bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Furosemide and Verapamil on the NaCl Dependency of Macula Densa–Mediated Renin Secretion
Authors: He Xiao-Rui , Greenberg Suzanne G. , Briggs Josie P. , Schnermann Jürgen
Published: June 2012

Abstract
The present studies in perfused specimens of the juxtaglomerular apparatus microdissected from rabbit kidneys were performed to quantitatively evaluate the relation between macula densa NaCl concentration and renin secretion and to study the effect of furosemide and verapamil on NaCl dependency of renin release. Renin secretion was found to decrease exponentially when macula densa NaCl concentration was increased from 26/7 mmol/L (Na/Cl) to 46/27, 66/47, and 86/67 mmol/L. Increasing Na/Cl concentrations from 86/67 to 106/87 mmol/L had no further effect on renin secretion. [Cl]
1/2
, the chloride concentration producing the half-maximal effect, was 30 mmol/L. Addition of 50 μmol/L furosemide to the luminal fluid caused renin secretion to become essentially independent of macula densa NaCl concentration. This effect was due to both an increase of renin secretion at high NaCl concentrations and a decrease of renin release at low NaCl concentrations. Verapamil added to the superfusate at a concentration of 1 μmol/L also abolished NaCl dependency of renin secretion; most of this effect was due to an increase of renin release at high luminal NaCl. These results suggest that Na-2Cl-K cotransport and calcium flux through voltage-gated channels are two mechanisms required for the expression of NaCl-dependent renin release. Identification of the cellular localizations of these two critical membrane proteins in the renin control pathway requires further study.
Divergent Effects of Dihydropyridine and Phenylalkylamine Calcium Channel Antagonist Classes on Autonomic Function in Human Hypertension
Authors: Kailasam Mala T. , Parmer Robert J. , Cervenka Justine H. , Wu Regina A. , Ziegler Michael G. , Kennedy Brian P. , Adegbile Isaac A. , O’Connor Daniel T.
Published: June 2012

Abstract
Calcium channel antagonists differ by class in reported frequency of side effects that suggest reflex sympathoadrenal activation. Do such differences result from differential effects on autonomic and baroreflex function? The present study compared acute and chronic effects of two classes of calcium channel antagonists, the dihydropyridine type (felodipine) and the phenylalkylamine type (verapamil), on efferent sympathetic outflow and baroreflex slope in 15 essential hypertensive subjects. Blood pressure, heart rate, hemodynamics, and biochemistries were determined at baseline and after acute (first dose) and chronic (4 weeks) administration of the drugs versus placebo. Acutely, felodipine caused a greater decrease in blood pressure associated with a larger decline in systemic vascular resistance than the corresponding effects produced by verapamil. Chronically, there were similar, significant declines in blood pressure (
P
=.001) and systemic vascular resistance (
P
=.001) after each drug. Acutely, increased sympathetic activity after felodipine was suggested by reflex tachycardia (from 69±3 to 74±2 beats per minute,
P
=.014) and elevation of plasma norepinephrine (from 264±25 to 323±25 pg/mL,
P
=.037), whereas after verapamil the corresponding changes were closely similar to those after placebo. Chronically, verapamil suppressed sympathetic activity, as evidenced by a decrease in resting heart rate (from 76±2 to 69±3 beats per minute,
P
=.002), decrease in plasma norepinephrine (from 264±25 to 178±21 pg/mL,
P
<.001), decrease in chromogranin A (from 33.0±2.4 to 27.8±1.7 ng/mL,
P
<.001), and lessened response of mean arterial pressure (
P
=.006) and heart rate (
P
=.016) to phentolamine α-adrenergic blockade; after chronic felodipine, all of these variables were unchanged. Neither drug affected baroreflex slope. We conclude that felodipine and verapamil have qualitatively different, time-dependent actions on efferent sympathetic nervous system activity, actions that may in part explain the disparity in autonomic/hemodynamic side effect profiles of the dihydropyridine and phenylalkylamine classes of calcium channel antagonists.
Flow-Diameter Phase Shift
Authors: Hayoz Daniel , Bernardi Luciano , Noll Georg , Weber Roger , Porret Claude-A. , Passino Claudio , Wenzel René , Stergiopulos Nikos
Published: June 2012

Abstract
This study assesses (1) the relation of the very-low-frequency vasomotion (<0.02 Hz) of the radial artery of young healthy volunteers to regional blood flow and (2) its distribution in the upper extremities. Radial artery diameters from comparable sites were measured on contralateral extremities in 18 young healthy volunteers by an echo tracking system simultaneously with blood flow velocity determined by continuous wave Doppler and blood pressure acquired by photoplethysmography in the middle finger. A synchronous global pattern of vasomotion was detected on contralateral radial arteries, suggesting the presence of either a centrally located pacemaker or a humoral system. Modulation of sympathovagal balance in 8 subjects did not significantly alter either the frequency or amplitude of the very-low-frequency vasomotor waves. Matching patterns of diameter and flow oscillations of the very-low-frequency type recorded at the same site were obtained in 10 strictly nonsmoking volunteers for given periods of time. A consistent phase lag was observed between flow and diameter signals. Flow always preceded the diameter fluctuations by a mean (±SEM) course of 20.8±1.56 seconds. Although the physiological basis for oscillatory behavior remains for the moment highly speculative, these results suggest that the very-low-frequency vasomotion pattern in this conduit vessel might be a flow- or shear stress–dependent phenomenon. Shear stress changes at the endothelium modulate vascular tone through the release of vasodilators. The noninvasive assessment of the diameter-flow relation may thus offer a new way of addressing vascular wall function in medium-sized and large arteries in subjects with cardiovascular risk factors.
Altered Angiotensinogen Amino Acid Sequence and Plasma Angiotensin II Levels in Genetically Hypertensive Rats
Authors: Hübner Norbert , Kreutz Reinhold , Takahashi Saori , Ganten Detlev , Lindpaintner Klaus
Published: June 2012

Abstract
The components of the renin-angiotensin system have been implicated in the development of primary hypertension in humans and genetically hypertensive rats. In humans a mutation in the angiotensinogen gene and elevated plasma angiotensinogen levels have been linked to primary hypertension. Although we had previously excluded a linkage of blood pressure to the angiotensinogen gene in the stroke-prone spontaneously hypertensive rat (SHRSP), elevated angiotensin II (Ang II) levels in this strain compared with the normotensive reference, the Wistar-Kyoto rat (WKY), prompted us to investigate further into the origins and effects of altered Ang II regulation using a range of physiological, biochemical, molecular, and genetic approaches. Ang II plasma levels determined by radioimmunoassay were confirmed to be significantly elevated in SHRSP compared with WKY. Sequence comparison among the two rat strains revealed a mutation in the coding region of the angiotensinogen gene that results in an isoleucine-to-valine substitution in SHRSP at amino acid position 154 (
I154V
). We performed a cosegregation analysis in an F
2
intercross cohort bred from SHRSP and WKY from the University of Heidelberg (SHRSP
HD
and WKY
HD
) to address the following questions: (1) whether this or another mutation of the angiotensinogen gene may be causally related to the observed differential Ang II plasma levels, (2) whether Ang II plasma levels may be correlated with blood pressure or organ hypertrophy, and (3) whether genetic linkage to the renin or angiotensin-converting enzyme (
ACE
) gene loci (the two classic regulatory enzymes of the renin-angiotensin system) may provide an explanation for elevated Ang II plasma levels. We measured Ang II plasma concentrations and determined systolic and diastolic pressures as well as heart rate by indwelling arterial catheters in conscious rats before and after dietary sodium loading. We found (1) no linkage of the angiotensinogen gene mutation to Ang II plasma levels, (2) no cosegregation of Ang II plasma levels with blood pressure or morphometric parameters, and (3) no linkage of Ang II plasma levels to either the renin gene or the
ACE
gene locus, excluding a genetically determined regulatory effect on Ang II plasma levels of either enzyme. Of all other parameters measured in this cross, only plasma renin activity showed a significant correlation with Ang II plasma levels. Thus, the demonstrated angiotensinogen mutation has no effect on plasma Ang II levels; Ang II plasma levels do not account for, do not contribute to, and are not caused by elevated blood pressure in SHRSP
HD
; and altered Ang II plasma levels in SHRSP
HD
are not genetically determined by the renin or
ACE
gene. We conclude that elevated Ang II levels in SHRSP
HD
are likely to represent an independent, unrelated phenomenon that is of no direct relevance to the pathogenesis of hypertension.
Gender and Dietary NaCl in Spontaneously Hypertensive and Wistar-Kyoto Rats
Authors: Calhoun David A. , Zhu Su-Tao , Chen Yu-Fai , Oparil Suzanne
Published: June 2012

Abstract
We recently reported that high dietary NaCl exposure significantly increases both daytime and nighttime mean arterial pressure in male spontaneously hypertensive rats (SHR) but only nighttime values in male normotensive Wistar-Kyoto rats (WKY). In the present study we used a telemetry monitoring system to evaluate the effects of high dietary NaCl exposure on diurnal variation of mean arterial pressure and heart rate in male and female SHR and WKY. After implantation of a radio-frequency transducer, rats were fed either high (8%) or basal (1%) NaCl diets for 2 weeks. High dietary NaCl ingestion significantly increased both daytime and nighttime mean arterial pressure in male SHR compared with males receiving a basal NaCl diet, resulting in greater 24-hour values (163±1 versus 154±1 mm Hg, high versus basal NaCl diet;
P
<.05). High dietary NaCl ingestion significantly increased only nighttime blood pressure in male WKY, with no significant effect on 24-hour mean arterial pressure (102±2 versus 101±3 mm Hg, high versus basal). High dietary NaCl exposure did not affect daytime or nighttime mean arterial pressure in female SHR (24-hour mean arterial pressure, 144±2 versus 141±2 mm Hg, high versus basal NaCl diet). Twenty-four-hour mean arterial pressure tended to be lower in female WKY receiving a high NaCl diet than females ingesting a basal diet (101±3 versus 106±1 mm Hg), but the difference was not significant. These results indicate a sexually dimorphic response to dietary NaCl ingestion, with males of both strains manifesting some degree of NaCl sensitivity, whereas females are NaCl resistant.
Insulin Modulation of Vascular Reactivity Is Already Impaired in Prehypertensive Spontaneously Hypertensive Rats
Authors: Lembo Giuseppe , Iaccarino Guido , Vecchione Carmine , Rendina Virgilio , Trimarco Bruno
Published: June 2012

Abstract
Hyperinsulinemia reduces the vasoconstrictive response to norepinephrine in Wistar-Kyoto rats (WKY) but not in spontaneously hypertensive rats (SHR). It has been hypothesized that this difference in the vascular effect of insulin could be a hallmark of the hypertensive state. To test this hypothesis we studied SHR before (5 weeks old, n=10) and after (15 weeks old, n=10) the establishment of hypertension as well as two groups of age- and sex-matched WKY (5 weeks old, n=14; 15 weeks old, n=13). Blood pressure was significantly higher in SHR compared with WKY (181±5 versus 118±6 mm Hg, respectively,
P
<.001) in the 15-week-old rats but not in the 5-week-old rats (121±5 versus 117±3 mm Hg,
P
<NS). We tested vascular reactivity using increasing amounts of norepinephrine (from 10
−10
to 10
−5
mmol/L) on isolated aortic rings in control conditions and after 30 minutes of exposure to 715 pmol/L insulin. In WKY insulin reduced the vascular response to norepinephrine in both the 5-week-old (repeated-measures ANOVA with grouping factor: F=2.443,
P
<.05) and 15-week-old (F=9.667,
P
<.01) groups. In SHR at both ages insulin failed to modify the vascular response to norepinephrine (5 weeks: F=0.107,
P
<NS; 15 weeks: F=0.075,
P
<NS). Sodium nitroprusside was able to attenuate the vascular response to norepinephrine in WKY and SHR at 5 and 15 weeks. Our data demonstrate that in SHR the vascular resistance to insulin action is specific and not acquired with the hypertensive condition; thus, it seems to be a genetically inherited trait.
Regional Hemodynamic and Endocrine Effects of Aldosterone and Cortisol in Conscious Sheep
Authors: May Clive N. , Bednarik Joerg A.
Published: June 2012

Abstract
We studied the cardiovascular responses to 5 days’ infusion of aldosterone (10 μg/h) and cortisol (5 mg/h) to determine the possible contribution of mineralocorticoid and glucocorticoid actions to the regional hemodynamic changes caused by corticotropin. These infusion rates produce plasma levels similar to those seen during corticotropin stimulation. In five conscious sheep aldosterone progressively increased mean arterial pressure (
P
<.001) to a maximum of 11 mm Hg on day 5, whereas cortisol increased pressure by 5 mm Hg (
P
<.01) within 24 hours. Cardiac outputs on the control day and on day 5 of infusion were 4.4±0.3 and 4.9±0.3 L/min, respectively, for aldosterone and 4.3±0.4 and 5.0±0.4 L/min for cortisol. Neither steroid significantly altered total peripheral conductance, but they had different, nonuniform regional hemodynamic effects. Mesenteric conductance fell progressively with aldosterone from 7.14±0.35 (mL/min)/mm Hg to a minimum of 6.17±0.38 (
P
<.01) on day 5 of infusion. Mesenteric conductance was transiently reduced with cortisol, but this was not significant over the 5 days. Renal conductance was unchanged with aldosterone, but cortisol caused a rapid, sustained increase in renal conductance from 2.9±0.3 to 4.0±0.4 (mL/min)/mm Hg (
P
<.001) within 24 hours, similar to the increase caused by corticotropin. As with corticotropin there were only minor changes in the coronary and iliac vascular beds. In summary, these two endogenous steroids had contrasting, nonuniform regional hemodynamic effects, aldosterone causing mesenteric vasoconstriction, and cortisol causing renal vasodilatation. These findings suggest that corticotropin-induced renal vasodilatation is caused by the cortisol released by corticotropin and the mesenteric vasoconstriction partly depends on the mineralocorticoid actions of the adrenocortical steroids released by corticotropin.
Glucocorticoids Regulate V
1a
Vasopressin Receptor Expression by Increasing mRNA Stability in Vascular Smooth Muscle Cells
Authors: Murasawa Satoshi , Matsubara Hiroaki , Kizima Kazuhisa , Maruyama Katsuya , Mori Yasukiyo , Inada Mitsuo
Published: June 2012

Abstract
Enhancement of vascular responsiveness is considered to be one of the major contributing factors observed in glucocorticoid-induced hypertension. We examined the effects of glucocorticoids on V
1a
arginine vasopressin receptor mRNA and protein levels in vascular smooth muscle cells. Dexamethasone (1 μmol/L) produced a 1.8-fold increase in V
1a
receptor density without changing its affinity. Steady-state values of V
1a
receptor mRNA, analyzed by Northern blotting, increased 2.7-fold after a 12-hour exposure to dexamethasone. This effect of dexamethasone was blocked by the glucocorticoid antagonist RU38486 and did not occur in the presence of the protein synthesis inhibitor cycloheximide. The V
1a
receptor gene transcription rate, determined by nuclear run-off assays, was unchanged in cells treated with dexamethasone for 12 hours. Dexamethasone increased the half-life of V
1a
receptor mRNA by 2.2-fold. These findings suggest that dexamethasone upregulates the expression of the V
1a
receptor by increasing mRNA stability rather than by gene transcription and that de novo protein synthesis is involved in this regulation.
Sympathetically Mediated Hypertension Caused by Chronic Inhibition of Nitric Oxide
Authors: Sander Mikael , Hansen Pernille G. , Victor Ronald G.
Published: June 2012

Abstract
Pharmacological inhibition of nitric oxide synthase causes sustained hypertension in many animal species. Although this hypertension has been attributed to inhibition of endothelium-dependent vasodilation, short-term studies in anesthetized preparations have advanced the hypothesis that there could be a sympathetic component to this hypertension. To test this hypothesis we measured intra-arterial pressure directly before and after 1 week of treatment with the nitric oxide synthesis inhibitor
N
ω
-nitro-
l
-arginine methyl ester (L-NAME, approximately 80 mg/kg per day in drinking water) in conscious unrestrained rats with or without chronic guanethidine-induced sympathectomy. The major new finding is that the hypertensive response to L-NAME was greatly attenuated by sympathectomy. With L-NAME, mean arterial pressure increased from 101±3 to 152±6 mm Hg in rats without sympathectomy (n=11) but only from 96±2 to 122±3 mm Hg in rats with sympathectomy (n=15, +52±5 versus +27±4 mm Hg,
P
<.01). Sympathectomy did not alter maximal endothelium-dependent vasodilation assessed by femoral vascular responses to intra-arterial acetylcholine or bradykinin, indicating that the differing hypertensive responses to L-NAME in rats with versus without sympathectomy could be related to inhibition of neuronal rather than endothelial nitric oxide synthesis. We also found that L-NAME–induced hypertension, once developed, is completely reversed by acute ganglionic blockade. In conclusion, these findings identify an important sympathetic neural component to the sustained hypertension produced by pharmacological inhibition of nitric oxide in the rat.
Renal Artery Stenosis Rapidly Enhances Atrial Natriuretic Peptide Gene Expression
Authors: Wolf Konrad , Kurtz Armin
Published: June 2012

Abstract
The aim of this study was to examine the influence of the systemic renin-angiotensin system on the gene expression of atrial natriuretic peptide in rat hearts. The renin-angiotensin system was stimulated (1) by unilateral renal artery clipping (0.2-mm clip, 2 days), producing a fourfold increase of circulating plasma renin activity and increasing blood pressure; (2) by furosemide infusion with simultaneous salt substitu- tion, increasing plasma renin activity values to 45 ng angiotensin I/h per milliliter without changing blood pressure; or (3) by administration of the calcium antagonist amlodipine, which increased plasma renin activity values to 42 ng angiotensin I/h per milliliter and lowered blood pressure. Unilateral renal artery clipping increased atrial natriuretic peptide mRNA levels approximately 20-fold in the left ventricles and approximately twofold in the right ventricles and atria. Furosemide infusion had no effect on cardiac atrial natriuretic peptide mRNA levels, and in amlodipine-treated rats, cardiac atrial natriuretic peptide mRNA levels decreased to 30% of control values. The increase of atrial natriuretic peptide mRNA in the ventricles during renal artery clipping was blunted by the administration of the angiotensin-converting enzyme inhibitor ramipril, which also attenuated the blood pressure rise. In clipped rats amlodipine did not change elevated plasma renin activity values but abolished the rise of blood pressure and also attenuated the rise of atrial natriuretic peptide mRNA in the hearts. These findings indicate that an increase of the activity of the systemic renin-angiotensin system does not result in an obligatory change in cardiac atrial natriuretic peptide gene expression. Moreover, our results suggest that activation of the renin-angiotensin system by renal artery stenosis preferentially stimulates left ventricular atrial natriuretic peptide gene expression by an angiotensin II–dependent mechanism that could be associated with the induction of myocardial hypertrophy.
Nitric Oxide Synthase Isoform Activities in Kidney of Dahl Salt-Sensitive Rats
Authors: Ikeda Yoshihiro , Saito Komei , Kim Jong-Il , Yokoyama Mitsuhiro
Published: June 2012

Abstract
An abnormal
l
-arginine–nitric oxide axis has been suggested to be relevant to the genesis of salt-sensitive hypertension. In the present study we investigated the activities of three isoforms of nitric oxide synthase (NOS) in the kidney of Dahl salt-sensitive and salt-resistant rats. Five-week-old Dahl Iwai salt-sensitive (n=9) and salt-resistant (n=10) rats were maintained on a high salt diet (4% sodium chloride) for 4 weeks. We measured calcium-dependent and calcium-independent NOS activities in each particulate and soluble fraction of kidney by conversion of
l
-[
3
H]arginine to
l
-[
3
H]citrulline. Systolic blood pressure was elevated significantly (
P
<.001) in salt-sensitive but not salt-resistant rats. Calcium-dependent NOS activity in the soluble fraction was significantly lower in salt-sensitive rats than in salt-resistant rats (25.8±9.0 versus 48.2±19.2 disintegrations per microgram protein, respectively;
P
<.01). There were no differences in calcium-dependent NOS activity in the particulate fraction and calcium-independent NOS activity in the soluble fraction between groups. Renal norepinephrine content was lower in salt-sensitive rats than in salt-resistant rats (
P
<.05) and was positively correlated with calcium-dependent NOS activity in the soluble fraction (
P
<.01). Although no differences in endothelial and inducible-type NOS activity were observed a significant reduction in calcium-dependent NOS activity in the soluble fraction of the kidney of salt-sensitive rats suggests that the decreased neural-type NOS activity may in part be involved in the mechanism of salt-sensitive hypertension, possibly through alterations in renal sympathetic nervous activity and sodium handling.
Heterogeneity of Adenovirus-Mediated Gene Transfer in Cultured Thoracic Aorta and Renal Artery of Rats
Authors: Yao Aqing , Wang Donna H.
Published: June 2012

Abstract
Replication-deficient recombinant adenovirus vectors have been used to transfer foreign genes effectively to a wide variety of cell types in vivo and in vitro. We have now used adenovirus containing either the
Escherichia coli
β-galactosidase (β-gal) gene (AdHCMVsp1LacZ) or the firefly luciferase gene (Ad5-luc3) to test the hypothesis that efficiencies of adenovirus-mediated gene delivery into organ cultures of smooth muscle differ according to the anatomic origin of the muscle. Thoracic aorta and renal artery were isolated from 9-week-old male Sprague-Dawley rats and exposed to adenovirus after 16 hours of incubation with serum-free medium (Dulbecco’s modified Eagle’s medium). With the use of histochemical methods, β-gal staining was noted in both endothelial and adventitial cells but not in the muscular media of thoracic aorta and renal artery exposed to AdHCMVsp1LacZ. The efficiency of the transfection, assessed either by counting of β-gal–stained cells in intact vessels or by measurement of β-gal activity in tissue extracts, was higher in renal artery than thoracic aorta (
P
<.05). Consistent with this result, luciferase activity in renal artery exposed to Ad5-luc3 (15.9±2.1×10
6
relative light units per milligram protein) was higher than that in thoracic aorta (8.3±2.0×10
6
,
P
<.05). To determine whether increased efficiency of adenovirus-mediated gene transfer into renal artery is a function of the replication status of vessels, we assessed [
3
H]thymidine incorporation. [
3
H]Thymidine uptake by thoracic aorta was only 63% of that in renal artery (
P
<.05), indicating that more proliferating cells are present in renal artery. We conclude that the efficiency of adenovirus-mediated gene transfer into cultured renal artery is enhanced compared with that into thoracic aorta and propose that the increase in efficiency is related to the higher proliferative activity of renal artery.
Calcium-ATPase and Insulin in Adolescent Offspring of Essential Hypertensive Parents
Authors: Grunfeld Beatriz , Gimenez María , Romo Miriam , Rabinovich Laura , Simsolo Rosa B.
Published: June 2012

Abstract
A number of abnormalities in calcium homeostasis have been reported in patients with essential hypertension. In turn, insulin has been shown to influence the activity of the Ca
2+
-ATPase. We have previously shown that normotensive offspring of essential hypertensive individuals have an exaggerated insulin response to a glucose overload. Therefore, the aim of the present study was to evaluate basal and calmodulin-activated Ca
2+
-ATPase in red blood cells and its relationship to the insulin response during an intravenous glucose tolerance test in 27 normotensive adolescents with a family history of essential hypertension (F+) (mean age, 13.9±0.5 years) and in 10 control subjects matched for age and body mass index with no family history of hypertension (F−). The results (mean±SD) were as follows (μmol Pi/[mg protein/h]10
−1
): basal Ca
2+
-ATPase, 4.5±1.2 in F+ and 5.1±1.6 in F− (
P
=NS); calmodulin-activated Ca
2+
-ATPase, 13.6±3.9 in F+ and 16.2±1.7 in F− (
P
<.04). The insulin area under the curve after the glucose load was 3413±1674 μU/mL per hour in F+ and 2752±928 in F− (
P
=NS). Calmodulin-activated Ca
2+
-ATPase showed a negative correlation with the insulin area under the curve (
r
=−.59,
P
<.005) and cholesterol levels (
r
=−.38,
P
<.03). Urinary calcium excretion was 1.82±0.9 mmol/d in F+ and 2.47±0.9 mmol/d in F− (
P
=NS). Our findings indicate a diminished activity of calmodulin-stimulated Ca
2+
-ATPase despite increased levels of insulin, a known activator of this pump, further suggesting the presence of insulin resistance in normotensive offspring of essential hypertensive individuals. Since Ca
2+
-ATPase is an extrusion pump, a drop in its activity may lead to an increase in intracellular calcium accumulation and thus contribute to the development of hypertension.
Serum Insulin Levels, 24-Hour Blood Pressure Profile, and Left Ventricular Mass in Nonobese Hypertensive Patients
Authors: Costa Claudia H.R.M. , Batista Marcelo C. , Moises Valdir A. , Kohlmann Narcia B. , Ribeiro Artur B. , Zanella Maria-Teresa
Published: June 2012

Abstract
In essential hypertensive patients, considered to be insulin-resistant, a blunted decline in nocturnal blood pressure is associated with increased adrenergic tone and left ventricular mass. Since insulin stimulates the sympathetic system, we tested whether insulin resistance and insulinemia influence left ventricular mass and the 24-hour blood pressure profile. We studied 29 nonobese hypertensive patients with office diastolic pressure between 95 and 110 mm Hg and normal oral glucose tolerance test after a 4-month washout period. They were then assigned to M-mode echocardiographic evaluation and 24-hour ambulatory blood pressure monitoring. The glucose and insulin responses to a 75-g oral glucose load were compared with those obtained in 16 weight-matched normotensive control subjects. During the oral glucose tolerance test the hypertensive patients compared with control subjects presented higher levels of glucose at 60 minutes (138.7±30.3 versus 108.7±35.7 mg/dL;
P
<.05) and 90 minutes (114.0±23.8 versus 94.8±31.1 mg/dL;
P
<.05) and insulin at 60 minutes (287.1±259.4 versus 142.1±83.9 pmol/L;
P
<.05). However, peak insulin levels after glucose load did not correlate with ambulatory blood pressure values or left ventricular mass index. Left ventricular mass index showed significant correlation with mean sleeping systolic pressure (
r
s
=.56,
P
<.05) and diurnal systolic pressure (
r
s
=.37,
P
<.05) but not with mean diurnal or sleeping diastolic pressures. In conclusion, our results indicate that in nonobese hypertensive patients, insulin resistance does not have any influence on the 24-hour blood pressure profile or on left ventricular mass index. Blood pressure levels during sleep in these patients seem to contribute to increases in left ventricular mass.
Antihypertensive Treatment Efficacy in Type II Diabetes Mellitus
Authors: Puig Juan G. , Ruilope Luis M. , Ortega Rafael
Published: June 2012

Abstract
Whole-day ambulatory blood pressure monitoring is used to confirm the diagnosis of hypertension and assess the response to antihypertensive therapy. Neither of these has been applied to patients with type II diabetes mellitus, in whom it has been proposed that the desirable blood pressure should be lower than in nondiabetics. This multicenter study was designed to examine whether there are differences in the efficacy of a first-line antihypertensive drug when assessed by casual and ambulatory blood pressure determinations in patients with type II diabetes mellitus in whom 24-hour ambulatory monitoring confirms or fails to confirm the diagnosis of hypertension. Forty-three patients (mean age, 57.7 years) with stable type II diabetes mellitus and mild hypertension (casual diastolic pressure, 90 to 104 mm Hg on at least two visits) were treated with an angiotensin-converting enzyme inhibitor (benazepril, 10 to 20 mg, once a day) for 8 weeks. Antihypertensive drug efficacy was assessed by casual (trough) and 24-hour ambulatory blood pressure monitoring. Diabetic patients were classified as nonconfirmed hypertensive if the mean 24-hour ambulatory diastolic pressure was below 85 mm Hg. Antihypertensive treatment significantly decreased both systolic and diastolic pressures when determined by either casual measurement (from a mean of 162.7/98.0 to 153.9/89.2 mm Hg;
P
<.001) or ambulatory monitoring (from a mean of 143.1/84.4 to 137.0/81.5 mm Hg;
P
<.05). Twenty-one patients (49%) were classified as confirmed hypertensive and 22 as nonconfirmed hypertensive. In confirmed hypertensive patients benazepril significantly reduced systolic and diastolic pressures when assessed by either casual or 24-hour ambulatory monitoring. In contrast, in nonconfirmed hypertensive patients benazepril significantly decreased casual diastolic pressure (mean decrease, 10.0 mm Hg) but did not substantially modify 24-hour ambulatory diastolic pressure (mean decrease, 1.3 mm Hg;
P
<.001). At the end of antihypertensive therapy the number of patients with diastolic pressure equal to, above, or below 90 mm Hg was remarkably different when assessed by casual versus 24-hour ambulatory determinations (κ, 0.348; 95% confidence interval, −0.020 to 0.716;
P
>.1). The results indicate that whole-day ambulatory blood pressure monitoring identifies a substantial number of type II diabetic patients with nonconfirmed hypertension. In these patients the discrepancy in diastolic pressure reduction between casual and 24-hour ambulatory monitoring suggests that the method of blood pressure assessment is important when evaluating antihypertensive drug efficacy.
Cardiovascular Effects of a Specific Nonpeptide Antagonist of Substance P (NK-1) Receptor in DOCA-Salt Hypertension
Authors: Kohlmann Osvaldo , Ginoza Milton , Cezaretti Mario Luis , Zanella Maria Tereza , Ribeiro Artur Beltrame , Tavares Agostinho , Ramos Oswaldo Luiz , Leeman Susan E. , Gavras Irene , Gavras Haralambos
Published: June 2012

Abstract
The neurotransmitter substance P acts also as a potent vasodilator. Its participation in the pathogenesis of deoxycorticosterone acetate (DOCA)–salt hypertension was evaluated by 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 rats but only small, transient, and nonsignificant rises in blood pressure of sham-treated control rats. The rise in blood pressure was not accompanied by changes in heart rate. Maximal blood pressure increase in DOCA-salt rats was 31.7±14.8 mm Hg. In a second series of experiments, the hemodynamic effects of this antagonist were evaluated under anesthesia in both DOCA-salt and sham-treated control rats by the thermodilution method. During CP 96 345 infusion, sustained increases in cardiac index and stroke volume and decreases in total peripheral resistance were observed in both DOCA-salt and control rats. In DOCA-salt rats, cardiac index rose by 79.4%, while total peripheral resistance fell by 27.9% of the baseline values. In control rats, the changes were smaller (+27.2% and −22.5%, respectively). Stroke volume changed in parallel to cardiac output in both groups. The data suggest that acute blockade of NK-1 receptors increases blood pressure in DOCA-salt rats mainly by an increase in cardiac output. We conclude that endogenous substance P tends to counteract the DOCA-salt–induced elevation of blood pressure by modulating both cardiac output and peripheral resistance.
Does Keloid Pathogenesis Hold the Key to Understanding Black/White Differences in Hypertension Severity?
Authors: Dustan Harriet P.
Published: June 2012

Abstract
Repeated national surveys have shown that in the United States hypertension is more common and more severe in the black than in the white population. This discussion presents the hypothesis that the racial difference in hypertension severity is because of differences in growth factors (cytokines) affecting vascular smooth muscle cell growth. This hypothesis is derived from studies of keloids, which occur almost exclusively in blacks. Keloid fibroblasts in culture have growth characteristics that differ substantially from those of normal skin. Furthermore, there is evidence that peripheral blood mononuclear cells from patients with keloids produce different amounts of cytokines than do similar preparations from the blood of individuals without keloids. A growing body of evidence indicates that growth factors play a pivotal role in the pathogenesis of atherosclerosis, in experimental forms of hypertension, and in various renal diseases; it may be that they function in clinical hypertension as well.
Regional Hemodynamic Effects of the AT
1
Receptor Antagonist CV-11974 in Conscious Renal Hypertensive Rats
Authors: Li Xiao C. , Widdop Robert E.
Published: June 2012

Abstract
Angiotensin II subtype 1 (AT
1
) receptor antagonists reduce mean arterial pressure in various experimental models of hypertension, including two-kidney, one clip (2K1C) renal hypertension. However, the regional hemodynamic mechanisms underlying the hypotensive effect of AT
1
receptor antagonists in 2K1C rats under dynamic conditions have not been documented. Therefore, in the present study we determined the hemodynamic profile of the AT
1
receptor antagonist CV-11974 in conscious 2K1C rats and sham-operated control rats. Approximately 4 weeks after clipping, rats underwent a further two-stage operation for implantation of Doppler flow probes on the contralateral (left) renal artery, superior mesenteric artery, and distal aorta as well as for the implantation of intravascular catheters. At least 24 hours after the last operation continuous recordings were made of mean arterial pressure; heart rate; and renal, mesenteric, and hindquarters flows and conductances (Doppler shift/mean arterial pressure) in response to three doses of CV-11974 (0.01, 0.1, and 1.0 mg/kg IV). CV-11974 caused a small hypotensive effect (decrease of approximately 15 mm Hg) in the sham group, but regional flows and vascular conductances did not change. By contrast, in 2K1C rats CV-11974 caused dose-dependent hypotension that was maximal (−19±6, −41±4, and −51±8 mm Hg, respectively) after 6 hours. These changes were associated with generalized vasodilatation (increased conductance) in all three vascular beds, although there were subtle differences with the different CV-11974 doses. The lowest dose of this compound tested (0.01 mg/kg, n=7) caused transient vasodilatation, and the intermediate dose (0.1 mg/kg, n=8) caused maximal vasodilatation in the mesenteric and hindquarters circulations (approximately 50% increase in conductances). A 10-fold higher dose of CV-11974 (1.0 mg/kg, n=7) produced sustained, hyperemic renal vasodilatation (approximately 30% and 70% increases in renal flow and conductance, respectively) in addition to mesenteric and hindquarters vasodilatation. Thus, CV-11974–induced hypotension was accompanied by widespread vasodilatation, although this was dose dependent only in the renal vascular bed. This study illustrates that AT
1
receptor blockade causes vasodilatation in both renal and nonrenal circulations in 2K1C hypertension, contrasting with the relatively selective renal vasodilatation observed previously in spontaneously hypertensive rats. In addition, it was demonstrated that the maximal hypotension caused by CV-11974 occurred much later than the blockade of the cardiovascular effects of angiotensin II. This temporal disparity may imply that in addition to inhibition of tonic vasoconstriction maintained by circulating and/or tissue renin angiotensin systems, other mechanisms may also be involved in the antihypertensive effect of CV-11974.
l
-Arginine Prevents Corticotropin-Induced Increases in Blood Pressure in the Rat
Authors: Turner Steven W. , Wen Cheng , Li Ming , Whitworth Judith A.
Published: June 2012

Abstract
In this study we examined whether
l
-arginine treatment could prevent corticotropin (ACTH)–induced increases in blood pressure in the Sprague-Dawley rat. Sixty rats were randomly divided into six groups (n=10): sham injection, ACTH injection (0.5 mg/kg per day in divided doses),
l
-arginine (0.6%) in food plus sham injection,
l
-arginine plus ACTH treatment,
d
-arginine (0.6%) in food plus sham injection, and
d
-arginine plus ACTH. Systolic pressure, water intake, urine volume, body weight, plasma and urinary electrolytes, and serum corticosterone concentrations were measured. ACTH increased systolic pressure (from 127±2 to 165±6 mm Hg,
P
<.001), water intake, and urine volume and decreased body weight.
l
-Arginine reduced ACTH-induced blood pressure rises (130±3 mm Hg,
P
<.001) but had no effect on blood pressure in sham-treated rats.
d
-Arginine did not affect blood pressure in sham-treated rats, and systolic pressure in
d
-arginine+ACTH–treated rats was similar to that of ACTH-treated rats.
l
-Arginine decreased serum corticosterone concentrations in sham-treated rats (424±43 versus 238±25 ng/mL,
P
<.01), but
d
-arginine had no effect. However, both drugs decreased serum corticosterone concentrations in ACTH-treated rats (1071±117 versus 739±95 and 695±72 ng/mL for
l
- and
d
-arginine, respectively; both
P
<.05). As
l
-arginine but not
d
-arginine prevented ACTH-induced increases in blood pressure in Sprague-Dawley rats and both
l
- and
d
-arginine reduced serum corticosterone concentrations in ACTH-treated rats, the effects of
l
-arginine in preventing ACTH-induced hypertension were not simply a consequence of decreased corticosterone secretion.
Endogenous Renal 11β-Hydroxysteroid Dehydrogenase Inhibitory Factors in Patients With Low-Renin Essential Hypertension
Authors: Takeda Yoshiyu , Miyamori Isamu , Iki Kazuhiro , Inaba Satoru , Furukawa Kenji , Hatakeyama Haruhiko , Yoneda Takashi , Takeda Ryoyu
Published: June 2012

Abstract
11β-Hydroxysteroid dehydrogenase (11β-HSD) modulates the access of corticosteroids to their receptors and is important in blood pressure control. The excretion of renal 11β-HSD (ie, NAD
+
-dependent isoform) is thought to protect renal mineralocorticoid receptors from cortisol. To examine whether endogenous renal 11β-HSD inhibitory factor(s) may be involved in the pathophysiology of hypertension, we studied the urinary excretion of such inhibitors in 30 patients with low-renin essential hypertension and 20 normotensive control subjects. The effect of sodium restriction on the urinary excretion of the inhibitors was also evaluated in six normotensive control subjects. Urine was extracted with Sep-Pak cartridges and high-performance liquid chromatography. Endogenous renal 11β-HSD inhibitors were measured by the inhibition of 11β-HSD bioactivity in microsomes from the human kidney. The urinary excretion of the inhibitors was significantly increased in patients with low-renin essential hypertension (1280±88 nmol/d, mean±SEM) compared with normotensive control subjects (704±56 nmol/d) (
P
<.05). Ratios of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone did not differ significantly. Sodium restriction reduced the urinary excretion of the endogenous renal 11β-HSD inhibitors but did not affect the ratio of urinary tetrahydrocortisol+allo-tetrahydrocortisol to tetrahydrocortisone. Endogenous renal 11β-HSD inhibitory factors may contribute to the pathogenesis of low-renin essential hypertension by modulating the activity of 11β-HSD. Sodium intake may directly or indirectly regulate the inhibitory factors.
Comparison of Early and Late Start of Antihypertensive Agents and Baroreceptor Reflexes
Authors: Kumagai Kazuhiro , Suzuki Hiromichi , Ichikawa Masashi , Jimbo Masahito , Nishizawa Masahiko , Ryuzaki Munekazu , Saruta Takao
Published: June 2012

Abstract
Along with arterial blood pressure reduction, maintenance of the integrity of baroreceptor reflex function contributes to preserving end-organ function in the treatment of hypertensive patients. The purpose of this study was to investigate the effects of antihypertensive agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on baroreceptor reflex function by comparing early and late starts of treatment. We administered each agent to spontaneously hypertensive rats (SHR) as early-start groups from 10 to 36 weeks of age and as late-start groups from 28 to 36 weeks of age. We evaluated the gain of the reflex control of renal sympathetic nerve activity and heart rate using ramp infusions of phenylephrine and nitroglycerin in untreated SHR at 10, 28, or 36 weeks of age and in treated SHR at 36 weeks of age. In 28- and 36-week-old untreated SHR, the renal sympathetic nerve activity gain was not altered and the heart rate gain was decreased (from −2.3±0.3 to −1.3±0.3 and −1.2±0.3 beats per minute [bpm]/mm Hg,
P
<.05, respectively) compared with 10-week-old SHR. Early and late start of therapy produced arterial pressure reductions (−18±4 and −12±5 mm Hg,
P
<.05, respectively). In the early-start groups, the renal sympathetic nerve activity gain was improved markedly in nicardipine- and enalapril-treated SHR (−4.2±0.2% and −4.9±0.2% of control/mm Hg,
P
<.01, respectively), and the heart rate gain was improved markedly in atenolol- and enalapril-treated SHR (−4.1±0.2 and −4.4±0.2 bpm/mm Hg,
P
<.01, respectively). In the late-start groups, the renal sympathetic nerve activity gain was improved moderately in nicardipine- and enalapril-treated SHR (−3.8±0.2% and −2.9±0.2% of control/mm Hg,
P
<.05, respectively). The heart rate gain was improved slightly only in nicardipine-treated SHR (−1.9±0.2 bpm/mm Hg,
P
<.05). These results demonstrate that an early start of antihypertensive treatment improves baroreceptor reflex function markedly compared with a late start of treatment. This supports the hypothesis that a possible critical phase sensitive to intervention with antihypertensive treatment exists during the development of hypertension and indicates that the early start of antihypertensive treatment would be required in clinical practice.
Role of Kinins in the Renal Response to Enalaprilat in Normotensive and Hypertensive Rats
Authors: Fitzgibbon Wayne R. , Jaffa Ayad A. , Mayfield Ronald K. , Ploth David W.
Published: June 2012

Abstract
This study examined the role of endogenous kinins in the alteration of renal hemodynamics induced by low-dose converting enzyme inhibition in hydropenic normotensive rats and in the nonclipped kidney of hydropenic two-kidney, one clip hypertensive rats. Infusion of a bradykinin B
2
receptor antagonist (
d-
Arg
0
,[Hyp
3
,Thi
5,8
,
d-
Phe
7
]-bradykinin, 1 or 10 μg · kg
−1
· min
−1
) did not alter renal function of normotensive rats. In a second series of experiments, infusion of enalaprilat at 0.1 mg · kg
−1
· h
−1
increased renal blood flow (
P
<.01) and decreased renal vascular resistance (
P
<.01). The superimposition of the kinin antagonist at 1 μg · kg
−1
· min
−1
during the enalaprilat infusion decreased renal blood flow to a value similar to the preenalaprilat baseline and significantly different from the mean of the two enalaprilat periods before and after the addition of the kinin antagonist—the “mean effect of enalaprilat.” The decrease in renal blood flow induced by the kinin antagonist was associated with an increase in renal vascular resistance above the mean effect of enalaprilat (
P
<.025). In two-kidney, one clip hypertensive rats, systemic infusion of enalaprilat augmented the hemodynamics of the nonclipped kidney by a degree similar to that in normotensive rats. In contrast to normotensive rats, superimposition of the kinin antagonist did not alter the enalaprilat-induced change in blood flow or vascular resistance of the nonclipped kidney. The results of this study suggest that endogenous kinins contribute to the increased renal function induced by low-dose converting enzyme inhibition in hydropenic normotensive rats but appear to contribute less to the enalaprilat-induced alterations of renal function in the nonclipped kidney of two-kidney, one clip hypertensive rats.
Impaired Regulation of Cell Communication by β-Adrenergic Receptor Activation in the Failing Heart
Authors: De Mello Walmor C.
Published: June 2012

Abstract
We investigated the influence of β-adrenergic receptor activation on the control of gap junctional conductance (gj) in the heart of cardiomyopathic hamsters (11 months old). We measured gj in isolated ventricular cell pairs using two voltage-clamp circuits. Administration of isoproterenol (10
−6
mol/L) to the bath had no effect on gj in myopathic cell pairs but increased gj by 45±3% (±SE) in normal hamsters. Moreover, forskolin (10
−7
mol/L), an activator of adenyl cyclase, did not change gj in myopathic cells but enhanced gj by 23±2.8% in controls. Similar results were obtained with isobutylmethylxanthine (10
−6
mol/L), a phosphodiesterase inhibitor. Dibutyryl-cAMP (10
−6
mol/L), however, increased gj of cardiomyopathic cell pairs by 58±2.1% within 2 minutes and enhanced gj in controls by 50±3.6%. The effect of dibutyryl-cAMP on gj of myopathic cells was suppressed by intracellular dialysis of an inhibitor of protein kinase A. These observations indicate that the regulation of gj by the β-adrenergic receptor–G protein–adenyl cyclase signaling system is greatly impaired in the failing heart but the ability of cAMP to increase gj is still preserved.