bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Nitric Oxide in the Regulation of the Mechanical Properties of Peripheral Conduit Arteries in Humans
Authors: Joannides Robinson , Richard Vincent , Haefeli Walter E. , Benoist Agathe , Linder Lilly , Lüscher Thomas F. , Thuillez Christian
Published: June 2012

Abstract
Whether nitric oxide (NO) contributes to the regulation of the mechanical properties of large arteries in humans is not known. We measured the effect of local administration of the inhibitor of NO synthesis
N
G
-monomethyl-
l
-arginine (L-NMMA; 1 and 4 μmol · L
−1
· min
−1
for 5 minutes) and acetylcholine (3 and 30 nmol · L
−1
· min
−1
for 3 minutes) on radial artery diameter and wall thickness in 11 healthy volunteers using an echo-tracking system coupled to a measurement of radial blood flow (Doppler) and arterial pressure. At the highest dose, L-NMMA reduced radial blood flow but surprisingly decreased incremental elastic modulus (from 1.36±0.22 to 1.00±0.22 kPa · 10
3
;
P
<.05) and increased arterial compliance (from 3.20±0.46 to 4.07±0.45 m
2
· kPa · 10
−8
,
P
<.05), without affecting radial artery internal diameter, wall thickness or midwall stress, thus reflecting a decrease in vascular tone. Acetylcholine decreased incremental elastic modulus (from 1.27±0.08 to 0.88±0.07 kPa · 10
3
;
P
<.05) and increased arterial diameter, radial blood flow, and compliance (from 2.82±0.16 to 5.30±0.62 m
2
· kPa · 10
−8
;
P
<.05). These results demonstrate in vivo that NO is involved in the regulation of the mechanical properties of large arteries in humans. However, the effects of L-NMMA, ie, a decrease in arterial wall rigidity and an increase in arterial compliance, which occur in the absence of any changes in blood pressure or arterial geometry, suggest that inhibition of NO synthesis is associated in humans with a paradoxical isometric smooth muscle relaxation. This effect could be due to the development of compensatory vasodilating mechanisms after NO synthesis inhibition.
Estrogen Supplementation Decreases Norepinephrine-Induced Vasoconstriction and Total Body Norepinephrine Spillover in Perimenopausal Women
Authors: Sudhir Krishnankutty , Esler Murray D. , Jennings Garry L. , Komesaroff Paul A.
Published: June 2012

Abstract
Estrogens are reported to provide protection against the development of cardiovascular disease in women, but the mechanisms underlying these effects are not well defined. We hypothesized that estrogen might reduce neural cardiovascular tone. We therefore studied responses to exogenous norepinephrine and norepinephrine spillover in 12 perimenopausal women randomized to 8 weeks of estrogen supplementation (estradiol valerate, 2 mg daily, n=7) 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. Total body and forearm norepinephrine spillover were measured by radiotracer methodology. Forearm vasoconstrictor responses to norepinephrine (25, 50, and 100 ng/min) were attenuated after estrogen supplementation (
P
=.002). Vasoconstrictor responses to angiotensin II (8, 16, and 32 ng/min) were unchanged postestrogen. There was a significant reduction in total body spillover of norepinephrine after estrogen supplementation (pre-estrogen, 700±152; postestrogen, 439±150 ng/min;
P
<.05), but there was no change after placebo. Total body clearance and forearm spillover of norepinephrine were unchanged by either estrogen or placebo. Estrogen supplementation also significantly decreased both systolic and diastolic blood pressures. Therefore, estrogen supplementation in perimenopausal women selectively attenuates vasoconstrictor responses to norepinephrine and reduces total body norepinephrine spillover, which is an index of sympathetic neural activity.
Relation of Fasting Insulin to Blood Pressure and Lipids in Adolescents and Parents
Authors: Sinaiko Alan R. , Gomez-Marin Orlando , Prineas Ronald J.
Published: June 2012

Abstract
This study was intended to clarify the relation between fasting insulin, lipids, and blood pressure in adolescents before the onset of hypertension and to examine the association of these data with similar data obtained in their parents. The participants in this study were 183 adolescents 14 to 18 years old (96 girls) completing a 4-year intervention trial and their parents (164 mothers, 122 fathers). Blood pressure was measured twice on the right arm in a seated position using a random-zero sphygmomanometer. Fasting blood samples were obtained for lipid and insulin analyses. Fasting insulin was significantly correlated with systolic blood pressure in the adolescents and also in the parents before and after adjustment for body mass index. Fasting insulin was correlated significantly with levels of cholesterol, triglycerides, and HDL and LDL cholesterol in the adolescents. It was correlated only with triglycerides and HDL-cholesterol in mothers and fathers. After adjustment for body mass index, the correlations between fasting insulin and lipids in the children were not significant. A significant relation was shown between children’s systolic blood pressure and mothers’ fasting insulin and systolic blood pressure. Significant correlations were found between the children’s and fathers’ triglycerides and HDL-cholesterol, whereas significant correlations were found for fasting insulin and all lipids between mothers and children, and these remained significant after adjustment for body mass index. These results show (1) a significant relation between fasting insulin and both lipids and systolic blood pressure in adolescents and (2) a significant relation for these factors between adolescents and their parents. Although weight appears to play an important role in this relation during adolescence, genetic and environmental factors other than those mediated via weight may control insulin metabolism within families. The data support a role for studies during early biological development to address these issues.
Endothelium-Derived Hyperpolarizing Factor, But Not Nitric Oxide, Is Reversibly Inhibited by Brefeldin A
Authors: Bauersachs Johann , Fleming Ingrid , Scholz Dimitri , Popp Rüdiger , Busse Rudi
Published: June 2012

Abstract
The subcellular localization of the enzymes synthesizing endothelium-derived vasodilator autacoids has been proposed to play a role in determining the ability of endothelial cells to enhance autacoid production in response to stimulation. We therefore investigated the effects of brefeldin A–induced disruption of the Golgi apparatus and Golgi-plasma membrane trafficking on the production of nitric oxide (NO), prostacyclin, and the endothelium-derived hyperpolarizing factor (EDHF) by native and cultured endothelial cells. In porcine coronary artery segments, brefeldin A (35 μmol/L, 90 minutes) did not affect relaxations to sodium nitroprusside or the K
+
channel opener cromakalim but elicited a rightward shift in the concentration-response curve to bradykinin without altering the maximum vasodilator response (R
max
). Brefeldin A failed to attenuate the bradykinin-induced, NO-mediated relaxation under depolarizing conditions but inhibited the bradykinin response under conditions of combined cyclooxygenase/NO synthase blockade, suggesting that this agent selectively interferes with the production of EDHF. Indeed, incubation of porcine coronary arteries with brefeldin A, which did not affect the bradykinin-induced accumulation of either cyclic GMP or 6-keto-prostaglandin F
1α
, markedly and reversibly attenuated the EDHF-mediated hyperpolarization of detector smooth muscle cells in a patch-clamp bioassay system. The microtubule destabilizer nocodazole also affected both the EC
50
and R
max
to bradykinin in porcine coronary arteries. Since EDHF is thought to be a cytochrome P450–derived metabolite of arachidonic acid and both brefeldin A and nocodazole are known to interfere with the targeting of cytochrome P450 from the Golgi apparatus to the plasma membrane, it is conceivable that brefeldin A inhibits EDHF formation by preventing the targeting of the EDHF-synthesizing enzymes to the plasma membrane.
Lacidipine Restores Endothelium-Dependent Vasodilation in Essential Hypertensive Patients
Authors: Taddei Stefano , Virdis Agostino , Ghiadoni Lorenzo , Uleri Stefano , Magagna Armando , Salvetti Antonio
Published: June 2012

Abstract
Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to test whether antihypertensive treatment with the calcium antagonist lacidipine can improve endothelium-dependent vasodilation in essential hypertensive patients. In 12 normotensive subjects (mean age, 47.8±8.6 years; blood pressure, 118.6±4.2/76.7±3.9 mm Hg) and 19 hypertensive patients (mean age, 49.4±10.2 years; blood pressure; 153.5±13.3/101.3±6.4 mm Hg), we studied forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute) and bradykinin (5, 15, and 50 ng/100 mL per minute), two endothelium-dependent vasodilators that act through different receptors and signal transduction pathways, and sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. In essential hypertensive patients, vascular reactivity was repeated during prolonged (8 weeks of oral treatment at 6 mg/d) lacidipine administration and 2 weeks after withdrawal of chronic (32-week) treatment. Hypertensive patients showed significantly (
P
<.01) blunted vasodilation in response to acetylcholine (vascular resistance, 31.5±4.9 to 7.6±2.4 SU) and bradykinin (vascular resistance, 32.3±5.8 to 8.5±3.0 SU) compared with control subjects (vascular resistance: acetylcholine, 24.3±3.9 to 3.7±1.2 SU; bradykinin, 24.7±0.4 to 4.1±1.3 SU), whereas the response to sodium nitroprusside was similar. After either 8 or 32 weeks of lacidipine treatment, the vasodilation in response to acetylcholine (30.6±7.7 to 5.7±1.5 and 34.3±6.6 to 5.9±1.9 SU, respectively) and bradykinin (31.3±7.2 to 6.4±1.6 and 33.7±5.4 to 6.1±1.5 SU, respectively), but not to sodium nitroprusside, proved to be significantly (
P
<.05) increased compared with baseline. In essential hypertensive patients, oral treatment with lacidipine increased forearm vasodilation in response to acetylcholine and bradykinin, suggesting that this drug can improve endothelial function in patients with essential hypertension.
Acute Effects of Blood Pressure Elevation on Insulin Clearance in Normotensive Healthy Subjects
Authors: O’Callaghan Christopher J. , Komersova Karla , Louis William J.
Published: June 2012

Abstract
—Reduced clearance of insulin from plasma contributes to the hyperinsulinemia associated with essential hypertension (EH); however, the association between impaired insulin clearance and EH remains unexplained. Whether elevated blood pressure (BP) affects insulin clearance is unknown; therefore, we used the hyperinsulinemic euglycemic clamp to determine the effects of BP elevation on insulin clearance and sensitivity in eight healthy volunteers. Placebo infusion increased mean BP by 2.6±1.6 mm Hg, which was significantly less than rises produced by phenylephrine, an α
1
-adrenoceptor agonist (+11±1.8 mm Hg,
P
<.05), or by angiotensin II (+13±1.3 mm Hg,
P
<.01). Although β-adrenoceptor stimulation with isoproterenol did not change mean BP (+3.6 mm Hg,
P
=NS), it significantly increased systolic pressure (+23±2.8 mm Hg versus +2.3±4.6 mm Hg with placebo
P
<.01). Insulin secretion (ie, C-peptide concentrations) was not affected by any of the treatments; however, phenylephrine significantly reduced the metabolic clearance rate of insulin (MCR
insulin
) (16.6±1.0 mL/kg per minute with placebo versus 13.6±0.7 mL/kg per minute with phenylephrine,
P
<.01) and thereby increased plasma insulin concentrations (66±5.1 μU/mL with placebo versus 79±4.1 μU/mL with phenylephrine,
P
<.05). Phenylephrine also increased glucose utilization (42±5.8 μmol/kg per minute during placebo versus 58±4.8 μmol/kg per minute during phenylephrine,
P
<.05); however, this was proportional to the increased insulin concentrations; therefore, insulin sensitivity was unchanged. MCR
insulin
and plasma insulin concentrations were not affected by angiotensin II; however, glucose utilization increased to 51±2.7 μmol/kg per minute (
P
<.01 versus placebo), indicating insulin sensitivity was increased. MCR
insulin
was unaffected by isoproterenol. Thus, α-adrenergic stimulation but not increased BP per se is a potent regulator of insulin clearance and plasma insulin concentrations.
Insulin, Sodium-Lithium Countertransport, and Microalbuminuria in Hypertensive Patients
Authors: Andronico Giuseppe , Ferrara Lidia , Mangano Mariateresa , Mulè Giuseppe , Cerasola Giovanni
Published: June 2012

Abstract
—Both microalbuminuria (>0.290 nmol/min [20 μg/min]) and high sodium-lithium countertransport (SLC) in diabetic or hypertensive humans are predictive of overt nephropathy and more aggressive cardiovascular complications, perhaps induced by insulin resistance. To analyze the relationships between microalbuminuria, SLC, microalbuminuria, and insulin in essential hypertension, we studied 90 hypertensive white patients, 25 of whom had microalbuminuria and 32 of whom were healthy. When urine sampling was completed for albuminuria determination, SLC was measured; all patients then underwent standard (75 g) oral glucose load to measure basal (0 minutes) and 2-hour glucose and insulin serum levels. Glucose-insulin ratio was used as insulin sensitivity index (ISI). In both hypertensive patients with normal microalbuminuria and those with pathological microalbuminuria, plasma insulin at 120 minutes was significantly higher than in control subjects. When the patients with pathological microalbuminuria were divided into thirds on the basis of their microalbuminuria, in the lower third, we found statistically significant less fasting insulin and higher basal ISI. SLC was higher in hypertensives than normotensives and, among hypertensives, higher in the subgroup with elevated microalbuminuria. In hypertensives, we found a weak but significant correlation between SLC and microalbuminuria, independent of insulin or ISI. The prevalence of high value of SLC (≥0.383 mmol · L
−1
· h
−1
) was significantly lower in hypertensives with normal rather than abnormal urinary albumin excretion. Our results indicate that in nondiabetic hypertensive whites, higher microalbuminuria is accompanied by signs of insulin resistance; moreover, a link exists between SLC and microalbuminuria, both predictive of aggressive complications of hypertension.
Insulin Resistance and Hypertension in Non-obese Africans in Tanzania
Authors: Mgonda Yasin M. , Ramaiya Kaushik L. , Swai Andrew B. M. , McLarty Donald G. , Alberti K. George M. M.
Published: June 2012

Abstract
—Insulin sensitivity was assessed using a glucose-insulin infusion test in 15 newly diagnosed non-obese hypertensive black Tanzanians with normal glucose tolerance and in 15 normotensive control subjects matched for age, sex, and body mass index. The steady-state blood glucose and metabolic clearance rate of glucose (MCR) were used as measures of insulin sensitivity. The mean MCR (glucose) was significantly reduced (7.12±0.57 versus 9.50±0.69 μmol/kg per minute;
P
<.05) and mean steady-state blood glucose was significantly elevated (5.0±0.3 versus 3.7±0.3 mmol/L;
P
<.01) in subjects with hypertension compared with the normotensive group. For all subjects there was a significant inverse correlation between MCR (glucose) and systolic (
P
=.003) and diastolic (
P
=.005) blood pressure; and a positive correlation was found between fasting serum insulin levels and systolic (
P
=.005) and diastolic (
P
=.004) blood pressure. These observations were independent of body mass index and serum lipid levels. These data indicate a strong association between insulin mediated glucose uptake and blood pressure in this population of normal weight untreated urban Africans.
Growth Factors and Mitogen-Activated Protein Kinases
Authors: Force Thomas , Bonventre Joseph V.
Published: June 2012

Mammalian cells respond to external stimuli by activation of a variety of signal transduction pathways, which culminate in stereotypical responses, such as proliferation, growth arrest, hypertrophy, differentiation, or apoptosis. In vertebrates the actions of many stimuli resulting in proliferative or hypertrophic growth converge on a set of cellular kinase cascades, which are collectively called the mitogen-activated protein (MAP) kinase cascades. These MAP kinases have been implicated in vascular smooth muscle cell proliferation and hypertrophy, responses that are central to the pathophysiology of hypertension. In this review, we will examine how proliferative and hypertrophic stimuli activate these MAP kinase cascades, what are the consequences of that activation on gene expression, and how do these signals drive the cell into one of the stereotypical responses noted above.
Strain-Responsive Regions in the Platelet-Derived Growth Factor-A Gene Promoter
Authors: Wilson Emily , Vives Franklin , Collins Tucker , Ives Harlan E.
Published: June 2012

Proliferation of cultured neonatal vascular smooth muscle (VSM) cells is enhanced by exposure to cyclic mechanical strain, in part through autocrine action of secreted platelet-derived growth factor (PDGF). We examined transcription factors and DNA response elements that may participate in the induction of PDGF-A gene transcription by mechanical strain. PDGF-A mRNA increased gradually over 4 to 24 hours exposure to cyclic (1Hz) strain. This was due, at least in part, to increased transcription since a full length (890bp) PDGF-A promoter reporter construct was induced 3.5-fold in transfected VSM cells exposed to strain for 24 hours. A series of PDGF-A promoter truncation reporter constructs was used to identify potential regions of the promoter involved in regulation by strain. Strain-responsive regions were found between -262bp and -92bp and between -92bp and -41bp of the promoter. Since these regions are GC-rich and contain response elements for Egr-1 and Sp-1, we examined expression of these transcription factors in response to strain. mRNA for both factors increased over 0.5 to 4 hours of strain, while protein expression for both increased gradually over a 24 hours period. Gel shift assays with a probe specific for Egr-1 demonstrated at least 1 prominent new shifted band after 4 to 12 hours exposure to strain. An Sp-1 probe demonstrated constitutive shifted bands that did not change in response to strain. Thus, GC-rich regions in the proximal 92bp of the PDGF-A promoter contain mechanical strain-responsive elements that bind Egr-1 and possibly Sp-1.
Interactions of Transforming Growth Factor-β and Angiotensin II in Renal Fibrosis
Authors: Border Wayne A. , Noble Nancy A.
Published: June 2012

Overproduction of transforming growth factor-β clearly underlies tissue fibrosis in numerous experimental and human diseases. Transforming growth factor-β’s powerful fibrogenic action results from simultaneous stimulation of matrix protein synthesis, inhibition of matrix degradation, and enhanced integrin expression that facilitates matrix assembly. In animals, overexpression of transforming growth factor-β by intravenous injection, transient gene transfer, or transgene insertion has shown that the kidney is highly susceptible to rapid fibrosis. The same seems true in human disease, where excessive transforming growth factor-β has been demonstrated in glomerulonephritis, diabetic nephropathy, and hypertensive glomerular injury. A possible explanation for the kidney’s particular susceptibility to fibrosis may be the recent discovery of biologically complex interactions between the renin-angiotensin system and transforming growth factor-β. Alterations in glomerular hemodynamics can activate both the renin-angiotensin system and transforming growth factor-β. Components of the renin-angiotensin system act to further stimulate production of transforming growth factor-β and plasminogen activator inhibitor leading to rapid matrix accumulation. In volume depletion, transforming growth factor-β is released from juxtaglomerular cells and may act synergistically with angiotensin II to accentuate vasoconstriction and acute renal failure. Interaction of the renin-angiotensin system and transforming growth factor-β has important clinical implications. The protective effect of inhibition of the renin-angiotensin system in experimental and human kidney diseases correlates closely with the suppression of transforming growth factor-β production. This suggests that transforming growth factor-β, in addition to blood pressure, should be a therapeutic target. Higher doses or different combinations of drugs that block the renin-angiotensin system or entirely new drug strategies may be needed to achieve a greater antifibrotic effect.
The Role of Eicosanoids in Angiotensin-Dependent Hypertension
Authors: Nasjletti Alberto
Published: June 2012

Many eicosanoids produced in vascular and renal structures are endowed with the ability to influence vascular and renal mechanisms of blood pressure regulation. Eicosanoids subserve both prohypertensive and antihypertensive mechanisms. The development of angiotensin-dependent hypertension in rats is accompanied by increased vascular production of thromboxane A
2
(TXA
2
) and of lipoxygenase-derived products with the ability to inhibit prostacyclin synthase. As a result of these abnormalities, the activity of pressor mechanisms mediated by TXA
2
and/or prostaglandin (PG) H
2
is increased. The cancellation of TXA
2
- and/or of PGH
2
-mediated pressor mechanisms, after treatment with thromboxane synthase inhibitors or TXA
2
/PGH
2
receptor blockers, lowers blood pressure in rats with angiotensin-dependent hypertension. Inhibitors of lipoxygenase also lower blood pressure in such animals, in part by decreasing the synthesis of lipoxygenase-derived inhibitors of prostacyclin synthase. Thus, the vasodepressor effect of these agents is accompanied by increased vascular formation of PGI
2
and can be prevented by cyclooxygenase inhibitors. Cyclooxygenase-derived eicosanoids, PGE
2
and PGI
2
, also subserve antihypertensive mechanisms in angiotensin-dependent models of hypertension. The level of blood pressure in such models of hypertension reflects, in part, the interplay among prohypertensive and antihypertensive functions subserved by cyclooxygenase- and lipoxygenase-derived eicosanoids.
Coordinate Expression of Cyclooxygenase-2 and Renin in the Rat Kidney in Renovascular Hypertension
Authors: Hartner Andrea , Goppelt-Struebe Margarete , Hilgers Karl F.
Published: June 2012

Prostaglandins contribute to the regulation of renin synthesis and secretion. We tested the hypothesis that the inducible isoform of prostaglandin G/H synthase, cyclooxygenase-2, contributes to the stimulation of renin synthesis in renovascular hypertension. The expression of cyclooxygenase-2 and renin was investigated in the kidneys of rats with two-kidney, one-clip renovascular hypertension or sham operation. Systolic blood pressure was increased 2 weeks after clipping (153±7 versus 112±4 mm Hg in controls, n=6 each,
P
<.05) and continued to rise until 4 weeks. Cyclooxygenase-2 mRNA levels were increased in clipped kidneys but remained unchanged or slightly decreased in nonclipped kidneys. Cyclooxygenase-2 protein was expressed mainly in the macula densa and occasionally in distal tubular cells not associated with the macula densa. Two weeks after clipping, the percentage of juxtaglomerular apparatus staining positive for cyclooxygenase-2 was 27.8±3.6 in clipped kidneys, 3.1±0.4 in contralateral kidneys, and 8.0±1.3 in controls; the percentages for immunoreactive renin staining in the afferent arteriole were 33.6±2 in clipped kidneys, 1.9±0.5 in contralateral kidneys, and 12.4±4.0 in controls, respectively. Similar parallel changes in renin and cyclooxygenase-2 staining were observed 4 weeks after clipping. The percentage of cyclooxygenase-2-positive juxtaglomerular apparatus correlated positively with the percentage that was renin positive (r=0.78,
P
<.05). Double immunostaining showed coexpression of cyclooxygenase-2 and renin protein in the same juxtaglomerular apparatus. Our data are consistent with a role for macula densa cyclooxygenase-2 in the regulation of renin in renovascular hypertension.
Evolution of Chronic Nitric Oxide Inhibition Hypertension
Authors: Qiu Changbin , Muchant Dianne , Beierwaltes William H. , Racusen Lorraine , Baylis Chris
Published: June 2012

Abstract
—We conducted longitudinal measurements of blood pressure and renal function in the conscious, chronically catheterized rat before and during acute nitric oxide synthase inhibition (
N
-nitro-
l
-arginine methylester [L-NAME], 37 μmol/kg IV) and then chronic administration of oral L-NAME (≈37 μmol/kg per 24 hours). These studies specifically investigate the impact on plasma and renal renin as well as volume status during the evolution of this hypertension in rats not subjected to acute experimental stress. Blood pressure progressively increased with chronic administration of L-NAME and reached values greatly above those seen with acute administration of L-NAME. There were parallel increases in renal vascular resistance and development of proteinuria, and glomerular filtration rate began to decline at day 21, coincident with the appearance of renal damage. Twenty-four-hour urinary nitrite and nitrate excretion remained depressed, reflecting reduced nitric oxide synthesis. The plasma renin activity was variable and only increased transiently at 21 days, thus the angiotensin II dependence of this hypertension is not caused by stimulated plasma renin activity. Despite severe hypertension, sodium intake and excretion were unchanged over the 21 days of L-NAME administration. Plasma volume was significantly reduced at days 2 and 12 of L-NAME administration; thus the prolonged plasma volume contraction must result from the acute natriuretic response to the initial acute L-NAME administration.
Lysophosphatidylcholine Stimulates MAP Kinase Activity in Rat Vascular Smooth Muscle Cells
Authors: Yamakawa Tadashi , Eguchi Satoru , Yamakawa Yuko , Motley Evangeline D. , Numaguchi Kotaro , Utsunomiya Hirotoshi , Inagami Tadashi
Published: June 2012

Lysophosphatidylcholine (lyso-PC) has been implicated in atherogenesis and the inflammatory process. Although lyso-PC has been reported to contribute to the mitogenic effect of oxidized LDL on rat cultured vascular smooth muscle cells (VSMCs), the signaling mechanisms by which lyso-PC promotes its proliferation are poorly characterized. Mitogen-activated protein (MAP) kinases are important mediators involved in the intracellular network of interacting proteins that transduces extracellular cues to intracellular responses. We therefore examined the effect of lyso-PC on MAP kinase activation, proto-oncogene expression, and AP-1 binding activity using cultured rat VSMC. Marked activation of MAP kinase occurred within 10 minutes of lyso-PC treatment, whereupon rapid inactivation ensued. MAP kinase activation by lyso-PC was concentration-dependent (6.25 to 25 μmol/L). Pertussis toxin treatment did not affect lyso-PC-induced MAP kinase phosphorylation. Lyso-PC (25 μmol/L) also increased the mRNA expression of c-
fos
and c-
jun
genes. An electrophoretic mobility shift assay showed that AP-1 binding activity was enhanced by lyso-PC. To examine the upstream signaling of MAP kinase, we used several inhibitors on MAP kinase activation induced by lyso-PC. Although lyso-PC induced sustained increase in intracellular Ca
2+
concentration, EGTA had no effect on MAP kinase activation induced by lyso-PC. However, protein kinase C inhibitor GF109203X and downregulation of protein kinase C activity by prolonged treatment with phorbol ester inhibited lyso-PC-induced MAP kinase activation. These data suggest that lyso-PC transmits its mitogenic activity through a MAP kinase-AP-1 pathway, which exists downstream of its protein kinase C activation in VSMCs.
Na
+
/H
+
Exchange in Vascular Smooth Muscle Cells Is Controlled by GTP-Binding Proteins
Authors: Orlov Sergei N. , Aksentsev Sergei L. , Pokudin Nickolai I. , Tremblay Johanne , Hamet Pavel
Published: June 2012

This study examines the involvement of GTP-binding proteins (Gps) in the regulation of Na
+
/H
+
exchange and Ca
2+
influx, which are increased in vascular smooth muscle cells from spontaneously hypertensive rats. Gp activity was modulated by fluoride, GTPγS, GDPβS, and antisense oligodeoxynucleotides complementary to conserved regions of the α- and β-subunits of Gps (α-comm and β-comm, respectively). β-Adrenergic-induced G
s
-mediated cAMP production was used as a positive control to estimate the efficiency of these compounds. Na
+
/H
+
exchange, measured as ethylisopropyl amiloride-sensitive
22
Na influx, was activated by 5- to 6-fold by a 30-minute preincubation of cells with 10 mmol/L NaF with a
K
0.5
for NaF of _13 mmol/L. In contrast, no activation of
45
Ca influx was observed under preincubation of vascular smooth muscle cells with NaF in Ca
2+
-free medium, whereas at [Ca
2+
]
o
>0.5 mmol/L, simultaneous addition of
45
Ca and 10 mmol/L NaF led to sharply increased isotope uptake. NaF-induced
45
Ca influx did not reach saturation up to 3 mmol/L [Ca
2+
]
0
and 20 mmol/L NaF and was correlated with the formation of calcium-fluoride complexes measured by light scattering. GTPγS increased basal cAMP production and Na
+
/H
+
exchange, whereas GDPβS decreased isoproterenol-induced cAMP production and Na
+
/H
+
exchange, α-comm reduced whereas β-comm augmented isoproterenol-induced cAMP production by 70%. Both oligodeoxynucleotides decreased basal Na
+
/H
+
exchange by 40% to 50%. NaF-induced Na
+
/H
+
exchange was not sensitive to α-comm but was inhibited by 60% in β-comm-loaded cells. Neither basal nor NaF-induced
45
Ca uptake was affected by GTPγS, GDPβS, and the oligodeoxynucleotides. Our results show that
45
Ca uptake is activated by NaF in vascular smooth muscle cells by nonspecific accumulation of calcium-fluoride complexes and is not related to modification of Gps. On the contrary, the Na
+
/H
+
exchanger is controlled by Gps, and Gp β-subunits are involved in [Ca
2+
]
0
-independent activation of this carrier by NaF.
Dopamine-2 Receptor Blockade Potentiates the Renal Effects of Nitric Oxide Inhibition in Humans
Authors: Montanari Alberto , Tateo Enrico , Fasoli Elena , Donatini Anna , Cimolato Barbara , Perinotto Patrizia , Dall’Aglio Pierpaolo
Published: June 2012

In eight young healthy subjects on a 240 mM Na diet mean arterial pressure (MAP), renal hemodynamics and renal handling of Na and exogenous Li were measured at baseline and during acute nitric oxide (NO) inhibition with 90-minute infusion of 3.0μg/kg.min
−1
of N
G
-L-arginine methyl ester (L-NAME). The same experiment was repeated with infusion of 50μg/kg.min
−1
of DA
2
receptor blocker L-Sulpiride (L-SULP) alone and, finally, with simultaneous infusion of both L-NAME and L-SULP. L-SULP alone did not elicit any effect. L-NAME alone produced no changes in MAP from 0 to 45 minutes (P
1
) and a 6.6% increase at 45 to 90 minutes (P2) of infusion. Effective renal plasma flow (ERPF, PAH clearance) and glomerular filtration rate (GFR, inulin clearance) declined by 10.2% and 7.6%, respectively, in P
1
and by 15.3% and 11.5% in P
2
. Filtration Fraction (FF) rose by 4.2% in P
2
. Calculated renal vascular resistance (RVR) increased by 13.0% to 25.6%. Fractional excretion of Na (FENa) and Li (FELi) fell by 20.0% and by 16.0%, respectively, in P
1
and by 40.0% and 25.1% in P
2
. All these variations, except for MAP and GFR, were significantly greater during coinfusion of L-NAME and L-SULP. ERPF declined by 17.8% to 33.7%, FENa by 26.7% to 53.3%, FELi by 13.8% to 34.8%, while RVR rose by 22.5% to 59.1% and FF by 10.1% to 29.3%. The present data confirm that NO blockade with low-dose systemic infusion of L-NAME produces renal vasoconstriction, reduced GFR with slight increase in FF, and enhanced tubular Li, and Na reabsorption. Since increase in RVR and FF and decrease in FENa and FELi are markedly potentiated by the simultaneous infusion of DA
2
blocker L-SULP, which exerts no effects by itself, we suggest that DA interactions between DA system at the level of DA
2
receptors and basal NO production play a physiological role in the regulation of renal function in humans.
Neural and Hypotensive Effects of Angiotensin II Receptor Blockade
Authors: Rongen Gerard A. , Brooks Steven C. , Ando Shin-ichi , Dajani Hilmi R. , Abramson Beth L. , Floras John S.
Published: June 2012

Angiotensin II participates in the neural regulation of the heart and circulation at both central and peripheral sites. To explore the role of endogenous angiotensin II in blood pressure regulation, we conducted a randomized double-blind crossover trial in nine young healthy men (aged 33±3 [mean±SE] years) studied in the absence of salt restriction, comparing the effect of 1 week treatment with the angiotensin II receptor antagonist losartan (100 mg daily) against placebo with respect to the following variables, recorded during supine rest: intra-arterial blood pressure (BP), heart rate (HR), forearm vascular resistance and norepinephrine appearance rate, total body norepinephrine spillover, variability of BP and HR (spectral analysis), and baroreflex sensitivity for HR (gain of the transfer function from systolic BP to HR). Blood pressure was 119±7/66±4 mm Hg (systolic BP/diastolic BP) after 1 week of placebo and 112±6/61±3 mm Hg after 1 week of losartan (
P
<.05). Forearm vascular resistance tended to fall, from 42.3±6.9 U on placebo to 32.8±5.0 U with losartan treatment (
P
=.07). Losartan had no effect on HR (60±3 on placebo versus 59±2 beats per minute with losartan), total body norepinephrine spillover (3.0±0.8 versus 3.3±1.2 nmol/min), forearm norepinephrine appearance rate (3.8±1.1 versus 5.3±1.1 pmol/100 mL forearm tissue per minute), power in the high- or low-frequency components of the HR variability and BP variability spectra or on baroreflex sensitivity for HR. Endogenous angiotensin II contributes to the maintenance of supine BP in normal subjects, studied in the absence of sodium restriction. The fall in BP caused by losartan is accompanied by a resetting of the baroreflex regulation of HR and sympathetic outflow, but baroreflex sensitivity for heart rate is not altered. Therefore, the reduction in BP observed after short-term angiotensin type 1 receptor antagonism may be achieved through a direct effect on vascular tone rather than through a primary reduction in sympathetic outflow.
Calcitonin Gene-Related Peptide Is a Depressor in Subtotal Nephrectomy Hypertension
Authors: Supowit Scott C. , Zhao Huawei , Hallman Diane M. , DiPette Donald J.
Published: June 2012

We previously demonstrated that the neuronal expression of calcitonin gene-related peptide (CGRP), a potent vasodilator, is increased in deoxycorticosterone-salt-induced hypertension where it acts as a compensatory vasodilator to attenuate the elevated blood pressure. To determine whether CGRP is playing a similar role in subtotal nephrectomy-salt-induced hypertension, hypertension was induced in Sprague-Dawley rats (n=6) by subtotal nephrectomy and 1.0% saline drinking water. Control rats (n=6) were sham operated and given tap water to drink. CGRP
(8–37)
, a CGRP receptor antagonist, was used to assess the hemodynamic role of CGRP in this setting. CGRP mRNA and peptide levels in dorsal root ganglia were also determined. Three weeks after either protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. CGRP
(8–37)
(3.2 or 6.4×10
4
pmol/L in 0.1 mL saline) and vehicle were administered intravenously to all rats. Baseline mean arterial pressure was higher in the subtotal nephrectomized rats compared with the controls (173±5 versus 113±5 mm Hg,
P
<.001). Vehicle administration did not change mean arterial pressure in either group, and CGRP
(8–37)
administration did not alter mean arterial pressure in the normotensive group. In contrast, CGRP
(8–37)
administration to the subtotal nephrectomized rats rapidly increased the already elevated mean arterial pressure at both the 3.2×10
4
pmol/L dose (7.8±1.1 mm Hg,
P
<.05) and the 6.4×10
4
pmol/L dose (9.6±0.8 mm Hg,
P
<.01). CGRP mRNA and peptide levels in the dorsal root ganglia were not significantly different between the two groups. These data suggest that in subtotal nephrectomy-salt-induced hypertension, CGRP may play a compensatory depressor role in an attempt to lower the elevated blood pressure.
Role of the Adrenal Medullae in Male and Female DOCA-Salt Hypertensive Rats
Authors: Lange Darrell L. , Haywood Joseph R. , Hinojosa-Laborde Carmen
Published: June 2012

Female rats treated with deoxycorticosterone acetate (DOCA) and salt do not get as hypertensive as male DOCA-salt treated rats. The adrenal gland contributes to the development and maintenance of DOCA-salt hypertension in male rats. However, little is known about adrenal medullary function in DOCA-salt hypertensive female rats. This study tested the hypothesis that bilateral removal of the adrenal medullae would result in a greater fall in blood pressure in male DOCA-salt compared to female DOCA-salt rats. Five weeks after initiating DOCA-salt treatment, average 24 hour mean arterial pressure (MAP) in female rats was significantly attenuated compared to male rats (142±4 versus 168±6 mm Hg, respectively). Female DOCA-salt rats consumed significantly more saline per day than male DOCA-salt rats (22.3±1.8 versus 33.4±1.8 mL/100 grams body weight, respectively). Following adrenal medullectomy, DOCA-salt males experienced a significant decrease in MAP during the dark period after surgery (182±4 to 154±4 mm Hg) that was not observed in female DOCA-salt rats (150±6 to 135±3 mm Hg). In the following light period, MAP remained significantly decreased when compared to the light period before surgery in DOCA-salt male (171±4 to 156±4 mm Hg), while no effect was observed in DOCA-salt female rats. Adrenal medullectomy significantly increased heart rate (HR) in all groups for 12 days. Male sham and DOCA-salt rats had significantly higher catecholamine content in the adrenal medulla than female sham and DOCA-salt rats, respectively. These data suggest that the adrenal medullae contribute more to the maintenance of blood pressure in DOCA-salt hypertension in male rats than female rats.
Inhibition of Growth of Human Vascular Smooth Muscle Cells by Overexpression of p21 Gene Through Induction of Apoptosis
Authors: Matsushita Hidetsugu , Morishita Ryuichi , Kida Iwao , Aoki Motokuni , Hayashi Shin-ichiro , Tomita Naruya , Yamamoto Kei , Moriguchi Atsushi , Noda Asao , Kaneda Yasufumi , Higaki Jitsuo , Ogihara Toshio
Published: June 2012

The senescent cell-derived inhibitor (sdi)-1 protein (p21 product) has been identified as a downstream mediator of the tumor suppressor p53 in the regulation of cell cycle progression through a G1 phase checkpoint. Given the importance of cell cycle inhibition for the treatment of restenosis, in this study we focused on the function of p21 gene in inhibiting proliferation of vascular smooth muscle cells (VSMC). To test the hypothesis, we transfected human p21 gene into human aortic VSMC using hemagglutinating virus of Japan-liposome-mediated transfer. Initially, we examined the successful transfection of human p21 gene into VSMC. p21 protein was increased in VSMC transfected with p21 vector as compared with control vector. Accompanied by increased p21 protein, transfection of p21 vector resulted in a significant decrease in number of VSMC induced by 2% serum (
P
<.01). Although p21 has been reported to play an important role in the regulation of apoptosis in some cells, apoptosis mediated by p21 is still controversial. Therefore, we hypothesized that overexpression of p21 mediates apoptosis in human VSMC, in addition to the blockade of cell cycle progression. First, we assessed the concordance between morphologic analysis and apoptosis as determined by nuclear staining with Hoechst 33342. Cells transfected with p21 gene exhibited the characteristic features of cell shrinkage, membrane blebbing, and rounding that are typical of apoptotic death. Of greater interest, a significant increase in apoptotic cells was observed in VSMC transfected with p21 vector as compared with control vector (
P
<.01). These results were confirmed by the measurement of DNA fragmentation. Consistent with nuclear staining, DNA fragmentation in VSMC transfected with human p21 gene was significantly increased as compared with that in VSMC transfected with control vector (
P
<.05). To study the molecular mechanisms of apoptosis mediated by overexpression of p21 gene, the protein levels of bax, a promoter of apoptosis, and bcl-2, an inhibitor of apoptosis, were also measured by Western blotting. Overexpression of p21 gene significantly increased protein of bax (
P
<.05), whereas transfection of p21 gene did not alter bcl-2 protein. Importantly, the ratio of bax to bcl-2 was significantly increased in VSMC transfected with human p21 vector as compared with control vector (
P
<.05). Overall, these results demonstrated that inhibition of VSMC growth by overexpression of human p21 gene was accompanied by induction of apoptosis through an inappropriate increase in bax protein. These results suggest that regulation of cell cycle by p21 may be closely linked to programmed cell death/apoptosis in human VSMC.
Antihypertensive Treatment and the Responsiveness to Glutamate in Ventrolateral Medulla
Authors: Tsuchihashi Takuya , Kagiyama Shuntaro , Ohya Yusuke , Abe Isao , Fujishima Masatoshi
Published: June 2012

Abstract
—We have recently reported that the cardiovascular responses to excitatory amino acids are augmented in the rostral ventrolateral medulla of spontaneously hypertensive rats (SHR). In the present study, we investigated whether the responsiveness to excitatory amino acids would be normalized by antihypertensive treatment. Thus we treated 4-week-old SHR and age-matched Wistar-Kyoto (WKY) rats with either enalapril (25 mg/kg per day in drinking water) or vehicle for 8 weeks. At 12 weeks of age, systolic blood pressure in the untreated SHR (248±9 mm Hg) was significantly (
P
<.01) higher than that in the enalapril-treated SHR (140±4 mm Hg), untreated WKY rats (148±4 mm Hg), and enalapril-treated WKY rats (117±1 mm Hg). The pressor responses to
l
-glutamate (2 nmol) microinjected into the rostral ventrolateral medulla were similar in enalapril-treated and untreated SHR (40±5 and 47±3 mm Hg, respectively, NS), and these responses were significantly greater than that seen in the untreated WKY rats (24±2 mm Hg,
P
<.01). On the other hand, the pressor response to either
N
-methyl-
d
-aspartate, an ionotropic glutamate receptor agonist, or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid, a metabotropic glutamate receptor agonist, in the enalapril-treated SHR was slightly but significantly smaller than that in the untreated SHR but was still markedly greater than those in untreated and enalapril-treated WKY rats. These results suggest that the augmented responsiveness to excitatory amino acids in the rostral ventrolateral medulla of SHR may be at least partly genetically determined and cannot be normalized by the treatment with enalapril.
Linoleic Acid Induces Relaxation and Hyperpolarization of the Pig Coronary Artery
Authors: Pomposiello Silvia I. , Alva Magaly , Wilde Dixon W. , Carretero Oscar A.
Published: June 2012

Abstract
—Linoleic acid, a polyunsaturated C
18
fatty acid, is one of the major fatty acids in the coronary arterial wall. Although diets rich in linoleic acid reduce blood pressure and prevent coronary artery disease in both humans and animals, very little is known about its mechanism of action. We believed that its beneficial effects might be mediated by changes in vascular tone. We investigated whether linoleic acid induces relaxation of porcine coronary artery rings and the mechanism involved in this process. Linoleic acid and two of its metabolites, 13-hydroxyoctadecadienoic acid (13-HODE) and 13-hydroperoxyoctadecadienoic acid (13-HPODE), induced dose-dependent relaxation of prostaglandin (PG) F
2α
–precontracted rings that was not affected by indomethacin (10
−5
mol/L), a cyclooxygenase inhibitor, or cinnamyl-3,4-dihydroxy-α-cyanocinnamate (CDC; 10
−5
mol/L), a lipoxygenase inhibitor. Removal of endothelial cells had no effect on vasorelaxation, suggesting a direct effect on the vascular smooth muscle cells (VSMC). When rings were contracted with KCl, linoleic acid failed to induce relaxation. Although tetrabutylammonium (5×10
−3
mol/L), a nonselective K
+
channel blocker, slightly inhibited the relaxation caused by linoleic acid, glibenclamide (10
−6
mol/L), an ATP-sensitive K
+
channel blocker, and charybdotoxin (7.5×10
−8
mol/L) or tetraethylammonium (5×10
−3
mol/L), two different Ca
2+
-activated K
+
channel blockers, had no effect. However, relaxation was completely blocked by ouabain (5×10
−7
mol/L), a Na
+
/K
+
-ATPase inhibitor, or by a K
+
-free solution. In addition, linoleic acid (10
−6
mol/L) caused sustained hyperpolarization of porcine coronary VSMC (from -49.5±2.0 to -60.7±4.2 mV), which was also abolished by ouabain. We concluded that linoleic acid induces relaxation and hyperpolarization of porcine coronary VSMC via a mechanism that involves activation of the Na
+
/K
+
-ATPase pump.
Renal Changes Induced by Nitric Oxide and Prostaglandin Synthesis Reduction
Authors: Llinás Maria T. , González Juan D. , Rodríguez Francisca , Nava Eduardo , Taddei Stefano , Salazar F. Javier
Published: June 2012

Abstract
—The benefits of the simultaneous administration of low doses of a calcium antagonist and a converting enzyme inhibitor in the treatment of hypertension and renal vasoconstriction are well established. The objective of this study was to evaluate whether the administration of low doses of a calcium antagonist and a converting-enzyme inhibitor have beneficial effects in treating the renal alterations induced by the acute administration of a cyclooxygenase inhibitor when nitric oxide synthesis is reduced. These effects were examined in anesthetized dogs before and during an acute sodium load. It was found that the intrarenal infusion of meclofenamate (5 μg · kg
−1
· min
−1
), simultaneously with a low dose of
N
G
-nitro-
l
-arginine methyl ester (1 μg · kg
−1
· min
−1
), produced a 40% decrease of renal blood flow and glomerular filtration rate and a reduction in the renal excretory response to the sodium load. In a second group of dogs, intrarenal verapamil (0.5 μg · kg
−1
· min
−1
) was effective in blocking the effects of nitric oxide and prostaglandin synthesis inhibition on sodium excretion and glomerular filtration rate but did not modify the effects on renal blood flow. An intrarenal infusion of trandolapril (0.3 μg · kg
−1
· min
−1
) was effective in a third group of dogs in reducing the renal hemodynamic effects but not in preventing the antinatriuretic effect observed in the first group. Finally, in a fourth group, the simultaneous administration of verapamil and trandolapril was effective in treating all the renal changes induced by the cyclooxygenase inhibitor when nitric oxide synthesis was reduced. These results suggest that the combination of low doses of trandolapril and verapamil has additive effects in treating the renal vasoconstriction and antinatriuresis induced by the acute administration of a cyclooxygenase inhibitor, when nitric oxide synthesis is reduced.