bluuebunny/crossref_metadata_2025 huggingface dataset:
Calcium- and Protein Kinase C–Dependent Basal Tone in the Aorta of Hypertensive Rats
Authors: Pucci Michael L. , Tong Xianglan , Miller Kathleen B. , Guan Hui , Nasjletti Alberto
Published: June 2012

Abstract
We examined the regulatory influence of nitric oxide on development of calcium- and protein kinase C–dependent basal tone in rings of thoracic aortas from rats with aortic coarctation–induced hypertension and from normotensive controls. Aortic rings from hypertensive rats but not those from normotensive rats, bathed in Krebs’ bicarbonate buffer and subjected to 2 g of passive stretch, were relaxed by removal of calcium from the buffer and by the protein kinase C inhibitors staurosporine and calphostin C. Protein kinase C activity was much greater in homogenates of aortae from hypertensive rats than in those from normotensive controls (2124±785 versus 608±73 pmol · min
−1
· mg protein
−1
, respectively). Relaxant responses to removal of calcium and to staurosporine were greater in aortic rings rubbed to remove the vascular endothelium than in endothelium-intact rings (−1.07±0.12 versus −0.70±0.10 g tension/mg tissue, respectively, for calcium removal and −1.10±0.12 versus −0.65±0.08 g tension/mg tissue, respectively, for staurosporine). Treatment with an inhibitor of nitric oxide synthesis increased calcium-dependent tone in both intact and endothelium-denuded aortic rings from hypertensive rats. Conversely, the administration of sodium nitroprusside or
l
-arginine reversed tone in both intact and denuded aortic rings from hypertensive rats, but acetylcholine reversed tone only in intact rings. The relaxant effects of these agents were paralleled by increases in cyclic guanosine monophosphate in aortic tissue. We conclude that aortic rings from rats with aortic coarctation–induced hypertension display calcium-dependent, protein kinase C–mediated tone in the absence of exogenous vasoconstrictors. Furthermore, endogenous nitric oxide from endothelial and nonendothelial sources suppresses the development of this tone.
Brain ‘Ouabain,’ Sodium, and Arterial Baroreflex in Spontaneously Hypertensive Rats
Authors: Huang Bing S. , Leenen Frans H. H.
Published: June 2012

Abstract
To assess the possible role of brain “ouabain” in modulating arterial baroreflex function in salt-sensitive hypertension, arterial baroreflex control of renal sympathetic nerve activity and heart rate was evaluated in conscious spontaneously hypertensive rats and compared with that in Wistar-Kyoto rats. A regular sodium or high sodium diet was provided from 5 to 9 weeks of age, with intracerebroventricular infusion of antibody Fab fragments, which bind ouabainlike substances with high affinity, or, as control, nonspecific γ-globulins (200 μg · 12 μL
−1
· d
−1
for both). Baroreflex function was assessed by plotting changes in renal sympathetic nerve activity or heart rate against changes in mean arterial pressure by phenylephrine and nitroprusside. In control Wistar-Kyoto rats, high sodium intake did not increase resting blood pressure but sensitized baroreflex control of renal sympathetic nerve activity. In control spontaneously hypertensive rats, high sodium intake significantly increased blood pressure but did not enhance renal sympathetic nerve activity responses. However, in spontaneously hypertensive rats given high sodium diets and treated with Fab fragments, blood pressure did not increase and the baroreflex control of renal sympathetic nerve activity was sensitized significantly. We conclude that in spontaneously hypertensive rats, increase of central “ouabain” by high sodium intake prevents an increase in the sensitivity of arterial baroreflex control of renal sympathetic nerve activity, as observed in Wistar-Kyoto rats on high sodium diets.
Acute Hypertension Increases Norepinephrine Release in the Anterior Hypothalamic Area
Authors: Peng Ning , Meng Qing C. , King Kathryn , Oparil Suzanne , Wyss J. Michael
Published: June 2012

Abstract
Neurons in the anterior hypothalamic area play an important role in NaCl-sensitive hypertension in spontaneously hypertensive rats, and previous studies have suggested that baroreceptor feedback modifies the activity of these neurons. To test the hypothesis that the release of norepinephrine in the anterior hypothalamic area is modified by arterial baroreceptor reflex feedback and that this reflex release is disturbed in spontaneously hypertensive rats on a high NaCl diet, we used the push-pull technique to measure the release of the norepinephrine metabolite 3-methoxy-4-hydroxy-phenylglycol in the anterior hypothalamic area. Seven-week-old male spontaneously hypertensive and normotensive Wistar-Kyoto rats were placed on a high (8%) or a basal (1%) NaCl diet for 2 weeks. The high NaCl diet elevated mean arterial pressure and greatly reduced basal norepinephrine metabolite levels in the anterior hypothalamic area of the spontaneously hypertensive (but not the control) rats (305±32 pg/10 min in the rats consuming 1% NaCl and 93±9 pg/10 min in the rats consuming 8% NaCl). An infusion of tramazoline (an imidizoline that causes long-lasting hypertension) that increased arterial pressure by 25 mm Hg elevated anterior hypothalamic area norepinephrine metabolite concentrations significantly more in the spontaneously hypertensive rats on the 1% NaCl diet (to 392±46 pg/10 min) than in those on the 8% NaCl diet (to 113±18 pg/10 min). In contrast, in Wistar-Kyoto rats the tramazoline-induced increase in arterial pressure elevated anterior hypothalamic area norepinephrine metabolite concentrations slightly more in rats on the 8% NaCl diet than in those on the 1% NaCl diet. These data suggest that baroreflex activation increases norepinephrine release in the anterior hypothalamic area of the awake rat and that a high NaCl diet blunts this response in spontaneously hypertensive (but not Wistar-Kyoto) rats.
Endothelin-1 and Its Receptors A and B in Human Aldosterone-Producing Adenomas
Authors: Rossi GianPaolo , Belloni Anna S. , Albertin Giovanna , Zanin Lucia , Biasolo Maria Angela , Nussdorfer Gastone G. , Palù Giorgio , Pessina Achille C.
Published: June 2012

Abstract
Endothelin-1 stimulates aldosterone secretion by interacting with specific receptors. Accordingly, we wished to investigate endothelin-1, endothelin-A (ET
A
) receptor, and endothelin-B (ET
B
) receptor gene expression, localization, and properties in aldosterone-producing adenomas and in the normal human adrenal cortex. We carried out
125
I–endothelin-1 displacement studies with cold endothelin-1, endothelin-3, the specific ET
A
antagonist BQ-123, and the specific ET
B
weak agonist sarafotoxin 6 C and coanalyzed data with the nonlinear iterative curve-fitting program
ligand
. We also studied gene expression with reverse transcription–polymerase chain reaction with specific primers for endothelin-1, ET
A
, and ET
B
complementary DNA. Normal adrenal cortices from consenting kidney cancer patients (n=2) and aldosterone-producing adenomas (n=4) were studied; for the latter, surrounding normal cortex and kidney biopsy tissue served as controls. To further localize the receptor subtypes, tissue sections were studied by autoradiography in the presence and absence of 500 nmol/L BQ-123, 100 nmol/L sarafotoxin 6 C, and 1 μmol/L cold endothelin-1. In all tissues examined, endothelin-1, ET
A
, and ET
B
messenger RNAs were easily detected. However, in aldosterone-producing adenomas, both receptors’ genes were expressed at a higher level than in the kidney. In aldosterone-producing adenomas (F=9.49,
P
<.01) as well as in the normal adrenal cortex (F=8.57,
P
<.01), but not in adrenocortical tissue surrounding aldosterone-producing adenomas (F=5.08,
P
=NS), the significantly best fitting of binding data was provided by a two-site model indicating the presence of two receptor subtypes with density (
B
max
) and affinity (
K
d
) similar to those previously found in other tissues. Autoradiography confirmed the presence of both ET
A
and ET
B
receptors on normal zona glomerulosa cells as well as on aldosterone-producing adenoma cells. Thus, the genes of endothelin-1 and of its receptors, ET
A
and ET
B
, are actively transcribed in the human adrenal cortex, and both receptor subtypes are translated into proteins in zona glomerulosa and aldosterone-producing adenoma cells. These data are consistent with an autocrine-paracrine role of endothelin-1 in the regulation of aldosterone secretion, both under normal conditions and in aldosterone-producing adenomas.
Identification of Arachidonate P-450 Metabolites in Human Platelet Phospholipids
Authors: Zhu Ying , Schieber Elimor Brand , McGiff John C. , Balazy Michael
Published: June 2012

Abstract
Phospholipase A
2
(
Naja mocambique
) catalyzed release of epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE) from phospholipids of isolated human platelets. The amount of EETs released by phospholipase A
2
measured by gas chromatography/mass spectrometry (GC/MS) was 4.3±0.9 pmol/10
6
platelets. No EETs were detected when phospholipase A
2
was omitted from the incubations. The relative abundance of EET isomers (14,15-EET, 11,12-EET, 8,9-EET, and 5,6-EET) from human platelets was 5.4:4.5:3.7:1, respectively, as established by a new method based on particle-beam liquid chromatography/mass spectrometry (LC/MS). Fractionation of platelet phospholipids by normal-phase high-performance liquid chromatography followed by hydrolysis and GC/MS analyses indicated that the amount of EETs was highest in fractions containing phosphatidylinositol and phosphatidylserine (142 and 61 pmol/nmol of phosphorus, respectively) while low in phosphatidylcholine and phosphatidylethanolamine (19 and 11 pmol/nmol of phosphorus, respectively). The majority of EETs associated with phosphatidylcholine was found in fractions containing 1-
O
-alkyl-phosphatidylcholine. Human platelet phospholipids also released 20-HETE on phospholipase treatment (9.7±1.6 fmol/10
6
cells) and at least three other HETEs, one of which was tentatively identified as 16-HETE. Activation of human platelets by thrombin or platelet-activating factor released 5 to 7 fmol EET/10
6
cells. Receptor-mediated hydrolysis of phospholipids containing EETs and 20-HETE may play a role in stimulus-response coupling in platelets.
Role of Endogenous Endothelins in the Renin System of Normal and Two-Kidney, One Clip Rats
Authors: Schricker Karin , Scholz Holger , Hamann Marlies , Clozel Martine , Krämer Bernhard K. , Kurtz Armin
Published: June 2012

Abstract
This study aimed to investigate the relevance of endogenous endothelins in the control of renin secretion and renin gene expression under basal conditions and stimulated conditions achieved with unilateral renal artery stenosis. To this end, we studied the effects of the orally active endothelin antagonist Ro 47-0203 (100 mg/kg per day) for 2 days on plasma renin activity and renal renin mRNA levels in normal rats and rats with unilateral renal artery clips (0.2 mm). Treatment with Ro 47-0203 did not change basal arterial pressure but significantly attenuated the rise of blood pressure in response to renal artery clipping. Although Ro 47-0203 tended to increase basal plasma renin activity, this effect was not significant. Basal renin mRNA levels of kidneys were also not changed by the drug. Unilateral renal artery clipping increased plasma renin activity from 12 to 34 ng angioten-sin I/mL per hour, increased renin mRNA levels to 328% of controls in the clipped kidneys, and decreased renin mRNA levels to 23% of controls in the contralateral intact kidneys. These changes were not influenced by Ro 47-0203. In isolated perfused rat kidneys, Ro 47-0203 (10 μmol/L) also had no effect on basal renin secretion or vascular resistance, but it substantially attenuated the decrease of renin secretion and renal flow in response to administration of exogenous endothelin. Taken together, these findings suggest that endogenous endothelins play no relevant role in the control of renin secretion and of renin gene expression in normal and hypoperfused rat kidneys.
Identification of Vasopressin mRNA in Rat Aorta
Authors: Simon Jason , Kasson Barry G.
Published: June 2012

Abstract
We have reported previously that several blood vessels of the rat and cow contain immunoreactive vasopressin and further suggested that this peptide might be produced locally. To provide additional support for this hypothesis, we conducted the present study to determine whether mRNA for arginine vasopressin is also present in blood vessels. Ribonuclease protection analysis of total RNA isolated from rat hypothalamus and aorta revealed the presence of arginine vasopressin message in both tissues but not in RNA isolated from liver, a tissue devoid of vasopressin. Subsequent comparison of the autoradiographic intensities of the signals in these two tissues indicated that vasopressin message was 100- to 1000-fold lower in aorta. Additional studies showed that RNA isolated from endothelium-denuded vessels contained levels of arginine vasopressin message similar to those in intact vessels, indicating that endothelium was not a major source of this message. These data were substantiated by further studies using a vasopressin radioimmunoassay, which showed that vasopressin peptide levels in intact and endothelium-denuded vessels did not differ. Thus, the present study showed that rat aorta contains arginine vasopressin mRNA as well as the vasopressin peptide and that both the message and the peptide are contained in nonendothelial structures. However, the data do not rule out endothelium as a possible source of vasopressin. These studies add further support to the hypothesis that blood vessels are capable of producing vasopressin.
Trends in Medication Choices for Hypertension in the Elderly
Authors: Monane Mark , Glynn Robert J. , Gurwitz Jerry H. , Bohn Rhonda L. , Levin Raisa , Avorn Jerry
Published: June 2012

Abstract
We studied the evolution in choice of antihypertensive therapy in the elderly over a seven-year period and defined factors associated with such prescribing. To accomplish this, we performed a retrospective analysis of 8428 enrollees older than 65 years of age in the New Jersey Medicaid and Medicare programs newly begun on antihypertensive therapy between 1982 and 1988. Diuretics were the most common agents prescribed (51%), followed by calcium channel blockers (14%), β-blockers (13%), central adrenergic antagonists (11%), and angiotensin-converting enzyme inhibitors (5%). However, the use of diuretics declined sharply during the latter part of the time interval studied. Using logistic regression modeling, we determined that the odds of a subject being started on a diuretic compared with any other antihypertensive drug decreased from 1.0 during the referent years 1982 to 1984 to 0.75 in 1985 to 1986 and to 0.41 in 1987 to 1988, after controlling for demographics, comorbidity, and hospital and physician visits (
P
<.001). The relative odds of diuretic use were significantly increased (
P
<.05) for the oldest subjects (odds ratio, 1.28 for age 85 and older versus ages 65 to 74 odds), women (odds ratio, 1.15), and blacks (odds ratio, 1.14). Despite the growing evidence during the study interval of the efficacy of diuretics in treating hypertension in the elderly, diuretic use diminished throughout this period in relation to other antihypertensive drugs. Subject characteristics (oldest subjects, women, and blacks) were important determinants of physicians’ choice of antihypertensive therapy.
Nitroxidergic Innervation in Dog and Monkey Renal Arteries
Authors: Okamura Tomio , Yoshida Kazuhide , Toda Noboru
Published: June 2012

Abstract
We analyzed mechanisms underlying neurogenic vasodilatation in dog and Japanese monkey renal arteries. Isometric mechanical responses of the arterial strip to nerve stimulation by nicotine were recorded. Nicotine-induced contractions were abolished by hexamethonium and potentiated by
N
G
-nitro-
l
-arginine, a nitric oxide synthase inhibitor. The potentiating effect was reversed by
l
-arginine.
N
G
-Nitro-
l
-arginine did not potentiate the contraction caused by norepinephrine. The nicotine-induced contraction was reversed to a relaxation by prazosin. The relaxation was not influenced by indomethacin, timolol, or atropine but was abolished by
N
G
-nitro-
l
-arginine, methylene blue (a guanylate cyclase inhibitor), oxyhemoglobin (a nitric oxide scavenger), and hexamethonium. In the strips treated with
N
G
-nitro-
l
-arginine, the nicotine-induced relaxation was restored by
l
-arginine. Histochemical study demonstrated perivascular nerves containing NADPH diaphorase and nitric oxide synthase immunoreactivity in dog and monkey arteries. We conclude that renal arteries are innervated by nitric oxide–mediated vasodilator and adrenergic vasoconstrictor nerves, and depression of the vasodilator nerve function by nitric oxide synthase inhibition potentiates the contraction caused by adrenergic nerve excitation.
Treatment in Hypertensive Cardiac Hypertrophy, I
Authors: Böhm Michael , Gräbel Claudia , Knorr Andreas , Erdmann Erland
Published: June 2012

Abstract
In the present study, we investigated serum and myocardial neuropeptide Y concentrations as measures of sympathetic activity as well as myocardial β-adrenoceptors and β-adrenoceptor–stimulated adenylyl cyclase activity in spontaneously hypertensive rats (SHR). SHR and control rats at 10 weeks of age were kept on oral treatment with captopril, nitrendipine, or both for 20 weeks. Treatment only slightly reduced but did not normalize blood pressure and cardiac hypertrophy in SHR. The elevated serum concentration of neuropeptide Y, the reduced number of β-adrenoceptors, and the depressed β-adrenoceptor–stimulated adenylyl cyclase activity were partly normalized compared with the values observed in control rats. We conclude that antihypertensive treatment, at doses that failed to normalize systolic pressure and to reverse cardiac hypertrophy completely, is able to reduce sympathetic activity in SHR, thereby resensitizing the depressed β-adrenoceptor–adenylyl cyclase system.
Treatment in Hypertensive Cardiac Hypertrophy, II
Authors: Böhm Michael , Gräbel Claudia , Flesch Markus , Knorr Andreas , Erdmann Erland
Published: June 2012

Abstract
We investigated the effect of pharmacological treatment with captopril, nitrendipine, and captopril plus nitrendipine on myocardial heterologous adenylyl cyclase desensitization and the underlying postreceptor defects in spontaneously hypertensive rats (SHR). In myocardial membranes from SHR, stimulation of adenylyl cyclase with guanylylimidodiphosphate (
P
<.001) and forskolin (
P
<.05) was significantly reduced, whereas no difference with forskolin was obtained in the presence of manganese chloride. Reconstitution of G
sα
into G
sα
-deficient S49 cyc
−
mouse lymphoma cells revealed no difference between SHR and control rats. In contrast, pertussis toxin labeling of G
iα
was significantly increased in SHR. The reduction of adenylyl cyclase in SHR was abolished after pertussis toxin treatment of membranes. Treatment with captopril, nitrendipine, or both reduced G
iα
and increased guanylylimidodiphosphate-stimulated adenylyl cyclase activity in SHR. In summary, heterologous adenylyl cyclase desensitization due to an increase of G
iα
but in the presence of an unchanged activity of G
sα
or the catalyst occurs in SHR. This alteration, which could contribute to the progression of contractile dysfunction by producing adrenergic subsensitivity, is sensitive to pharmacological treatment most likely because of a reduction of sympathetic activity.
Influence of Intracellular Renin on Heart Cell Communication
Authors: De Mello Walmor C.
Published: June 2012

Abstract
The influence of intracellular renin and angiotensinogen on the control of cell-to-cell communication in heart muscle was investigated in cell pairs isolated from adult rat ventricle. Junctional conductance was measured with two separated voltage-clamp circuits. Intracellular dialysis of renin (0.2 pmol/L) caused a decrease in junctional conductance of 29±3.8% (±SEM,
P
<.05) in 7 minutes. The effect of renin on junctional conductance seems to be mainly due to the synthesis of Ang II because enalaprilat (10
−9
mol/L) dialyzed into the cell caused an appreciable reduction in the effect of renin. The intracellular administration of renin (0.2 pmol/L) plus angiotensinogen (0.4 pmol/L) produced a faster and stronger fall in junctional conductance (84.3±1.35%,
P
<.05), and the effect was greatly reduced by enalaprilat. The effects of both renin and angiotensinogen on junctional conductance were not related to a fall in surface cell membrane resistance or a change in series resistance. The effect of renin on junctional conductance was blocked by intracellular administration of a renin inhibitor (S 2864). Moreover, renin dialyzed into just one cell of the pair induced rectification of the junctional membrane, which was prevented by enalaprilat. The results support the view that an intracrine renin-angiotensin system in the heart regulates intercellular communication.
Nitric Oxide Modulates but Does Not Impair Myogenic Vasoconstriction of the Afferent Arteriole in Spontaneously Hypertensive Rats
Authors: Hayashi Koichi , Suzuki Hiromichi , Saruta Takao
Published: June 2012

Abstract
Renal autoregulation curves are reset toward higher renal arterial pressure in spontaneously hypertensive rats (SHR) compared with those in Wistar-Kyoto rats (WKY). We previously demonstrated that myogenic afferent arteriolar constriction is shifted to higher renal arterial pressure. To investigate whether nitric oxide participates in the regulation of myogenic tone, we examined the effect of nitro-
l
-arginine on myogenic afferent arteriolar constriction in kidneys from SHR and WKY, using the isolated perfused hydronephrotic kidney. Elevating pressures from 40 to 80 mm Hg caused increases in afferent arteriolar diameter in WKY (from 18.2±0.4 to 19.0±0.3 μm) and SHR (from 17.3±0.6 to 18.4±0.6 μm). Further pressure elevation elicited constriction at 100 mm Hg in WKY (17.9±0.3 μm), but significant constriction was observed at 120 mm Hg in SHR (17.3±0.6 μm), indicating a resetting in myogenic responses to higher pressures. In WKY, after treatment with 10 μmol/L nitro-
l
-arginine, afferent arterioles exhibited pressure-dependent constriction, with a threshold pressure for constriction at 80 mm Hg. The addition of 100 μmol/L nitro-
l
-arginine had no further effect on myogenic responsiveness in WKY. In contrast, in SHR, nitro-
l
-arginine dose-dependently shifted the myogenic responses toward lower renal arterial pressure, with threshold pressures for constriction observed at 100 mm Hg (10 μmol/L) and 80 mm Hg (100 μmol/L). Finally, in the presence of 100 μmol/L nitro-
l
-arginine, afferent arterioles manifested 24±3% and 20±2% constriction at 180 mm Hg in WKY and SHR, respectively, not different from those in the absence of nitro-
l
-arginine (WKY, 21±1%; SHR, 19±2%). In conclusion, the present study demonstrates that nitric oxide modulates but does not impair myogenic afferent arteriolar contractility. Furthermore, elimination of the resetting in afferent arteriolar response by nitric oxide blockade suggests an augmented effect of nitric oxide on this vessel in SHR. The enhanced nitric oxide effect on afferent arterioles from SHR kidneys may account for the adaptive mechanisms of renal microvessels to hypertension.
Dietary Sodium Intake Modulates Vasodilation Mediated by Nitroprusside But Not by Methacholine in the Human Forearm
Authors: Stein C. Michael , Nelson Richard , Brown Michael , Wood Margaret , Wood Alastair J. J.
Published: June 2012

Abstract
Studies in animals suggest that nitric oxide production is increased under conditions of salt loading and that this increase protects against the development of salt-induced hypertension. To determine the effect of dietary sodium intake on nitric oxide–mediated vascular responses, we studied seven healthy male volunteers twice 4 weeks apart while they were receiving a diet containing 10 or 250 mmol Na
+
per 24 hours. Methacholine (0.25 to 8 μg/min) and sodium nitroprusside (0.25 to 8 μg/min) were infused intra-arterially in incremental doses, and forearm blood flow was measured. The response of forearm blood flow to sodium nitroprusside was greater when subjects received a high sodium diet than when they received a low sodium diet (F=7.11,
P
<.05); however, the response to methacholine was not altered by sodium intake (F=0.57,
P
=NS). Plasma renin activity was significantly higher (3.99 versus 1.0 ng angiotensin I/mL per hour) when subjects received a low salt diet (
P
<.05). Systolic pressure, diastolic pressure, heart rate, and baseline forearm blood flow were not affected by sodium status. We conclude that under conditions of salt loading, vasodilation in response to sodium nitroprusside was enhanced, whereas the response to methacholine was not affected, suggesting a differential effect of sodium intake on endothelium-dependent and endothelium-independent responses after the administration of methacholine and sodium nitroprusside, respectively.
Analysis of the Role of Angiotensinogen in Spontaneous Hypertension
Authors: Lodwick David , Kaiser Michael A. , Harris Janet , Cumin Frederic , Vincent Madeleine , Samani Nilesh J.
Published: June 2012

Abstract
Allelic variants at the human angiotensinogen locus have recently been reported to increase susceptibility to the development of essential hypertension. In this study we analyzed the role played by angiotensinogen in the elevated blood pressure of the spontaneously hypertensive rat (SHR). The SHR angiotensinogen locus (on chromosome 19) cosegregated with a significant (
P
=.003) and specific increase in pulse pressure in F
2
rats derived from a cross of the SHR with the normotensive Wistar-Kyoto rat (WKY), accounting for 20% of the genetic (10% of total) variance in this phenotype. To identify potential mechanisms underlying the effect of the locus, we further examined angiotensinogen structure and expression in the two strains. Sequence analysis of the respective coding regions revealed no differences in the primary structure of angiotensinogen between the strains. Likewise, plasma angiotensinogen level did not differ in adult rats of the two strains. However, gene expression studies showed tissue-specific, age-related differences in angiotensinogen mRNA levels between SHR and WKY, particularly in the aorta. The findings suggest that pulse pressure, which significantly influences cardiovascular risk, has independent genetic determinants. They further suggest that the effect of the angiotensinogen locus on this phenotype in the SHR may be mediated through a tissue-specific abnormality of angiotensinogen gene expression.
Tachyphylaxis of Human Forearm Vascular Responses Does Not Occur Rapidly After Exposure to Isoproterenol
Authors: Stein C. Michael , Nelson Richard , Deegan Robert , He Huaibing , Inagami Tadashi , Frazer Marshall , Badr Kamal F. , Wood Margaret , Wood Alastair J. J.
Published: June 2012

Abstract
In vitro and limited in vivo data suggest that rapid desensitization of β-adrenoceptor responses occurs after exposure to agonist. Tachyphylaxis to a β-adrenoceptor agonist would represent a potentially important mechanism for the short-term regulation of vascular tone. The effects of a 4-hour infusion of 400 ng/min intra-arterial isoproterenol on forearm blood flow and presynaptic β-adrenoceptor–mediated norepinephrine release were determined in eight healthy volunteers. Intra-arterial isoproterenol at 400 ng/min resulted in a significant increase in forearm blood flow in all eight subjects at all time points, with no evidence of tachyphylaxis. In fact, forearm blood flow after 4 hours of the isoproterenol infusion (22.8±3.3 mL/100 mL per minute) was significantly greater than after 7 minutes (14.6±2.8 mL/100 mL per minute), 15 minutes (15.4±2.4 mL/100 mL per minute), and 30 minutes (17.4±3.0 mL/100 mL per minute) of the infusion (
P
<.05). Similarly, presynaptic β-adrenoceptor responses showed no evidence of tachyphylaxis, so forearm norepinephrine spillover values after 7 minutes (6.6±0.94 ng/min), 15 minutes (7.6±1.5 ng/min), and 4 hours (8.8±1.1 ng/min) of isoproterenol infusion were increased and similar. Minimal systemic effects were observed, and there was no evidence of tolerance, there being no difference in heart rate after 7 minutes (70.7±2.7 beats per minute) and 4 hours (72.2±3.6 beats per minute) of isoproterenol infusion. Similarly, systemic norepinephrine spillover values at 7 minutes (422.6±60.6 ng/min), 15 minutes (436.3±48.7 ng/min), and 240 minutes (491.4±52.9 ng/min) all increased from a baseline value of 294±28.2 ng/min (
P
<.05) but were not significantly different from each other. Tachyphylaxis does not occur rapidly after exposure of forearm vascular smooth muscle to the β-adrenoceptor agonist isoproterenol and is unlikely to play a major role in the rapid regulation of vascular response to a β-adrenoceptor agonist.
Dissociation Between the Antiatherosclerotic Effect of Trandolapril and Suppression of Serum and Aortic Angiotensin-Converting Enzyme Activity in the Watanabe Heritable Hyperlipidemic Rabbit
Authors: Chobanian Aram V. , Hope Susan , Brecher Peter
Published: June 2012

Abstract
This study was undertaken to determine whether low doses of the angiotensin-converting enzyme (ACE) inhibitor trandolapril affected atherosclerosis in the Watanabe heritable hyperlipidemic (WHHL) rabbit. Trandolapril (10 μg/kg body weight per 48 hours) was begun at 3 months of age and continued for 9 months. The selected dose reduced serum ACE activity but did not influence blood pressure. Both serum and aortic ACE activity were reduced by more than 80% in the trandolapril-treated compared with control WHHL rabbits, similar to the suppression achieved with the 25-fold-higher dose that in our previous studies induced marked inhibition of aortic atherosclerotic lesions in the WHHL rabbit. In contrast to these prior findings, low-dose trandolapril had no effect on aortic surface involvement by atherosclerosis, aortic cholesterol content, or aortic morphology. The data suggest that the antiatherosclerotic action of ACE inhibitors in the WHHL rabbit may not be related directly to arterial enzyme inhibition.
Biaxial Mechanical Properties of Carotid Arteries From Normotensive and Hypertensive Rats
Authors: Lichtenstein Oscar , Safar Michel E. , Poitevin Pierre , Levy Bernard I.
Published: June 2012

Abstract
Hypertension is known to decrease arterial distensibility and volumetric compliance, as reported from pressure-volume experiments and ring and strip studies of human and animal large arteries. However, recent data using noninvasive in vivo recording of vessel diameter suggest that the cross-sectional compliance of large arteries can be unchanged or even increased in hypertensive subjects. The present study was performed to test the hypothesis that differences between volumetric and cross-sectional compliance could be related to differences in biaxial mechanical properties in normotensive and hypertensive rats. In normotensive (Wistar-Kyoto [WKY]) rats and spontaneously hypertensive rats (SHR) we measured the simultaneous changes in length and diameter of in situ isolated carotid arteries submitted to static pressures (50 to 200 mm Hg by steps of 25 mm Hg each). Carotid artery diameters and lengths were determined by video microscopy and computer-assisted image analysis. At low transmural pressure (50 mm Hg), carotid artery diameter was 710±41 μm in WKY rats and 980±31 μm in SHR (
P
<.01). In response to pressure increases, the carotid diameter increased by 91±6% in WKY rats and by 41±4% in SHR (
P
<.01). In parallel, the percent increase in carotid length was much larger in WKY rats than in SHR (31±2% versus 7±1%, respectively;
P
<.01). In WKY rats, longitudinal distensibility causes significantly larger volumetric values than cross-sectional compliance values; in contrast, because of the very small longitudinal distensibility, volumetric and cross-sectional compliances are almost identical in SHR. In conclusion, the present study suggests that biaxial mechanical properties of arteries could play a role in the damping function of the arterial tree and that measurements of cross-sectional compliance should be interpreted cautiously in normotensive and hypertensive rats when compared with volumetric compliance.
Genetic and Environmental Factors in the Function and Structure of the Arterial Wall
Authors: Avolio Alberto
Published: June 2012

Abstract
In large arteries the structure of the arterial wall determines pulsatile hemodynamics of pressure and flow. Mechanical wall stiffness, wall thickness, and elastin and collagen content vary along the arterial tree. The contribution of genetic and environmental factors to such structural properties is not yet known, but some data are available on possible functional correlates. In hypertensive rats diastolic and pulse pressure have been shown to be linked to two different genes on separate chromosomes. Although a genetic component contributes to intimal calcification, medial hypertrophy is not associated with genetic factors. A study of French West Indies families showed a preferential genetic determinant for pulse pressure in contrast to systolic or diastolic pressure. Environmental and geographic factors are associated with markedly different prevalences of hypertension and age-related increases in arterial stiffening in urban and rural communities in China. Salt consumption has also been implicated in modifications of pulse wave velocity. Recent data on structural parameters of the aortic trunk in oriental (Chinese) and occidental (American and Australian) subjects have shown that the ascending aorta in oriental subjects is of a relatively larger diameter and thinner media. This suggests that in this population a relatively higher primary pressure pulse would be generated because of increased stiffness of the proximal aorta. This suggests that factors other than arterial pressure are responsible for structural differences in the aortic wall and that oriental populations may have a predisposition to increased arterial pressure based on structural factors that affect the interaction between ventricular ejection and arterial load.
Mechanical Factors Associated With the Development of Intimal and Medial Thickening in Vein Grafts Subjected to Arterial Pressure
Authors: Dobrin Philip B.
Published: June 2012

Abstract
Arteries exposed to sustained hypertension undergo a moderate degree of intimal thickening and a marked amount of medial thickening. Autogenous veins that are used as bypass grafts undergo similar histological changes. In this study autogenous vein grafts were used as an indirect model of arteries exposed to sustained hypertension. It was hypothesized that it is not pressure per se but rather mechanical changes brought about by exposure to increased pressures that act as a stimulus inducing histological changes. Exposure to arterial pressure increases the following nine mechanical factors: deformation in the circumferential, longitudinal, and radial directions; stresses in each of these three directions; pulsatile deformations and pulsatile stresses; and flow velocity. All of these mechanical changes occur simultaneously. Accordingly, a three-step algorithm was devised to separate each of the nine mechanical factors and correlate them with histological changes. Three sequential experimental studies were performed in 38 dogs following the algorithm. These experiments demonstrated that intimal thickening was best correlated with low flow velocity, a correlate of low shear stress, whereas medial thickening was best correlated with deformation in the circumferential direction.
Endopeptidase Inhibition in Angiotensin-Induced Hypertension
Authors: Charles Christopher J. , Espiner Eric A. , Richards A. Mark , Sybertz Edmund J.
Published: June 2012

Abstract
To assess the efficacy of neutral endopeptidase 24.11 inhibition in the setting of elevated plasma levels of angiotensin II (Ang II), we studied the hemodynamic, renal, and hormonal effects of bolus injections of the potent and specific neutral endopeptidase inhibitor SCH 39370 or vehicle (control) in 10 sheep with Ang II–induced hypertension. Ang II infusion (5 ng/kg per minute for 6 days) sufficient to increase plasma Ang II levels 50% to 100% induced a consistent rise in mean arterial pressure (mean increment, 15 mm Hg;
P
<.0001) and increased plasma atrial natriuretic peptide (
P
=.017) and its second messenger cGMP (
P
=.049). Compared with time-matched control observations after vehicle alone, SCH 39370 (2.5 mg/kg) further increased plasma atrial natriuretic peptide (
P
=.0006), cGMP (
P
=.006), and plasma Ang II (
P
=.054). Systolic and mean arterial pressures tended to fall after SCH 39370, but these changes were not significant compared with control. No significant changes were observed in urinary volume and sodium excretion. Viewed in relation to previous studies in normotensive sheep, the current findings indicate that the vasodepressor response to neutral endopeptidase inhibition is blunted in hyperangiotensinemic sheep, in which neutral endopeptidase inhibition further augments plasma Ang II levels.
Chronic Nitric Oxide Synthase Inhibition and Carotid Artery Distensibility in Renal Hypertensive Rats
Authors: Delacrétaz Etienne , Zanchi Anne , Nussberger Jürg , Hayoz Daniel , Aubert Jean-François , Brunner Hans R. , Waeber Bernard
Published: June 2012

Abstract
The goal of the present study was to examine the viscoelastic properties of the carotid artery in genetically identical rats exposed to similar levels of blood pressure sustained by different mechanisms. Eight-week-old male Wistar rats were examined 2 weeks after renal artery clipping (two-kidney, one clip [2K1C] Goldblatt rats, n=53) or sham operation (n=49). One half of the 2K1C and sham rats received the nitric oxide synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME, 1.48 mmol/L) in their drinking water for 2 weeks after the surgical procedure. Mean blood pressure increased significantly in the 2K1C-water (182 mm Hg), 2K1C–L-NAME (197 mm Hg), and sham–L-NAME (170 mm Hg) rats compared with the sham-water rats (127 mm Hg). Plasma renin activity was not altered by L-NAME but significantly enhanced after renal artery clipping. A significant and similar increase in the cross-sectional area of the carotid artery was observed in L-NAME– and vehicle-treated 2K1C rats. L-NAME per se did not modify cross-sectional area in the sham rats. There was a significant upward shift of the distensibility-pressure curve in the L-NAME– and vehicle-treated 2K1C rats compared with the sham–L-NAME rats. L-NAME treatment did not alter the distensibility-pressure curve in the 2K1C rats. These results demonstrate that the mechanisms responsible for artery wall hypertrophy in renovascular hypertension are accompanied by an increase in arterial distensi-bility that is not dependent on the synthesis of nitric oxide.
Structural and Functional Properties of Isolated, Pressurized, Mesenteric Resistance Arteries From a Vasopressin-Deficient Rat Model of Genetic Hypertension
Authors: Dunn William R. , Gardiner Sheila M.
Published: June 2012

Abstract
In this study we examined the structural and functional properties of mesenteric resistance arteries isolated from normotensive and hypertensive vasopressin-deficient rats. Hypertensive rats had a significantly higher mean arterial pressure (176±3 mm Hg) than normotensive controls (121±2 mm Hg). First- and second-order mesenteric resistance arteries were set up in a pressure myograph and pressurized to the mean arterial pressure of the rat from which they had been isolated. Vessels were fixed with glutaraldehyde, embedded in Araldite, sectioned, and examined histologically. First- and second-order mesenteric resistance arteries from hypertensive rats displayed a reduced internal diameter and increased media-to-lumen ratio compared with their normotensive controls. However, there was no evidence for an increased media content, indicating that the reduced internal diameter of hypertensive arteries was consequent to either remodeling of similar amounts of wall material or a reduced artery distensibility but not vascular growth. Pressurized arteries were also examined with respect to their responsiveness to the vasoconstrictors norepinephrine and arginine vasopressin and to the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator papaverine. Both first- and second-order mesenteric arteries from hypertensive rats displayed enhanced sensitivity to norepinephrine compared with their normotensive controls. This effect was specific for norepinephrine, because responses to arginine vasopressin were similar in vessels isolated from normotensive and hypertensive rats. No evidence was found for an impaired endothelium-dependent vasodilatation in arteries from hypertensive rats. Indeed, in hypertensive vasopressin-deficient rats responses to acetylcholine were increased in first-order arteries compared with those from normotensive rats. Responses to papaverine were similar in arteries isolated from either normotensive or hypertensive rats. These observations indicate that increased blood pressure in this genetic model of hypertension may result from an altered structure of resistance arteries and/or an increased sensitivity to norepinephrine rather than from impaired endothelium-dependent vasodilatation.
Stimulation of Endogenous Nitric Oxide Pathway by
l
-Arginine Reduces Declamp Mortality and Attenuates Hypertension Associated With Aortic Cross-Clamp–Induced Hindlimb Ischemia in Rats
Authors: Jin Jong-Shiaw , D’Alecy Louis G.
Published: June 2012

Abstract
We tested the hypotheses that maintaining the activity of nitric oxide by
l
-arginine infusion would counteract the release of an endogenous nitric oxide synthase inhibitor, improve survival, and decrease intraoperative hypertension after infrarenal aortic cross-clamp surgery. Hindlimb ischemia was generated by infrarenal aortic cross-clamping and tying of the left femoral artery for 5 hours in rats with bilateral femoral and sciatic nerves cut. Mean blood pressure significantly increased during the 5-hour ischemic period in ischemic rats (no drug treatment). Baroreceptor function was inhibited in ischemic rats assessed by intravenous dose response to phenylephrine and nitroprusside after 5 hours of ischemia, suggesting baroreceptor resetting. In ischemic rats infused with
l
-arginine the intraoperative hypertension was prevented during the 5-hour period, suggesting that this hypertension may be mediated by nitric oxide inhibition. The rates of survival and arrhythmias 2 hours after declamping were 50% in ischemic rats and 100% in ischemic rats treated with
N
ω
-nitro-
l
-arginine (a nitric oxide synthase inhibitor) 10 minutes before declamping. In ischemic rats infused with
l
-arginine the survival rate was significantly increased to 100% and the arrhythmic rate was inhibited. We conclude that
l
-arginine prevents hypertension during cross-clamping and decreases the mortality rate and arrhythmias after declamping by maintaining nitric oxide synthesis. These results suggest that humoral factors released from the ischemic hindlimb may inhibit endogenous nitric oxide production, thus contributing to intraoperative hypertension, arrhythmias, and high mortality rate after aortic cross-clamp surgery.
Chronic Infusion of Angiotensin II Resets Baroreflex Control of Heart Rate by an Arterial Pressure–Independent Mechanism
Authors: Brooks Virginia L.
Published: June 2012

Abstract
The purpose of this study was to test the hypothesis that chronic infusion of angiotensin II (Ang II) in rabbits resets the cardiac baroreflex to a higher arterial pressure level by a pressure-independent mechanism. This hypothesis was tested by determining whether the resetting would be reversed soon after the Ang II infusion was stopped even if the hypertension was maintained by infusion of another vasoconstrictor. Relationships between arterial pressure and heart rate were determined by infusion of increasing doses of nitroprusside to decrease pressure and increase heart rate, followed by increasing doses of phenylephrine to increase pressure and decrease heart rate. After 9 to 10 days of Ang II infusion (20 ng · kg
−1
· min
−1
) arterial pressure was increased from 62±2 to 94±3 mm Hg (
P
<.001), and heart rate was unchanged from control values of 126±7 beats per minute. The baroreflex relationship between arterial pressure and heart rate was shifted to a higher pressure level after 3 to 4 and 9 to 10 days of Ang II infusion. On these same days the Ang II infusion was replaced with phenylephrine (5.0±0.4 μg · kg
−1
· min
−1
), and 30 minutes later arterial pressure decreased slightly (
P
<.05); however, despite the relative hypotension, heart rate was decreased (
P
<.005) from 126±5 to 98±7 beats per minute (days 3 to 4) and from 132±4 to 103±7 beats per minute (days 9 to 10). Moreover, the cardiac baroreflex relationships were shifted back to a lower pressure level (
P
<.05). Similar results were found when Ang II was replaced with methoxamine (1.7 μg · kg
−1
· min
−1
). These data indicate that angiotensin-induced chronic baroreflex resetting is partially reversed soon after Ang II infusion is stopped, despite maintenance of the hypertensive state, and suggest that long-term increases in angiotensin reset the cardiac baroreflex in part by an arterial pressure–independent mechanism.
Neuropeptide Y Prevents Agonist-Stimulated Increases in Contractility
Authors: Woo Nobby D. , Ganguly Pallab K.
Published: June 2012

Abstract
Neuropeptide Y has been shown to inhibit contractility in the rat heart. Although the reasons for this effect are not known, it is possible that postsynaptic adrenergic mechanisms involving neuropeptide Y may be responsible. To ascertain whether this neuromodulatory effect is possible for decreasing contractility, we investigated the effect of neuropeptide Y on agonist-stimulated contractility of the isolated rat myocardium. Receptor binding studies of purified cardiac membranes showed that incubating membrane in the presence of neuropeptide Y (10
−7
mol/L) decreased the number of α-/β-adrenoceptor binding sites without affecting the affinity of these receptors. Isolated hearts perfused with phenylephrine (10
−5
to 10
−10
mol/L) or isoproterenol (10
−5
to 10
−10
mol/L) in a nonrecirculating Langendorff setup demonstrated a significant increase in contractility over control values, whereas no change in contractility was observed when the hearts were perfused with neuropeptide Y (10
−7
mol/L). However, in the presence of both agonist and neuropeptide Y the increase in contractility previously seen with agonist alone was not evident. Comparisons made with hearts taken from aortic banded rats yielded similar results. Although neuropeptide Y itself was ineffective in decreasing contractility, it prevented the agonists from stimulating contractility when perfused together. We conclude that neuropeptide Y does not directly decrease contractility but prevents agonist-stimulated increases in contractility through α-/β-adrenoceptor pathways. This neuromodulatory effect of neuropeptide Y is unchanged in situations of increased sympathetic activity, such as hypertension.