bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain ‘Ouabain’ and Desensitization of Arterial Baroreflex by High Sodium in Dahl Salt-Sensitive Rats
Authors: Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
In Dahl salt-sensitive (S) rats, high sodium intake further desensitizes arterial baroreflex function. To assess the possible involvement of brain “oubain,” we gave Dahl S rats a regular or high sodium diet from 4 to 7 weeks of age and administered intracerebroventricular antibody Fab fragments, which bind ouabain with high affinity, or γ-globulins as control (200 μg/12 μL per day for both) using osmotic minipumps. We assessed arterial baroreflex function by plotting changes in renal sympathetic nerve activity or heart rate against changes in mean arterial pressure of conscious rats elicited by intravenous phenylephrine and nitroprusside. Dahl S rats on high sodium treated with γ-globulins showed a significantly higher resting mean arterial pressure versus other rats (130 to 140 versus 95 to 105 mm Hg). In rats treated with γ-globulins, high sodium desensitized baroreflex control of renal sympathetic nerve activity compared with rats on regular sodium (average gain: −1.88±0.12 versus −2.73±0.13,
P
<.05). In contrast, in rats treated with Fab fragments, high sodium did not increase blood pressure and did not desensitize but slightly sensitized reflex control of renal sympathetic nerve activity. Changes in reflex control of heart rate were similar to those of renal sympathetic nerve activity. These data indicate that blockade of brain “oubain” prevents sodium-induced hypertension as well as the desensitization of the arterial baroreflex in Dahl S rats. Increased brain “oubain” may desensitize the arterial baroreflex and thereby facilitate the hypertension in Dahl S rats on high sodium.
Increased Calcium Stores in Platelets From African Americans
Authors: Cho Jwa Hwa , Nash Frederic , Fekete Zoltan , Kimura Masayuki , Reeves John P. , Aviv Abraham
Published: June 2012

Abstract
Differences in cation transport have been observed between African Americans and whites. These differences may underlie the increased predisposition of African Americans to essential hypertension. To further explore these racial differences, we used platelets as a cellular model for calcium regulation. We measured
45
Ca fluxes in platelets from 21 African American and 25 white men. Additionally, using fura 2, we measured cytosolic free calcium levels in resting platelets and platelets treated with ouabain and thrombin. Platelet
45
Ca uptake was described by two exchangeable pools: a small, rapidly exchangeable pool and a larger, slowly exchangeable pool. Both pools were larger in platelets from African Americans than from whites (263 versus 185 pmol per 1×10
8
platelets for the rapidly exchangeable pool,
P
<.05; 744 versus 532 pmol per 1×10
8
platelets for the slowly exchangeable pool,
P
<.01).
45
Ca washout was described by a rapidly exchangeable pool and a static pool. The former was also higher in platelets from African Americans than from whites (246 versus 202 pmol per 1×10
8
platelets,
P
<.01). The cytosolic free calcium concentrations in resting platelets were lower in African Americans than in whites. After treatment with ouabain and thrombin, the sustained posttransient levels of cytosolic free calcium increased to a greater extent in platelets from African Americans (46.7 nmol/L) than from whites (34.5 nmol/L,
P
=.033). Platelets from African Americans demonstrate higher intracellular calcium stores than platelets from whites. This racial difference could explain the sensitivity of African Americans to vasoactive agents acting through calcium mobilization from intracellular stores and cytosolic calcium.
Endothelin Production in Cultured Mesangial Cells of Spontaneously Hypertensive Rats
Authors: Ikeda Miwako , Kohno Masakazu , Takeda Tadanao
Published: June 2012

Abstract
Cultured glomerular mesangial cells have been shown to produce a potent vasoconstrictive peptide, endothelin-1 (ET-1). We examined whether basal or stimulated ET-1 production by angiotensin II (Ang II) or arginine vasopressin (AVP) is enhanced in cultured mesangial cells of spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Basal ET-1 production in SHR mesangial cells was not different from that in WKY cells although a trend toward increased ET-1 production was observed in SHR cells. Ang II and AVP stimulated ET-1 production in a concentration-dependent manner in cells of both rat strains, but the agonist-induced stimulation was clearly greater in SHR cells than WKY cells. The protein kinase C–activating phorbol ester phorbol myristate acetate stimulated ET-1 production in a concentration-dependent manner in cells of both rat strains, but this stimulation was significantly greater in SHR cells than in WKY cells. These results suggest that Ang II– and AVP-induced mesangial cell production of ET-1 is clearly enhanced in SHR compared with WKY. Increased response of ET-1 production to protein kinase C activation appears to contribute in part to the observed enhancement of ET-1 production in SHR mesangial cells.
Regional Heterogeneity of Arterial Structural Changes
Authors: Daemen Mat J.A.P. , De Mey Jo G.R.
Published: June 2012

Abstract
Arterial structural changes in experimental models of hypertension and restenosis differ between vessel types and within vessels. Inspired by the diversity of short-term functional responses to vasoactive agents, hypotheses are presented with respect to the heterogeneity of structural alterations. Considered are the multifactorial nature of smooth muscle cell growth control and the possibility that vascular smooth muscle is not homogeneous but composed of different smooth muscle cell populations. These hypotheses may help explain the origin of both intervascular and intravascular heterogeneity of vascular structural responses.
pH
i
, [Ca
2+
]
i
, and Myosin Phosphorylation in Histamine- and NH
4
+
-Induced Swine Carotid Artery Contraction
Authors: Chen Xiao-Liang , Rembold Christopher M.
Published: June 2012

Abstract
We examined the interaction among changes in pH
i
, [Ca
2+
]
i
, myosin light-chain phosphorylation, and contraction in arterial smooth muscle stimulated by histamine, NH
4
+
, Tris
+
, and/or changes in extracellular pH (pH
o
). We loaded swine carotid medial tissues with 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein to measure pH
i
or aequorin to measure [Ca
2+
]
i
. Incubation of tissues in NH
4
+
increased pH
i
, [Ca
2+
]
i
, myosin phosphorylation, and force. Washout of NH
4
+
decreased pH
i
and transiently further increased in [Ca
2+
]
i
and force. Incubation of tissues in a similar concentration of Tris
+
or increasing pH
o
also increased pH
i
; however, there were only modest changes in [Ca
2+
]
i
and force. Increasing extracellular pH coincidentally with washout of NH
4
+
prevented the decrease in pH
i
but did not affect the NH
4
+
washout-induced contraction. These data suggest that NH
4
+
altered [Ca
2+
]
i
and contraction by mechanisms other than its effects on pH
i
. The type of pH buffer did not affect the [Ca
2+
]
i
, myosin phosphorylation, or stress response to histamine stimulation. The time course of changes in pH
i
was much slower than the time course of histamine-induced changes in [Ca
2+
]
i
, myosin phosphorylation, and stress. Addition of 10 mmol/L NH
4
+
concurrently with histamine aborted the histamine-induced decrease in pH
i
and significantly slowed the histamine-induced increase in [Ca
2+
]
i
, myosin phosphorylation, and stress. There was little effect on histamine-induced increases in [Ca
2+
]
i
, myosin phosphorylation, or contraction when three other protocols aborted the histamine-induced decrease in pH
i
. These data show that incubation in NH
4
+
can alter [Ca
2+
]
i
and contraction in both unstimulated and histamine-stimulated smooth muscle. However, these effects were not caused by NH
4
+
-dependent changes in pH
i
. It appears that histamine-induced changes in pH
i
have at most minor effects on [Ca
2+
]
i
and contraction of swine carotid artery.
ET
A
and ET
B
Receptors Mediate Contraction to Endothelin-1 in Renal Artery of Aging SHR
Authors: Seo Bonggwan , Lüscher Thomas F.
Published: June 2012

Abstract
We characterized vascular endothelin receptors of the renal artery from adult (12 to 16 weeks of age) and old (72 to 76 weeks) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto rats (WKY). Vessels were suspended in organ chambers (37°C, aerated with 95% O
2
/5% CO
2
), and isometric tension was recorded. The endothelin-A (ET
A
) receptor antagonist FR139317, the combined ET
A
/ET
B
receptor antagonist bosentan, and the ET
B
-selective agonist sarafotoxin S6c were used. In old (and less so in adult) SHR, cumulative concentration-contraction curves to endothelin-1 showed a small contraction resistant to FR139317 (10
−5
mol/L) at 3×10
−9
to 10
−8
mol/L endothelin-1, which was completely inhibited by bosentan (10
−5
mol/L). This FR139317-resistant contraction to endothelin-1 was not present in WKY. Furthermore, in the presence of FR139317 (10
−5
mol/L), sarafotoxin S6c induced a stronger contraction in old SHR than in WKY (
P
<.05). In rings contracted with norepinephrine, sarafotoxin S6c caused endothelium-dependent relaxations in both strains; these relaxations were blocked by
N
ω
-nitro-
l
-arginine methyl ester, indicating that nitric oxide is the mediator. In WKY but not SHR, release of nitric oxide by sarafotoxin S6c increased with age (
P
<.05). Thus, both ET
A
and ET
B
receptors mediate contraction to endothelin-1 in the renal artery from SHR but not WKY. ET
B
receptors on vascular smooth muscle seem to be unmasked with age in SHR, whereas those on endothelium (mediating nitric oxide release) exhibit more efficient responses with age in WKY.
Cardiovascular Development After Enalapril in Spontaneously Hypertensive and Wistar-Kyoto Rats
Authors: Korner Paul I. , Bobik Alexander
Published: June 2012

Abstract
We studied the long-term effects after withdrawal of enalapril, an angiotensin-converting enzyme inhibitor, on tail systolic pressure and cardiovascular structural properties in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Observations in control rats were from 4 to 35 weeks of age, whereas treated rats received enalapril from 4 to 20 weeks and were studied for a further 15 weeks. We measured blood pressure and the ratio of left ventricle weight to body weight and derived methoxamine log dose–perfusion pressure curves in the isolated hindquarter bed. From the changes in resistance properties we also estimated the changes in structure using a model developed previously. During therapy, blood pressure was depressed to a common value in both strains. After drug withdrawal, by age 35 weeks, previously treated SHR developed only mild hypertension, whereas blood pressure of WKY had recovered to the corresponding control level. At 21 weeks, soon after enalapril was stopped, left ventricular development was depressed in both strains; the depression was slightly greater in SHR, but that of vascular resistance was proportionately similar in each strain. Late cardiovascular development between 21 and 35 weeks was attenuated in the previously treated groups. For the left ventricle, it was similar in each strain, but for the vasculature, late development was relatively smaller in SHR than WKY. In the former, the pattern of development between 21 and 35 weeks was the same as in untreated controls and appeared to be mediated in response to the rise in blood pressure. In previously treated WKY, the rise in blood pressure was smaller, so that their relatively greater late vascular development was largely through another mechanism, probably involving a direct action on smooth muscle growth, through a product of the converting enzyme. This non–blood pressure–dependent component of late development was absent in previously treated SHR. We conclude that the products of angiotensin-converting enzyme play an important role in the normal development of each strain. The between-strain differences in late development contribute to the relatively greater restoration of blood pressure in previously treated WKY compared with SHR and for the mildness of the hypertension in the latter. In normal cardiovascular development, the action of converting enzyme is relatively nonspecific, suggesting that it does not play other than a general role in the pathogenesis of hypertension.
11β-Hydroxysteroid Dehydrogenase and Its Inhibitors in Hypertensive Pregnancy
Authors: Walker Brian R. , Williamson Paula M. , Brown Mark A. , Honour John W. , Edwards Christopher R. W. , Whitworth Judith A.
Published: June 2012

Abstract
Preeclampsia is accompanied by amplification of the sodium retention that is a feature of normal pregnancy. Recent evidence suggests that mineralocorticoid receptor activation is increased in preeclampsia, but classic mineralocorticoids (aldosterone, 11-deoxycorticosterone) are not present in excess. Cortisol can act as a mineralocorticoid receptor agonist only when its renal inactivation to cortisone by 11β-hydroxysteroid dehydrogenase is impaired, for example, in congenital enzyme deficiency and after administration of exogenous inhibitors (eg, licorice). Endogenous inhibitors of this enzyme have been detected in human urine and are increased in pregnancy. To establish whether cortisol causes mineralocorticoid excess in hypertensive pregnancy and whether endogenous inhibitors of 11β-hydroxysteroid dehydrogenase are responsible, we studied 25 hypertensive pregnant patients (13 with preeclampsia and 12 with gestational hypertension), 16 normotensive pregnant subjects, and 13 nonpregnant control subjects. Concentrations of plasma renin and aldosterone were increased in pregnancy, but less so in hypertensive pregnancy. Plasma potassium and urinary electrolytes were not different between the groups. Plasma cortisol was increased in pregnancy but not different in hypertensive pregnancy, and urinary cortisol, plasma and urinary cortisone, and urinary tetrahydrocortisol and tetrahydrocortisone were not different between the groups. Endogenous inhibitors of 11β-hydroxysteroid dehydrogenase were more active in urine from pregnant women but were not increased further in hypertensive pregnancy. There were no differences in these parameters between patients with preeclampsia and gestational hypertension. We conclude that deficient inactivation of cortisol to cortisone does not contribute to the sodium retention of normotensive or hypertensive pregnancy and that endogenous inhibitors of 11β-hydroxysteroid dehydrogenase have no evident pathophysiological significance in pregnancy.
Characterization and Functional Analysis of the Rat Endothelin-1 Promoter
Authors: Paul Martin , Zintz Martin , Böcker Wolfgang , Dyer Mark
Published: June 2012

Abstract
To define the molecular mechanisms of endothelin-1 (ET-1) gene regulation, we cloned, sequenced, and characterized the rat ET-1 promoter. A sequence consisting of the first 1329 bp of the rat ET-1 promoter was investigated in greater detail. Sequence analysis identified putative binding sites for a number of transcriptional factors that may be involved in ET-1 gene regulation. Several of these factors have been proposed earlier to be involved in cell-specific gene regulation and may be responsible for directing ET-1 expression in vivo. For functional analysis of the ET-1 promoter, we generated a reporter gene construct using luciferase as reporter gene under control of the promoter fragment isolated. The construct was transfected transiently into bovine aortic endothelial cells, and luciferase expression was evaluated. The results indicated that the promoter segment used showed high expression in endothelial cells comparable to that induced by viral promoters. Since ET-1 is regulated by a number of vasoactive substances, we studied the effect of angiotensin II on endothelin transcription. We could demonstrate a dose-dependent transcriptional activation of ET-1 transcription by angiotensin.
Mutational Inactivation of the Catalytic Domain of Guanylate Cyclase-A Receptor
Authors: Miao Zhen-Hua , Song Dong-Li , Douglas Janice G. , Chang Chung-Ho
Published: June 2012

Abstract
Guanylate cyclase-A, the receptor for atrial natriuretic factor, contains a protein kinase–like domain and a catalytic domain in the intracellular region. To investigate the active site (the catalytic cavity) of guanylate cyclase-A, we amplified the catalytic domain plus three amino acids from the kinase-like domain of guanylate cyclase-A (GC-c) with polymerase chain reaction (PCR) and expressed it in
Escherichia coli
. During the screening of the PCR-cloned gene products with guanylate cyclase assay, a mutant that lacks enzyme activity was identified. Results of cDNA sequencing revealed that Leu 817 was replaced by an Arg residue in the mutated protein. The mutated GC-c bound to GTP-agarose as well as the wild-type protein, indicating that the binding capability of mutated GC-c to GTP is not significantly affected by the Arg substitution. Gel-filtration column chromatography showed that, like the wild-type GC-c, the mutated protein also formed a high-molecular-weight complex. Since mutation of Leu 817 to Arg abolishes the catalytic activity, Leu 817 is likely located near the active site of guanylate cyclase-A. These results demonstrate that the carboxyl fragment of guanylate cyclase-A is an ideal system for studying the active site of guanylate cyclase-A.
Relaxation of the Aorta During Hypoxia Is Impaired in Chronically Hypertensive Rats
Authors: Taguchi Hisao , Faraci Frank M. , Kitazono Takanari , Heistad Donald D.
Published: June 2012

Abstract
We investigated mechanisms by which hypoxia produces relaxation of the aorta and tested the hypothesis that these mechanisms are altered during chronic hypertension. Tension of thoracic aortae from normotensive Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP) was measured in an organ bath under control conditions and at two levels of hypoxia. In WKY rats, mild and severe hypoxia produced relaxation of the aortae (precontracted with phenylephrine) by 33±4% and 82±3%, respectively (mean±SEM). Removal of endothelium or administration of
N
G
-nitro-
l
-arginine (10
−4
mol/L), an inhibitor of nitric oxide synthase, abolished relaxation of the aortae in response to mild hypoxia but did not affect relaxation during severe hypoxia. Glibenclamide (10
−6
mol/L), an inhibitor of potassium channels, attenuated relaxation of the aortae during mild and severe hypoxia by 49±16% and 74±4%, respectively. In SHRSP, mild hypoxia produced little relaxation of the aortae (3±4%,
P
<.05 compared with WKY). Indomethacin did not increase relaxation to mild hypoxia in SHRSP, which suggests that a cyclooxygenase-derived contracting factor does not contribute to impaired relaxation. Severe hypoxia relaxed the aortae by 86±4% in SHRSP, and glibenclamide inhibited this response by 60±9%. These findings suggest that relaxation of the aorta in response to mild hypoxia in WKY rats is mediated primarily by endothelium-derived relaxing factor, and the response to mild hypoxia is markedly impaired in SHRSP. In contrast, relaxation during severe hypoxia is mediated, in large part, by activation of glibenclamide-sensitive potassium channels, and the response to severe hypoxia is preserved in SHRSP.
Fatty Acids Enhance Vascular α-Adrenergic Sensitivity
Authors: Stepniakowski Konrad T. , Goodfriend Theodore L. , Egan Brent M.
Published: June 2012

Abstract
Hypertensive patients are heavier and have a more centralized body fat distribution, which is associated with risk factor clustering and resistance to insulin’s actions, including suppression of plasma nonesterified fatty acids. We postulated that abnormalities of nonesterified fatty acids contribute to the increased vascular α-adrenergic reactivity and tone observed in our previous studies of obese hypertensive subjects. To test this hypothesis, in two separate protocols 10% Intralipid was infused into a dorsal hand vein with heparin to activate lipoprotein lipase and raise fatty acid levels locally. In protocol 1, the effects of Intralipid/heparin compared with those of 5% dextrose/heparin on dorsal hand vein sensitivity to phenylephrine were assessed by use of the linear variable differential transformer technique in 8 normotensive subjects. In protocol 2, the effects of Intralipid/heparin were compared with those of saline/heparin on hand vein responses to both phenylephrine and angiotensin II in 11 normotensive African American women. Intralipid/heparin reduced the dose of phenylephrine required to produce 50% of the maximal venoconstrictor response from 582 to 137 ng/min (compared with dextrose/heparin,
P
<.01) in protocol 1 and from 293 to 137 ng/min (compared with saline/heparin,
P
<.01) in protocol 2. Intralipid/heparin did not significantly alter hand vein responses to angiotensin compared with saline/heparin. These data suggest that abnormalities of nonesterified fatty acids in obese hypertensive patients with risk factor clustering may contribute to their increased neurovascular tone.
Insulin Attenuates Norepinephrine- Induced Venoconstriction
Authors: Grover Anil , Padginton Clay , Wilson Michael F. , Sung Bong Hee , Izzo Joseph L. , Dandona Paresh
Published: June 2012

Abstract
To directly assess insulin-related venomotor changes objectively and quantitatively, we used a modified ultrasonographic technique to measure venous diameter. Ten healthy men and women were studied by use of an Acuson 128 XP ultrasonograph with a linear 7.5-MHz ultrasonographic transducer (sensitivity, ±0.1 mm). Venous diameter was measured with the arm kept at 30° elevation and with a pneumatic cuff above the elbow inflated at 40 mm Hg for the last 2 minutes of each 5-minute observation period. Norepinephrine was infused at incremental concentrations of 12.5, 25, 50, and 100 ng/min (75, 150, 300, and 600 pmol/min, respectively) for 5 minutes each. Maximal venoconstriction was achieved by the dose of 100 ng/min norepinephrine, which was then combined with insulin doses of 8, 16, 24, and 32 μU/min (60, 120, 180, and 230 fmol/min, respectively) for 5 minutes each. In six different subjects, methylene blue, an inhibitor of guanylate cyclase, was infused simultaneously with 32 μU/min insulin and 100 ng/min norepinephrine. Mean resting diameter of the vein (1.8±0.6 mm [mean±SD]) increased (to 3.0±1.0 mm) after cuff inflation. Incremental doses of norepinephrine caused highly reproducible dose-dependent decreases in venous diameter (to 1.8±0.6 mm,
P
<.001). Incremental doses of insulin, when combined with the maximum dose of norepinephrine, caused highly reproducible dose-dependent increases in mean venous diameter (
P
<.001) compared with norepinephrine alone. Methylene blue, which had no independent effect on venous diameter, inhibited the venodilator effect of insulin (
P
<.05). Infusion of these substances caused no systemic changes in heart rate, blood pressure, or blood glucose. Modified venous ultrasonography can measure, in vivo, venomotor changes with hormones or drugs in doses that do not produce any systemic effects. Norepinephrine is a potent venoconstrictor whose local effects can be attenuated by insulin in normal subjects. Insulin-induced venodilation is blocked by methylene blue and is therefore probably cyclic guanylate monophosphate dependent.
Endothelium-Derived Constricting Factor in Renovascular Hypertension
Authors: Sigmon David H. , Beierwaltes William H.
Published: June 2012

Abstract
We have reported that in two-kidney, one clip hypertensive rats, renal perfusion is maintained by a balance between the vasodilator endothelium-derived nitric oxide and the vasoconstrictor angiotensin II. Others have suggested that endothelium-derived constricting factor, reported to be thromboxane A
2
and/or endoperoxide, contributes to increased blood pressure in angiotensin II–dependent hypertension. We hypothesized that in angiotensin II–dependent two-kidney, one clip hypertension, endothelium-derived constricting factor contributes to vasoconstriction of the clipped kidney following nitric oxide synthesis inhibition. Using radioactive microspheres, we studied renal blood flow to the stenotic kidney of two-kidney, one clip hypertensive rats 4 weeks after clipping. The influence of nitric oxide on systemic and renal hemodynamics was evaluated by determining the response to nitric oxide synthesis inhibition using 10 mg/kg
N
ω
-nitro-
l
-arginine methyl ester in these rats, which were either not treated (n=8) or treated (n=8) with 4 mg/kg of the constricting factor receptor antagonist BMS 180,291. Mean basal blood pressure in rats was 167±9 mm Hg (mean±SEM).
N
ω
-Nitro-
l
-arginine methyl ester increased blood pressure by 35±7 mm Hg (
P
<.001). In the clipped kidney,
N
ω
-nitro-
l
-arginine methyl ester decreased renal blood flow by 40% (from 4.5±0.9 to 2.7±0.6 mL · min
−1
· g kidney
−1
;
P
<.01) and increased renal vascular resistance by 100% (from 51.9±9.6 to 105.0±19.2 mm Hg · mL
−1
· min
−1
· g kidney
−1
;
P
<.005). Pretreatment with BMS 180,291 had no effect on basal blood pressure (167±7 mm Hg) or blood flow to the clipped kidney. However, constricting factor blockade diminished the pressor response to
N
ω
-nitro-
l
-arginine methyl ester by 63%, decreasing the response to only 13±4 mm Hg (
P
<.02). In rats treated with BMS 180,291,
N
ω
-nitro-
l
-arginine methyl ester decreased blood flow to the clipped kidney by only 12% (from 5.4±0.6 to 4.7±0.5 mL · min
−1
· g kidney
−1
;
P
<.05), while renal vascular resistance increased by only 17% (from 36.7±7.1 to 43.0±7.2 mm Hg · mL
−1
· min
−1
· g kidney
−1
;
P
<.005). In conclusion, although blocking endothelium-derived constricting factor in hypertensive rats affected neither basal blood pressure nor renal blood flow, it dramatically blunted both the systemic pressor and renal constrictor responses to inhibition of endothelium-derived nitric oxide synthesis. These data suggest a significant regulatory interaction between endothelium-derived constricting factor and endothelium-derived nitric oxide in renovascular hypertension.
Relation Between Pressure Natriuresis and Urinary Excretion of Nitrate/Nitrite in Anesthetized Dogs
Authors: Majid Dewan S. A. , Godfrey Murrell , Grisham Matthew B. , Navar L. Gabriel
Published: June 2012

Abstract
Alterations in intrarenal nitric oxide (NO) formation during changes in renal arterial pressure (RAP) have been suggested as a mechanism mediating pressure natriuresis. To test this hypothesis further, we examined the relation between RAP and the urinary excretion rate of nitrate/nitrite (NO
3
−
/NO
2
−
; NO metabolites) in anesthetized sodium-replete dogs before (n=9) and during (n=6) intrarenal infusion of the NO synthesis inhibitor nitro-
l
-arginine (NLA; 50 μg · kg
−1
· min
−1
). Urinary NO
3
−
/NO
2
−
concentrations were measured with the Griess reaction and spectrophotometry methods after enzymatic reduction of NO
3
−
to NO
2
−
in the samples. During control conditions, there were decreases in the urinary NO
3
−
/NO
2
−
excretion rate in response to reductions in RAP (150 to 75 mm Hg; slope, 0.04±0.01 nmol · min
−1
· g
−1
· mm Hg
−1
) in association with decreases in urinary sodium excretion (U
Na
V). There was a positive correlation between changes in NO
3
−
/NO
2
−
excretion rate and changes in RAP (
r
=.48;
P
<.005) or U
Na
V (
r
=.59;
P
<.001). NLA infusion resulted in decreases in NO
3
−
/NO
2
−
excretion rate (4.8±1.4 to 1.0±0.3 nmol · min
−1
· g
−1
) in association with reductions in U
Na
V (4.3±0.3 to 0.7±0.2 μL · min
−1
· g
−1
), fractional excretion of sodium (2.9±0.2% to 0.5±0.1%), and renal blood flow (4.8±0.3 to 3.3±0.2 mL · min
−1
· g
−1
), without changes in glomerular filtration rate. Furthermore, there was a marked attenuation of the NO
3
−
/NO
2
−
and sodium excretory responses to alterations in RAP during NO synthesis inhibition. In another four dogs, it was observed that urinary NO
3
−
/NO
2
−
excretion rate did not change during administration of thiazide and amiloride diuretics, indicating that the NO
3
−
/NO
2
−
excretory responses to alterations in RAP were not simply due to changes in urine flow rate or sodium excretion. These findings are consistent with the hypothesis that during acute changes in RAP, intrarenal changes in NO production rate may be responsible for the changes in sodium excretion.
Renal Afferent Denervation Prevents Hypertension in Rats With Chronic Renal Failure
Authors: Campese Vito M. , Kogosov Ella
Published: June 2012

Abstract
Increased activity of the sympathetic nervous system has been described in chronic renal failure, but its role in the genesis and maintenance of hypertension associated with this condition has not been established. The kidney has an intense network of chemoreceptors and baroreceptors that send impulses to the brain. To what extent activation of these receptors by the scarred kidney or the uremic milieu may contribute to this model of hypertension is unknown. In the present study, we evaluated the effect of bilateral dorsal rhizotomy on the development of hypertension and neuroadrenergic activity in the anterior, lateral, and posterior hypothalamic nuclei, in the locus ceruleus, and in the nucleus tractus solitarius of Sprague-Dawley rats that underwent 5/6 nephrectomy or were sham operated. Neuroadrenergic activity was determined by calculating norepinephrine turnover rate after inhibition of norepinephrine synthesis with α-methyl-
dl
-
p
-tyrosine methyl ester hydrochloride. The endogenous norepinephrine concentration was significantly greater in the posterior and lateral hypothalamic nuclei and the locus ceruleus, but not in the nucleus tractus solitarius, and the anterior hypothalamic nuclei of uremic rats compared with control rats. In rats with chronic renal failure and sham rhizotomy, the turnover rate of norepinephrine in the posterior (15.3±1.61 nmol · g
−1
· h
−1
) and lateral hypothalamic nuclei (11.7±2.12 nmol · g
−1
· h
−1
) and in the locus ceruleus (26.6±2.42 nmol · g
−1
· h
−1
) was significantly faster (
P
<.01) than in rats with renal failure and dorsal rhizotomy (4.1±0.51, 4.7±0.77, and 5.1±1.13 nmol · g
−1
· h
−1
, respectively) or control animals with or without rhizotomy. The turnover rate of norepinephrine in the anterior hypothalamic nuclei and the nucleus tractus solitarius was not different among the three groups of rats. These studies demonstrated that in rats with chronic renal failure, bilateral dorsal rhizotomy in the dorsolateral aspect of the vertebral bodies (T10 to L2) prevents in large part the development of hypertension and the increase in norepinephrine turnover rate in the posterior and lateral hypothalamic nuclei and the locus ceruleus. The data provide evidence that renal afferent impulses from the kidneys of rats with chronic renal failure may activate areas of the brain involved in the neuroadrenergic regulation of blood pressure. This mechanism may contribute to the genesis of hypertension in uremic rats.
Reduction of Salt Intake During Converting Enzyme Inhibitor Treatment Compared With Addition of a Thiazide
Authors: Singer Donald R. J. , Markandu Nirmala D. , Cappuccio Francesco P. , Miller Michelle A. , Sagnella Giuseppe A. , MacGregor Graham A.
Published: June 2012

Abstract
A moderate reduction in salt intake lowers blood pressure in individuals with hypertension and improves blood pressure control in those taking a converting enzyme inhibitor. However, it is unclear how effective reduction of salt intake is compared with addition of other drugs, in particular, thiazide diuretics. We directly compared the separate effects on blood pressure of reducing sodium intake or adding a thiazide diuretic in the presence of a converting enzyme inhibitor in a double-blind, randomized, crossover study. We studied 11 subjects with essential hypertension who had been taking 25 mg captopril twice daily for at least 1 month. In the double-blind study, after 1 month of captopril alone, supine blood pressure was 151±5/95±4 (SEM) mm Hg. With the addition of 25 mg hydrochlorothiazide once daily for 1 month, blood pressure fell to 137±5/87±3 mm Hg. When a moderate reduction in salt intake (from 206±26 to 109±20 mmol urinary sodium/24 h) was added to captopril for 1 month, blood pressure was reduced by a similar amount (to 137±4/90±3 mm Hg). Plasma potassium fell during the diuretic treatment (3.9±0.1 to 3.7±0.1 mmol/L,
P
<.05) but increased nonsignificantly during salt reduction (3.9±0.1 to 4.1±0.2 mmol/L). These results clearly demonstrate that moderate salt reduction, which can be easily achieved, is as effective as a thiazide diuretic in lowering blood pressure in the presence of a converting enzyme inhibitor and has the particular advantage that plasma potassium does not decrease. We recommend that all patients on a converting enzyme inhibitor be advised to reduce their dietary salt intake. This would lead to improved blood pressure control and avoids the need for thiazide treatment in many patients.
Cardiovascular Effects of Brain Natriuretic Peptide in Essential Hypertension
Authors: La Villa Giorgio , Bisi Gianni , Lazzeri Chiara , Fronzaroli Caterina , Stefani Laura , Barletta Giuseppe , Del Bene Riccarda , Messeri Gianni , Strazzulla Gaetano , Franchi Franco
Published: June 2012

Abstract
We evaluated the cardiovascular effects of pathophysiological plasma levels of brain natriuretic peptide in seven patients with mild to moderate essential hypertension by performing equilibrium radionuclide angiocardiography at baseline and during brain natriuretic peptide infusion at increasing doses (4, 8, 10, and 12 pmol/kg per minute for 20 minutes each). Brain natriuretic peptide induced a progressive reduction of left ventricular end-diastolic volume (from 107.5±10.3 to 89.0±11.0 mL at the end of all infusion periods) and end-systolic volume, whereas stroke volume did not show any significant change (from 64.9±5.9 to 62.7±7.8 mL). Cardiac output, arterial pressure, and peripheral vascular resistance did not change significantly. The lack of effects on systemic hemodynamics was probably due to compensatory activation of the sympathetic nervous system, as indicated by the significant increase in plasma norepinephrine levels (from 1.75±0.18 to 2.19±0.21 nmol/L), heart rate (from 68±6 to 81±6 beats per minute), peak ejection rate, and peak filling rate. These results indicate that brain natriuretic peptide, at the pathophysiological plasma concentrations reached in this study, influences cardiovascular homeostasis mainly by reducing cardiac preload.
Intrarenal Angiotensin II Formation in Humans
Authors: Fisher Naomi D. L. , Allan Donald R. , Gaboury Cynthia L. , Hollenberg Norman K.
Published: June 2012

Abstract
The intrarenal production of angiotensin II (Ang II) as a local hormone, suggested by multiple lines of investigation, has been difficult to buttress with evidence of functional significance in humans. During studies designed to assess the renal vascular responses to the renin inhibitor enalkiren, an agent (like others in its class) with great substrate specificity, we noted in some subjects that the time course of the effect of enalkiren on renal plasma flow was not congruent with the time course of its influence on the renin-angiotensin system in the plasma compartment. We pursued this discrepancy in the current study of 18 healthy men and 9 men with essential hypertension, who each received one or more doses of enalkiren while on a fixed sodium diet. Plasma enalkiren and Ang II concentration and renal plasma flow were measured in each subject at intervals during and after discontinuation of the enalkiren infusion. Plasma enalkiren concentration fell progressively in each subject after administration was discontinued, the fall becoming evident 10 minutes after discontinuation without exception. In plasma samples obtained 90 minutes after the end of the infusion, drug levels were generally less than half of their peak value. Plasma Ang II concentration, at nadir levels by the end of the enalkiren administration, rose consistently during recovery. Renal plasma flow, in contrast, rose during infusion but did not begin to fall when enalkiren was discontinued. In 26 of 31 studies, renal plasma flow remained at peak level or even continued to rise; this discordance in the effects on plasma Ang II concentration and on renal plasma flow after discontinuation of enalkiren was highly significant (
P
<.0005). Sustained renal vascular activity of the renin inhibitor, in marked contrast to waning enalkiren concentration and activity in the plasma compartment, provides strong evidence for an action at the tissue level and for a biological influence of intrarenal Ang II formation in humans.
Microalbuminuria and Erythrocyte Sodium-Hydrogen Exchange in Essential Hypertension
Authors: Giampietro Ottavio , Matteucci Elena , Catapano Giosué , Dell’Omo Giulia , Talarico Luigi , Di Muro Carmine , Di Bello Vitantonio , Pedrinelli Roberto
Published: June 2012

Abstract
Microalbuminuria (urinary albumin excretion between 20 and 200 μg/min) and abnormalities of red blood cell sodium-hydrogen exchange coexist in essential hypertensive patients. To evaluate how the two phenomena relate, we recruited 10 untreated microalbuminuric male essential hypertensive patients without diabetes to be compared with an equal number of matched essential hypertensive patients excreting albumin in normal amounts as well as 10 healthy control subjects. Sodium-hydrogen exchange values were increased to a comparable extent in microalbuminuric and normoalbuminuric hypertensive patients. Systolic and mean blood pressures were higher in microalbuminuric patients. Fasting insulin was greater and high-density lipoprotein cholesterol lower in patients than control subjects. Urinary albumin excretion correlated positively with both mean blood pressure and left ventricular mass values in the absence of a relationship with circulating lipid and insulin levels. In contrast with microalbuminuria, sodium-hydrogen exchange covaried only with high-density lipoprotein cholesterol and insulin levels. Thus, microalbuminuria and an abnormal sodium-hydrogen exchange are unrelated phenomena in essential hypertensive patients. Microalbuminuria appears to be a hemodynamically driven biological variable, while an accelerated sodium-hydrogen exchange seems primarily conditioned by the metabolic abnormalities of hypertension, possibly in the context of an insulin-resistant syndrome.
Hemodynamic and Renal Responses to Chronic Hyperinsulinemia in Obese, Insulin-Resistant Dogs
Authors: Hall John E. , Brands Michael W. , Zappe Dion H. , Dixon William N. , Mizelle H. Leland , Reinhart Glenn A. , Hildebrandt Drew A.
Published: June 2012

Abstract
We previously reported that chronic hyperinsulinemia does not cause hypertension in normal insulin-sensitive dogs. However, resistance to the metabolic and vasodilator effects of insulin may be a prerequisite for hyperinsulinemia to elevate blood pressure. The present study tested this hypothesis by comparing the control of systemic hemodynamics and renal function during chronic hyperinsulinemia in instrumented normal conscious dogs (n=6) and in dogs made obese and insulin resistant by feeding them a high-fat diet for 6 weeks (n=6). After 6 weeks of the high-fat diet, body weight increased from 24.0±1.2 to 40.9±1.2 kg, arterial pressure rose from 83±5 to 106±4 mm Hg, and cardiac output rose from 2.98±0.29 to 5.27±0.54 L/min. Insulin sensitivity, assessed by fasting hyperinsulinemia and by the hyperinsulinemic euglycemic clamp technique, was markedly reduced in obese dogs. Insulin infusion (1.0 mU/kg per minute for 7 days) in obese dogs elevated plasma insulin from 42±12 μU/mL to 95 to 219 μU/mL but failed to increase arterial pressure, which averaged 106±4 mm Hg during control and 102±4 mm Hg during 7 days of insulin infusion. Hyperinsulinemia for 7 days in obese dogs elevated heart rate from 116±8 to 135±7 beats per minute but caused no significant changes in cardiac output, in contrast to normal dogs (n=6), in which marked increases in cardiac output (31±5% after 7 days) and decreases in total peripheral resistance occurred during chronic insulin infusion. Thus, chronic hyperinsulinemia did not raise blood pressure in obese dogs even though they were resistant to the metabolic and vasodilator effects of insulin. These observations provide no evidence that hyperinsulinemia causes hypertension, even in the presence of insulin resistance, in obese dogs.
Influence of Atrial Natriuretic Factor on Spontaneous Baroreflex Sensitivity for Heart Rate in Humans
Authors: Butler Gary C. , Senn Beverley L. , Floras John S.
Published: June 2012

Abstract
Our objective in these experiments was to evaluate the effects of atrial natriuretic factor on the gain of the spontaneous baroreceptor–heart rate reflex in humans. On two separate study days, we gave either atrial natriuretic factor during supine rest (16 nmol over 3 minutes, then 16 pmol/kg per minute) or saline (as vehicle) to nine healthy men (age, 23±1 years; mean±SEM) according to a random, double-blind design. Beat-by-beat RR interval and systolic pressure were recorded noninvasively. Sequences during which systolic pressure and the RR interval of the following beat changed in parallel (either increasing [Up] or decreasing [Down]) over at least three consecutive beats were identified and classified as baroreceptor–heart rate reflex sequences. Regression lines relating RR interval to the preceding systolic pressure were derived for each individual sequence. The mean value of the slopes of these regression lines was calculated to obtain the mean spontaneous baroreflex sensitivity for heart rate for each subject. Saline infusion did not change RR interval, systolic pressure, or number of baroreflex sequences nor the slope of the mean spontaneous baroreflex sensitivity for heart rate or slopes of Up or Down sequences. Atrial natriuretic factor, at a dose that lowers central venous pressure, did not affect systolic pressure, respiratory rate, or the number of baroreflex sequences but reduced RR interval from 952±35 to 930±40 ms (
P
<.04) and the mean slope of spontaneous baroreflex sensitivity for heart rate from 32.7±4.8 to 23.1±2.8 ms · mm Hg
−1
(
P
<.04). Baroreflex sensitivity during Up sequences decreased during atrial natriuretic factor infusion, from 32.9±5.5 to 24.2±3.3 ms · mm Hg
−1
(
P
<.05). The slope of Down sequences did not change (from 27.9±4.2 to 23.0±3.2 ms · mm Hg
−1
) compared with baseline values, but when compared with the slope during saline infusion (35.0±5.2 ms · mm Hg
−1
), this effect of atrial natriuretic factor on baroreflex sensitivity during Down sequences was significant (
P
<.05). These data indicate that atrial natriuretic factor reduces the vagal component of the arterial baroreflex control of heart rate in healthy humans. The cardioacceleration observed in humans during atrial natriuretic factor infusion may be in part due to diminished parasympathetic modulation of heart rate.
Endothelin Production in Cultured Mesangial Cells of Spontaneously Hypertensive Rats
Authors: Ikeda Miwako , Kohno Masakazu , Takeda Tadanao
Published: June 2012

Abstract
Cultured glomerular mesangial cells are shown to produce a potent vasoconstrictive peptide, endothelin-1 (ET-1). We examined whether basal or stimulated ET-1 production by angiotensin II (Ang II) and arginine vasopressin (AVP) is enhanced in cultured mesangial cells of spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). In addition, we examined which receptor subtypes of Ang II and AVP mediate ET-1 production in these cells. Basal ET-1 production in SHR mesangial cells was not different from that in WKY cells, although a trend toward increased ET-1 production was observed in the SHR cells. Ang II and AVP stimulated ET-1 production in a concentration-dependent manner in mesangial cells of both rat strains, but Ang II– and AVP-induced stimulation of ET-1 production was clearly greater in SHR than WKY cells. The protein kinase C (PKC)–activating phorbol ester phorbol myristate acetate stimulated ET-1 production in a concentration-dependent manner in cells of both rat strains, but this stimulation was significantly greater in SHR than WKY cells. Neither Ang II nor AVP stimulated ET-1 production in PKC-depleted cells of both strains. Ang II– and AVP-induced stimulation was completely abolished by selective angiotensin subtype 1 (AT
1
) and vasopressin subtype 1 (V
1
) receptor antagonists, respectively, in cells of both rat strains. These results suggest that AT
1
and V
1
-receptor–mediated mesangial cell production of ET-1 is clearly enhanced in SHR compared with WKYs. Increased response of ET-1 production to PKC activation appears to contribute in part to the observed enhancement of ET-1 production in SHR mesangial cells.
Spectral Analysis of Blood Pressure and Heart Rate Variability in Evaluating Cardiovascular Regulation
Authors: Parati Gianfranco , Saul J. Philip , Di Rienzo Marco , Mancia Giuseppe
Published: June 2012

Abstract
Blood pressure variability includes rhythmic and nonrhythmic fluctuations that, with the use of spectral analysis, appear as clear peaks or broadband power, respectively. This review offers a concise and critical description of the spectral methods most commonly used (fast Fourier transform versus autoregressive modeling, time-varying versus broadband spectral analysis) and an evaluation of their advantages and disadvantages. It also provides insight into the problems that still affect the physiological and clinical interpretations of data provided by spectral analysis of blood pressure and heart rate variability. In particular, the assessment of blood pressure and heart rate spectra aimed at providing indexes of autonomic cardiovascular modulation is discussed. Evidence is given that multivariate models—which allow evaluation of the interactions between changes in blood pressure, heart rate, and other biological signals (such as respiratory activity) in the time or frequency domains—offer a more comprehensive approach to the assessment of cardiovascular regulation than that represented by the separate analysis of fluctuations in blood pressure or heart rate only.
Arterial Hemodynamics in Human Hypertension
Authors: Ting Chih-Tai , Chen Jaw-Wen , Chang Mau-Song , Yin Frank C. P.
Published: June 2012

Abstract
Previous studies have shown some distinct hemodynamic alterations in essential hypertension, including increased resistance, wave reflections, and pulse wave velocity and decreased arterial compliance. These abnormalities are completely normalized by nonspecific smooth muscle dilation with nitroprusside but not by combined α- and β-adrenergic blockade or angiotensin-converting enzyme inhibition, suggesting an enhanced smooth muscle tone that cannot be attributed solely to the sympathetic nervous or renin-angiotensin systems. Since hypertensive patients have an enhanced calcium influx–dependent vasoconstriction, we performed the present study to examine the extent to which the dihydropyridine calcium channel antagonist nifedipine could normalize the hemodynamic abnormalities in essential hypertension. An essential hypertensive patient group was compared with a normotensive group similar in age, body size, and proportion of men and women. During diagnostic cardiac catheterization, ascending aortic micromanometer pressures and electromagnetic flows were measured at baseline and after sufficient sublingual nifedipine (mean, 24 mg) to normalize blood pressure. From the pressures and flows, aortic input impedance, wave reflection magnitude, and compliance were computed. In the hypertensive group, the hemodynamic alterations were indistinguishable from those summarized above. Nifedipine produced sufficient vasodilation to completely normalize all of these hemodynamic alterations, including wave reflections. From these results, together with those reported in our previous studies, it is clear that the various classes of antihypertensive agents affect hemodynamics differently. All are capable of decreasing blood pressure to normotensive levels, but only nitroprusside and nifedipine can also completely normalize all the other pulsatile hemodynamic alterations. Thus, these hemodynamic effects of the different classes of antihypertensive agents should be considered in choosing a therapeutic modality.