bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular Function in the Vitamin E–Deprived Rat
Authors: Davidge Sandra T. , Ojimba Jacqueline , McLaughlin Margaret K.
Published: June 2012

Abstract
—We tested the hypothesis that oxidative stress, mediated by dietary vitamin E deprivation, would alter vascular function through the interaction of oxygen-derived free radicals and nitric oxide (NO). This interaction may play an important role in the vascular pathophysiology of many diseases associated with oxidative stress. Mesenteric arteries from control (n=12) and vitamin E–deprived (n=12) Sprague-Dawley rats were studied with a myograph. Superoxide dismutase, which scavenges superoxide anions, produced a significantly greater relaxation in the arteries from the vitamin E–deprived rats compared with the controls (
P
<.05). Superoxide dismutase and catalase produced results similar to superoxide dismutase alone. Pretreatment with an NO synthase inhibitor eliminated the superoxide dismutase–induced relaxation in arteries from both control and vitamin E–deprived rats.
l
-Arginine induced a greater relaxation in arteries of the vitamin E–deprived group (
P
<.05). Agonist-induced relaxation with methacholine was not altered by superoxide dismutase for either group of animals, indicating that stimulated release of NO was not influenced by superoxide anions. With the use of Western immunoblot analysis, nitrotyrosine residues were shown to be present in arteries from both the vitamin E–deprived and control rats, but the amount of nitrotyrosine observed was not different between the two groups. In summary, our data indicate that there is a greater inhibition of NO caused by superoxide anions in the vitamin E–deprived group. We speculate that in conditions of oxidative stress (reduced vitamin E levels), altered vascular function may be due to increased destruction of NO by oxygen-derived free radicals.
Circadian Blood Pressure Variation in Hypertensive Patients With Primary Hyperaldosteronism
Authors: Mansoor George A. , White William B.
Published: June 2012

Abstract
—A less-than-normal decline in nocturnal blood pressure (BP) has been associated with excessive hypertensive complications. This is concerning because secondary hypertension is often associated with this so-called nondipper BP profile. A nondipping pattern is more frequently found in the presence of pheochromocytoma, Cushing’s syndrome, and sleep apnea syndrome, but the prevalence is unclear in patients with primary hyperaldosteronism. We therefore studied ambulatory BP profiles in 16 hypertensive patients with primary hyperaldosteronism and an equal number of essential hypertensive subjects. The awake−sleep BP difference of the hyperaldosteronism patients was similar to that of essential hypertensives (15/14±3/2 versus 14/9±3/2 mm Hg,
P
=NS). The prevalence of dippers and nondippers (according to two distinct criteria) in the two groups was similar. Repeat ambulatory BP monitoring in 12 subjects with primary hyperaldosteronism after specific intervention (3 after surgical removal of an adrenal adenoma and 9 after commencement and titration of spironolactone therapy) showed highly significant reductions in office BP (22/10±6/4 mm Hg,
P
<.05) and awake and sleep BP. However, the extent of nocturnal BP decline was unchanged between the two studies (17/16±3/3 versus 16/12±2/2 mm Hg,
P
=NS). There was no correlation between the awake−sleep difference and serum or urinary aldosterone levels or the aldosterone-to-renin ratio. In this study, we did not detect any differences in the awake−sleep differences between a group of hypertensives with primary hyperaldosteronism and a control group of essential hypertensives.
Streptozotocin-Induced Diabetes Enhances Cardiac Heparin-Releasable Lipoprotein Lipase Activity in Spontaneously Hypertensive Rats
Authors: Shepherd Greg , Cam Margaret C. , Sambandam Nandakumar , Abrahani Mohammed A. , Rodrigues Brian
Published: June 2012

Abstract
—Vascular endothelial-bound lipoprotein lipase (LPL), also known as heparin-releasable LPL, catalyzes the breakdown of the triglyceride component of lipoproteins and is rate-limiting for free fatty acid transport to tissues. We previously demonstrated that heparin-releasable LPL activity increases in diabetic Wistar rat hearts, whereas with the development of hypertension in spontaneously hypertensive rats (SHR), there is a concomitant and progressive reduction in LPL activity. The objective of the present study was to examine the regulation of cardiac LPL activity in SHR-diabetic rats. Heparin perfusion of the isolated Langendorff heart induced the release of LPL activity. SHR hearts demonstrated a reduction in peak heparin-releasable LPL activity, relative to Wistar controls. However, induction of streptozotocin-induced diabetes in SHR, as in Wistar rats, increased peak heparin-releasable LPL activity in perfused hearts. The elevated heparin-releasable LPL peak could not be accounted for by enhanced LPL synthesis in that both cellular and surface-bound LPL activities in myocytes from SHR-diabetic rats were low relative to control. Chronic (12-day) insulin treatment of SHR-diabetic rats reduced the augmented heparin-releasable LPL activity and increased cell-associated LPL activity. Moreover, acute (90-minute) treatment of SHR-diabetic rats with rapid-acting insulin also reduced the heparin-releasable LPL activity to normal, although it had no effect on the low cellular LPL activity. These results demonstrate that the diabetes-induced augmentation of cardiac LPL counteracts the reduction in enzyme activity associated with hypertension. This may serve to increase the delivery of free fatty acid to the heart, and the resultant metabolic changes may lead to the severe cardiomyopathy observed in the hypertensive-diabetic rat heart.
Perindopril Treatment Affects Both Preglomerular Renal Vascular Lumen Dimensions and In Vivo Responsiveness to Vasoconstrictors in Spontaneously Hypertensive Rats
Authors: Bergström Göran , Johansson Inger , Stevenson Kathleen M. , Kett Michelle M. , Anderson Warwick P.
Published: June 2012

Abstract
—We have previously shown that chronic treatment with angiotensin-converting enzyme inhibition (ACEI) did not reverse hypertrophy of the renal arterial wall in spontaneously hypertensive rats (SHR). In this study we determined the effects of perindopril on the functional properties of the renal vasculature in vivo and on its resistance to flow at maximal dilatation in vitro, a measure of vessel lumen diameter. Two groups of SHR were studied: untreated or treated with perindopril (3 mg/kg per day) in their drinking water from 4 weeks of age. At 10 weeks, (1) vessel lumen characteristics were assessed using a maximally dilated in vitro isolated kidney perfusion and (2) the renal vasoconstrictor responses to bolus doses of vasoactive agents (angiotensin II and phenylephrine) administered into the renal artery were measured in vivo (anesthetized rats). Mean arterial pressure was significantly lower in conscious SHR treated with perindopril (132±2 versus 97±2 mm Hg,
P
<.001). In vitro, the pressure-flow relationship and the pressure–glomerular filtration rate relationship were both shifted significantly to the left (
P
<.001). The perindopril-treated kidneys began filtering at a significantly lower threshold perfusion pressure than nontreated controls (
P
<.001). In vivo, renal vasoconstrictor responses to increasing doses of both vasoconstrictor agents were significantly less marked in the perindopril-treated SHR than in untreated SHR (
P
<.05). Thus, chronic ACEI increased average renal vessel lumen diameter in SHR, predominantly in preglomerular vessels, and reduced renal vasoconstrictor responsiveness in vivo, findings compatible with remodeling of the preglomerular vasculature around a greater lumen.
Increased Glucocorticoid Activity in Men With Cardiovascular Risk Factors
Authors: Walker Brian R. , Phillips David I.W. , Noon Joseph P. , Panarelli Maurizio , Andrew Ruth , Edwards Hugh V. , Holton David W. , Seckl Jonathan R. , Webb David J. , Watt Graham C. M.
Published: June 2012

Abstract
—The association between hypertension and insulin resistance might be explained by increased activity of the principal glucocorticoid, cortisol. Recent data show that the intensity of dermal vasoconstriction after topical application of glucocorticoids is increased in patients with essential hypertension. In this report, we examine whether increased glucocorticoid sensitivity or secretion is associated with insulin resistance and is a cause or consequence of hypertension. We studied 32 men (aged 47 to 56 years) from a cross-sectional study and 105 men (aged 23 to 33 years) in whom predisposition to high blood pressure has been defined by their own blood pressure and the blood pressures of their parents. In both populations, increased dermal glucocorticoid sensitivity was associated with relative hypertension, insulin resistance, and hyperglycemia. In young men with higher blood pressure whose parents also had high blood pressure, enhanced glucocorticoid sensitivity was accompanied by enhanced secretion of cortisol, enhanced ligand-binding affinities for dexamethasone in leukocytes, and impaired conversion of cortisol to inactive metabolites (cortisone and 5β-dihydrocortisol). Increased tissue sensitivity to cortisol, amplified by enhanced secretion of cortisol, is a feature of the familial predisposition to high blood pressure rather than a secondary effect of high blood pressure. It may be mediated by an abnormal glucocorticoid receptor, and it may contribute to the association between hypertension and insulin resistance.
Chronic AT
1
Receptor Blockade Alters Aortic Nerve Activity in Hypertension
Authors: Santos Claudia M. dos , Moreira Edson D. , Krieger Eduardo M. , Michelini Lisete C.
Published: June 2012

Abstract
—In the chronic phase of coarctation hypertension (CH) we have shown both reduction in baroreceptor sensitivity (
Hypertension
. 1992;19[suppl II]:II-198–II-201.) and normalization of the depressed baroreceptor reflex control of heart rate, even with the persistence of hypertension in losartan-treated animals (
Am J Physiol
. 1995;269:H812-H818). In the present study we analyzed the effects of angiotensin II blockade on afferent aortic nerve activity of CH and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day PO). CH was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 8 days (4 control and 4 experimental days). Aortic pressure (conscious rats) and aortic nerve activity simultaneous to pressure (anesthetized rats) were recorded on the fourth day of the experimental period. Losartan-treated rats showed reduced tail pressure (104±3 versus 117±3 mm Hg in the vehicle group). In both groups, aortic coarctation caused a significant increase in pressure (25% and 28%, respectively) and a depression of the aortic nerve activity/pressure relationship when compared with sham-operated coarcted animals. In the physiological range of pressure changes, the depression was significantly smaller after losartan treatment (3.30±0.33 versus 2.18±0.37%/mm Hg in the losartan- and vehicle-treated CH groups, respectively, versus 5.05±0.33%/mm Hg in the sham-operated vehicle-treated group). Angiotensin type 1 (AT
1
) receptor blockade was also accompanied by reduced variability of the afferent discharge. The data suggested that apart from its pressure effect, angiotensin II acts at AT
1
receptors to decrease the sensitivity of aortic afferents during physiological (±10 mm Hg) increases and decreases in pressure. Thus, angiotensin II may contribute to reductions of baroreceptor gain in chronic hypertension.
Transforming Growth Factor-β and Receptor Tyrosine Kinase–Activating Growth Factors Negatively Regulate Collagen Genes in Smooth Muscle of Hypertensive Rats
Authors: Bray Paula , Agrotis Alex , Bobik Alex
Published: June 2012

Abstract
—Previous studies have suggested that differences in vascular smooth muscle cell (VSMC) proliferative responses between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats can be attributed to transforming growth factor-β (TGF-β) actions. Because vascular collagen content is reported to be lower in SHR than in WKY rats, in this study we investigated in cell culture whether the differences in collagen content might also be attributed to differential actions of TGF-β on VSMCs from the two strains. Exposure of VSMCs from WKY to the TGF-β isoforms -β
1
, -β
2
, or -β
3
induced rapid, transient elevations in mRNAs encoding collagens α
1
(I), α
2
(I), and α
1
(III); maximum increases were apparent by 2 hours and ranged from twofold [collagen α
1
(III)] to ninefold [collagen α
1
(I)]. Thereafter they returned to near basal levels. When VSMCs from SHR were exposed to these TGF-β isoforms, only reductions in collagen mRNA levels were observed, persisting for 24 hours. Basic fibroblast growth factor and epidermal growth factor, factors known to stimulate production of the TGF-β
1
isoform in VSMCs, also induced a pattern of gene responses similar to those induced by the TGF-β isoforms in VSMCs from SHR and WKY rats. The simultaneous presence of TGF-β did not affect the time course or magnitude of the changes in collagens α
1
(I), α
2
(I), or α
1
(III) mRNA levels in SHR or WKY VSMCs. Examination of the induction of c
-myc
mRNA and immunoreactive oncoprotein content indicated that c-
myc
is a likely contributor to the downregulation of the collagen gene activity in both SHR and WKY VSMCs despite the differential regulation of its mRNA by TGF-β
1
in the two VSMC lines. Together these data suggest that in VSMCs from SHR, a number of gene responses to TGF-β, in addition to cell proliferation, appear to be abnormal compared with WKY rats, and the lower than normal collagen levels observed in the vasculature of SHR may be in part due to abnormalities in TGF-β responsiveness.
Kallikrein Gene Delivery Attenuates Hypertension and Cardiac Hypertrophy and Enhances Renal Function in Goldblatt Hypertensive Rats
Authors: Yayama Katsutoshi , Wang Cindy , Chao Lee , Chao Julie
Published: June 2012

Abstract
—To demonstrate potential therapeutic effects of kallikrein gene delivery, we delivered adenovirus (Ad.CMV-cHK) carrying the human tissue kallikrein gene into two-kidney, one-clip Goldblatt hypertensive rats. A single intravenous injection of the recombinant adenovirus caused a delay of blood pressure increase that began 1 day after injection and continued for 24 days. A maximal blood pressure reduction was observed in rats receiving kallikrein gene delivery compared with control rats receiving Ad.CMV-LacZ (160±5 versus 186±7 mm Hg, n=6,
P
<.01). The expression of human tissue kallikrein mRNA was identified in the kidney, heart, aorta, and liver of rats receiving kallikrein gene delivery. Immunoreactive human kallikrein levels were measured in rat serum and urine in a time-dependent manner. Adenovirus-mediated kallikrein gene delivery caused a significant reduction in the left ventricular mass and cardiomyocyte size, as well as an increase in renal blood flow, urine flow, glomerular filtration rates, electrolyte output, and urine excretion. Enhanced renal responses were accompanied by significant increases in urinary kinin, nitrite/nitrate, and cyclic GMP levels. These findings show that the expression of human tissue kallikrein via gene delivery has protective effects against renovascular hypertension and cardiovascular and renal dysfunction.
Cerebral Blood Flow in Hypertensive Patients
Authors: Jennings J. Richard , Muldoon Matthew F. , Ryan Christopher M. , Mintun Mark A. , Meltzer Carolyn C. , Townsend David W. , Sutton-Tyrrell Kim , Shapiro Alvin P. , Manuck Stephen B.
Published: June 2012

Abstract
—We asked whether the altered cerebral vasculature associated with essential hypertension might dampen or redirect the regional cerebral blood flow (rCBF) response to cognitive work. Relative rCBF was assessed with [
15
O]water positron emission tomography during a working memory task, a memory span task, and two perceptual control tasks. Unmedicated hypertensive patients and control subjects differed in rCBF response during both memory tasks. Hypertensives showed relatively diminished rCBF responses in right hemisphere areas combined with compensatory activation of homologous areas in the left cerebral cortex. Essential hypertension appears to selectively influence the circulatory reserve of portions of cerebral cortex and secondarily induce recruitment of other cortical areas to process certain tasks.
Racial Differences in Nitric Oxide–Mediated Vasodilator Response to Mental Stress in the Forearm Circulation
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Cannon Richard O. , Panza Julio A.
Published: June 2012

Abstract
—An abnormal hemodynamic response to stressful stimuli has been proposed as a mechanism involved in the higher prevalence of hypertension in blacks. Given the important role of nitric oxide (NO) in the regulation of cardiovascular homeostasis, we investigated the possibility of racial differences in vascular NO activity during mental stress. To test this hypothesis, we compared the forearm blood flow (FBF) response to mental stress in 14 white and 12 black healthy subjects during intra-arterial infusion of either saline or NO synthesis inhibitor
N
G
-monomethyl-
l
-arginine (L-NMMA; 4 μmol/min). We also examined vascular responses of the two groups to intra-arterial infusion of sodium nitroprusside (0.8 to 3.2 μg/min), an exogenous NO donor. During saline infusion, the increase in FBF from baseline induced by mental stress was significantly higher in whites than in blacks (109±20% versus 58±8%;
P
=0.03). L-NMMA significantly reduced stress-induced increase in FBF in whites (from 109±20% to 54±11%;
P
=0.004) but not in blacks (from 58±8% to 42±10%;
P
=0.24); thus, the vasodilator effect of stress testing during L-NMMA was similar in whites and blacks (54±11% versus 42±10%;
P
=0.44). The vasodilator response to sodium nitroprusside was also lower in blacks than in whites (maximum flow, 6.9±2 versus 11.6±3.5 mL · min
−1
· dL
−1
;
P
=0.001) and was not significantly modified by L-NMMA in either group. Our findings indicate that blacks have a reduced NO-dependent vasodilator activity during mental stress. This difference seems related to reduced sensitivity of smooth muscle to the vasodilator effect of NO and may play some role in the increased prevalence of hypertension and its complications in blacks.
Upregulation of Renal and Vascular Nitric Oxide Synthase in Young Spontaneously Hypertensive Rats
Authors: Vaziri Nosratola D. , Ni Zhenmin , Oveisi Fariba
Published: June 2012

Abstract
—The available data on the role of the
l
-arginine/nitric oxide (NO) pathway in the genesis of hypertension in spontaneously hypertensive rats (SHR) are limited and contradictory. In an attempt to address this issue, male SHR were studied during the early phase of evolution of hypertension (age 8 to 12 weeks) to distinguish the primary changes of NO metabolism from those caused by advanced hypertension, vasculopathy, and aging late in the course of the disease. A group of age-matched male Wistar-Kyoto rats (WKY) served as controls. The SHR exhibited a marked rise in arterial blood pressure and a significant increase in urinary excretion and plasma concentration of NO metabolites (nitrite/nitrate [NOx]). Likewise, the SHR showed a significant elevation of thoracic aorta NO synthase (NOS) activity coupled with significant increases of kidney, aorta, inducible NOS (iNOS), and endothelial NOS (eNOS) proteins. In an attempt to determine whether the enhanced
l
-arginine/NO pathway is a consequence of hypertension, studies were repeated using 3-week-old animals before the onset of hypertension. The study revealed significant increases in urinary NOx excretion as well as vascular eNOS and renal iNOS proteins. In conclusion, the
l
-arginine/NO pathway is upregulated in young SHR both before and after the onset of hypertension. Thus, development of hypertension is not due to a primary impairment of NO production in SHR. On the contrary, NO production is increased in young SHR both before and after the onset of hypertension.
Dose-Related Efficacy of Irbesartan for Hypertension
Authors: Reeves Richard A. , Lin Chen-Sheng , Kassler-Taub Kenneth , Pouleur Hubert
Published: June 2012

Abstract
—Results of eight multicenter, randomized, placebo-controlled, double-blind, parallel-group studies were pooled to assess the efficacy of the angiotensin II–receptor blocker irbesartan over the dose range of 1 to 900 mg. A total of 2955 adults with a seated diastolic blood pressure of 95 to 110 mm Hg were randomized to treatment with oral irbesartan once daily or placebo for 6 to 8 weeks. Office blood pressure was measured at trough (24±3 hours after the last dose) and peak (3±1 hours after the last dose) by mercury sphygmomanometry. Demographic characteristics (mean blood pressure; 151/101 mm Hg; mean age, 54 years; 63% male; and 82% white) were similar across all dose groups. After the groups were pooled, antihypertensive efficacy was assessed by therapeutic response (trough seated diastolic blood pressure <90 mm Hg or a reduction from baseline of ≥10 mm Hg) and by modeling of the maximum reductions in trough and peak seated diastolic and systolic blood pressure. Antihypertensive effects increased with increasing doses and reached a plateau at ≥300 mg. Irbesartan 150 mg provided placebo-subtracted reductions in trough seated systolic and diastolic blood pressure of ≈8 and ≈5 mm Hg, respectively, with 56% of patients displaying a favorable response. In conclusion, irbesartan provides clinically significant blood pressure lowering, with a clear relationship between (log) dose and antihypertensive effect.
Resistance to Endotoxin Shock in Spontaneously Hypertensive Rats
Authors: Bernard Catherine , Merval Régine , Esposito Bruno , Tedgui Alain
Published: June 2012

Abstract
—Septic shock involves systemic vasodilation mediated by proinflammatory cytokines. In essential hypertension, vascular and immune dysfunctions are closely associated. The response of hypertensive animals compared with normotensive controls to endotoxin (lipopolysaccharide; LPS) challenge is not known. Age-matched (12 weeks) normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were exposed to intravenous injection of 10 mg/kg LPS. Survival rate at 24 hours was markedly higher in SHR than in WKY (12 of 15 and 3 of 15, respectively;
P
<0.01). Survival of LPS-injected SHR was not related to their hypertension because hydralazine-treated SHR with normalized pressure had similar survival rates, and WKY made hypertensive by clipping of one renal artery showed fatality similar to that of normotensive WKY. Continuous arterial pressure and sequential plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF) were measured in LPS-treated SHR and WKY. Both the duration of the delayed hypotensive phase and the systemic release of IL-6 were much lower in SHR than WKY, whereas both acute hypotension and plasma TNF peak were equivalent. We further explored in vitro the inflammatory response and showed that LPS-activated whole blood from SHR produced less TNF and IL-6 than WKY LPS-activated whole blood. Our results indicate that SHR have a greater ability to resist endotoxic shock than WKY. This is not related to their hypertension but is associated with an attenuated inflammatory response to LPS.
High Sodium Intake Decreases Pressure-Induced (Myogenic) Tone and Flow-Induced Dilation in Resistance Arteries From Hypertensive Rats
Authors: Matrougui Khalid , Schiavi Pierre , Guez David , Henrion Daniel
Published: June 2012

Abstract
—High sodium intake has been associated with a higher blood pressure level. Resistance arteries are the main determinants of blood pressure. They are largely regulated by pressure (tensile stress)–induced tone (myogenic tone, MT) and by flow (shear stress)–induced dilation (FD). Thus, we studied the effect of NaCl (8%) intake for 8 weeks on FD and MT in mesenteric resistance arteries of spontaneously hypertensive rats. Arteries were cannulated and mounted in an arteriograph. Intraluminal diameter was measured continuously. High NaCl intake increased mean arterial pressure (186±5 to 217±6 mm Hg,
P
<0.01). Passive arterial diameter ranged from 112±6 to 185±9 μm (pressure from 25 to 125 mm Hg, no effect of NaCl). MT developed in response to pressure (tone from 89±1% to 83±3% of passive diameter, 25 to 125 mm Hg). High NaCl intake significantly decreased MT (89±1% versus 83±3% of passive diameter when pressure was 125 mm Hg,
P
<0.023). High NaCl intake also decreased FD (6.5±0.8 versus 10±1.3 μm dilation under a pressure of 100 mm Hg and a flow rate of 160 μL/min,
P
<0.012). Thus, high salt intake decreased both flow (shear stress)–induced dilation and pressure (tensile stress)–induced tone in mesenteric resistance arteries. These findings might reflect attenuation by NaCl of flow and pressure mechanosensor processes.
Role of Nitric Oxide and Prostaglandins in the Long-term Control of Renal Function
Authors: González Juan D. , Llinás Maria T. , Nava Eduardo , Ghiadoni Lorenzo , Salazar F. Javier
Published: June 2012

Abstract
—Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 μg · kg
−1
· min
−1
) during 4 consecutive days (n=8) elicited a continuous decrease (
P
<0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion.
N
G
-Nitro-
l
-arginine methyl ester (L-NAME) infusion (5 μg · kg
−1
· min
−1
) during 6 days (n=8) produced a significant increase in arterial pressure and a transitory decrease (
P
<0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (n=7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (
P
<0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced.
Overexpression of Bax Protein and Enhanced Apoptosis in the Left Ventricle of Spontaneously Hypertensive Rats
Authors: Fortuño María Antonia , Ravassa Susana , Etayo Juan Carlos , Díez Javier
Published: June 2012

Abstract
—An association of increased apoptosis with overactivity of the local angiotensin-converting enzyme has been reported in cells from the left ventricle of adult rats with spontaneous hypertension (SHR). To gain insight into the regulation of cardiac apoptosis in arterial hypertension, we investigated the expression of the proteins Bcl-2 (an inhibitor of apoptosis) and Bax (an inducer of apoptosis) in the left ventricle of 30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR treated with the angiotensin II type 1 receptor (AT
1
) antagonist losartan (20 mg · kg
−1
· d
−1
) during 14 weeks before death. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridin nucleotides. The expression of Bcl-2 and Bax was assessed by Western blot analysis. Compared with WKY, untreated SHR exhibited increased (
P
<0.05) apoptosis, increased (
P
<0.01) Bax, and similar Bcl-2. The Bcl-2/Bax ratio (an inverse index of cell susceptibility to apoptosis) was lower (
P
<0.05) in untreated SHR than in WKY. The chronic administration of losartan was associated with the normalization of apoptosis, Bax expression, and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of Bcl-2 were observed in these rats after treatment. No significant changes in the apoptotic density were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. These results suggest that an association exists between increased apoptosis and overexpression of Bax oncoprotein in cells from the left ventricle of adult SHR. Chronic blockade of AT
1
receptors prevents Bax overexpression and normalizes apoptosis in the left ventricle of SHR independently of its hemodynamic effect. On the basis of our findings, it can be proposed that the interaction of angiotensin II with its AT
1
receptors may participate in the stimulation of Bax protein, which in turn renders cells from the left ventricle of SHR more susceptible to apoptosis.
Expression of α
2
-Adrenergic Receptors in Normal and Atherosclerotic Rabbit Aorta
Authors: Handy Diane E. , Johns Conrado , Bresnahan Margaret R. , Tavares Agostinho , Bursztyn Michael , Gavras Haralambos
Published: June 2012

Abstract
—α
2
-Adrenergic receptors (α
2
-ARs) in vascular smooth muscle cells are known to mediate vasoconstriction; however, it is unknown which of the 3 subtypes of α
2
-AR (α
2A
, α
2B
, or α
2C
) is expressed in vascular tissue. We have used subtype-specific probes in in situ hybridization and RNase protection assays to analyze the expression of α
2
-AR in the thoracic aorta of New Zealand White (NZW) and Watanabe heritable hyperlipidemic (WHHL) rabbits, a model for atherosclerosis. We found that the α
2A
-AR mRNA was in endothelial and smooth muscle cells in both NZW and WHHL aorta. In addition, the shoulders and subendothelial regions of the atherosclerotic lesions in WHHL aorta showed abundant expression of α
2A
-AR mRNA. Antibodies to macrophage (RAM-11) and smooth muscle cell (HHF-35) antigens were used to localize macrophage and smooth muscle cells in aortic sections from WHHL rabbits. The expression of α
2A
-AR mRNA within the lesions of WHHL rabbits correlated with the presence of infiltrating macrophages. We discuss the potential role of α
2A
-ARs in macrophage function and in promoting atherosclerosis.
Static and Dynamic Mechanical Properties of the Carotid Artery From Normotensive and Hypertensive Rats
Authors: Lichtenstein Oscar , Safar Michel E. , Mathieu Eric , Poitevin Pierre , Levy Bernard I.
Published: June 2012

Abstract
—Several recent results obtained in hypertensive animals and subjects under in vivo isobaric conditions do not confirm the classic view of stiffer arteries in hypertensive subjects. We compared the mechanical behavior of in situ isolated common carotid arteries from normotensive Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR) under both static and dynamic conditions for transmural pressure ranging from 50 to 200 mm Hg. The static pressure (P)–diameter (D) relationship was shifted to higher values of diameters in the SHR mainly because of a larger unstressed carotid diameter (D
o
) in hypertensive rats. The carotid mechanical strain, calculated as (D−D
o
)/D
o
, was significantly reduced in SHR at pressure levels between 100 and 200 mm Hg. The static carotid compliance and distensibility were markedly smaller in SHR than in WKY carotid arteries, indicating a stiffer wall in hypertensive animals. In contrast, carotid compliance and distensibility were similar under dynamic conditions close to the in vivo pulse pressure (frequency, 300 bpm; peak amplitude of the oscillatory pressure, 20 to 25 mm Hg). However, marked differences in dynamic compliance- and distensibility-strain relationships in SHR and WKY are evidence of clearly different arterial wall material properties in both strains. We therefore conclude that larger lumen carotid arteries in hypertensive rats could compensate for a stiffer arterial wall, resulting in similar dynamic compliance and distensibility in normotensive and hypertensive rats.
Transcription-Modulating Drugs
Authors: Kurtz Theodore W. , Gardner David G.
Published: June 2012

Abstract
—While the promises of gene therapy may be years away from realization, the therapeutic use of drugs that act by modifying gene transcription is a well-established practice in clinical medicine. Although transcription-modulating drugs are frequently used in many different specialties, the deliberate development and use of these agents in cardiovascular medicine has been comparatively limited. However, research advances in the area of gene transcription and in the molecular genetic regulation of blood pressure, insulin resistance, lipid metabolism, and cell growth are providing new opportunities for controlling the expression of genes that are relevant to the pathogenesis of cardiovascular disease and essential hypertension. These research advances are beginning to converge in the development of transcription-modulating drugs with the potential to attack genetically determined risk factors that often cluster in patients with essential hypertension. Ligand-activated transcription factors that serve as receptors for small lipophilic compounds such as the thiazolidinediones and retinoids represent examples of potential therapeutic targets with direct effects on the expression of genes relevant to the pathogenesis of essential hypertension and its complications. Mounting evidence suggesting that the superior cardiorenal protective properties of converting enzyme inhibitors are related in part to their ability to indirectly modify the expression of genes in the heart and vasculature provides provisional support for the clinical value of this therapeutic approach. Given the success of transcription-modulating drugs in the treatment of type II diabetes and many other clinical disorders, it is anticipated that these agents will be developed as tools for the prevention and treatment of hypertension and cardiovascular disease in the not too distant future.
Impact of Shift Work and Race/Ethnicity on the Diurnal Rhythm of Blood Pressure and Catecholamines
Authors: Yamasaki Fumiyasu , Schwartz Joseph E. , Gerber Linda M. , Warren Katherine , Pickering Thomas G.
Published: June 2012

Abstract
—To evaluate the effects of shift work and race/ethnicity on the diurnal rhythm of blood pressure and urinary catecholamine excretion of healthy female nurses, 37 African American women and 62 women of other races underwent ambulatory blood pressure monitor and urine collection for 24 hours that included a full work shift: day shift (n=61), evening shift (n=11), and night shift (n=27). Awake and sleep times were evaluated from subjects’ diaries. Of African Americans, 79% who were working evenings or nights and 32% working day shifts were nondippers (<10% drop in systolic pressure during sleep), whereas only 29% of others working evening+night and 8% working day shifts were nondippers. Regression analyses indicated that evening+night shift workers had a 5.4 mm Hg (
P
<0.001) smaller drop than day shift workers, and African Americans had a 4.0 mm Hg (
P
<0.01) smaller drop than others. The odds of an evening+night shift worker being a nondipper were 6.1 times that of a day shift worker (
P
<0.001), and the odds of an African American were 7.1 times that of others (
P
<0.001). Total sleep time was significantly greater in the non–African American day shift workers than in the other 3 groups. After controlling for work shift and race/ethnicity, we determined that longer sleep times predicted less dipping (absolute and relative) in blood pressure. Urinary norepinephrine and epinephrine were higher during work than nonwork in both racial groups of day shift workers, but in evening+night shift workers the difference was small and in the opposite direction. These results indicate that being African American and working evening or night shifts are independent predictors of nondipper status. Higher sleep blood pressure may contribute to the known adverse effects of shift work.
Acute Endothelium-Mediated Vasodilation Is Not Impaired at the Onset of Diabetes
Authors: Brands Michael W. , Fitzgerald Sharyn M.
Published: June 2012

Abstract
—Vascular injury and impaired vascular function are central to the increased mortality associated with diabetes. Hyperglycemia in diabetes has been suggested to play a role in this process, in part by impairing the function of the vascular endothelium. It has been difficult, however, to isolate the direct effect of glucose in both humans and in animal models of diabetes. This was evaluated in the present study in 7 rats that were chronically instrumented with a Transonic flow probe at the iliac bifurcation of the abdominal aorta, a nonoccluding catheter inserted immediately anterior to the flow probe, and a femoral vein catheter. Acute infusions of acetylcholine and sodium nitroprusside (1 and 10 μg/min IA) increased hindquarter blood flow significantly by approximately 27 and 10 mL/min over baseline, respectively, at the high dose. Streptozotocin (70 mg/kg IV) was administered, but normoglycemia was maintained with continuous intravenous insulin infusion to control for potential streptozotocin side effects. Diabetes was induced 5 to 7 days later by stopping the insulin infusion. Hindlimb blood flow (measured 24 hours per day) decreased during the diabetic period and was accompanied by an increase in mean arterial pressure, suggesting a vasoconstrictor response. However, the responses to acetylcholine and sodium nitroprusside were not altered significantly on either day 2 or day 6 of the diabetic period. This suggests that neither endothelium-mediated vasorelaxation nor responsiveness to nitric oxide is impaired during the initial phase of diabetes and that diabetic hyperglycemia does not have a significant, direct effect to impair endothelium-mediated relaxation in insulin-dependent diabetes mellitus. The mechanism for the change in baseline blood flow and its potential influence on endothelial function, however, are not known.
Determinants of Pulse Pressure
Authors: Stergiopulos Nikos , Westerhof Nico
Published: June 2012

Abstract
—We have searched to define the major arterial parameters that determine aortic systolic (P
s
) and diastolic (P
d
) pressure in the dog. Measured aortic flows were used as input to the 2-element windkessel model of the arterial system, with peripheral resistance calculated as mean pressure divided by mean flow and total arterial compliance calculated from the decay time in diastole. The windkessel model yielded an aortic pressure wave from which we obtained the predicted systolic (P
s,wk
) and diastolic (P
d,wk
) pressures. These predicted pressures were compared with the measured systolic and diastolic pressures. The measurements and calculations were performed for 7 dogs under control conditions during aortic occlusion at 4 locations (the trifurcation, between the trifurcation and diaphragm, the diaphragm, and the proximal descending thoracic aorta) and during occlusion of both carotid arteries. Under all conditions studied, the predicted systolic and diastolic pressures matched the experimental ones very well: P
s,wk
=(1.000±0.0055) P
s
with
r
=0.958 and P
d,wk
=(1.024±0.0035) P
d
with
r
=0.995. Linear regression for pulse pressure (PP) resulted in PP
wk
=(0.99±0.016) PP with
r
=0.911. We found the accuracy of prediction equally good under control conditions and in the presence of aortic or carotid artery occlusion. Multiple regression between pulse pressure and arterial resistance and total arterial compliance yielded a poor regression constant (
R
2
=0.19), suggesting that the 2 arterial parameters alone cannot explain pulse pressure and that flow is an important determinant as well. We conclude that for a given ejection pattern (aortic flow), 2 arterial parameters, total arterial resistance and total arterial compliance, are sufficient to accurately describe systolic and diastolic aortic pressure.
Regulation of Mitogen-Activated Protein Kinase Phosphatase-1 in Vascular Smooth Muscle Cells
Authors: Bokemeyer Dirk , Lindemann Marion , Kramer Herbert J.
Published: June 2012

Abstract
—Mitogen-activated protein (MAP) kinase cascades are major signaling systems by which cells transduce extracellular cues into intracellular responses. In general, MAP kinases are activated by phosphorylation on tyrosine and threonine residues and inactivated by dephosphorylation. Therefore, MAP kinase phosphatase-1 (MKP-1), a dual-specificity protein tyrosine phosphatase that exhibits catalytic activity toward both regulatory sites on MAP kinases, is suggested to be responsible for the downregulation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK), and p38 MAP kinase. In the present study, we examined the role of these MAP kinases in the induction of MKP-1 in vascular smooth muscle cells (VSMCs). Extracellular stimuli such as platelet-derived growth factor (PDGF), 12-O-tetradecanoylphorbol 13-acetate (TPA), and angiotensin II, which activated ERK but not SAPK/p38 MAP kinase, induced a transient induction of MKP-1 mRNA and its intracellular protein. In addition, PD 098059, an antagonist of MEK (MAP kinase/ERK kinase), the upstream kinase of ERK, significantly reduced the PDGF-induced activation of ERK and potently inhibited the expression of MKP-1 after stimulation with PDGF, thereby demonstrating the induction of MKP-1 in response to activation of the ERK signaling cascade. Furthermore, anisomycin, a potent stimulus of SAPK and p38 MAP kinase, also induced MKP-1 mRNA expression. This effect of anisomycin was significantly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. These data suggest the induction of MKP-1, not only after stimulation of the cell growth–promoting ERK pathway but also in response to activation of stress-responsive MAP kinase signaling cascades. We suggest that this pattern of MKP-1 induction may be a negative feedback mechanism in the control of MAP kinase activity in VSMCs.
Evidence for a Difference in Nitric Oxide Biosynthesis Between Healthy Women and Men
Authors: Forte Pablo , Kneale Barry J. , Milne Eric , Chowienczyk Phil J. , Johnston Atholl , Benjamin Nigel , Ritter James M.
Published: June 2012

Abstract
—There is indirect evidence for a gender difference in nitric oxide (NO) synthesis from vascular endothelium. The aim of the present study was to determine NO production more directly in healthy women and men by the measurement of
15
N nitrate excreted in urine after the intravenous administration of
l
-[
15
N]
2
-guanidino arginine. Twenty-four healthy volunteers (13 men aged 22 to 40 years and 11 women aged 23 to 42 years) participated in this study. No subjects were receiving any medication. Women were studied between the 7th and 14th days of their menstrual cycles. Arterial blood pressure was measured oscillometrically, and 1.13 μmol
l
-[
15
N]
2
arginine was administered intravenously after an overnight fast. Urine was collected for the next 36 hours in separate 12-hour periods. Urinary
15
N/
14
N nitrate ratio was assessed by dry combustion in an isotope ratio mass spectrometer. Mean 36-hour urinary
15
N nitrate excretion was greater in women than in men (2111±139 versus 1682±87 ηmol;
P
<0.05). Furthermore, total urinary
15
N nitrate excretion was associated inversely with the mean arterial blood pressure in the whole group of subjects (coefficient of correlation, 0.47;
P
=0.022). The present data show that whole-body production of NO is greater in healthy premenopausal women than in men under ambulatory conditions. The cellular origin of NO measured in this study is unknown, but differences in endothelial production could underlie differences in vascular function between men and women.
Vasodilator Response to Systemic But Not to Local Hyperinsulinemia in the Human Forearm
Authors: Cardillo Carmine , Kilcoyne Crescence M. , Nambi Sridhar S. , Cannon Richard O. , Quon Michael J. , Panza Julio A.
Published: June 2012

Abstract
—Insulin-mediated vasodilation has been proposed as an important determinant of whole-body insulin-stimulated glucose disposal. However, it is not clear whether the vasodilator effect of insulin results from a direct action of the hormone or whether alternative mechanisms are involved. To better characterize the mechanism of insulin-mediated vasorelaxation, we compared forearm blood flow (FBF) responses to local (intra-arterial) and systemic (intravenous, euglycemic clamp) hyperinsulinemia in 10 healthy lean subjects using venous occlusion plethysmography. In addition, we assessed the effect of nitric oxide (NO) synthase inhibition by
N
G
-monomethyl-
l
-arginine (L-NMMA) on the vasodilator and metabolic responses to hyperinsulinemia. Similar forearm concentrations of insulin were achieved during local and systemic infusion (231±39 versus 265±22 μU/mL;
P
=0.54). Of note, FBF did not change significantly in response to local hyperinsulinemia (from 2.6±0.3 to 2.4±0.3 mL · min
−1
· dL
−1
;
P
=0.50). In contrast, systemic hyperinsulinemia caused a 52% increase in FBF (from 2.5±0.2 to 3.8±0.5 mL · min
−1
· dL
−1
;
P
<0.004), which was reversed by L-NMMA (FBF decreased from 3.8±0.5 to 2.3±0.2 mL · min
−1
· dL
−1
;
P
=0.004). We conclude that systemic, but not local, hyperinsulinemia induces vasodilation in the forearm. Our findings suggest that insulin-mediated vasodilation is not due solely to a direct stimulatory effect of insulin but involves additional mechanisms activated only during systemic hyperinsulinemia.
Effects of Eprosartan on Renal Function and Cardiac Hypertrophy in Rats With Experimental Heart Failure
Authors: Brodsky Sergey , Gurbanov Konstantin , Abassi Zaid , Hoffman Aaron , Ruffolo Robert R. , Feuerstein Giora Z. , Winaver Joseph
Published: June 2012

Abstract
—Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (−33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (−12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.