bluuebunny/crossref_metadata_2025 huggingface dataset:
Tyrosine Kinase Signaling Pathways Modulate Angiotensin II–Induced Calcium ([Ca
2+
]
i
) Transients in Vascular Smooth Muscle Cells
Authors: Touyz R.M. , Schiffrin E.L.
Published: June 2012

Abstract
Tyrosine kinases have been implicated in vascular smooth muscle cell proliferation and contraction. Underlying mechanisms may involve Ca
2+
-dependent pathways. This study assesses relationships between angiotensin II (Ang II)–stimulated phospholipase C–mediated Ca
2+
transients and tyrosine kinase–dependent pathways in vascular smooth muscle cells. Intracellular free Ca
2+
concentration ([Ca
2+
]
i
) was measured in primary cultured unpassaged vascular smooth muscle cells derived from mesenteric resistance vessels of Wistar-Kyoto rats with the use of fura 2 methodology. [Ca
2+
]
i
effects of Ang II (1 nmol/L) were determined in vascular smooth muscle cells in which tyrosine kinase pathways were stimulated by insulin (70 μU/mL; 0.5 nmol/L), insulin-like growth factor-I (1 ng/mL; 0.13 nmol/L), or platelet-derived growth factor-BB (1 ng/mL; 0.04 nmol/L) and in cells in which tyrosine kinase was inhibited by specific inhibitors (1 μmol/L tyrphostin A-23 and genistein). Ang II elicited a rapid and transient [Ca
2+
]
i
response (from 94±8 to 239±5.8 nmol/L). Activation of the receptor tyrosine kinase by insulin, platelet-derived growth factor, and insulin-like growth factor-I significantly reduced (
P
<.01) Ang II–induced [Ca
2+
]
i
to 161±7, 189±3.7, and 183±5 nmol/L, respectively. In the presence of tyrphostin A-23 and genistein, Ang II–stimulated [Ca
2+
]
i
remained persistently elevated and failed to return to basal levels. Tyrphostin A-1, the inactive tyrphostin analogue, had no significant effect on Ang II–induced [Ca
2+
]
i.
This study demonstrates that activation of tyrosine kinase pathways reduces Ang II–elicited [Ca
2+
]
i
responses, whereas tyrosine kinase inhibition prevents [Ca
2+
]
i
recovery after agonist stimulation. Interaction between tyrosine kinase– and phospholipase C–dependent signaling pathways modulates vascular smooth muscle cell [Ca
2+
]
i
responses to Ang II.
Polymorphism of the Apolipoprotein E and Angiotensin-Converting Enzyme Genes in Japanese Subjects With Silent Myocardial Ischemia
Authors: Nakata Yukiko , Katsuya Tomohiro , Rakugi Hiromi , Takami Seiju , Ohishi Mitsuru , Kamino Kouzin , Higaki Jitsuo , Tabuchi Yoshikatsu , Kumahara Yuichi , Miki Tetsuro , Ogihara Toshio
Published: June 2012

Abstract
The apolipoprotein ε4 allele and homozygous deletion allele (
DD
) of the angiotensin-converting enzyme gene are reported to be associated with an increase in the incidence of ischemic heart disease. In this study, we examined whether the apolipoprotein ε4 genotype and angiotensin-converting enzyme/
DD
allele are associated with silent myocardial ischemia. We screened 3920 subjects undergoing general checkups who had no symptoms of ischemic heart disease. Seventy subjects (2%) showed ischemic ST-segment depression during the double two-step exercise test. One hundred and twenty control subjects without ischemic ST-segment depression were recruited from the same population and matched for sex, age, and blood pressure. We performed genotyping of the apolipoprotein E gene (ε2, ε3, and ε4) and angiotensin-converting enzyme gene (
I
and
D
) using polymerase chain reaction–restriction fragment length polymorphism and polymerase chain reaction, respectively. Allele frequency of ε4 of the apolipoprotein E gene was higher in the ischemic group (11%) than the nonischemic group (5%) (χ
2
=5.35,
P
<.05), but there was no significant association between the allele or the genotype frequency of the angiotensin-converting enzyme gene and the incidence of ischemic ST-segment depression. Furthermore, stepwise multiple regression analysis also revealed that total cholesterol level and ε4 genotype were predictors of ischemic change in the exercise tolerance test (χ
2
=12.8,
P
<.005,
R
2
=.051). These results suggest that the apolipoprotein ε4 allele is an independent genetic risk factor for silent myocardial ischemia in Japanese subjects.
Adrenomedullin Increases Inducible Nitric Oxide Synthase in Rat Vascular Smooth Muscle Cells Stimulated With Interleukin-1
Authors: Ikeda Uichi , Kanbe Toshiko , Shimada Kazuyuki
Published: June 2012

Abstract
We investigated the effects of adrenomedullin on nitric oxide synthesis by measuring the production of nitrite, a stable metabolite of nitric oxide, in cultured rat vascular smooth muscle cells. Incubation of cultures with interleukin-1β (10 ng/mL) for 24 hours caused a significant increase in nitrite generation. The interleukin-1β–induced nitrite production by vascular smooth muscle cells was significantly increased by adrenomedullin in a dose-dependent manner (10
−10
to 10
−6
mol/L). This effect of adrenomedullin was significantly inhibited in the presence of
N
G
-monomethyl-
l
-arginine. The adrenomedullin-induced nitrite production by interleukin-1β–stimulated cells was accompanied by increased inducible nitric oxide synthase mRNA accumulation. In the presence of the phosphodiesterase inhibitor isobutylmethylxanthine, interleukin-1β–induced nitrite accumulation was further increased, but the effect of adrenomedullin was not additive or synergistic. Adrenomedullin dose dependently increased intracellular cAMP levels of vascular smooth muscle cells. These results indicate that adrenomedullin augments nitric oxide synthesis in interleukin-1β–stimulated vascular smooth muscle cells, at least partially through a cAMP-dependent pathway.
Differential Contribution of Endothelial Function to Vascular Reactivity in Conduit and Resistance Arteries From Deoxycorticosterone-Salt Hypertensive Rats
Authors: White Richard M. , Rivera Carlos O. , Davison Cathy Bruner
Published: June 2012

Abstract
The purpose of these studies was to compare changes in conduit and resistance artery function in deoxycorticosterone-salt hypertensive rats. We hypothesized that if there was a common mechanism producing changes in vascular function in hypertension, then there would be similar alterations in reactivity of conduit and resistance arteries. Helically cut strips of common carotid artery were prepared for measurement of isometric force generation, and segments of small mesenteric arteries were pressurized for video dimension analysis. Sensitivity of arteries to phenylephrine and acetylcholine was determined. Carotid arteries from deoxycorticosterone-salt hypertensive rats were more sensitive to phenylephrine than arteries from control rats, whereas mesenteric resistance arteries from hypertensive rats were less sensitive to phenylephrine. In carotid arteries, endothelial denudation or incubation with
N
ω
-nitro-
l
-arginine increased phenylephrine sensitivity in control rats to the level seen in deoxycorticosterone-salt rats. These manipulations had no effect on phenylephrine sensitivity in arteries from deoxycorticosterone-salt rats. In mesenteric resistance arteries, endothelium denudation normalized the depressed phenylephrine sensitivity in arteries from hypertensive rats but had no effect on arteries from normotensive rats. This depressed phenylephrine sensitivity in deoxycorticosterone-salt mesenteric arteries was not reversed by incubation with
N
ω
-nitro-
l
-arginine. Acetylcholine-induced relaxation was depressed in carotid arteries from deoxycorticosterone-salt hypertensive rats, and
N
ω
-nitro-
l
-arginine blocked these relaxations. In contrast, acetylcholine relaxation in the mesenteric arteries from normotensive and hypertensive rats did not differ.
N
ω
-nitro-
l
-arginine slightly but significantly attenuated acetylcholine dilation only in mesenteric resistance arteries from the hypertensive rats. We conclude that qualitatively different changes in vasoconstrictor sensitivity to phenylephrine occur in carotid arteries and mesenteric resistance arteries of deoxycorticosterone-salt hypertensive rats. The increased phenylephrine sensitivity in carotid arteries in this model of hypertension is due to the loss of endothelium-derived nitric oxide production. In contrast, the decreased phenylephrine sensitivity in mesenteric resistance arteries from deoxycorticosterone-salt rats is due to a non–nitric oxide–mediated influence of the endothelium that is absent in arteries from normotensive rats.
Effect of Angiotensin II Receptor Blockade on Fibrinolysis During Acute Hyperinsulinemia in Patients With Essential Hypertension
Authors: Seljeflot Ingebjørg , Moan Andreas , Kjeldsen Sverre , Sandvik Endre , Arnesen Harald
Published: June 2012

Abstract
We performed the present study to investigate indirectly the in vivo effects of angiotensin II on fibrinolysis and catecholamines by treatment with losartan, a selective angiotensin II type 1 receptor antagonist. The effects were evaluated in basal conditions as well as in two different models of acute hyperinsulinemia physiologically induced by oral glucose ingestion and by a euglycemic glucose clamp technique. Twenty subjects with moderate hypertension were included in a randomized, double-blind, placebo-controlled crossover study of 4-week treatment periods. Plasma levels of catecholamines, tissue plasminogen activator activity and antigen, and plasminogen activator inhibitor type 1 activity and antigen were unchanged in the basal state after 4 weeks of treatment. During both models of hyperinsulinemia, plasminogen activator inhibitor activity and antigen decreased significantly (both
P
<.001), and tissue plasminogen activator activity increased significantly (
P
<.01). Norepinephrine did not change during any of the procedures, whereas epinephrine increased significantly after 3 hours of the oral glucose tolerance test. Changes from baseline did not differ between the treatment and placebo regimens during the hyperinsulinemic procedures with regard to either of the fibrinolytic variables or the catecholamines. In conclusion, we could not demonstrate any effects of 4 weeks of treatment with losartan on plasma levels of fibrinolytic variables or catecholamines either in basal conditions or during acute hyperinsulinemia. However, the present findings do not preclude more direct effects of angiotensin II or involvement of other receptor subtypes on fibrinolysis.
Effects of Insufficient Sleep on Blood Pressure Monitored by a New Multibiomedical Recorder
Authors: Tochikubo Osamu , Ikeda Akihiko , Miyajima Eiji , Ishii Masao
Published: June 2012

Abstract
Blood pressure varies in relation to factors such as physical activity, body position, ambient temperature, and autonomic nervous system activity. Therefore, we have developed a portable multibiomedical (PMB) recorder that monitors five parameters: indirect blood pressure, physical activity, body position, ambient temperature, and RR interval of the electrocardiogram. In the present study, we applied the PMB recorder over a 24-hour period to study the effect of insufficient sleep on blood pressure in subjects doing extensive overtime work. The parameters listed above were measured by the PMB recorder throughout a normal workday (mean period of sleep, 8 hours) and throughout a day with insufficient sleep (mean period of sleep, 3.6 hours) in 18 male technical workers aged 23 to 48 years old. Blood pressure (mean systolic/diastolic pressure±SD) significantly increased the day after a sleep-insufficient night (129±8/79±6 mm Hg) compared with the day after a normal night (123±8/76±7 mm Hg,
P
<.05). However, ambient temperature, mean number of steps per minute, and percentage of time spent in a standing position showed no significant difference between these days. Spectral analysis of RR intervals showed that the ratio of the low-frequency component on the RR power spectrum (0.05 to 0.15 Hz) to the high-frequency component (0.15 to 0.40 Hz) was higher on the sleep-insufficient day (2.17±0.37 versus 1.81±0.37), as was the urinary excretion of norepinephrine (
P
<.05). Heart rate was significantly higher on the sleep-insufficient day (81±11 versus 76±8 beats per minute), after the data of two subjects with abnormal levels of physical activity were excluded (
P
<.01). These data suggest that lack of sleep may increase sympathetic nervous system activity on the following day, leading to increased blood pressure. The PMB recorder was useful for precisely evaluating the relationship between blood pressure and environmental factors.
Bosentan Ameliorates Cyclosporin A–Induced Hypertension in Rats and Primates
Authors: Bartholomeusz Briony , Hardy Kenneth J. , Nelson Angela S. , Phillips Paddy A.
Published: June 2012

Abstract
Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134±1 to 122±3 mm Hg (
P
<.01) and in the cyclosporine-hypertensive marmosets from 156±2 to 139±4 mm Hg (
P
<.01). There were no differential effects on plasma creatinine concentration, endothelin concentration, or end-organ weights. Bosentan had no effect in the vehicle-treated rats. These data provide further evidence to support a role for endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness of endothelin receptor antagonism as a novel treatment in cyclosporine-induced hypertension.
High Sodium Sensitivity Implicates Nocturnal Hypertension in Essential Hypertension
Authors: Uzu Takashi , Kazembe Frida S. , Ishikawa Kazuhiko , Nakamura Satoko , Inenaga Takashi , Kimura Genjiro
Published: June 2012

We investigated the relationship between sodium sensitivity and diurnal variation of blood pressure in patients with essential hypertension. Twenty-eight inpatients with essential hypertension were maintained on high sodium (12 to 15 g NaCl per day) and low sodium (1 to 3 g NaCl per day) diets for 1 week each. Twenty-four-hour blood pressure and urinary sodium excretion were measured at the end of each diet period, and the sodium sensitivity index was calculated as the ratio of the change in mean arterial pressure to the change in urinary sodium excretion rate by sodium restriction. Patients whose average mean arterial pressure was lowered more than 10% by sodium restriction were assigned to the sodium-sensitive group (n=16); the remaining patients, whose mean arterial pressure was lowered by less than 10%, were assigned to the non-sodium-sensitive group (n=12). In the non-sodium-sensitive group, mean arterial pressure and heart rate fell during the nighttime, and average values of systolic, diastolic, and mean arterial pressures during the night were significantly lower than those during the day during both low and high sodium diets. On the other hand, in the sodium-sensitive group, there was no nocturnal fall in mean arterial pressure, and none of the systolic, diastolic, and mean arterial pressure values during the nighttime was different from the respective pressure values during the daytime during either sodium diet. The sodium sensitivity index was positively correlated with the fall in mean arterial pressure during the nighttime during a high sodium diet (
r
=.55,
P
<.01). These results indicate that in patients with sodium-sensitive essential hypertension, blood pressure fails to fall during the night. High sodium sensitivity may be a marker of greater risk of renal and cardiovascular complications, as has been found in nondippers, patients whose blood pressure fails to fall during the night.
Orthostatic Hypertension Due to Vascular Adrenergic Hypersensitivity
Authors: Benowitz Neal L. , Zevin Shoshana , Carlsen Sandra , Wright Janet , Schambelan Morris , Cheitlin Melvin
Published: June 2012

Autoregulatory mechanisms ensure relatively small fluctuations of blood pressure with postural changes in healthy people. Although orthostatic hypotension is well recognized and commonly encountered, there are only a few reports of orthostatic hypertension. Most of the reported cases of orthostatic hypertension were related to excessive venous pooling, with an initial drop in cardiac output followed by overcompensation with an excessive release of catecholamines, or to nephroptosis with orthostatic activation of the renin-angiotensin system. We describe a 44-year-old woman with normal supine blood pressure and severe orthostatic hypertension who did not demonstrate an initial decrease in cardiac output and had normal plasma and urinary catecholamines and renin release. Pharmacological tests of autonomic nervous system function showed an increased pressor sensitivity to norepinephrine (11 to 14 times normal), normal sensitivity to isoproterenol, diminished baroreceptor reflex sensitivity, and exquisite sensitivity to α-adrenergic blockers. This unusual case of orthostatic hypertension appears to be secondary to vascular adrenergic hypersensitivity.
Aberrant Adenylyl Cyclase/cAMP Signal Transduction and G Protein Levels in Platelets From Hypertensive Patients Improve With Antihypertensive Drug Therapy
Authors: Marcil Josée , Schiffrin Ernesto L. , Anand-Srivastava Madhu B.
Published: June 2012

We have previously demonstrated a decreased expression of G
i
α
2
protein in platelets from spontaneously hypertensive rats that was associated with an altered responsiveness of adenylyl cyclase to hormone stimulation and inhibition. In the present studies, we have used platelets from hypertensive patients and examined the hormonal regulation of adenylyl cyclase as well as the levels of G proteins and their modulation by antihypertensive drug therapy. We performed these studies in platelets from four groups of subjects: normotensive subjects (group 1), untreated mildly essential hypertensive patients (group 2), and treated moderately to severely hypertensive patients whose blood pressure was uncontrolled (group 3) or controlled with drug treatment (group 4). GTPγS, 5′-(
N
-ethylcarboxamido)adenosine (NECA), and prostaglandin E
1
stimulated adenylyl cyclase activity to a greater extent in hypertensive patients (group 2). This effect was partially corrected (by approximately 50% to 80%) in the patients under antihypertensive drug therapy (groups 3 and 4). In addition, inhibition of adenylyl cyclase mediated by a ring-deleted analogue of atrial natriuretic factor (C-ANF
4-23
) observed in control normotensive subjects was blunted in hypertensive patients (group 2) and was not corrected in treated patients. G
s
α
levels determined by immunoblotting were in the same range for the four groups, whereas G
i
α
2
and G
i
α
3
levels were decreased by 70% and 60%, respectively, in hypertensive patients (group 2) compared with normotensive subjects. Antihypertensive drug therapy (groups 3 and 4) partially restored G
i
α
2
levels toward normal (group 1) by about 60% and 70%, respectively; however, the reduced G
i
α
3
levels in group 2 hypertensive patients were not improved in group 3 but were raised toward normal levels in group 4 by about 55%. These results suggest that the altered responsiveness of platelet adenylyl cyclase to hormones in hypertension and the normalization of the response with antihypertensive drug therapy could partly be due to the ability of the latter to modulate G
i
α
protein expression. These effects on platelet function may underlie the beneficial effects of antihypertensive agents on some of the complications of hypertension.
Role of Nitric Oxide, Adenosine, and ATP-Sensitive Potassium Channels in Insulin-Induced Vasodilation
Authors: McKay Mary K. , Hester Robert L.
Published: June 2012

The resistance of various tissues to the vasodilator and metabolic effects of insulin may be an important risk factor in the genesis of hypertension observed in several pathological states. Because of this, it is important to understand the mechanisms by which insulin causes vasodilation. Because insulin is known to raise metabolism, one mechanism by which insulin causes vasodilation could be through metabolic vasodilation. Recently, however, it has been suggested that the insulin-induced vasodilation is mediated by the release of endothelium-derived nitric oxide. Using a model of muscle microcirculation (hamster cremaster), we examined the interactions between insulin, nitric oxide, and tissue metabolism to understand the potential mechanisms by which insulin causes vasodilation. Topical application of insulin (200 μU/mL) to the cremaster resulted in significant increases in arteriolar diameter. Second-order arteriolar diameter increased from 69.6±6 to 79.8±5 μm and fourth-order arteriolar diameter from 11.3±1 to 15.1±2 μm (n=8). During nitric oxide synthase inhibition, topical application of insulin caused significant vasodilation in both second- and fourth-order arterioles. In contrast, both adenosine receptor antagonism and blockade of ATP-sensitive potassium channels prevented insulin-induced increases in arteriolar diameter. Our findings suggest a role for increased tissue metabolism, particularly the metabolite adenosine, in mediating insulin-induced vasodilation.
Angiotensin II Increases Left Ventricular Mass Without Affecting Myosin Isoform mRNAs
Authors: Susic Dinko , Nuñez Eduardo , Frohlich Edward D. , Prakash Om
Published: June 2012

We studied the effect of chronic (7 days) angiotensin II (Ang II) infusion in nonpressor and pressor doses on cardiovascular mass and expression of α- and β-myosin heavy chain genes in the left ventricle in normotensive Wistar rats. An increased left ventricular mass was observed in rats receiving nonpressor and pressor doses of Ang II, but only high doses increased arterial pressure. Normalization of arterial pressure during Ang II infusion by losartan, a specific Ang II receptor antagonist, or hydralazine had different effects on left ventricular mass. Losartan prevented the increased left ventricular mass, and hydralazine did not affect left ventricular mass. Northern blot analysis showed that the switch in left ventricular myosin isoform mRNA from the adult to the fetal pattern occurred only in rats given the pressor Ang II dose. Both losartan and hydralazine, in parallel with the normalization of arterial pressure, prevented this myosin isoform switch. Thus, these data suggest that the Ang II-induced increase in left ventricular mass was not dependent on pressure overload, but the switch in myosin isoform mRNA from the adult to the fetal pattern was dependent on pressure overload.
Estrogen Enhances Basal Nitric Oxide Release in the Forearm Vasculature in Perimenopausal Women
Authors: Sudhir Krishnankutty , Jennings Garry L. , Funder John W. , Komesaroff Paul A.
Published: June 2012

The mechanisms of estrogen-induced cardiovascular protection are incompletely understood. Acute estrogen administration enhances acetylcholine-induced vasorelaxation, suggesting that endothelium-dependent factors may be important. The effect of long-term estrogen supplementation on endothelial function has not been well defined. In this double-blind, randomized study, we examined endothelial function in forearm resistance arteries in 11 perimenopausal women before and after 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=6) or placebo (n=5). Forearm blood flow was measured by venous-occlusion plethysmography, and vasoactive agents were infused through a brachial artery cannula in doses that did not influence blood pressure or heart rate. Estrogen supplementation significantly reduced systolic and diastolic pressures but had no effect on plasma lipoproteins. Estrogen did not alter the vasodilator responses to acetylcholine at doses of 9.25, 18.5, and 37 μg/min (rise in forearm blood flow before estrogen: 263±72%, 288±66%, and 383±84%, respectively; after estrogen: 205±34%, 260±44%, and 359±54%,
P
>.05.). Vasodilator responses to the endothelium-independent agent sodium nitroprusside (1.6 μg/min) were also unchanged after estrogen supplementation. However, estrogen enhanced vasoconstrictor responses to the nitric oxide synthase inhibitor
N
G
-monomethyl-
l
-arginine at doses of 1, 2, and 4 μmol/min (fall in forearm blood flow before estrogen: 13±9%, 20±7%, and 26±8%, respectively; after estrogen: 18±9%, 36±7%, and 47±7%,
P
=.04). Responses to vasoactive agents were unchanged after administration of placebo. Thus, in perimenopausal women, estrogen supplementation reduces blood pressure and enhances basal but not acetylcholine-induced nitric oxide release in forearm resistance arteries.
Neural Mechanism of Pressor Action of Nitric Oxide Synthase Inhibitor in Anesthetized Monkeys
Authors: Okamura Tomio , Ayajiki Kazuhide , Toda Noboru
Published: June 2012

Intravenous injection of
N
G
-nitro-
l
-arginine (L-NA), a nitric oxide synthase inhibitor, elevated mean blood pressure by 29.0±4.9 mm Hg and decreased heart rate by 40.7±5.6 beats per minute in anesthetized Japanese monkeys (n=6), whereas
N
G
-nitro-
d
-arginine was without effect. After pretreatment with pentolinium, the magnitude of the pressure elevation by L-NA was significantly less than that after pretreatment with phentolamine. The reduced blood pressure by either of the pretreatment drugs was compensated to control levels by a continuous infusion of angiotensin II before L-NA administration. Isolated monkey distal mesenteric arteries (150 to 200 μm OD) without endothelium responded to nerve stimulation by nicotine with a contraction, which was abolished by prazosin alone or in combination with α,β-methylene ATP. In the strips thus treated and contracted with prostaglandin F
2α
, nicotine caused a relaxation that L-NA abolished. L-NA but not
N
G
-nitro-
d
-arginine reversed the inhibition. Histochemical staining of NADPH diaphorase, considered to be identical to nitric oxide synthase in neuronal tissues, demonstrated that positively stained nerve fibers were consistently present in the adventitia of monkey distal mesenteric arteries and arterioles. These results strongly suggest that nitroxidergic vasodilator nerves innervate peripheral small arteries and arterioles in the monkey and that these nerves participate in the regulation of systemic blood pressure. High blood pressure caused by nitric oxide synthase inhibitors is associated with an elimination of nitroxidergic nerve function together with an impairment of the basal release of nitric oxide from the endothelium.
A Vascular Modulator, Hepatocyte Growth Factor, Is Associated With Systolic Pressure
Authors: Nakamura Yoshio , Morishita Ryuichi , Nakamura Shigefumi , Aoki Motokuni , Moriguchi Atsushi , Matsumoto Kunio , Nakamura Toshikazu , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

Endothelial cells are known to secrete various antiproliferative and vasodilating factors, such as nitric oxide and natriuretic peptides. The presence of endothelial dysfunction, well known in hypertensive individuals, potentially results in the development and progression of atherosclerosis. Therefore, it is important to know the factors that might influence endothelial cell growth. We examined the mitogenic actions of hepatocyte growth factor (HGF) on human endothelial and vascular smooth muscle cells. Exogenously added human recombinant HGF stimulated endothelial but not vascular smooth muscle cell growth in a dose-dependent manner. We also compared the mitogenic action of HGF with that of basic fibroblast growth factor and vascular endothelial growth factor. Interestingly, the mitogenic action of HGF on endothelial cells was greater than the actions of basic fibroblast growth factor and vascular endothelial growth factor, whereas basic fibroblast growth factor but not HGF and vascular endothelial growth factor stimulated vascular smooth muscle cell growth. Given the characteristics of HGF as an endothelium-specific growth factor, we evaluated the relationship of circulating HGF and blood pressure in normotensive and hypertensive subjects. Serum HGF concentration has been reported to be elevated in response to organ damage, such as in hepatitis and nephritis, and recent findings show that HGF may play an important role in tissue regeneration. We hypothesized that HGF might contribute to the protection or repair of vascular endothelial cells. If so, serum HGF level might be elevated in response to endothelial cell damage induced by hypertension. To test this hypothesis, we measured serum levels of HGF, lipoprotein(a), plasminogen activator inhibitor-1, tissue plasminogen activator, total cholesterol, and blood pressure in 41 normotensive and hypertensive subjects without liver, kidney, or lung damage. Serum HGF concentration was significantly correlated with systolic pressure (
P
<.01,
r
=.43) but not diastolic pressure. Serum HGF concentration in hypertensive subjects was significantly higher than in normotensive subjects. None of the other factors showed any correlation with blood pressure. We have demonstrated that HGF is an endothelium-specific growth factor whose serum concentration is significantly associated with systolic pressure. These results suggest that HGF secretion might be elevated in response to high blood pressure as a counterregulatory system against endothelial dysfunction.
Altered Lens Short-Circuit Current in Adult Cataract-Prone Dahl Hypertensive Rats
Authors: Rodríguez-Sargent Carmen , Estapé Estela S. , Fernández Nadia , Irizarry Jaime E. , Cangiano José L. , Candia Oscar A.
Published: June 2012

We assessed components of lenticular short-circuit current in adult hypertensive Dahl salt-sensitive rats (DS) during chronic control (0.4% sodium) versus high (3% sodium) dietary NaCl intake begun at the age of 4 weeks until rats were studied. We also evaluated the influence of barium, a potassium channel blocker, and ouabain, a specific inhibitor of Na
+
,K
+
-ATPase activity, by adding them to the anterior lens surface, thus measuring barium-sensitive, ouabain-sensitive, and barium- and ouabain-insensitive short-circuit currents. During control NaCl intake, short-circuit current in DS and their control group, Dahl salt-resistant rats (DR), did not differ significantly. DS were subclassified into cataract-prone rats and rats unlikely to develop cataracts on the basis of their initial pressor response to the change from a normal to high NaCl diet during the first weeks of age. Although only transparent lenses were studied, total lens short-circuit current was already markedly decreased in the cataract-prone subgroup compared with DS unlikely to develop cataracts and control DR. This was in sharp contrast to the increase in short-circuit current previously reported in Sprague-Dawley rats and now observed in control DR in response to high dietary NaCl. The decrease in lens short-circuit current in cataract-prone rats was associated with lower absolute values of barium- and ouabain-sensitive short-circuit currents as well as with low barium- and ouabain-insensitive short-circuit current. Although the barium- and ouabain-sensitive components of the short-circuit current were similar in DS unlikely to develop cataracts and DR, the barium- and ouabain-insensitive component of the short-circuit current was lower in DS unlikely to develop cataracts than values in DR. Interestingly, this component of lens short-circuit current also increased in DR during chronic high NaCl, whereas the opposite change occurred in cataract-prone DS and DS unlikely to develop cataracts. Thus, the barium- and ouabain-insensitive short-circuit current may be a mechanism that protects the normal lens from developing cataracts. Possible candidates for this short-circuit current component are voltage-dependent potassium channels, calcium-activated potassium channels, or both. Our studies show altered lens short-circuit current in response to high NaCl intake in cataract-prone DS and suggest the possibility of altered lens potassium transport during sustained hypertension but before loss of lens transparency.
Effects of an Angiotensin-Converting Enzyme Inhibitor, a Calcium Antagonist, and an Endothelin Receptor Antagonist on Renal Afferent Arteriolar Structure
Authors: Skov Karin , Fenger-Grøn Jesper , Mulvany Michael J.
Published: June 2012

Narrowed afferent arteriolar diameter in young, spontaneously hypertensive rats (SHR) may be a contributor to later development of high blood pressure. Thus, treatment that causes dilation of the afferent arterioles in SHR may inhibit the redevelopment of high blood pressure when treatment is withdrawn. We treated SHR with an ACE inhibitor (cilazapril, 5 to 10 mg/kg per day, high; 1 mg/kg per day, low), a calcium antagonist (mibefradil, 20 to 30 mg/kg per day), and an endothelin receptor antagonist (bosentan, 100 mg/kg per day) from age 4 to 20 weeks. Untreated SHR and Wistar-Kyoto rats were also investigated. At 20 weeks, the rats were killed, and morphology of the afferent arterioles was studied. Other SHR (untreated, high cilazapril, low cilazapril, mibefradil) were treated in exactly the same way and then followed to 32 weeks without treatment. The morphometric studies showed that cilazapril increased the lumen diameter in the afferent arterioles and decreased the media-lumen ratio in a dose-dependent manner. On withdrawal of cilazapril treatment, the reduction in blood pressure persisted. Mibefradil tended to increase afferent arteriolar diameter, whereas it did not alter media-lumen ratio. The persistent effect on blood pressure was only moderate after withdrawal of mibefradil. Bosentan had no effect on renal afferent arteriolar structure or blood pressure. In conclusion, cilazapril was more effective than mibefradil in altering afferent arteriolar structure and caused the most persistent effect on blood pressure after treatment withdrawal. The association of increased afferent arteriolar diameter and lower blood pressure level after withdrawal of treatment may suggest a pathogenic role for afferent arteriolar diameter in the development of high blood pressure in SHR.
Menopause Is Associated With Endothelial Dysfunction in Women
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Mattei Paola , Sudano Isabella , Bernini Gianpaolo , Pinto Stefania , Salvetti Antonio
Published: June 2012

To evaluate the effect of endogenous estrogens on endothelial function in humans, we examined whether menopause is associated with impairment in endothelium-dependent vasodilation in normotensive and essential hypertensive women. In 73 normotensive subjects (37 women, 36 men) and 73 hypertensive patients (36 women, 37 men), we studied endothelial function by measuring forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute), an endothelium-dependent vasodilator, and sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. Women younger than 45 years had normal menstrual cycles. In essential hypertensive patients, responses to acetylcholine but not to sodium nitroprusside were significantly (
P
<.001) reduced compared with responses in normotensive subjects. Moreover, in both groups, vasodilation to acetylcholine showed a marked negative correlation with advancing age (normotensive subjects:
r
=−.88,
P
<.001; hypertensive patients:
r
=−.87,
P
<.001). In contrast, vasodilation to sodium nitroprusside showed a less evident negative correlation with advancing age (normotensive subjects:
r
=−.46,
P
<.01; hypertensive patients:
r
=−.48,
P
<.01). However, in normally menstruating normotensive women, no endothelial dysfunction was observed, and age-related impairment in endothelium-dependent vasodilation was evident only after menopause. In normally menstruating hypertensive women, aging was associated with endothelial dysfunction although the deterioration of endothelium-dependent vasodilation was less marked than that in men. In contrast, after menopause, the age-related endothelial dysfunction in hypertensive women was similar to that observed in men. Finally, no sex-related difference in the response to sodium nitroprusside was observed in either normotensive subjects or essential hypertensive patients. Age-related endothelial dysfunction is attenuated in premenopausal normotensive and hypertensive women compared with men, whereas no sex-induced difference is observed after menopause, suggesting a protective effect of endogenous estrogens on endothelial function.
Arterial Compliance by Cuff Sphygmomanometer
Authors: Brinton Todd J. , Kailasam Mala T. , Wu Regina A. , Cervenka Justine H. , Chio Shiu-Shin , Parmer Robert J. , DeMaria Anthony N. , O'Connor Daniel T.
Published: June 2012

Abnormalities of the arterial pulse waveform reflect changes in cardiovascular structure and function. These abnormalities may occur early in the course of essential hypertension, even before the onset of blood pressure elevation. Previous studies of cardiovascular structure and function have relied on invasive intra-arterial cannulation to obtain the arterial pulse wave. We evaluated arterial structure and function using a noninvasive cuff sphygmomanometer in hypertensive (n=15) and normotensive (n=36) subjects stratified by genetic risk (family history) for hypertension. Using a simple physical model in which the aorta was assumed to be a T tube and the brachial artery a straight tube, we determined vascular compliance and peripheral resistance by analyzing the brachial artery pulsation signal from a cuff sphygmomanometer. Essential hypertensive subjects tended to have higher peripheral resistance (
P
=.06) and significantly lower vascular compliance (
P
=.001) than normotensive subjects. Vascular compliance correlated with simultaneously determined pulse pressure in both groups (n=51,
r
=.74,
P
<.0001). Higher peripheral resistance (
P
=.07) and lower vascular compliance (
P
=.04) were already found in still-normotensive offspring of hypertensive parents (ie, normotensive subjects with a positive family history of hypertension) than in normotensive subjects with a negative family history of hypertension. Multivariate analysis demonstrated that both genetic risk for hypertension (
P
=.030) and blood pressure status (
P
=.041), although not age (
P
=.207), were significant predictors of vascular compliance (multiple
R
=.47,
P
=.011). However, by two-way ANOVA, genetic risk for hypertension was an even more significant determinant (F=7.84,
P
=.007) of compliance than blood pressure status (F=2.69,
P
=.089). Antihypertensive therapy with angiotensin-converting enzyme inhibitors (10 days, n=10) improved vascular compliance (
P
=.02) and reduced resistance (
P
=.003) significantly; treatment with calcium channel antagonists (4 weeks, n=8) tended to improve vascular compliance (
P
=.07) and significantly reduced peripheral resistance (
P
=.006). We conclude that arterial vascular compliance abnormalities detected by a noninvasive cuff sphygmomanometer reflect treatment-reversible changes in vascular structure and function. Early changes in vascular compliance in still-normotensive individuals at genetic risk for hypertension may be a heritable pathogenetic feature of this disorder.
Increased Wall-Lumen Ratio of Mesenteric Vessels From the Spontaneously Hypertensive Rat Is Not Associated With Increased Contractility Under Isobaric Conditions
Authors: Izzard Ashley S. , Bund Stuart J. , Heagerty Anthony M.
Published: June 2012

We investigated the morphological (wall-lumen ratio) and contractile characteristics of distal mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls at a distending pressure of 63% of the mean aortic pressure of each rat using a pressure arteriograph. The wall-lumen ratios obtained were compared with those obtained at a pressure of 100 mm Hg. Experiments were carried out at 5 and 20 weeks. Mean aortic pressure of SHR was significantly increased at 5 weeks compared with that of WKY and was further increased by 20 weeks. At 63% of mean aortic pressure, no difference in the wall-lumen ratio of the arteries was observed between strains at 5 weeks; at 20 weeks, the wall-lumen ratio of SHR arteries was significantly increased compared that in WKY arteries. The wall-lumen ratio of SHR vessels did not differ at 63% mean aortic pressure compared with 100 mm Hg at either 5 or 20 weeks, whereas this parameter was significantly reduced in WKY vessels at 100 mm Hg compared with 63% mean aortic pressure at 5 and 20 weeks. In the presence of spontaneous myogenic tone, there was a borderline reduction in the lumen diameter of SHR vessels compared with WKY vessels and with increasing norepinephrine concentrations at 5 weeks. At 20 weeks, lumen diameter between strains did not differ in the presence of myogenic tone nor with increasing norepinephrine concentrations. Similar results were obtained when vessels from both rat strains were pressurized to 80 mm Hg. Thus, the increased wall-lumen ratio in the distal mesenteric arteries from adult SHR compared with those from WKY is not associated with an increased contractility under isobaric conditions when studied at physiological distending pressure.
Receptor-Mediated Intrarenal Angiotensin II Augmentation in Angiotensin II–Infused Rats
Authors: Zou Li-Xian , Imig John D. , Von Thun Annette M. , Hymel Anka , Ono Hidehiko , Navar L. Gabriel
Published: June 2012

Chronic low-dose angiotensin II (Ang II) infusion for 13 days mimics two-kidney, one clip Goldblatt hypertension and increases intrarenal Ang II levels. We performed studies to determine the time course for the enhancement of intrarenal Ang II levels and whether the increased intrarenal Ang II is a tissue-specific event and requires a receptor-mediated step. Male Sprague-Dawley rats were uninephrectomized, and either vehicle or Ang II (40 ng/min) was infused via a subcutaneous osmotic minipump. Plasma and renal Ang II levels were measured 3, 7, 10, and 13 days after minipump implantation. Compared with controls (126±2 mm Hg), systolic pressure in Ang II–infused rats exhibited a detectable increase by day 6 (146±2 mm Hg) and continued to increase to 189±5 mm Hg by day 12. Plasma Ang II levels were elevated by day 3, whereas intrarenal Ang II levels were not significantly elevated until 10 days of Ang II infusion. Renal injury characterized by focal and segmental glomerulosclerosis was evident after 13 days of Ang II infusion. Losartan (30 mg/kg per day) prevented the development of hypertension in the Ang II–infused rats for the duration of the infusion period (125±1 mm Hg) and reduced the degree of glomerular injury. Plasma renin activity was suppressed in the Ang II–infused group but was elevated markedly in both losartan-treated groups. Plasma Ang II levels were elevated in the Ang II–infused rats and were even higher during losartan treatment. Intrarenal Ang II levels were enhanced significantly (354±60 versus 164±23 fmol/g) in the Ang II–infused rats. However, losartan treatment prevented the augmentation of intrarenal Ang II caused by Ang II infusion. Heart and adrenal Ang II levels were not significantly increased in the Ang II–infused rats but were significantly elevated during losartan treatment. These results suggest that the tissue-specific elevations of intrarenal Ang II levels caused by chronic Ang II infusion are mediated by angiotensin type 1 receptor activation, which leads to either receptor-mediated internalization of Ang II, enhancement of intrarenal Ang II formation, or both.
Endothelial Modulation of Contractile Responses in Arteries From Hypertensive Rats
Authors: Dohi Yasuaki , Kojima Masayoshi , Sato Koichi
Published: June 2012

The endothelium plays an important role in the circulation by modulating contractile responses of vascular smooth muscle. We designed this study to investigate the alterations of endothelial modulation in hypertension. Rings of femoral arteries were prepared from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR), and changes in isometric tension were recorded. In rings with endothelium, norepinephrine (in either the presence or absence of yohimbine) evoked concentration-dependent contractions. Endothelium removal markedly enhanced the contraction; both the maximal response and sensitivity were increased, and these responses were less pronounced in SHR than WKY. In contrast to norepinephrine-induced contractions, the enhancement of prostaglandin F
2α
- or serotonin-induced contractions after endothelium removal was small and comparable in WKY and SHR; sensitivity was increased, but the maximal response was not.
N
ω
-Nitro-
l
-arginine methyl ester enhanced the contractions induced by these agonists in arteries with but not without endothelium and thereby abolished the enhancement of the contractions after endothelium removal. Thus, the endothelium plays an inhibitory role against contractions in rat femoral arteries by releasing nitric oxide, but the characteristics of the endothelial inhibition are not identical against various types of contractions. The negative endothelial modulation is more pronounced during α
1
-adrenoceptor–mediated contractions than during contractions mediated by other receptors. The inhibitory role of the endothelium against α
1
-adrenoceptor agonist–induced but not serotonin- or prostaglandin F
2α
–induced contraction is impaired in hypertension.
Upregulation of Nitric Oxide Synthase Correlates Temporally With Onset of Pulmonary Vascular Remodeling in the Hypoxic Rat
Authors: Xue Chun , Johns Roger A.
Published: June 2012

Alterations in nitric oxide signaling have been hypothesized to have an etiologic role in the development of hypoxic pulmonary hypertension. However, changes in the expression of nitric oxide synthase (NOS) in hypoxic lungs remains controversial. In this study, we used (1) Northern and Western analyses to measure NOS mRNA and protein expressions, (2) lung histology together with measurements of lung and heart weights to monitor pulmonary vascular remodeling, and (3) immunohistochemistry to localize NOS proteins. The data demonstrated that endothelial NOS mRNA and protein were upregulated over 1 to 7 days of hypoxia that temporally correlated with and preceded the vascular remodeling that occurred in the course of the development of hypoxic pulmonary hypertension. Hypoxia also induced brain NOS in bronchial epithelium and inducible NOS in vascular smooth muscle but did not affect inducible NOS expression in macrophages or basal guanylyl cyclase activity in the lung. These findings showed that upregulation of endothelial NOS was tightly correlated with the vascular remodeling induced by hypoxia, suggesting a role for nitric oxide in the development of pulmonary hypertension.