Authors: Ergul Sitki , Parish David C. , Puett David , Ergul Adviye
Published: June 2012

Hypertension is more prevalent in blacks than whites, and the reasons for this difference remain unclear. To test whether endothelin may play a role in these racial variations, we analyzed plasma samples from black and white women and men with high blood pressure by an enzyme-linked immunoassay specific for endothelin-1 (ET-1), a potent vasoconstrictor, and compared them with those obtained from similar subjects with normal blood pressure. Both female and male hypertensive blacks had elevated levels of immunoreactive ET-1 (11.3±1.0 and 12.3±1.3 nmol/L, respectively) compared with values in normotensive control blacks (1.5±0.2 and 1.4±0.2 nmol/L). Corresponding values in female and male hypertensive whites were 3.8±0.6 and 3.8±0.6 nmol/L, respectively, compared with respective values of 1.4±0.1 and 2.8±0.4 nmol/L in normotensive control whites. These results indicate that plasma concentrations of immunoreactive ET-1 levels differ significantly between black and white individuals with high blood pressure. This finding may be an important factor in the etiology of racial differences in the prevalence and severity of hypertension and deserves further study.
Change in Pressor Responsiveness to Angiotensin II as a Determinant of Blood Pressure After Unclipping in Two-Kidney, One Clip Hypertensive Rats
Authors: Melaragno Matthew G. , Fink Gregory D.
Published: June 2012

The hypotensive effect of correction of renal artery stenosis in humans or experimental animals with renovascular hypertension is commonly attributed to decreasing renin secretion from the formerly stenotic kidney. However, plasma renin activity is normal in 50% of individuals with renovascular hypertension. We studied conscious, chronically instrumented two-kidney, one clip (2K1C) rats. The renal artery clip was removed and mean arterial pressure measured for 3 days. The majority of the fall in blood pressure occurred between 2 and 48 hours after unclipping. Measurement of water balance and urinary sodium excretion revealed no effect of unclipping. In another experiment, 2K1C hypertensive rats were chronically treated with enalapril and concomitant infusion of angiotensin II (3.8 pmol/min [4 ng/min] IV) to maintain blood pressure at hypertensive levels and prevent a fall in angiotensin II levels on unclipping. After 5 days, the clip was removed or sham removed, and treatment was continued. Blood pressure was recorded for 7 days. Blood pressure remained elevated in the sham unclipped rats. Unclipped rats exhibited a dichotomous response: blood pressure fell significantly within 48 hours in the majority of rats (responders) but remained elevated in a minority (nonresponders). All treatment was then withdrawn for 2 days. Sham unclipped rats remained hypertensive, and responders exhibited a further small decline in blood pressure. Blood pressure fell to normal in the nonresponders. Blood pressure falls after correction of renal artery stenosis in renovascular hypertension in part because of a decrease in pressor responsiveness to angiotensin II.
Angiotensin II Type 2 Receptor Subtype Mediates Phospholipase A
2
–Dependent Signaling in Rabbit Proximal Tubular Epithelial Cells
Authors: Jacobs Leila S. , Douglas Janice G.
Published: June 2012

We investigated the ability of angiotensin II (Ang II) or the stable analogue [Sar
1
]-Ang II to increase intracellular and extracellular free arachidonic acid in primary cultures of rabbit proximal tubular epithelial cells to better characterize the receptor subtype and orientation of phospholipase A
2
(PLA
2
)–mediated signaling. Proximal tubular cells were labeled with [
3
H]arachidonic acid for 4 hours and then treated with Ang II or [Sar
1
]-Ang II. Lipids were extracted from labeled cells, separated by thin-layer chromatography, and quantified by liquid scintillation counting. Ang II (10 μmol/L, 1 minute) stimulated an increase in intracellular free [
3
H]arachidonic acid from 21.0±2.0 to 32.2±2.8 disintegrations per minute/μg protein, an effect that was potentiated by EGTA. [Sar
1
]-Ang II stimulated a time- and concentration-dependent increase in [
3
H]arachidonic acid release from labeled cells. Release of [
3
H]arachidonic acid was maximal at 10 μmol/L [Sar
1
]-Ang II, with an EC
50
of approximately 3 μmol/L. Ang II receptor antagonists caused concentration-dependent inhibition of [Sar
1
]-Ang II–stimulated [
3
H]arachidonic acid release with the following order of potency: CGP 42112=PD 123319>losartan. Furthermore, in proximal tubular epithelial cells grown on polyester membrane filters, the Ang II receptor that mediated arachidonic acid release was predominantly apical rather than basolateral. These observations are consistent with activation of a Ca
2+
-independent, apical PLA
2
isoform in epithelial cells through an Ang II type 2 receptor subtype.
New Staging System of the Fifth Joint National Committee Report on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) Alters Assessment of the Severity and Treatment of Hypertension
Authors: Pogue Velvie Anne , Ellis Charlotte , Michel Julienne , Francis Charles K.
Published: June 2012

The fifth Joint National Committee report on the detection, evaluation, and treatment of high blood pressure (JNC-V) introduced a new system of blood pressure classification that incorporated systolic blood pressure (SBP) and established new diastolic blood pressure (DBP) cut points. With the previous JNC classification, subjects were classified according to DBP alone. In this study, our purpose was to assess the effect of the new staging system on the assessment of hypertension severity and to determine whether the new JNC-V staging system better identifies individuals at risk for hypertensive target-organ damage. We compared the assessment of hypertension severity using JNC-IV with that using JNC-V in 1158 subjects enrolled in the Harlem Hospital Hypertension Clinic database from 1975 to 1992. We used pretreatment DBP to classify subjects according to JNC-IV criteria. These subjects were reclassified into one of the four stages of JNC-V. The assessment of hypertension severity and prevalence of organ damage in subjects who remained in the same category of severity in both systems was compared with damage in subjects who were upstaged. With the JNC-V classification, 321 subjects remained in the same category, and 837 were upstaged. Six hundred and four subjects moved up because of the new cut points of DBP, and 275 were upstaged because of higher SBP. Upstaged subjects had more manifestations of hypertensive target-organ damage. With the new JNC-V classification system, hypertension is assessed as severe or very severe in more individuals than with JNC-IV. Subjects who are upstaged in JNC-V are more likely to have evidence of renal disease and other target-organ damage.
Contribution of Nitric Oxide to the Beneficial Effects of Enalapril in the Fructose-Induced Hyperinsulinemic Rat
Authors: Erlich Yael , Rosenthal Talma
Published: June 2012

We examined accumulating evidence of the positive contribution of nitric oxide to the pharmacological effects of converting enzyme inhibitors in 36 rats rendered hypertensive, hyperinsulinemic, and hypertriglyceridemic by a fructose-enriched diet. We studied the response of blood pressure, insulin, and triglyceride levels to inhibition of either converting enzyme–kininase II, nitric oxide synthase, or both. Two weeks of the converting enzyme inhibitor enalapril (20 mg/kg) reduced blood pressure from 137±2 to 105±7 mm Hg, insulin from 7.6±2.0 to 2.2±1.1 pg/mL, and triglycerides from 292±37 to 163±37 mg/dL. Treatment with
N
G
-nitro-
l
-arginine methyl ester (100 mg/kg) raised blood pressure from 144±7 to 170±8 mm Hg without affecting the other parameters. Two weeks of concomitant treatment with both agents blunted the hypotensive and beneficial metabolic effects of enalapril; thus, final blood pressure (141±7 mm Hg), insulin (6.4±2.4 pg/mL), and triglyceride (231±51 mg/dL) values were no different from those of untreated fructose-fed rats. These data suggest that persistent synthesis of nitric oxide contributes to the vasodilator and metabolic effects of enalapril in the fructose-fed rat model.
Angiotensin II–Stimulated Phospholipase C Responses of Two Vascular Smooth Muscle–Derived Cell Lines
Authors: Baines Richard J. , Brown Colin , Ng Leong L. , Boarder Michael R.
Published: June 2012

Vascular smooth muscle cells of the spontaneously hypertensive rat (SHR) are known to show increased responsiveness to angiotensin II (Ang II) compared with cells of normotensive control Wistar-Kyoto rats (WKY). We investigated the hypothesis that differential levels of cGMP lead to the different responsiveness of the cells, using vascular smooth muscle cells in culture. cGMP levels in extracts of SHR-derived cells were lower than those of WKY-derived cells. This was true for both unstimulated cells and cells treated with equal concentrations of either sodium nitroprusside or
S
-nitroso-
N
-acetylpenicillamine. Stimulation of cells with Ang II did not affect levels of cGMP but increased levels of inositol 1,4,5-trisphosphate (IP
3
) and Ca
2+
, which were greater in SHR- than in WKY-derived cells. When SHR and WKY cells were preincubated with different concentrations of
S
-nitroso-
N
-acetylpenicillamine to generate similar cGMP levels in each cell type, the subsequent IP
3
response to Ang II was the same in the two cell types. To reduce any influence of cGMP on responses, we permeabilized the cells with α-toxin. Stimulation of α-toxin–permeabilized cells with high Ca
2+
revealed an IP
3
response in SHR- but not WKY-derived cells. Similarly, permeabilized SHR cells responded to Ang II but WKY cells did not. However, GTP and GTPγS elevated IP
3
in both cell types. Taken together, these results indicate that the low response of WKY cells can be accounted for by the inhibitory influence of cGMP. However, when this inhibition is removed by permeabilization, further differences between the cells are revealed that will contribute to the elevated SHR response.
Vascular Hypertrophy and Remodeling in Secondary Hypertension
Authors: Rizzoni Damiano , Porteri Enzo , Castellano Maurizio , Bettoni Giorgio , Muiesan Maria Lorenza , Muiesan Paolo , Giulini Stefano Maria , Agabiti-Rosei Enrico
Published: June 2012

It has been proposed that several neurohumoral factors may be involved in the genesis of vascular structural changes (remodeling or hypertrophy) frequently observed in essential hypertension. Therefore, in this study we investigated vascular structural alterations of subcutaneous small resistance arteries in patients with secondary forms of hypertension. The study included 70 participants: 11 with pheochromocytoma, 13 with primary aldosteronism, and 17 with renovascular hypertension; 13 normotensive subjects and 16 patients with essential hypertension served as controls. All subjects were submitted to a biopsy of subcutaneous fat. Small resistance arteries were dissected and mounted on a micromyograph, and media-lumen ratio, media thickness, remodeling index, and growth index were evaluated. Endothelial function was evaluated according to the dose-response curve to acetylcholine. In patients with either primary aldosteronism or renovascular hypertension, a marked increase in media-lumen ratio was observed, whereas in patients with pheochromocytoma, the extent of vascular structural alterations was similar to that observed in patients with essential hypertension. The increase in media-lumen ratio in patients with essential hypertension and with pheochromocytoma was mainly due to vascular remodeling (remodeling index, 93% to 94%), whereas in patients with renovascular hypertension, there was vascular growth (remodeling index, 70%; growth index, 53%). Patients with primary aldosteronism had an intermediate pattern compared with the other two forms of secondary hypertension. An evident impairment of endothelial function was observed in all four hypertensive groups. In conclusion, the renin-angiotensin-aldosterone system seems to be more powerful than the adrenergic system in inducing vascular growth.
Prohormone Convertase PC5 Is a Candidate Processing Enzyme for Prorenin in the Human Adrenal Cortex
Authors: Mercure Chantal , Jutras Isabelle , Day Robert , Seidah Nabil G. , Reudelhuber Timothy L.
Published: June 2012

We isolated a cDNA clone encoding the human prohormone convertase PC5 from human adrenal gland mRNA. The deduced protein sequence would encode a 915 amino acid preproPC5 that shares a very high degree of homology with previously cloned rat and mouse homologues. PC5 mRNA was detected in multiple human tissues, including the brain, adrenal and thyroid glands, heart, placenta, lung, and testes. PC5 mRNA was undetectable in the liver and was present at lower levels in skeletal muscle, kidney, pancreas, small intestine, and stomach. Cotransfection of human PC5 and human prorenin expression vectors in cultured GH
4
C1 cells led to secretion of active renin. The activation of human prorenin by PC5 depended on a pair of basic amino acids at positions 42 and 43 of the prorenin prosegment and occurred only in cells containing dense core secretory granules. Human PC5 was colocalized with renin by immunohistochemistry in the zona glomerulosa of the adrenal gland, suggesting that it could participate in the activation of a local renin-angiotensin system in the human adrenal cortex.
Brain “Ouabain” and Angiotensin II in Salt-Sensitive Hypertension in Spontaneously Hypertensive Rats
Authors: Huang Bing S. , Leenen Frans H.H.
Published: June 2012

Spontaneously hypertensive rats (SHR) received from 5 to 9 weeks of age a high or regular sodium diet and concomitant intracerebroventricular infusions via minipumps of the following compounds: antibody Fab fragments (200 μg/d), which bind ouabain and related steroids with high affinity; the angiotensin II (Ang II) type 1 receptor blocker losartan (1 mg/kg per day); a combination of Fab fragments and losartan; and as control, γ-globulins (200 μg/d). The same doses of Fab fragments and losartan were also given intravenously. At 9 weeks of age, compared with SHR on regular sodium, SHR on high sodium that were treated with γ-globulins had higher resting blood pressure and showed significantly enhanced excitatory responses of blood pressure, renal sympathetic nerve activity, and heart rate to air stress and inhibitory responses to the central α
2
-agonist guanabenz. Central Fab fragments and losartan alone or combined prevented all these effects of high sodium. Intravenous Fab fragments or losartan was ineffective. Compared with control SHR on high sodium, SHR on high sodium that were treated with Fab fragments had significantly increased sympathoexcitatory and pressor responses to central Ang II injection, consistent with a decrease in brain Ang II receptor occupancy. These data indicate that both increased brain “ouabain” and Ang II contribute to salt-sensitive hypertension in SHR. Brain Ang II receptor stimulation appears to be downstream of “ouabain” in the pathways mediating sympathoexcitatory and pressor effects of high sodium.
Markers of Adenosine Removal in Normotensive and Hypertensive Rat Nervous Tissue
Authors: Castillo-Meléndez Margie , Jarrott Bevyn , Lawrence Andrew J.
Published: June 2012

Adenosine mechanisms are altered in brain stem nuclei associated with cardiovascular control in spontaneously hypertensive rats (SHR). Therefore, in the present study we used a number of techniques to compare the binding of the adenosine transport inhibitor [
3
H]nitrobenzylthioinosine ([
3
H]NBMPR) as well as adenosine deaminase immunoreactivity (ADA-IR) in brain stems and nodose ganglia of SHR and age-matched normotensive Donryu rats (DRY). Saturation binding revealed a single class of [
3
H]NBMPR binding sites in the dorsal brain stem of both strains, with
K
d
and
B
max
values of 65±9 pmol/L and 282±31 fmol/mg protein, respectively, in SHR and 129±2 pmol/L and 217±23 fmol/mg protein in DRY. The
K
d
for [
3
H]NBMPR was significantly lower in SHR than in DRY. In competition assays, NBMPR, dilazep, dipyridamole, and adenosine displaced [
3
H]NBMPR binding, with
K
d
values of 0.21±0.04, 57.16±16.20, 1340±100, and 87 000±12 500 nmol/L, respectively, in DRY and 0.17±0.04, 28.24±3.60, 621±100, and 32 000±6820 in SHR.
K
d
values for all displacers were lower in SHR; however, only values for dipyridamole and adenosine reached statistical significance. Autoradiography of adenosine transport sites with [
3
H]NBMPR revealed that unilateral nodose ganglionectomy reduced [
3
H]NBMPR binding on the denervated side of the nucleus tractus solitarius by 20.6±1.1% in DRY and 18.7±2.3% in SHR. The density of [
3
H]NBMPR binding in nodose ganglia was significantly lower in SHR (0.99±0.06 Bq/mm
2
) than in DRY (1.25±0.08). Immunohistochemical studies demonstrated ADA-IR in the dorsal vagal complex, associated with both nerve cells and fibers. Measurement of ADA-IR in the dorsal vagal complex with an
125
I-labeled secondary antibody revealed a significantly higher level of ADA-IR in SHR (122%) than in DRY. In the nodose ganglia, ADA-IR was associated with a population of vagal perikarya. The present study helps provide a molecular explanation for the previously reported impaired cardiovascular responses to intra–nucleus tractus solitarius microinjection of adenosine in hypertensive rats.
Antisense Inhibition of the Brain Kallikrein-Kinin System
Authors: Madeddu Paolo , Parpaglia Paolo Pinna , Glorioso Nicola , Chao Lee , Chao Julie
Published: June 2012

We used antisense oligodeoxynucleotide (ODN) strategy, based on interference of information flow from gene to protein, to determine the role of kininogen and bradykinin B
2
receptor genes in the pathogenesis of genetic hypertension in rats. Mean blood pressure of 9-week-old spontaneously hypertensive rats (SHR) increased 4 hours after acute intracerebroventricular injection of synthetic 18-mer antisense ODNs targeting the translation initiation codon of kininogen mRNA (from 164±5 to 181±4 mm Hg,
P
<.01) or bradykinin B
2
receptor mRNA (from 161±5 to 185±8 mm Hg,
P
<.01) and then returned to basal levels within 24 hours. Prolonged vasopressor effects were observed after repeated injections of antisense ODN targeting kininogen mRNA. Antisense ODNs to kininogen and B
2
receptor mRNAs increased blood pressure of normotensive Wistar-Kyoto rats only slightly compared with SHR (from 116±3 to 124±1 and from 116±2 to 126±4 mm Hg, respectively;
P
<.05). Cardiovascular responses were confirmed by the use of antisense ODNs targeted to bind to different nonoverlapping regions of kininogen or B
2
receptor mRNA. Microinjection of antisense ODN to B
2
receptor mRNA into the nucleus tractus solitarii increased mean blood pressure in SHR and prevented the vasodepressor effect induced by intranuclear microinjection of bradykinin. No significant change in mean blood pressure was induced in either strain by intravenous injection of antisense ODNs or by central injection of sense or scrambled ODNs. A strong fluorescent signal was detected at the level of the hippocampus, thalamus, hypothalamus periventricularis, midbrain, and cerebrum 1 hour after central injection of fluorescein isothiocyanate–conjugated antisense ODNs. Kininogen levels were significantly lower in the brain of rats given intracerebroventricular antisense kininogen ODN compared with controls. Our results indicate that the brain kallikrein-kinin system plays a role in the central regulation of blood pressure and suggest that this system may exert a protective action against further elevations of blood pressure levels in SHR.
Region-Specific Neuropeptide Y Overflows at Rest and During Sympathetic Activation in Humans
Authors: Morris Margaret J. , Cox Helen S. , Lambert Gavin W. , Kaye David M. , Jennings Garry L. , Meredith Ian T. , Esler Murray D.
Published: June 2012

Neuropeptide Y coexists with norepinephrine in sympathetic nerves and is coreleased into the circulation on sympathetic activation. Little is known about the regional release of neuropeptide Y in humans under normal conditions or in pathophysiological situations of sympathetic activation or denervation. We measured plasma neuropeptide Y–like immunoreactivity and norepinephrine concentrations in samples taken from the brachial artery; coronary sinus; and internal jugular, antecubital, or hepatic veins in volunteers aged 20 to 64 years. Regional neuropeptide Y overflow at rest was calculated from venoarterial plasma concentration differences and plasma flow, and norepinephrine spillover was determined by [
3
H]norepinephrine infusion techniques. Cardiac release of neuropeptide Y and norepinephrine was examined in response to various stressors as well as in clinical models of sympathetic activation, cardiac failure, and denervation after cardiac transplantation. In healthy volunteers, cardiac, forearm, and jugular venous sample neuropeptide Y concentrations were similar to arterial levels. Hepatic vein plasma neuropeptide Y was greater than arterial both at rest (119±5% of arterial, n=7) and after a meal (132±12%, n=7), with neuropeptide Y overflows of 6±2 and 11±2 pmol/min, respectively. In contrast, hepatomesenteric norepinephrine spillover was not significantly increased by feeding. Although coronary sinus plasma norepinephrine concentrations increased significantly with the cardiac sympathetic activation accompanying mental arithmetic, coffee drinking, isotonic exercise, and bicycle exercise, only the latter powerful sympathetic stimulus increased neuropeptide Y overflow. Cardiac failure was associated with increased resting release of both norepinephrine and neuropeptide Y from the heart, whereas postcardiac transplant norepinephrine spillover from the heart was reduced. The net overflow of neuropeptide Y to plasma observed at rest across the hepatic circulation, but not the cardiac, forearm, or cerebral circulations, indicates that the gut, the liver, or both make a major contribution to systemic plasma neuropeptide Y levels in humans. Sympathetic activation by exercise produced a modest increase in cardiac neuropeptide Y overflow but to only approximately 25% of the resting input from the gut and without a change in arterial neuropeptide Y concentration. Plasma neuropeptide Y measurements are less sensitive than those of plasma norepinephrine concentrations as an index for quantifying sympathetic neural responses regulating the systemic circulation.
Pressure Natriuresis and Autoregulation of Inner Medullary Blood Flow in Canine Kidney
Authors: Majid Dewan S.A. , Godfrey Murrell , Omoro Sophia A.
Published: June 2012

We have evaluated the responses to changes in arterial pressure on regional blood flows in the renal medulla and sodium excretion simultaneously in denervated kidneys of six anesthetized sodium-replete dogs. Renal regional blood flow responses were determined using laser-Doppler needle flow probes and whole-kidney blood flow was assessed using an electromagnetic flow probe. The responses to stepwise reductions in renal arterial pressure (140 to 70 mm Hg) were examined first with a laser-Doppler needle probe inserted in the outer medulla and then repeated after advancing the same probe in the inner medulla. There were no differences in the control values of total renal blood flow (4.4±0.7 to 4.5±0.5 mL·min
−1
·g
−1
), glomerular filtration rate (0.89±0.7 to 0.94±0.9 mL·min
−1
·g
−1
), sodium excretion (3.6±0.6 to 3.4±0.5 μmol·min
−1
·g
−1
), and urinary excretion rate of nitric oxide metabolites (nitrate/nitrite, 1.6±0.2 to 1.5±0.2 nmol·min
−1
·g
−1
) at the start of both experimental periods. During changes in renal arterial pressure, inner medullary blood flow exhibited efficient autoregulation similar to that in outer medullary blood flow. Usual excretory responses to reductions in renal arterial pressure as well as autoregulation of cortical and whole-kidney blood flows and glomerular filtration rate were observed in these dogs. The slopes of the relationship between arterial pressure and sodium excretion (0.046±0.007 to 0.044±0.009 μmol·min
−1
·g
−1
·mm Hg
−1
) or nitrate/nitrite excretion (0.014±0.003 to 0.013±0.003 nmol·min
−1
·g
−1
·mm Hg
−1
) were similar in both experimental periods. These data indicate that blood flow to the inner medulla is efficiently autoregulated as in outer medulla and cortex of the kidney in anesthetized dogs and demonstrate further that the arterial pressure-induced natriuretic responses do not require associated changes in medullary blood flow.
α-Thrombin Stimulates
sis
-Inducing Factor-A DNA Binding Activity in Rat Aortic Smooth Muscle Cells
Authors: Bhat G. Jayarama , Abraham S. Thomas , Singer Harold A. , Baker Kenneth M.
Published: June 2012

Exposure of rat aortic vascular smooth muscle cells to α-thrombin resulted in the appearance of
sis
-inducing factor-A (SIF-A)-like DNA binding activity. This response to α-thrombin was delayed (detectable at 1 hour) compared with the rapid activation (15 to 30 minutes) by platelet-derived growth factor and the cytokine interleukin-6. α-Thrombin-induced SIF-A was sensitive to treatment with the tyrosine kinase inhibitor genistein. The thrombin inhibitor hirudin prevented the α-thrombin-mediated SIF-A induction. Cycloheximide had no effect on the ability of α-thrombin to induce SIF-A, suggesting that induction does not require new protein synthesis. α-Thrombin-induced SIF-A could be resolved into two additional subcomplexes termed SIF-A
F
and SIF-A
S
. Antibodies against Stat3 reacted with α-thrombin-induced SIF-A
F
, suggesting that Stat3 or a related protein is present in this subcomplex. Induction of SIF-A DNA binding activity may contribute to α-thrombin-mediated cellular responses, including wound healing, cell proliferation, and inflammation in the vasculature.
Role of Renal Nerves in Afferent Arteriolar Reactivity in Angiotensin-Induced Hypertension
Authors: Ichihara Atsuhiro , Inscho Edward W. , Imig John D. , Michel Robert E. , Navar L. Gabriel
Published: June 2012

The objective of this study was to determine the contribution of renal nerves to the enhanced afferent arteriolar reactivity observed in angiotensin II (Ang II)-induced hypertension. Uninephrectomized Sprague-Dawley rats were divided into four groups: sham rats, renal-denervated rats, Ang II-infused (at 40 ng/min for 13 days) rats, and Ang II-infused+renal-denervated rats. With the use of an implanted arterial catheter, mean arterial pressure (MAP) was monitored in conscious rats. Ang II infusion resulted in a progressive increase in MAP from 98±1 (day 0) to 166±7 mm Hg (day 13). This increase in MAP was attenuated in denervated rats and averaged 136±3 mm Hg on day 13. Kidneys were harvested on day 13 for microcirculatory experiments or measurement of intrarenal Ang II levels. Basal afferent arteriolar diameter was similar in all groups, and group averages ranged from 19.6 to 20.7 μm. Chronic Ang II infusion increased intrarenal Ang II levels. Renal denervation did not alter this effect. Increasing perfusion pressure from 100 to 160 mm Hg reduced afferent arteriolar diameter significantly by 11.2±0.6% in the sham group and by a similar degree in the remaining three groups. Superfusion with Ang II (10 nmol/L) reduced afferent arteriolar diameter by 34.3±2.0% in the sham group. This response was enhanced in Ang II-infused (62.3±3.4%) but not in renal-denervated or Ang II-infused+renal-denervated rats. Additionally, the enhanced afferent arteriolar reactivity to Ang II was not influenced by adrenergic receptor blockade. The afferent arteriolar response to norepinephrine was enhanced in renal-denervated, Ang II-infused, and Ang II-infused+renal-denervated rats compared with sham controls. Administration of the calcium ionophore A23187 decreased afferent arteriolar diameter similarly in all four groups. These results indicate that renal nerves contribute to the development of hypertension and to the enhanced afferent arteriolar responsiveness to Ang II elicited by chronic Ang II infusion.
Improvement in Baroreflex Function by an Oral Angiotensin Receptor Antagonist in Rats With Myocardial Infarction
Authors: Nishizawa Masahiko , Kumagai Hiroo , Ichikawa Masashi , Oshima Naoki , Suzuki Hiromichi , Saruta Takao
Published: June 2012

Impaired baroreflex function is a factor responsible for poor prognosis in myocardial infarction patients. Using logistic function curves, we calculated the maximal gain of the baroreflex control of renal sympathetic nerve activity (RSNA) and heart rate in conscious Wistar-Kyoto and spontaneously hypertensive rats whose left anterior descending artery had been ligated 4 weeks earlier. We further investigated whether 3-week oral treatment with the angiotensin II type I receptor antagonist TCV-116 would improve the baroreflex in rats with myocardial infarction. The maximal gain of the mean arterial pressure-RSNA relation in spontaneously hypertensive rats with myocardial infarction and treated with vehicle (1.7±0.1% control per mm Hg) was smaller than the gain in sham-operated hypertensive rats (2.3±0.1% control per mm Hg). After 3-week oral treatment with TCV-116, the maximal gain of the arterial pressure-RSNA relation in hypertensive rats with myocardial infarction was 2.3±0.1% control per mm Hg and significantly greater than the gain in infarcted and vehicle-treated hypertensive rats. In hypertensive rats, the maximal gain of the arterial pressure-heart rate relation of infarcted and TCV-116-treated rats was larger than in infarcted and vehicle-treated rats but significantly smaller than in sham-operated rats. These results demonstrate that oral treatment with an angiotensin receptor antagonist is effective in restoring the impaired baroreflex caused by myocardial infarction and that endogenous angiotensin II is one of the critical factors involved in the impaired baroreflex in myocardial infarction.
Blockade of Bradykinin B
2
Receptors Prevents the Increase in Capillary Density Induced by Chronic Angiotensin-Converting Enzyme Inhibitor Treatment in Stroke-Prone Spontaneously Hypertensive Rats
Authors: Gohlke Peter , Kuwer Ingo , Schnell Angela , Amann Kerstin , Mall Gerhard , Unger Thomas
Published: June 2012

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B
2
-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B
2
-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577±279, n=11 and 3988±300 mm/mm
3
; n=10;
P
<.05) compared with vehicle-treated animals (2935±137 mm/mm
3
; n=13). These effects were abolished by chronic bradykinin B
2
-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429±309 mm/mm
3
; n=7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B
2
-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.
Absence of Linkage for ‘Endothelial’ Nitric Oxide Synthase Locus to Blood Pressure in Dahl Rats
Authors: Deng Alan Y. , Rapp John P.
Published: June 2012

Nitric oxide is thought to be involved in blood pressure regulation. Nitric oxide synthase (NOS) genes are logical candidates for genetic hypertension. Of the three known forms of NOS, the “neuronal” and “inducible”
Nos
genes have been tested as candidate genes for causing inherited hypertension in Dahl salt-sensitive rats. In the present work, we analyzed the endothelial
Nos
gene, designated
Nos3
, directly and indirectly for cosegregation with blood pressure in six F
2
populations independently generated from crosses of Dahl salt-sensitive rats with rats of various other strains. The
Nos3
alleles did not cosegregate with blood pressure in these populations. Therefore,
Nos3
is an improbable, if not impossible, candidate gene for causing hypertension in the Dahl salt-sensitive rat.
Left Ventricular Hypertrophy Precedes Other Target-Organ Damage in Primary Aldosteronism
Authors: Shigematsu Yuji , Hamada Mareomi , Okayama Hideki , Hara Yuji , Hayashi Yutaka , Kodama Koji , Kohara Katsuhiko , Hiwada Kunio
Published: June 2012

To elucidate whether there is a difference in the progression of target-organ damage between primary aldosteronism and essential hypertension, we compared left ventricular hypertrophy and extracardiac target-organ damage in 23 patients with primary aldosteronism and 116 patients with essential hypertension. The severity of hypertensive retinopathy and the renal involvement in primary aldosteronism were subclinical and similar to those in essential hypertension without left ventricular hypertrophy but significantly milder than those in essential hypertension with left ventricular hypertrophy. There was a strongly significant correlation between the degree of left ventricular mass index and the severity of hypertensive retinopathy and renal involvement independent of office blood pressure in essential hypertension. In contrast, left ventricular hypertrophy markedly progressed despite the mild extracardiac target-organ damage in primary aldosteronism. Left ventricular end-diastolic dimension index in primary aldosteronism (3.16±0.50 cm/m
2
) was significantly larger than in essential hypertension without (2.87±0.23) and with (2.88±0.22) left ventricular hypertrophy. On the other hand, there was no difference in extracardiac target-organ damage between 13 primary aldosteronism patients with eccentric left ventricular hypertrophy and the 26 essential hypertensive patients with eccentric left ventricular hypertrophy. The results suggest that predominantly volume load, be it due to aldosteronism or other mechanisms, resulting in eccentric left ventricular hypertrophy is less likely to cause extracardiac target-organ damage than hemodynamic or nonhemodynamic mechanisms resulting in concentric left ventricular hypertrophy.
Is the Regulation of Apoptosis Altered in Smooth Muscle Cells of Adult Spontaneously Hypertensive Rats?
Authors: Díez Javier , Panizo Angel , Hernández Marta , Pardo Javier
Published: June 2012

Whereas the protein product of the Bcl-2 gene inhibits apoptosis, the protein product of the Bax gene acts as a promoter of apoptosis. To gain insight into the regulation of apoptosis in vascular smooth muscle cells in arterial hypertension, we investigated the expression of the proteins Bcl-2 and Bax in small intramyocardial arteries of 36-week-old normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In addition, 16-week-old SHR were treated for 20 weeks with the angiotensin-converting enzyme inhibitor quinapril and killed at 36 weeks of age. We measured the percentages of smooth muscle cells expressing these proteins using monoclonal antibodies and the avidin-biotin immunoperoxidase method. Compared with WKY, untreated SHR exhibited increased (
P
<.001) Bcl-2 expression and similar Bax expression. Values of Bcl-2 measured in quinapril-treated SHR were significantly lower than values measured in untreated SHR and similar to values measured in WKY. Quinapril-treated SHR showed higher (
P
<.001) Bax expression than WKY and untreated SHR. Bcl-2 expression was directly correlated with systolic pressure. Inverse correlations were found between the expression of Bax and the activities of both cardiac and circulating angiotensin-converting enzyme. These findings suggest that smooth muscle cell apoptosis might be inhibited in small arteries of adult SHR as a consequence of an excess of the protein Bcl-2. In addition, our results suggest that chronic angiotensin-converting enzyme inhibition might restore the susceptibility to apoptosis in these cells through stimulation of the protein Bax.
Dose Effects of Human Renin in Rats Transgenic for Human Angiotensinogen
Authors: Bohlender Jürgen , Ménard Joel , Luft Friedrich C. , Ganten Detlev
Published: June 2012

Abstract
We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We infused incremental doses of human renin (1 to 500 ng/h) with minipumps for 10 days into rats harboring the human angiotensinogen gene [TGR(hAOGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increase blood pressure, whereas 10 ng/h caused systolic blood pressure to increase to 215±13 mm Hg. Heart rate decreased initially but then increased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ng/h did not increase blood pressure further. A linear relationship was found between the log of plasma renin activity and systolic blood pressure that increased in slope from days 2 to 9. Rat angiotensinogen levels were low and not influenced by human renin infusion. Human angiotensinogen levels remained stable until 500 ng/h human renin was infused, at which time they decreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human angiotensinogen gene expressions in liver and kidney as well as angiotensin-converting enzyme gene expression in kidney were not affected. The human renin inhibitor Ro 42-5892 was given by gavage repeatedly to rats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressure promptly to basal values. High human renin hypertension in this model is dose dependent, features a steeper relationship between blood pressure and plasma renin activity over time, and is associated with tachycardia and increased drinking. We conclude that the human angiotensinogen transgenic rat offers new perspectives in the study of human renin–induced hypertension.
Incremental Bias in Finapres Estimation of Baseline Blood Pressure Levels Over Time
Authors: Ristuccia Heather L. , Grossman Paul , Watkins Lana L. , Lown Bernard
Published: June 2012

Abstract
Finapres finger blood pressure monitoring appears to provide a reliable alternative to intra-arterial blood pressure measurement under many circumstances. However, few studies have focused on the limitations of Finapres assessment. In a previous pilot investigation, we observed that Finapres pressure following mental stressors failed to return to initial resting levels. Our objectives in the present study were to (1) replicate earlier findings, (2) examine whether local changes in the measured finger were responsible for the observed drift, and (3) test a method to facilitate the return of pressure to systemic baseline levels. We studied two groups of healthy subjects who underwent a protocol consisting of two mental stressors preceded and followed by baseline periods. In the control group, the Finapres continuously monitored pressure on a single finger for the entire protocol. The intervention group periodically had the Finapres cuff removed and the measured finger exercised to prevent local changes that might influence Finapres estimation of blood pressure. Comparisons indicated a group×baseline interaction effect for systolic and diastolic pressures (
P
<.0004 and
P
<.003, respectively). The group with the exercise intervention showed much greater recovery during the final baseline than the control group. Recovery of pressures in the control group but not the intervention group was inversely related to the stress level of blood pressure (
r
=.86,
P
<.0002), indicating a relationship between blood pressure rise and the degree of distortion of subsequent baseline values. On the basis of our results, we propose that in prolonged protocols, the measurement finger be exercised to facilitate accurate measurements of finger pressure with the Finapres.
Increased Membrane Ratios of Metabolite to Precursor Fatty Acid in Essential Hypertension
Authors: Russo Carla , Olivieri Oliviero , Girelli Domenico , Guarini Patrizia , Pasqualini Roberta , Azzini Margherita , Corrocher Roberto
Published: June 2012

Abstract
Desaturase enzymes are responsible for the conversion of essential fatty acids to the longer-chain eicosanoid precursors. These enzymes require zinc as an essential cofactor, and the following ratios—C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5—are considered indexes of their activity. We analyzed these parameters in plasma and erythrocyte membranes of 105 essential hypertensive patients, 20 white coat hypertensive patients, and 100 age-matched normotensive control subjects. Dietary analysis excluded significant quantitative and qualitative differences in fatty acid dietary intake between essential hypertensive patients and normotensive control subjects. Zinc levels and C20:4/C18:2, C20:5/C18:3, and C22:6/C20:5 ratios were significantly higher in essential hypertensive patients than control subjects, whereas white coat hypertensive patients showed intermediate values for all these parameters. These data provide evidence for an alteration in fatty acid metabolism of essential hypertensive patients, consistent with increased activity of desaturase enzymes. The consequent greater bioavailability of eicosanoid precursors, and in particular of arachidonic acid, could affect several vascular functions and have a bearing on the pathogenesis or complications of hypertension.
FR 173657: A New, Potent, Nonpeptide Kinin B
2
Receptor Antagonist
Authors: Rizzi Anna , Gobeil Fernand , Calò Girolamo , Inamura Noriaki , Regoli Domenico
Published: June 2012

Abstract
FR 173657, the first effective nonpeptide kinin B
2
receptor antagonist, has been tested in four preparations from different species (human, pig, rabbit, and guinea pig). The new compound shows high apparent affinity for the four B
2
receptors, with pA
2
values ranging from 8.2 to 9.4. FR 173657 is a selective B
2
receptor antagonist that does not interact with human, pig, or rabbit B
1
receptors. The new compound is extremely specific for the kinin B
2
receptors as it does not affect the myotropic effects of norepinephrine, endothelin-1, or 5-hydroxytryptamine in the human umbilical vein; the contractions elicited by substance P and angiotensin II in the rabbit jugular vein or those produced by acetylcholine and histamine in the guinea pig ileum; or the relaxation of the pig coronary artery induced by norepinephrine and substance P. FR 173657 acts as a competitive antagonist over an extended range of concentrations on human and rabbit B
2
receptors, whereas on pig and guinea pig receptors, it depresses the maximal effect of bradykinin and thus appears to act as a noncompetitive antagonist.