bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expression and Autoradiographic Localization of Atrial Natriuretic Peptide Receptor in Spontaneously Hypertensive and Normotensive Rat Testes: Diminution of Testosterone in Hypertension
Authors: Kapasi Aditi A. , Kumar Ravindra , Pauly James R. , Pandey Kailash N.
Published: June 2012

Previous studies have shown that the diuretic hormone atrial natriuretic peptide (ANP) also regulates the steroidogenic responsiveness in isolated Leydig cells from mouse and rat testes. In the present study, we examined the distribution of specific receptors for ANP and C-type natriuretic peptide (CNP) in the testicular compartments of 12-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). We used an in vitro autoradiographic procedure on slide-mounted frozen testicular sections to localize the receptors of the natriuretic peptide hormone family using
125
I-ANP and
125
I-CNP as radioligands. A high level of specific
125
I-ANP binding sites was localized largely in the Leydig cells of the interstitial compartment; other testicular cells were not significantly labeled. On the other hand, no significant difference was observed in
125
I-CNP binding sites in the testicular cells of SHR and WKY. Semiquantitative analysis of the binding sites indicated that the density of
125
I-ANP receptor binding in Leydig cells of WKY testis was ninefold higher than in those of SHR testis. A moderate level of
125
I-ANP binding was also observed in seminiferous tubules, particularly in the spermatids of both SHR and WKY.
125
I-ANP binding in WKY spermatids was approximately 2.5-fold higher than in SHR spermatids. Northern blot analysis showed that mRNA specific for guanylyl cyclase type A (Npra) was expressed at approximately twofold higher levels in WKY than in SHR testis. ANP (1×10
−8
mol/L) stimulated fourfold to fivefold increased levels of testosterone production in isolated Leydig cells from normotensive WKY compared with those from SHR. These findings support a new physiological role of ANP in Leydig cells, in which a functional relationship seems to exist between testicular ANP receptor expression and testosterone production and the state of hypertension in SHR.
Quantitative Trait Loci in Genetically Hypertensive Rats
Authors: Clark James S. , Jeffs Baxter , Davidson Anne O. , Lee Wai Kwong , Anderson Niall H. , Bihoreau Marie-Therese , Brosnan M. Julia , Devlin Alison M. , Kelman Andrew W. , Lindpaintner Klaus , Dominiczak Anna F.
Published: June 2012

We performed a total genome screen in an F
2
cross derived from the stroke-prone spontaneously hypertensive rat and the normotensive Wistar-Kyoto rat. Blood pressure at baseline and after 1% NaCl was measured by radiotelemetry; other phenotypes included heart rate, motor activity, left ventricle weight to body weight ratio, and vascular smooth muscle cell polyploidy, a measure of vascular hypertrophy. Quantitative trait loci affecting a given phenotype were mapped relative to microsatellite markers by using the
mapmaker/qtl
1.1 computer package. We identified three blood pressure quantitative trait loci, two on rat chromosome 2 and one on rat chromosome 3. The quantitative trait loci close to genetic markers D2Mgh12 (“suggestive” linkage, with a maximal logarithm of the odds [LOD] score of 3.1) and D3Mgh16 (significant linkage, with a maximal LOD score of 5.6) showed possible sex specificity in the male F
2
cohort only. This was confirmed by the likelihood ratio test for the difference in locus effects between the sexes. We also identified a new quantitative trait locus for LV hypertrophy on rat chromosome 14 (“suggestive” linkage, with a maximal LOD score of 3.1). The sex specificity of blood pressure quantitative trait loci will be important in designing congenic strains and substrains for fine genetic mapping and for identifying genes that regulate blood pressure.
Autosomal Dominant Hypertension and Brachydactyly in a Turkish Kindred Resembles Essential Hypertension
Authors: Schuster Herbert , Wienker Thomas F. , Toka Hakan R. , Bähring Sylvia , Jeschke Eva , Toka Okan , Busjahn Andreas , Hempel Albrecht , Tahlhammer Christoph , Oelkers Wolfgang , Kunze Jürgen , Bilginturan Nihat , Haller Hermann , Luft Friedrich C.
Published: June 2012

We examined a Turkish kindred with a unique form of autosomal dominant hypertension that cosegregates 100% with brachydactyly and maps to chromosome 12p. Affected adults were 10 to 15 cm shorter than unaffected people; however, their body mass index (27 kg/m
2
) was not different. Blood pressure increased steeply with age in the affected people so that by age 40 years, they had a mean blood pressure of 140 mm Hg, compared with 92 mm Hg in unaffected individuals. Complete clinical, roentgenographic, and laboratory evaluation was performed in 6 subjects, including 24-hour blood pressure measurements and humoral determinations before and after volume expansion with 2 L normal saline over 4 hours followed by volume contraction on the following day with a 20-mmol sodium diet and 40 mg furosemide at 8
am
, noon, and 4
pm
. Two affected men aged 46 and 31 years; 3 affected women aged 40, 31, and 30 years; and 1 unaffected man aged 29 years were studied. Systolic pressures ranged from 170 to 250 mm Hg, and diastolic pressures ranged from 100 to 150 mm Hg in affected people; the unaffected man had a blood pressure of 120/70 mm Hg. Thyroid, adrenal, and renal functions were normal; electrolyte and acid-base statuses were normal. Calcium and phosphate homeostasis was normal. Day-night circadian blood pressure rhythm was preserved. The subjects were not salt sensitive; renin, aldosterone, and catecholamine values reacted appropriately to volume expansion and contraction. Affected people had mild cardiac hypertrophy and increased radial artery wall thickness. Fibroblasts from affected people grew more rapidly in culture than from unaffected people. We conclude that this novel form of inherited hypertension resembles essential hypertension.
Spinal Nicotinic Receptor Expression in Spontaneously Hypertensive Rats
Authors: Khan Imran M. , Youngblood Kenna L. , Printz Morton P. , Yaksh Tony L. , Taylor Palmer
Published: June 2012

Intrathecal administration of nicotinic agonists previously has been shown to result in exaggerated pressor and heart rate responses as well as greater nociceptive behavior in adult (12-week-old) spontaneously hypertensive rats (SHR) than in age-matched normotensive Wistar-Kyoto rats (WKY). Paradoxical to these augmented responses to nicotinic agonists in SHR, nicotinic receptor number in the spinal cord as measured by cytisine binding sites is lower in adult SHR than normotensive WKY and Sprague-Dawley rats. Using the high-affinity agonist epibatidine, we found similar differences in receptor number between strains in both in vitro ligand binding experiments with spinal cord membranes and in situ autoradiographic analyses. Spinal nicotinic receptor number did not differ in 5-week-old prehypertensive SHR and age-matched WKY; however, receptor numbers were higher in young rats of both strains than in their adult counterparts. Antihypertensive treatment (25 mg/kg per day hydralazine PO) in 6-week-old SHR from 6 to 12 weeks of age markedly reduced the progressive rise in blood pressure yet did not alter nicotinic receptor number compared with untreated rats. Similar treatment of WKY with hydralazine produced a slight fall in blood pressure but no change in receptor number. Thus, normalization of blood pressure by hydralazine in SHR does not result in a return of receptor expression to levels seen in normotensive rats. Higher centrally mediated pressor activity or augmented postcoupling events after neuronal nicotinic receptor stimulation may slowly downregulate expression of spinal nicotinic receptors in this genetically hypertensive rat strain.
Angiotensinogen in Human Essential Hypertension
Authors: Caulfield Mark , Lavender Paul , Newell-Price John , Kamdar Sejal , Farrall Martin , Clark Adrian J.L.
Published: June 2012

The candidacy of angiotensinogen for a role in the genetic basis of hypertension is supported by the observation that plasma angiotensinogen levels track with raised blood pressure through families. In addition, transgenic mice with overexpression of a rat angiotensinogen gene develop hypertension, and knockout mice with a disrupted gene and absent angiotensinogen production develop low blood pressure. There are now two studies in populations of white European origin and one in African Caribbeans providing support for a role of the angiotensinogen gene locus in human essential hypertension.
Losartan Blocks Aldosterone and Renal Vascular Responses to Angiotensin II in Humans
Authors: Gandhi Sanjay K. , Ryder Diane H. , Brown Nancy J.
Published: June 2012

In vitro and animal studies have demonstrated that the effect of angiotensin II (Ang II) on aldosterone is mediated through the Ang II type 1 receptor. However, it has been difficult to demonstrate an effect of Ang II type 1 receptor blockade on aldosterone levels in human studies. One possible explanation is that subjects have not been studied under salt-controlled conditions. Therefore, we examined the effects of losartan on the aldosterone and renal plasma flow responses to Ang II infusion in six normotensive subjects under low and high salt conditions. Ang II was infused in graded doses (0.3 to 10 ng/kg per minute) in the presence and absence of losartan (a single 50-mg oral dose). Renal plasma flow was assessed by measurement of para-aminohippurate clearance. Blood pressure, plasma aldosterone levels (low salt conditions only), and para-aminohippurate clearance were measured before and after each Ang II dose. Losartan had no effect on baseline systolic pressure but attenuated the systolic pressure response to exogenous Ang II during both low salt (0.7±1.9 versus 6.7±1.4 mm Hg,
P
=.001) and high salt (2.0±1.9 versus 12.3±2.1 mm Hg,
P
=.006) conditions. Under low salt conditions, losartan reduced the baseline plasma aldosterone level from 1135±204 to 558±102 pmol/L (
P
=.015) and blocked the aldosterone response to Ang II (−49±110 versus +436±83 pmol/L,
P
=.019). During high salt conditions, losartan had no effect on baseline renal plasma flow but attenuated the renal plasma flow response to Ang II (−90.1±15.1 versus −185.1±2.6 mL/min per 1.73 m
2
,
P
=.013). These data confirm that losartan lowers both basal and exogenous Ang II–stimulated aldosterone levels under low salt conditions. Losartan does not significantly affect baseline renal plasma flow but does attenuate the renal plasma flow response to exogenous Ang II under high salt conditions.
Induction of Growth Hormone Receptor and Insulin-Like Growth Factor-I mRNA in Aorta and Caval Vein During Hemodynamic Challenge
Authors: Wickman Anna , Friberg Peter , Adams Michael A. , Matejka Göran L. , Brantsing Camilla , Guron Gregor , Isgaard Jörgen
Published: June 2012

Induction of two-kidney, one clip hypertension (renal hypertension) is characterized by a slow increase in left ventricular tension and aortic wall stress, as opposed to aortocaval fistula or shunt volume overload, which induces a marked and rapid onset of wall stress in the caval vein and right ventricle. In the present study, we applied hemodynamic challenge to study the growth response involving gene expression of insulin-like growth factor-I (IGF-I) and growth hormone receptor (GH-R) mRNA in aorta and caval vein. Volume overload and pressure overload were induced in Wistar rats by means of shunt and renal hypertension, respectively. Systolic pressure was measured before excision of the great vessels, which was performed between 2 and 12 days postoperatively. Aortic and caval vein IGF-I and GH-R mRNA expressions were measured by means of a solution hybridization assay, and the caval vein was analyzed for IGF-I protein by immunohistochemistry. In the volume-distended but not pressurized caval vein in shunt rats, verified by telemetry recordings, there was an eightfold increase in IGF-I and 3.5-fold increase in GH-R mRNA at day 4 versus control. The IGF-I protein appeared to be localized in smooth muscle cells. In the aorta of the renal hypertension group, changes were of a slower onset. At day 7, there was a fourfold increase in IGF-I and fivefold increase of GH-R mRNA expressions versus sham-operated rats. Both the shunt caval vein and renal hypertension aorta showed evidence of a structural adaptation of the growth response. The present study suggests that acute elevation in vascular wall stress is an important triggering factor for overexpression of IGF-I and GH-R mRNA in great vessels. The growth hormone/insulin-like growth factor axis may be an important link in mediating structurally adaptive growth responses in the blood vessel wall.
Role of the α-, β-, and γ-Subunits of Epithelial Sodium Channel in a Model of Polygenic Hypertension
Authors: Kreutz Reinhold , Struk Berthold , Rubattu Speranza , Hübner Norbert , Szpirer Josiane , Szpirer Claude , Ganten Detlev , Lindpaintner Klaus
Published: June 2012

The pathophysiological basis of Liddle's syndrome, a rare autosomal dominant form of arterial hypertension, has been found to rest on missense mutations or truncations of the β- and γ-subunits of the epithelial sodium channel. The hypothesis has been advanced that molecular variants of these genes might also contribute to the common polygenic forms of hypertension. We tested this hypothesis by performing a cosegregation study in a reciprocal cross between the stroke-prone spontaneously hypertensive rat (SHRSP
HD
) and a Wistar-Kyoto rat (WKY-1
HD
) reference strain. We carried out genetic mapping and chromosomal assignment of the α-, β-, and γ-subunits of the epithelial sodium channel using both linkage analysis and fluorescent in situ hybridization techniques. We demonstrate that in the rat, the β- and γ-subunits, as in humans, are in close linkage; they map to rat chromosome 1 and cosegregate with systolic pressure after dietary NaCl (logarithm of the odds [LOD] score, 3.7), although the peak LOD score of 5.0 for this quantitative trait locus was detected 4.4 cM away from the β-/γ-subunit locus. The α-subunit was mapped to chromosome 4 and exhibited no linkage to blood pressure phenotype. Comparative analysis of the complete coding sequences of all three subunits in the SHRSP
HD
and WKY-1
HD
strains revealed no biologically relevant mutations. Furthermore, Northern blot comparison of mRNA levels for all three subunits in the kidney showed no differences between SHRSP
HD
and WKY-1
HD
. Our results fail to support a material contribution of the epithelial sodium channel genes to blood pressure regulation in this model of polygenic hypertension.
Angiotensin-Converting Enzyme Gene Mutations, Blood Pressures, and Cardiovascular Homeostasis
Authors: Krege John H. , Kim Hyung-Suk , Moyer Jeffrey S. , Jennette J. Charles , Peng Li , Hiller Sylvia K. , Smithies Oliver
Published: June 2012

A common polymorphism of the angiotensin-converting enzyme (ACE) gene (
ACE
in humans,
Ace
in mice) is associated with differences in circulating ACE levels that may confer a differential risk for cardiovascular diseases. To study the effects of genetically determined changes in
Ace
gene function within a defined genetic and environmental background, we have studied mice having one, two, or three functional copies of the
Ace
gene at its normal chromosomal location. ACE activities in the serum increased progressively from 62% of normal in the one-copy animals to 144% of normal in the three-copy animals (
P
<10
−15
, n=132). The blood pressures of the mice having from one to three copies of the
Ace
gene did not differ significantly, but the heart rates, heart weights, and renal tubulointerstitial volumes decreased significantly with increasing
Ace
gene copy number. The level of kidney renin mRNA in the one-copy mice was increased to 129±9% relative to that of the normal two-copy mice (100±4%,
P
=.01, n=16). We conclude that significant homeostatic adaptations successfully normalize the blood pressures of mice that have quantitative changes in
Ace
gene function. Our results suggest only that quantitative changes in expression of the
Ace
gene will observably affect blood pressures when accompanied by additional environmental or genetic factors that together with
Ace
exceed the capacity of the homeostatic mechanisms.
Linkage Analysis Using Platelet-Activating Factor Ca
2+
Response in Transformed Lymphoblasts
Authors: Brzustowicz Linda M. , Gardner Jeffrey P. , Hopp Laszlo , Jeanclos Elisabeth , Ott Jurg , Yang Xiao Yan , Fekete Zoltan , Aviv Abraham
Published: June 2012

Epstein-Barr virus-transformed lymphoblasts from patients with essential hypertension demonstrate enhanced G protein-mediated cytosolic free calcium ([Ca
2+
]

i

) response to platelet-activating factor (PAF). To map genes responsible for variation in G protein-coupled signaling, we used this cellular phenotype for a linkage study of transformed cell lines from the Centre d’Etude du Polymorphisme Humain (CEPH) reference pedigrees. The PAF-evoked change in [Ca
2+
]

i

ranged from 20 to 392 mmol/L and was highly reproducible within each cell line. PAF-elicited [Ca
2+
]

i

responses were obtained in lymphoblastic cell lines from five densely mapped pedigrees of the CEPH collection. Using PAF-evoked [Ca
2+
]

i

responses as a quantitative trait, two-point sibpair linkage analyses were conducted using 5150 markers from the Collaborative Human Linkage Center (CHLC) database. Nine loci, located on chromosomes 1, 4, 10, 11, 13, 16, and 17, were suggestive of linkage, with values of
P
<7.4×10
−4
. Multipoint linkage analysis produced a significant linkage finding (
P
=2.1×10
−5
) in one family at D16S151, with suggestive linkage results for seven additional markers spanning a 40-cM interval of chromosome 16. Multipoint analysis produced suggestive findings of linkage to eight loci from two distinct regions of chromosome 11 in another family. These results indicate that loci involved in the control of G protein-mediated mechanisms, suggested to be involved in the pathophysiology of essential hypertension, can be identified using cell lines from general pedigrees selected without any knowledge of the blood pressure status of the donors. This strategy represents an approach to rapidly and inexpensively mapping loci related to common, complex disorders, using phenotypes that are stable in immortalized lymphoblasts together with existing reference pedigree cell lines and genotype databases.
Nocturnal Blood Pressure Fall on Ambulatory Monitoring in a Large International Database
Authors: Staessen Jan A. , Bieniaszewski Leszek , O'Brien Eoin , Gosse Philippe , Hayashi Hiroshi , Imai Yutaka , Kawasaki Terukazu , Otsuka Kuniaki , Palatini Paolo , Thijs Lutgarde , Fagard Robert
Published: June 2012

A wide range of definitions is used to distinguish subjects in whom blood pressure (BP) falls at night (dippers) from their counterparts (nondippers). In an attempt to standardize the definition of nondipping, we determined the nocturnal BP fall and night-day BP ratio by 24-hour ambulatory monitoring in 4765 normotensive and 2555 hypertensive subjects from 10 to 99 years old. In all subjects combined, the systolic/diastolic nocturnal fall and corresponding ratio averaged (±SD) −16.7±11.0/−13.6±8.1 mm Hg and 87.2±8.0%/83.1±9.6%, respectively. In normotensive subjects, the 95th percentiles were −0.3/−1.1 mm Hg for the nocturnal fall and 99.7%/98.3% for the night-day ratio. Both the fall and ratio showed a curvilinear correlation with age. The smallest fall and largest ratio were observed in older (≥70 years) subjects. A higher BP on conventional sphygmomanometry was associated with a larger systolic (partial
r
=.11) and diastolic (
r
=.12) nocturnal BP fall. The diastolic (
r
=.08) but not the systolic night-day ratio increased with higher conventional BP. The nocturnal BP fall was larger and the corresponding night-day ratio smaller in oscillometric (n=5884) than in auscultatory (n=1436) recordings, in males (n=3730) than in females (n=3590), and in Europe (n=4556) than in the other continents (n=2764). The distributions of the nocturnal BP fall and night-day ratio showed considerable overlap among normotensive and hypertensive subjects, but the overlap tended to be larger for the ratio than for the fall. Of all subjects, 3.2% had systolic and diastolic ratios of 100% or more. With adjustments applied for confounders, the probability of being a nondipper increased 2.8 times (95% confidence interval, 2.0-4.0) from 30 to 60 years and 5.7 times (4.4-7.4) from 60 to 80 years. The odds ratios were 1.0 (0.8-1.4) for males versus females, 1.6 (1.2-2.1) for subjects with definite hypertension versus normotensive subjects, 2.4 (1.2-4.7) for Asians (n=2213, 96% Japanese) versus inhabitants of the other continents, and 2.4 (1.5-3.8) for subjects examined with auscultatory versus oscillometric devices. In conclusion, the mathematical definition of nondipping, ie, having a night-day ratio of 100% or more for systolic and diastolic BPs, closely approximated the 95th percentiles of the night-day ratio in normotensive subjects. The ratio depends less on BP level than the nocturnal BP fall and is therefore to be preferred in the definition of dipping status. Notwithstanding the present findings, the reproducibility of nondipping and its prognostic significance need further clarification.
Angiotensin-(1–7) Augments Bradykinin-Induced Vasodilation by Competing With ACE and Releasing Nitric Oxide
Authors: Li Ping , Chappell Mark C. , Ferrario Carlos M. , Brosnihan K. Bridget
Published: June 2012

Recent studies have shown that angiotensin-(1–7) [Ang-(1–7)] interacts with kinins and augments bradykinin (BK)-induced vasodilator responses by an unknown mechanism. In this study, we evaluated whether the potentiation of the BK-induced vasodilation by Ang-(1–7) may be attributable to inhibition of BK metabolism, release of nitric oxide, or both. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers.
125
I-[Tyr
0
]-BK metabolism was determined in vascular rings by assessing the degradation of the peptide by high-performance liquid chromatography. Ang-(1–7) augmented the vasodilation induced by BK in a concentration-dependent manner in rings preconstricted with the thromboxane analog U46619. The EC
50
of BK (2.45±0.51 nmol/L versus 0.37±0.08 nmol/L) was shifted leftward by 6.6-fold in the presence of 2 μmol/L concentration of Ang-(1–7). The response was specific for BK, since Ang-(1–7) did not augment the vasodilation induced by either acetylcholine (0.05 μmol/L) or sodium nitroprusside (0.1 μmol/L). Moreover, neither angiotensin I nor angiotensin II (Ang II) duplicated the augmented BK response of Ang-(1–7). Pretreatment of vascular rings with the nitric oxide synthase inhibitor,
N
ω
-nitro-
l
-arginine (L-NA; 100 μmol/L) completely abolished the effects of Ang-(1–7) on BK-induced vasodilation whereas pretreatment with indomethacin (10 μmol/L) was without effect. The potent specific BK B
2
receptor antagonist, Hoe 140, nearly abolished the BK and the Ang-(1–7) potentiated responses at 2 μmol/L, whereas at a lower concentration (20 nmol/L) Hoe 140 shifted the response curve to the right for both Ang-(1–7) and vehicle; however, the augmented response to Ang-(1–7) persisted. Preincubation of vascular rings with 20 μmol/L of the AT
1
(CV11974), AT
2
(PD123319), or nonselective (Sar
1
Thr
8
-Ang II) receptor antagonists had no significant effect on the Ang-(1–7)-enhanced vasodilator response to BK. Lisinopril (2 μmol/L) significantly enhanced the BK-induced vasodilator response while at the same time it abolished the synergistic action of Ang-(1–7) on BK. In addition, pretreatment with 2 μmol/L Ang-(1–7) significantly inhibited the degradation of
125
I-[Tyr
0
]-BK and the appearance of the BK-(1–7) and BK-(1–5) metabolites in coronary vascular rings. Ang-(1–7) inhibited purified canine angiotensin converting enzyme activity with an IC
50
of 0.65 μmol/L. In conclusion, Ang-(1–7) acts as a local synergistic modulator of kinin-induced vasodilation by inhibiting angiotensin converting enzyme and releasing nitric oxide.
Angiotensin II Stimulates Secretion of Endogenous Ouabain From Bovine Adrenocortical Cells via Angiotensin Type 2 Receptors
Authors: Laredo James , Shah Jui R. , Lu Zhuo-ren , Hamilton Bruce P. , Hamlyn John M.
Published: June 2012

Angiotensin II stimulates secretion of corticosteroids and ouabain-like activity from adrenocortical cells. Distinct adrenocortical angiotensin II receptor subtypes (AT
1
, AT
2
) have been described, and the present studies investigated their roles in steroid secretion. Using primary bovine adrenocortical cell cultures under serum free conditions, angiotensin II stimulated the secretions of aldosterone, cortisol, and endogenous ouabain as verified by high-performance chromatography. The dose-response curves for stimulated steroid secretion were parallel with unitary slopes while the half-maximally effective concentrations of angiotensin II were 0.31 to 0.38 nmol/L for secretions of aldosterone and cortisol and 2.3 nmol/L for endogenous ouabain. The nonselective mammalian antagonist (Sar
1
-Ile
8
) angiotensin II blocked stimulated secretion of all three steroids without affecting basal output. In the presence of the AT
1
antagonist DuP753, angiotensin II—stimulated secretions of aldosterone and cortisol were blocked while secretion of endogenous ouabain was unaffected. In the presence of the AT
2
antagonist PD123319, both basal and angiotensin II-stimulated secretions of aldosterone and cortisol were normal while stimulated secretion of endogenous ouabain was inhibited. The secretion of endogenous ouabain was activated maximally by the AT
2
agonist
CGP42112
under conditions in which aldosterone secretion was unaffected. These results demonstrate that AT
2
receptors stimulate secretion of endogenous ouabain from bovine adrenocortical cells. The specificity of AT
1
and AT
2
receptor stimulation indicates that separate signaling mechanisms having minimal cross talk control the adrenocortical secretions of corticosteroids and cardiac-active steroids. Adrenocortical AT
2
receptors may be important in the adaptation to low salt diets and other conditions in which angiotensin II is increased.
Regulation of Growth of the Adrenal Gland in DOC-Salt Hypertension
Authors: Elijovich Fernando , Zhao Hua-Wei , Laffer Cheryl L. , Du Yong , DiPette Donald J. , Inagami Tadashi , Wang Donna H.
Published: June 2012

To investigate the role of the renin-angiotensin system in the regulation of adrenal growth in deoxycorticosterone (DOC)-salt hypertensive rats, and the adrenal gene expression of angiotensin AT
1
and AT
2
receptors, three groups of uninephrectomized rats+DOC pellet+0.9% NaCl were given water (DOC), losartan (DOC-L), or ramipril (DOC-R) by gavage. Controls had sham surgery and water gavage. Tail-cuff systolic and mean intra-arterial blood pressures were significantly higher in the three DOC groups than in controls and not different among the groups. Adrenal weight of DOC was slightly but not significantly greater than that of controls, while those of DOC-L and DOC-R were greater than that of controls (
P
<.01). Northern blots showed that AT
1
and AT
2
gene expression was significantly reduced in DOC (by 33% and 60%), while that of AT
1
(but not AT
2
) was significantly reduced further (versus control and DOC) in DOC-L and DOC-R. There were negative correlations between adrenal weight and AT
1
(
r
=−.80,
P
<.0001) or AT
2
(
r
=−.60,
P
<.005). We conclude that DOC-salt hypertension downregulates adrenal AT
1
and AT
2
gene expression by different mechanisms. Removal of the effects of angiotensin by losartan or ramipril downregulates AT
1
further and promotes adrenal growth, indicating the presence of an AT
1
-mediated growth-inhibitory action of angiotensin II on the adrenal gland. These observations constitute an additional example of a growth-inhibitory role for the AT
1
receptor, opposite to its more common growth-promoting actions in other organs and tissues.
Kidney 11β-HSD2 Is Inhibited by Glycyrrhetinic Acid-Like Factors in Human Urine
Authors: Lo Ying H. , Sheff Michael F. , Latif Syed A. , Ribeiro Carla , Silver Helene , Brem Andrew S. , Morris David J.
Published: June 2012

We have previously shown that human urine contains substances that, like glycyrrhetinic acid, inhibit 11β-HSD1. We have named these substances “glycyrrhetinic acid-like factors” or GALFs. We now have found that human urine contains measurable quantities of both 11β(HSD1)- and 11β(HSD2)-GALF inhibitory substances. Both are markedly elevated in pregnancy. Their chemical and high-performance liquid chromatography (HPLC) characteristics suggest that several of the GALFs are steroidal. Large quantities of neutral 11β(HSD1)- and 11β(HSD2)-GALFs can be extracted directly from urine into ethyl acetate, yielding fraction EA
1
. Hydrolysis of the GALFs remaining in the aqueous phase by β-glucuronidase markedly increases the total amounts of GALFs, with the majority now being ethyl acetate extractable (fraction EA
2
). These EA
2
posthydrolysis GALFs can be separated by HPLC resulting in at least six components with inhibitory activity against each isoenzyme. Only two GALF peaks are active against both 11β-HSD1 and 11β-HSD2. The others are peaks with specific 11β(HSD 1)- and 11β(HSD2)-GALF inhibitory activity. The GALFs in the same posthydrolysis EA
2
extract are also inhibitory toward the 11β-HSD1 that is present in vascular smooth muscle where they may play a role in the mechanisms controlling blood pressure. We have also found that 11β-HSD2 is selectively inhibited by 5α-(but not by 5β-) reduced steroids. GC-MS analysis of the 11β(HSD2)-GALFs in EA
2
is now being performed to determine whether this group includes 3α,5α-ring A-tetrahydro-reduced derivatives of steroids.
Role of Substance P in Blood Pressure Regulation in Salt-Dependent Experimental Hypertension
Authors: Kohlmann Osvaldo , Cesaretti Mario Luis , Ginoza Milton , Tavares Agostinho , Zanella Maria Teresa , Ribeiro Artur Beltrame , Ramos Oswaldo Luiz , Leeman Susan E. , Gavras Irene , Gavras Haralambos
Published: June 2012

The participation of substance P in the pathogenesis of five models of experimental hypertension, ie, DOCA-salt, subtotal nephrectomy, one-kidney-one clip renovascular, two-kidney-one clip renovascular, and spontaneous hypertension, was evaluated via an acute infusion of a newly synthesized potent, specific nonpeptide antagonist of substance P at the NK-1 receptor, the agent CP 96,345. In conscious unrestrained rats, CP 96,345 induced significant and sustained increases in mean arterial pressure of DOCA-salt, subtotal nephrectomy, and one-kidney-one clip renovascular hypertensive rats but only small and nonsignificant changes in blood pressure of two-kidney-one clip renovascular and spontaneously hypertensive rats. CP 96,345 had no effect on the blood pressure of sham-treated controls and Wistar-Kyoto rats. This NK-1 receptor antagonist did not significantly affect the heart rate of any experimental model studied. The data suggest that endogenous substance P may act as a partial counterregulatory mechanism against vasoconstriction in models of salt-dependent hypertension.
Hypothalamic Substance P Release
Authors: Diz Debra I. , Falgui Burt , Bosch Susan M. , Westwood Brian M. , Kent Jessica , Ganten Detlev , Ferrario Carlos M.
Published: June 2012

Increases in arterial pressure and paraventricular nucleus vasopressin release in response to intracerebroventricular injections of angiotensin peptides are blunted in mRen2(27) renin transgenic [TG(+)] rats. Intraventricular injections of tachykinin peptides mimic several of the actions of angiotensin peptides, and angiotensin peptides evoke substance P release from hypothalamic brain slices. The present study assessed whether diminished substance P release occurs in response to angiotensin peptides in TG(+) rats. Systolic blood pressure at 8 to 12 weeks of age averaged 197±4 mm Hg (n=20;
P
<.05) in TG(+) rats compared with 123±4 mm Hg in normotensive control [TG(−)] rats (n=18). Body weight was lower in hypertensive than in normotensive rats (305±14 versus 344±13 g, respectively;
P
<.05). Brain slices from hypothalamus were perfused at 37°C with oxygenated Krebs’ bicarbonate buffer. Substance P was measured before (basal) and during perfusion with either Krebs’ buffer (control) or 2 μmol/L angiotensin-(1–7) or angiotensin II. Basal substance P release was 92±10 pg/g wet tissue in TG(+) and 98±12 pg/g in TG(−) rats (
P
>.05). Angiotensin-(1–7) and angiotensin II significantly increased substance P release from hypothalamus of TG(−) rats (82% and 70% above control;
P
<.05) but not TG(+) rats. These studies further support the hypothesis that the cardiovascular effects of angiotensin peptides are mediated in part by substance P and that this relationship is blunted in a hypertensive model that results from excess tissue production of angiotensins.
Enalapril and Losartan Reduced Cardiac Mass and Improved Coronary Hemodynamics in SHR
Authors: Nunez Eduardo , Hosoya Kazuyoshi , Susic Dinko , Frohlich Edward D.
Published: June 2012

Among the multiple mechanisms postulated for the increased risk of hypertensive left ventricular hypertrophy (LVH), coronary hemodynamic alterations remain a strong possibility. This study was designed to compare the effects of treatment with an ACE inhibitor (enalapril) and an angiotensin AT
1
receptor antagonist (losartan) on systemic and coronary hemodynamics and to determine whether the combination of these two renin-angiotensin system (RAS) inhibitors would be as or more effective in reducing mean arterial pressure (MAP), left ventricular (LV) mass, and improving coronary hemodynamics than either regimen alone. Thus, 23 week old spontaneously hypertensive rats (SHR) were treated (12 weeks) with tap water (C), enalapril (30 mg·kg
−1
· d
−1
), losartan (30 mg·kg
−1
·d
−1
), or combination (15 mg·kg
−1
·d
−1
). Age-matched Wistar-Kyoto (WKY) rats served as normotensive controls. After 12 weeks, systemic and coronary hemodynamics were determined (15 μm radiolabeled microspheres) at baseline, during maximal treadmill exercise, and during maximal dilation (dipyridamole). Enalapril and losartan equally reduced MAP and LV mass in association with a decreased total peripheral resistance. The RAS combination reduced MAP and LV mass more than either drug alone. Resting cardiac index and coronary blood flow (CBF) per unit of LV mass did not differ among the groups. Although enalapril did not improve coronary flow reserve (CFR), it diminished minimal coronary vascular resistance (MCVR); losartan improved both. However, the combination was more effective than either agent alone, reaching values close to normotensive WKY controls. In conclusion, these data demonstrated significantly impaired maximal CBF, CFR, and MCVR in untreated SHR, but losartan alone and in combination with enalapril improved systemic and coronary hemodynamics more than enalapril alone.
Combined Sympathetic Suppression and Angiotensin-Converting Enzyme Inhibition in Congestive Heart Failure
Authors: Manolis Athanasios J. , Olympios Christoforos , Sifaki Maria , Handanis Stelios , Cokkinos Dennis , Bresnahan Margaret , Gavras Irene , Gavras Haralambos
Published: June 2012

Neurohormonal activation is a pathogenic contributor and prognostic marker in congestive heart failure (CHF). While angiotensin-converting enzyme (ACE) inhibition is now first-line therapy, sympathetic inhibition has only lately been proposed to this aim. Recently, we reported improvement of preload parameters by sympathetic suppression with clonidine. In the present paper we studied the effects of a single oral dose of clonidine 0.15 mg+captopril 6.25 mg combination, compared with captopril 6.15+placebo in a single-blind parallel study on 16 patients with Class III or IV CHF (13 males, 3 females, aged 62±8 years, with an ejection fraction of 33±8%). Hemodynamic and hormonal measurements were taken at baseline after a diagnostic cardiac catheterization and again 2 hours after treatment. The results indicate that preload parameters such as RAP, PCWP and MPAP decreased significantly with the combination therapy but not with captopril alone. On the contrary, SVR decreased significantly with both treatments and SVI increased significantly with both—but the latter change was significantly greater with the captopril/clonidine combination than with captopril alone. Suppression of plasma norepinephrine occurred with the combination only (evidently attributable to clonidine), whereas plasma renin activity increased with both regimens, due apparently to captopril.

Our results indicate that the combination of clonidine with captopril induces significant improvements in both preload and afterload parameters of CHF and correction of activated neurohormones, suggesting additive hemodynamic and hormonal benefits from the two treatment modalities.
Receptor Subtype for Vasopressin-Induced Release of Nitric Oxide From Rat Kidney
Authors: Hirata Yasunobu , Hayakawa Hiroshi , Kakoki Masao , Tojo Akihiro , Suzuki Etsu , Nagata Daisuke , Kimura Kenjiro , Goto Atsuo , Kikuchi Kazuya , Nagano Tetsuo , Hirobe Masaaki , Omata Masao
Published: June 2012

The vasopressin receptor subtype that causes nitric oxide (NO) release remains controversial. To elucidate this receptor-ligand interaction, we examined the effects of vasopressin receptor antagonists on vasopressin-induced release of NO from isolated perfused rat kidneys by using a sensitive chemiluminescence assay. Vasopressin increased renal perfusion pressure and NO signals in the perfusate in a dose-dependent manner.
N
G
-Monomethyl-
l
-arginine abolished this increase in NO release; however, a similar increase in renal perfusion pressure induced by prostaglandin F
2α
was not associated with the increase in NO release. OPC-21268, a V
1
receptor antagonist, significantly reduced the vasopressin-evoked renal vasoconstriction and NO release, whereas OPC-31260, a V
2
receptor antagonist, had no effects. Moreover, desmopressin, a selective V
2
receptor agonist, did not increase the NO signal. NO release by vasopressin was markedly attenuated in deoxycorticosterone acetate (DOCA)–salt hypertensive rat kidneys compared with control kidneys (10
−10
mol/L vasopressin: +0.8±0.3 versus +6.9±1.4 fmol/min per gram kidney, DOCA versus control;
P
<.001). Histochemical analysis for renal NO synthase revealed a substantial attenuation of the staining of endothelial NO synthase in DOCA-salt rats. These results directly demonstrate that vasopressin stimulates NO release via the endothelial V
1
receptor in the rat kidney.
Angiotensin II Enhances Baroreflex Control of Sympathetic Outflow in Heart Failure
Authors: Murakami Hiroshi , Liu Jun-Li , Zucker Irving H.
Published: June 2012

Enhanced sympathetic outflow is seen in both patients with congestive heart failure and animals with experimental heart failure. In a previous study, we demonstrated that the baroreflex control of heart rate was impaired in conscious rabbits with pacing-induced heart failure and that this impairment was partially restored by blockade of angiotensin II type 1 (AT
1
) receptors. In the present study, we determined the interaction between the renin-angiotensin system and baroreflex control of renal sympathetic nerve activity in normal conscious rabbits and conscious rabbits with pacing-induced heart failure before and after AT
1
receptor blockade. Heart failure was induced by rapid ventricular pacing at a rate of 360 to 380 beats per minute for an average of 16.7±0.6 days. To generate baroreflex curves, we altered arterial pressure by administering phenylephrine and sodium nitroprusside. A sigmoidal logistic function was fit to renal sympathetic nerve activity–mean arterial pressure relationships for analysis of several components of baroreflex function. AT
1
receptors were blocked by intravenous administration of the specific antagonist L-158,809. In normal rabbits, there was no significant difference in any parameter of baroreflex function before and after blockade of AT
1
receptors. In contrast, blockade of AT
1
receptors enhanced baroreflex sensitivity in heart failure rabbits. The maximal gain increased to 5.0±0.7% renal sympathetic nerve activity/mm Hg from 2.6±0.3 (
P
<.05). Although L-158,809 had no effect on baseline renal sympathetic nerve activity in normal rabbits, analysis of the data in the heart failure rabbits indicated that baseline renal sympathetic nerve activity was reduced from 33±5% to 17±4% after L-158,809 administration after adjustment for changes in arterial pressure. These data suggest that angiotensin II plays a role in baroreflex impairment in this model of heart failure and may be in part responsible for the depressed baroreflex sensitivity observed in heart failure.
Achievement and Safety of a Low Blood Pressure Goal in Chronic Renal Disease
Authors: Lazarus J. Michael , Bourgoignie Jacques J. , Buckalew Vardaman M. , Greene Tom , Levey Andrew S. , Milas N. Carole , Paranandi Lata , Peterson John C. , Porush Jerome G. , Rauch Sally , Soucie J. Michael , Stollar Carol
Published: June 2012

The Modification of Diet in Renal Disease Study showed a beneficial effect of a lower-than-usual blood pressure (BP) goal on the progression of renal disease in patients with proteinuria. The purpose of the present analyses was to examine the achieved BP, baseline characteristics that helped or hindered achievement of the BP goals, and safety of the BP interventions. Five hundred eighty-five patients with baseline glomerular filtration rate between 13 and 55 mL/min per 1.73 m
2
(0.22 to 0.92 mL/s per 1.73 m
2
) were randomly assigned to either a usual or low BP goal (mean arterial pressure ≤107 or ≤92 mm Hg, respectively). Few patients had a history of cardiovascular disease. All antihypertensive agents were permitted, but angiotensin-converting enzyme inhibitors (with or without diuretics) followed by calcium channel blockers were preferred. The mean (±SD) of the mean arterial pressures during follow-up in the low and usual BP groups was 93.0±7.3 and 97.7±7.7 mm Hg, respectively. Follow-up BP was significantly higher in subgroups of patients with preexisting hypertension, baseline mean arterial pressure >92 mm Hg, a diagnosis of polycystic kidney disease or glomerular diseases, baseline urinary protein excretion >1 g/d, age ≥61 years, and black race. The frequency of medication changes and incidence of symptoms of low BP were greater in the low BP group, but there were no significant differences between BP groups in stop points, hospitalizations, or death. When data from both groups were combined, each 1–mm Hg increase in follow-up systolic BP was associated with a 1.35-times greater risk of hospitalization for cardiovascular or cerebrovascular disease. Lower BP than usually recommended for the prevention of cardiovascular disease is achievable by several medication regimens without serious adverse effects in patients with chronic renal disease without cardiovascular disease. For patients with urinary protein excretion >1 g/d, target BP should be a mean arterial pressure of ≤92 mm Hg, equivalent to 125/75 mm Hg.
Association of Body Mass Index With Blood Pressure in Elderly Japanese American Men
Authors: Masaki Kamal H. , Curb J. David , Chiu Darryl , Petrovitch Helen , Rodriguez Beatriz L.
Published: June 2012

Few data are available on the association between body mass index (BMI) and blood pressure in elderly individuals, particularly among minority groups. We studied the cross-sectional association of BMI with systolic and diastolic pressures in 1378 Japanese American men 60 to 82 years of age who were participants in the population-based Third Lipoprotein Examination of the Honolulu Heart Program conducted between 1980 and 1982. When the subjects were divided into 5-year age groups, mean BMI decreased linearly with increasing age. Mean systolic pressure rose from 134.8 mm Hg in the first quintile of BMI to 138 in the second and 141.8 in the third quintiles, with levels of 139.2 and 142 in the fourth and fifth quintiles, respectively (test for trend,
P
=.083). Mean diastolic pressure rose from 78.1 mm Hg in the lowest quintile of BMI to 83.9 in the highest (test for trend,
P
=.008). We performed multiple regression analysis, controlling for factors known to influence blood pressure values, including age, physical activity index, alcohol intake, current smoking status, and diabetes mellitus. The association between BMI and both systolic and diastolic pressures remained highly statistically significant in these analyses. These results show that obesity and high blood pressure continue to be highly correlated even in old age and suggest that it may be possible to modify rates of hypertension by changes in body weight.
Contrasting Autonomic and Hemodynamic Effects of Insulin in Healthy Elderly Versus Young Subjects
Authors: Hausberg Martin , Hoffman Robert P. , Somers Virend K. , Sinkey Christine A. , Mark Allyn L. , Anderson Erling A.
Published: June 2012

Acute increases in plasma insulin produce both sympathoexcitation and vasodilation in normal young adults. Aging is associated with insulin resistance and may alter the sympathetic or the vascular responses to insulin. Therefore, we assessed sympathetic and vascular responses to acute physiological increases in plasma insulin levels in 10 healthy, normotensive elderly (65±2 years) and 12 normal young (27±1 years) subjects matched for body mass index (25±1 kg/m
2
in both groups). We measured muscle sympathetic nerve activity (microneurography), FBF (plethysmography), heart rate, and blood pressure and calculated forearm vascular resistance and insulin sensitivity (M value) during a 90-minute hyperinsulinemic/euglycemic clamp. M values were 4.3±0.4 mg·kg
−1
·min
−1
in the elderly and 8.4±1.4 mg·kg
−1
·min
−1
in the young subjects (
P
<.05). Baseline muscle sympathetic nerve activity was higher in the elderly subjects (33±3 versus 15±2 bursts per minute,
P
<.05); however, the absolute and percent increases in muscle sympathetic nerve activity were smaller in the elderly than in the young subjects (+10±1 versus +15±1 bursts per minute, or +37±11% versus +110±16%,
P
<.05). Forearm vascular resistance decreased with insulin from 46±2 to 31±3 units in the young but increased with insulin in the elderly subjects from 37±3 to 47±7 units (
P
<.05). Heart rate increased in young but not in elderly subjects. Insulin did not change blood pressure in either group. In conclusion, as opposed to vasodilation in young adults, insulin caused vasoconstriction in healthy elderly individuals. The failure of the vasodilator action of insulin in the elderly may permit even modest insulin-induced sympathoexcitation to elicit vasoconstriction. We speculate that the vasoconstrictor response to insulin may further potentiate insulin resistance in the elderly.