bluuebunny/crossref_metadata_2025 huggingface dataset:
5-Hydroxytryptamine–Induced Potentiation of Endothelin-1– and Norepinephrine-Induced Contraction Is Mitogen-Activated Protein Kinase Pathway Dependent
Authors: Watts Stephanie W.
Published: June 2012

Abstract
—5-Hydroxytryptamine (5-HT)–induced arterial contraction depends on activation of the tyrosine kinase–dependent extracellular signal-regulated mitogen-activated protein kinase (Erk MAPK) pathway. The importance of 5-HT in the control of peripheral resistance has been questioned because circulating free levels of 5-HT are low (in the nanomolar range). We tested the hypothesis that physiologically relevant concentrations of 5-HT potentiate arterial contraction in response to agonists proved to have importance in blood pressure maintenance (norepinephrine [NE] and endothelin-1 [ET-1]) in a tyrosine kinase– and an Erk MAPK–dependent manner. Strips of endothelium-denuded rat tail artery were used for the measurement of isometric force. The general tyrosine kinase inhibitor genistein (5 μmol/L) and the inhibitor of MAPK/Erk kinase activation PD098059 (10 μmol/L) shifted concentration-response curves to 5-HT (1×10
−9
to 3×10
−4
mol/L) rightward but did not shift concentration-response curves to NE or ET-1. In separate experiments, 5-HT (10 nmol/L) potentiated contraction in response to NE (20 nmol/L) by ≈200% to 300% and to ET-1 (0.3 and 1 nmol/L) by 640% and 180%, respectively. Genistein and PD098059 significantly (66% to 100%) reduced 5-HT–induced potentiation of both NE (20 nmol/L)- and ET-1 (0.3 and 1 nmol/L)–induced contraction. Thus, these data support the ability of low physiological concentrations of 5-HT to amplify arterial responses to hormones with bona fide effects on blood pressure in the novel manner of depending on a tyrosine kinase/Erk MAPK pathway. Although these findings were generated in large arteries, we speculate that they may be applicable to vascular functioning in the deoxycorticosterone acetate salt model of hypertension in which all 3 hormones, 5-HT, NE, and ET-1, have been implicated as causal factors.
Expression and Actions of Heme Oxygenase in the Renal Medulla of Rats
Authors: Zou Ai-Ping , Billington Heather , Su Na , Cowley Allen W.
Published: June 2012

Abstract
—Recent studies have shown that the heme oxygenase (HO) product, carbon monoxide (CO), induces vasodilation and that inhibition of HO produces a sustained hypertension in rats. Given the importance of renal medullary blood flow (MBF) in the long-term control of arterial blood pressure, we hypothesized that the HO/CO system may play an important role in maintaining the constancy of blood flow to the renal medulla, which in turn contributes to the antihypertensive effects of the renal medulla. To test this hypothesis, we first determined the expression of 2 isoforms of HO (HO-1 and HO-2) in the different kidney regions. By Northern blot analyses, the abundance of both isozyme mRNAs was found highest in the renal inner medulla and lowest in the renal cortex. The transcripts for HO-1 in the renal outer medulla and inner medulla were 2.5 and 3.7 times that expressed in the renal cortex and those for HO-2 in the outer medulla and inner medulla were 1.3 and 1.6 times that expressed in the renal cortex, respectively. Western blot analyses of both enzymes showed the same expression pattern in these kidney regions as the mRNAs. To determine the role that HO plays in the control of renal MBF, we examined the effect of the HO inhibitor zinc deuteroporphyrin 2,4-
bis
glycol (ZnDPBG) on cortical blood flow and MBF in anesthetized rats. ZnDPBG was given by renal medullary interstitial infusion, and cortical blood flow and MBF were measured by laser Doppler flowmetry. Renal medullary interstitial infusion of ZnDPBG at a dose of 60 nmol/kg per minute produced a 31% decrease in MBF over a period of 60 minutes as measured by laser Doppler flow signal (0.62±0.02 vs 0.43±0.04 V in control vs ZnDPBG). With the use of an in vivo microdialysis technique, ZnDPBG was found to significantly reduce renal medullary cGMP concentrations when infused into the renal medullary interstitial space. These results suggest that both HO-1 and HO-2 are highly expressed in the renal medulla, that HO and its products play an important role in maintaining the constancy of blood flow to the renal medulla, and that cGMP may mediate the vasodilator effect of HO products in the renal medullary circulation.
Elevated Sympathetic Activity Contributes to Hypertension and Salt Sensitivity in Diabetic Obese Zucker Rats
Authors: Carlson Scott H. , Shelton Jonathon , White C. Roger , Wyss J. Michael
Published: June 2012

Abstract
—Zucker rats are a useful model in which to define the mechanisms that link obesity to diabetes and associated cardiovascular disease. The present study tests the hypothesis that diabetic obese (compared with nondiabetic lean) Zucker rats are hypertensive and display a further increase in arterial pressure when fed a high salt diet. Male, nondiabetic lean and diabetic obese Zucker rats were chronically instrumented with telemetry probes and fed a basal salt diet for 3 weeks followed by exposure to a high salt diet for 11 days. On the basal diet, obese (vs lean) rats had significantly higher arterial pressures (≈13 mm Hg), and the high salt diet significantly elevated mean arterial pressure (MAP) in obese (but not lean) Zucker rats (≈12 mm Hg). Blockade of the sympathetic nervous system with hexamethonium caused a significantly larger decrease in MAP in obese (vs lean) Zucker rats fed the basal diet (51 vs 33 mm Hg), but the high salt diet did not increase the hexamethonium-induced reduction in arterial pressure in obese rats. Acute blockade of angiotensin receptors with losartan resulted in similar decreases in MAP in both groups on either diet. Acetylcholine-induced vasodilatory capacity of the carotid artery was significantly less in the obese (vs lean) Zucker rats. Together these data indicate that increased sympathetic nervous system activity and decreased vascular reactivity may contribute to elevated arterial pressure in type 2 diabetic, obese Zucker rats, but the sympathetic nervous system does not appear to contribute to the dietary salt-sensitive hypertension in this model.
The Brain Renin-Angiotensin System Modulates Angiotensin II–Induced Hypertension and Cardiac Hypertrophy
Authors: Baltatu Ovidiu , Silva José Antonio , Ganten Detlev , Bader Michael
Published: June 2012

Abstract
—The potential involvement of the brain renin-angiotensin system in the hypertension induced by subpressor doses of angiotensin II was tested by the use of newly developed transgenic rats with permanent inhibition of brain angiotensinogen synthesis [TGR(ASrAOGEN)]. Basal systolic blood pressure monitored by telemetry was significantly lower in TGR(ASrAOGEN) than in Sprague-Dawley rats (parent strain) (122.5±1.5 versus 128.9±1.9 mm Hg, respectively;
P
<0.05). The increase in systolic blood pressure induced by 7 days of chronic angiotensin II infusion was significantly attenuated in TGR(ASrAOGEN) in comparison with control rats (29.8±4.2 versus 46.3±2.5 mm Hg, respectively;
P
<0.005). Moreover, an increase in heart/body weight ratio was evident only in Sprague-Dawley (11.1%) but not in TGR(ASrAOGEN) rats (2.8%). In contrast, mRNA levels of atrial natriuretic peptide (ANP) and collagen III in the left ventricle measured by ribonuclease protection assay were similarly increased in both TGR(ASrAOGEN) (ANP, ×2.5; collagen III, ×1.8) and Sprague-Dawley rats (ANP, ×2.4; collagen III, ×2) as a consequence of angiotensin II infusion. Thus, the expression of these genes in the left ventricle seems to be directly stimulated by angiotensin II. However, the hypertensive and hypertrophic effects of subpressor angiotensin II are at least in part mediated by the brain renin-angiotensin system.
Excitatory Amino Acids in the Rostral Ventrolateral Medulla Support Blood Pressure in Spontaneously Hypertensive Rats
Authors: Ito Satoru , Komatsu Kazutoshi , Tsukamoto Kazuyoshi , Sved Alan F.
Published: June 2012

Abstract
—Injection of the excitatory amino acid (EAA) antagonist kynurenic acid (KYN) into the rostral ventrolateral medulla (RVLM) of anesthetized rats has no effect on arterial pressure. However, we recently reported that after inhibition of the caudal ventrolateral medulla, injection of KYN into the RVLM decreased arterial pressure to the same level as produced by complete inhibition of the RVLM. We have suggested that these results reflect tonically active EAA-mediated inputs to the RVLM producing both direct excitation of RVLM vasomotor neurons and indirect inhibition of these neurons. On the basis of this model, we hypothesize that the balance between these EAA-driven direct excitatory and indirect inhibitory influences on the RVLM may be altered in models of experimental hypertension. To begin to test this hypothesis, the effects of injecting KYN into the RVLM of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared. In chloralose-anesthetized WKY, bilateral injection of KYN into the RVLM did not alter arterial pressure, whereas similar injections in SHR reduced mean arterial pressure by ≈40 mm Hg. After inhibition of the caudal ventrolateral medulla, which similarly increased arterial pressure in both strains, injection of KYN into the RVLM reduced mean arterial pressure to the same level as produced by autonomic blockade. These results suggest that the balance of excitatory and inhibitory influences on RVLM vasomotor neurons driven by tonically active EAA-mediated inputs to the RVLM is disrupted in SHR and may contribute to the hypertension in SHR.
Gender Differences in Development of Hypertension in Spontaneously Hypertensive Rats
Authors: Reckelhoff Jane F. , Zhang Huimin , Srivastava Kumud
Published: June 2012

Abstract
—Previous data strongly support a role for androgens in promoting the gender difference in hypertension in the spontaneously hypertensive rat(s) (SHR), but the mechanism is not clear. Because males develop higher blood pressures than do females, we hypothesize that androgens may affect the renin-angiotensin system to promote the development of hypertension in male SHR. The present study was performed to determine the effect of converting enzyme inhibition (CEI) on the development of hypertension in SHR. Male, female, castrated male, and ovariectomized (ovx) female SHR (n=10 per gender per treatment group) received enalapril (250 mg/L) in drinking water for 8 to 10 weeks. Some ovx females were also given testosterone chronically. At 17 to 19 weeks of age, 24-hour protein excretion and mean arterial pressure were measured. By 13 weeks of age, male rats had higher systolic blood pressures by tail plethysmography than did the other rats, and CEI reduced blood pressures to similar levels in all groups. At 17 to 19 weeks, the same trend was found by direct measurement of mean arterial pressure. The ovx females treated with testosterone had serum testosterone and blood pressure levels similar to those found in males. CEI reduced mean arterial pressure to similar levels in all gender groups. Untreated males and ovx females given testosterone had significantly higher levels of urinary protein excretion than did the other groups, and CEI had no effect on proteinuria in any of the rats. These data suggest that the development of hypertension in SHR regardless of sex steroids is mediated by the renin-angiotensin system. However, the data further suggest that androgens promote the exacerbation of hypertension in male SHR via a mechanism involving the renin-angiotensin system.
Effect of the Angiotensin II Type 1 Receptor Blocker Candesartan on Endothelial Function in Patients With Essential Hypertension
Authors: Ghiadoni Lorenzo , Virdis Agostino , Magagna Armando , Taddei Stefano , Salvetti Antonio
Published: June 2012

Abstract
—Patients with essential hypertension are characterized by impaired basal and agonist-evoked nitric oxide release and increased endogenous endothelin (ET)-1–induced vasoconstriction. To assess whether candesartan, an angiotensin II type 1 receptor blocker, can improve endothelial function, we studied the changes in forearm blood flow (FBF) induced in 15 hypertensive patients and in 15 control subjects by the intrabrachial infusion of
N
G
-monomethyl-
l
-arginine (L-NMMA), norepinephrine, the ET A/B receptor antagonist TAK 044, sodium nitroprusside, and acetylcholine. In hypertensive patients, the FBF study was repeated 2 and 12 months after the start of treatment with candesartan cilexetil (8 to 16 mg daily). Compared with controls (maximal FBF decrease, −46±11%), hypertensive patients showed a reduced (
P
<0.001) vasoconstrictor response to L-NMMA (maximal FBF decrease, −28±7%); the response to norepinephrine was only slightly impaired, and the response to sodium nitroprusside was similar to that of controls. Finally, TAK-044 caused greater vasodilation in hypertensive patients (maximal FBF increase, 77±9%) than in controls (maximal FBF increase, 17±10%). In hypertensive patients, candesartan cilexetil significantly enhanced vasoconstriction to L-NMMA after 2 and 12 months (maximal FBF decrease, 37±2% [
P
<0.05] and 42±2% [
P
<0.001], respectively). The responses to norepinephrine, acetylcholine, and sodium nitroprusside were not modified after 2 months. After 12 months, the responses to acetylcholine and sodium nitroprusside were significantly (
P
<0.05) enhanced at the highest rates. Vasodilation to TAK-044 was abolished after treatment with candesartan cilexetil; this effect is associated with a reduced plasma ET-1 concentration. This study demonstrated that the angiotensin II receptor blocker candesartan improves tonic nitric oxide release and reduces vasoconstriction to endogenous ET-1 in the forearm of hypertensive patients.
Insulin Action Is Associated With Endothelial Function in Hypertension and Type 2 Diabetes
Authors: Cleland Stephen J. , Petrie John R. , Small Michael , Elliott Henry L. , Connell John M. C.
Published: June 2012

Abstract
—A primary defect in the vascular action of insulin may be a key intermediate mechanism that links endothelial dysfunction with reduced insulin-mediated cellular glucose uptake in metabolic and cardiovascular disorders. The present study was designed to characterize more fully the relations between insulin action and endothelial function in male patients with essential hypertension (H, n=9) or type 2 diabetes (D, n=9) along with healthy control subjects (C) matched for age, body mass index, and lipid profile. They attended for measurement of whole-body insulin sensitivity (MCR) by the hyperinsulinemic clamp technique (day 1) and forearm vasoreactivity in response to intra-arterial infusions of insulin/glucose (day 2) and
N
G
-monomethyl-
l
-arginine (L-NMMA) and norepinephrine (day 3) by bilateral venous-occlusion plethysmography. Results expressed as mean±SE MCR (mL/kg per minute) were 7.22±0.99 (C), 6.32±0.78 (H), and 5.06±0.53 (D). Insulin/glucose-mediated vasodilation (IGMV) was 17.1±5.6% (C), 17.2±5.5% (H), and 12.3±6.4% (D). L-NMMA vasoconstriction (LNV) was 37.9±5.1% (C), 37.5±2.3% (H), and 33.6±2.8% (D). There were no significant differences among groups for these parameters. Pooled correlation analyses revealed associations between MCR and IGMV (
r
=0.46,
P
<0.05), MCR and LNV (
r
=0.44,
P
<0.05), and IGMV and LNV (
r
=0.52,
P
<0.01). This study supports functional coupling between insulin action (both metabolic and vascular) and basal endothelial nitric oxide production in humans.
Long-Term Absolute Benefit of Lowering Blood Pressure in Hypertensive Patients According to the JNC VI Risk Stratification
Authors: Ogden Lorraine G. , He Jiang , Lydick Eva , Whelton Paul K.
Published: June 2012

Abstract
—Blood pressure (BP) levels alone have been traditionally used to make treatment decisions in patients with hypertension. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) recently recommended that risk strata, in addition to BP levels, be considered in the treatment of hypertension. We estimated the absolute benefit associated with a 12 mm Hg reduction in systolic BP over 10 years according to the risk stratification system of JNC VI using data from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study. The number-needed-to-treat to prevent a cardiovascular event/death or a death from all causes was reduced with increasing levels of baseline BP in each of the risk strata. In addition, the number-needed-to-treat was much smaller in persons with ≥1 additional major risk factor for cardiovascular disease (risk group B) and in those with a history of cardiovascular disease or target organ damage (risk group C) than in those without additional major risk factors for cardiovascular disease (risk group A). Specifically, the number-needed-to-treat to prevent a death from all causes in patients with a high-normal BP, stage 1 hypertension, or stage 2 or 3 hypertension was, respectively, 81, 60, and 23 for those in risk group A; 19, 16, and 9 for those in risk group B; and 14, 12, and 9 for those in risk group C. Our analysis indicated that the absolute benefits of antihypertensive therapy depended on BP as well as the presence or absence of additional cardiovascular disease risk factors and the presence or absence of preexisting clinical cardiovascular disease or target organ damage.
Long-Term Effects of Weight Loss and Dietary Sodium Reduction on Incidence of Hypertension
Authors: He Jiang , Whelton Paul K. , Appel Lawrence J. , Charleston Jeanne , Klag Michael J.
Published: June 2012

Abstract
—To examine the long-term effects of weight loss and dietary sodium reduction on the incidence of hypertension, we studied 181 men and women who participated in the Trials of Hypertension Prevention, phase 1, in Baltimore, Md. At baseline (1987 to 1988), subjects were 30 to 54 years old and had a diastolic blood pressure (BP) of 80 to 89 mm Hg and systolic BP <160 mm Hg. They were randomly assigned to one of two 18-month lifestyle modification interventions aimed at either weight loss or dietary sodium reduction or to a usual care control group. At the posttrial follow-up (1994 to 1995), BP was measured by blinded observers who used a random-zero sphygmomanometer. Incident hypertension was defined as systolic BP ≥160 mm Hg and/or diastolic BP ≥90 mm Hg and/or treatment with antihypertensive medication during follow-up. Body weight and urinary sodium were not significantly different among the groups at the posttrial follow-up. After 7 years of follow-up, the incidence of hypertension was 18.9% in the weight loss group and 40.5% in its control group and 22.4% in the sodium reduction group and 32.9% in its control group. In logistic regression analysis adjusted for baseline age, gender, race, physical activity, alcohol consumption, education, body weight, systolic BP, and urinary sodium excretion, the odds of hypertension was reduced by 77% (odds ratio 0.23; 95% confidence interval 0.07 to 0.76;
P
=0.02) in the weight loss group and by 35% (odds ratio 0.65; 95% confidence interval 0.25 to 1.69;
P
=0.37) in the sodium reduction group compared with their control groups. These results indicate that lifestyle modification such as weight loss may be effective in long-term primary prevention of hypertension.
β-2 Adrenergic Receptor Gene Variations, Blood Pressure, and Heart Size in Normal Twins
Authors: Busjahn Andreas , Li Guo-Hua , Faulhaber Hans-Dieter , Rosenthal Magda , Becker Albert , Jeschke Eva , Schuster Herbert , Timmermann Bernd , Hoehe Margret R. , Luft Friedrich C.
Published: June 2012

Abstract
—Genetic variability, which influences cardiovascular phenotypes in normal persons, is likely to be relevant to cardiovascular disease. We studied normal monozygotic and dizygotic twins and found strong genetic influences on blood pressure and heart size. We then relied on the dizygotic twins and their parents to apply molecular genetic techniques. We performed a linkage analysis with markers close to the β-2 adrenergic receptor (AR) gene locus in the dizygotic twins and their parents and found strong evidence for linkage to the quantitative traits of blood pressure and heart size. We then used allele-specific polymerase chain reaction to genotype the subjects further. We performed an association analysis and found that 4 functionally relevant polymorphisms in the β-2 AR gene, namely Arg16/Gly, Gln27/Glu, Thr164/Ile, and a variant in the promoter region (−47C/T), were variably associated with blood pressure and heart size differences but were in linkage dysequilibrium with each other. A subsequent conditional analysis suggested that the Arg16/Gly polymorphism exerted the predominant effect. These findings underscore the importance of the β-2 AR gene to blood pressure regulation, heart size, and probably to the development of hypertension. We suggest that a combined linkage and association approach will elucidate the genetic variability influencing blood pressure and other cardiovascular phenotypes.
Continuous Relation Between Left Ventricular Mass and Cardiovascular Risk in Essential Hypertension
Authors: Schillaci Giuseppe , Verdecchia Paolo , Porcellati Carlo , Cuccurullo Olga , Cosco Carmela , Perticone Francesco
Published: June 2012

Abstract
—The detection of left ventricular (LV) hypertrophy on echocardiography is a powerful risk indicator in essential hypertension. However, the prognostic impact of LV mass values within the “normal” range and the shape of the relation between LV mass and prognosis remain unclear. Thus, 1925 white subjects with uncomplicated essential hypertension underwent off-therapy 24-hour blood pressure monitoring and M-mode echocardiography. During 4.0±2 years of follow-up, there were 181 major cardiovascular events (2.4/100 patient-years) and 49 deaths from all causes. In the 5 gender-specific quintiles of LV mass distribution (partition values: 92, 105, 120, and 138 g/m
2
in men and 79, 91, 102, and 116 g/m
2
in women), cardiovascular event rates were 0.8, 1.7, 2.2, 2.9, and 4.3 per 100 patient-years. After adjustment for several risk factors, including 24-hour ambulatory blood pressure, the relative risk (RR) of developing a cardiovascular event increased progressively from the first quintile (RR 1) to the second (RR 1.6, 95% CI 0.8 to 3.1), third (RR 1.9, 95% CI 1.01 to 4.0), fourth (RR 3.0, 95% CI 1.5 to 5.8), and fifth (RR 3.5, 95% CI 1.8 to 6.8) quintile. For all-cause death, the RR in the fifth quintile compared with the first quintile was 4.3 (95% CI 1.2 to 13.4). In conclusion, the powerful relation between LV mass and risk of cardiovascular disease in subjects with uncomplicated essential hypertension is continuous over a wide range of LV mass values, even below the current “upper normal” limits. The relation remains significant after control for traditional risk factors, including ambulatory blood pressure.
Amlodipine, Enalapril, and Dependent Leg Edema in Essential Hypertension
Authors: Pedrinelli Roberto , Dell’Omo Giulia , Melillo Elio , Mariani Mario
Published: June 2012

Abstract
—Calcium channel blockers (CCBs) blunt postural skin vasoconstriction, an autoregulatory mechanism that minimizes gravitational increases in capillary pressure and avoids fluid extravasation when standing. To evaluate the dose-response relation between this pharmacological interference and dependent edema, a frequent side effect of CCBs during antihypertensive treatment, skin blood flow (laser Doppler flowmetry) at the dorsum of the foot, both supine and with the limb passively placed 50 cm below the heart level, and leg weight (Archimedes principle) were measured at baseline, during increasing doses of the dihydropyridine amlodipine (5 and 10 mg UID each for 2 weeks), and after drug withdrawal in 10 hypertensive men. Because angiotensin-converting enzyme inhibitors may attenuate ankle swelling by CCBs, those parameters were evaluated according to a similar design during amlodipine (10 mg UID) and enalapril (20 mg UID) combined (n=10). As a control, the effect of enalapril monotherapy (10 and 20 mg UID for 2 weeks each) was evaluated in a third series of patients (n=8). Amlodipine (5 mg UID) increased leg weight without modifying postural vasoconstriction (the percent skin blood flow decrease from horizontal to dependent position), which indicates that extravascular fluid shift was independent of postural skin vasoconstriction. At 10 mg UID, however, amlodipine blunted postural vasoconstriction and increased leg weight further, which suggests that skin blood flow autoregulation limited additional fluid transfer. Both parameters normalized after drug withdrawal. Enalapril per se did not affect cutaneous vasomotion or leg weight but reduced the amount of dependent fluid extravasation by the CCB despite a persistent antagonism for postural vasoconstrictor responses.
Long-Term Telemetric Recording of Arterial Pressure and Heart Rate in Mice Fed Basal and High NaCl Diets
Authors: Carlson Scott H. , Wyss J. Michael
Published: June 2012

Abstract
—Research examining the control of arterial pressure in mice has primarily relied on tail-cuff plethysmography and, more recently, on tethered arterial catheters. In contrast, the radiotelemetry method has largely become the “gold standard” for long-term monitoring of arterial pressure and heart rate in rats. Whereas smaller telemetry probes have recently been developed, no published studies have used radiotelemetric monitoring of arterial pressure in mice, largely because of a relatively low success rate in small mice (ie, <30 g body weight). We report on the development of a protocol for the use of these probes to continuously monitor arterial pressure and heart rate in mice as small as 19 g body weight. To test the accuracy and reliability of this method, adult C57/BL6 mice were monitored for 3 weeks during exposure to a basal followed by a high NaCl diet. The results demonstrate that carotid and aortic placements of the telemetry probe provide equally accurate monitoring of arterial pressure and heart rate, but the carotid placement has a much greater rate of success. Exposure to a high NaCl diet increases both the amplitude of the arterial pressure rhythm (+ 6.0±0.6 mm Hg, ≈32%) and the average mean arterial pressure (+ 8.6±1.1 mm Hg, ≈8%), as would be predicted from previous studies in NaCl-resistant rats. Thus, the data demonstrate that telemetric recording of long-term arterial pressure and heart rate provides a powerful tool with which to define the mechanisms of cardiovascular control in mice.
Lys
173
Arg and −344T/C Variants of
CYP11B2
in Japanese Patients With Low-Renin Hypertension
Authors: Komiya Ichiro , Yamada Takashi , Takara Masaki , Asawa Takayuki , Shimabukuro Michio , Nishimori Takeshi , Takasu Nobuyuki
Published: June 2012

Abstract
—We analyzed the association of 2 biallelic polymorphisms of
CYP11B2
(P450c11AS) gene (1 in the Lys
173
Arg of exon 3 and the other in the promoter at position −344T/C) with hypertension in 73 hypertensive patients and 134 normotensive subjects. The association between low-renin hypertension and angiotensin I–converting enzyme (
ACE
) gene was also analyzed. An elevated ratio of plasma aldosterone concentration to plasma renin activity was used to identify low-renin hypertension. Genotypes for
CYP11B2
and
ACE
were determined through polymerase chain reactions. The Arg
173
allele frequency did not differ between hypertensive patients considered as 1 group (34%) and normotensive control subjects (37%). However, only 22% of 58
CYP11B2
alleles studied in 29 patients with low-renin hypertension were Arg
173
alleles, whereas the frequency of this allele was 41% in patients with normal- or high-renin hypertension (
P
=0.033). An analysis of the distribution of −344C and Arg
173
genotypes indicated that these 2 variants were in complete linkage disequilibrium: −344C was present in a subset of chromosomes carrying the Arg
173
(
P
<0.001 in low-renin hypertension). Therefore, the frequency of the −344C allele was low in the patients with low-renin hypertension compared with those with normal- or high-renin hypertension. Deletion (D) allele frequencies of the
ACE
gene were 31% in the patients with low-renin hypertension, 39% in the patients with normal- or high-renin hypertension, and 29% in normotensive control subjects. We detected an association between the
CYP11B2
gene polymorphisms and low-renin hypertension with inappropriate elevation of aldosterone. The decreased frequencies of the Arg
173
and −344C variants in the
CYP11B2
appear to be genetically linked to low-renin hypertension in the Japanese population studied.
Mechanisms of Big Endothelin-1–Induced Diuresis and Natriuresis
Authors: Hoffman Aaron , Abassi Zaid A. , Brodsky Sergey , Ramadan Rawi , Winaver Joseph
Published: June 2012

Abstract
—Endothelin-1 (ET-1) at high concentrations has marked antidiuretic and antinatriuretic activities, whereas its precursor, big endothelin-1 (big ET-1), has surprisingly potent diuretic and natriuretic actions. The mechanisms underlying the excretory effects of big ET-1 have not been fully elucidated. To explore these mechanisms, we examined the effects of a highly selective ET
B
antagonist (A-192621.1), a calcium channel blocker (verapamil), a nitric oxide synthase inhibitor (
N
-nitro-
l
-arginine methyl ester [L-NAME]), and a cyclooxygenase inhibitor (indomethacin) on the systemic and renal actions of big ET-1 in anesthetized rats. An intravenous bolus injection of incremental doses of big ET-1 (0.3, 1.0, and 3.0 nmol/kg) produced a significant hypertensive effect that was dose dependent and prolonged (from 113±7 mm Hg to a maximum of 148±6 mm Hg). The administration of big ET-1 induced marked diuretic and natriuretic responses (urinary flow rate increased from 8.5±1 to 110±14 μL/min, and fractional excretion of sodium increased from 0.38±0.13% to 7.51±1.24%). Glomerular filtration rate and renal plasma flow significantly decreased only at the highest dose of big ET-1. Pretreatment with A-192621.1 (3 mg/kg plus 3 mg · kg
−1
· h
−1
) significantly abolished the diuretic (17±5 μL/min to a maximum of 19±3 μL/min) and natriuretic (0.29±0.1% to a maximum of 1.93±0.37%) responses induced by big ET-1. Moreover, A-192621.1 potentiated the decline in glomerular filtration rate and renal plasma flow and the increase in mean arterial blood pressure produced by the low doses of big ET-1. Similar to A-192621.1, pretreatment with a nitric oxide synthase inhibitor (L-NAME, 10 mg/kg plus 5 mg · kg
−1
· h
−1
) significantly and comparably reduced the diuretic and natriuretic actions of big ET-1 and augmented the hypoperfusion/hypofiltration and systemic vasoconstriction induced by high doses of the peptide. Pretreatment with verapamil (2 mg · kg
−1
· h
−1
) slightly inhibited the diuretic/natriuretic effects of the high-dose big ET-1 and completely prevented the increase in mean arterial blood pressure provoked by the peptide. Unlike verapamil and L-NAME, only indomethacin administration was associated with significant natriuretic/diuretic responses and did not influence the pressor effect and renal actions of big ET-1. Taken together, these results suggest that big ET-1–induced diuretic and natriuretic responses are mediated mainly by stimulation of nitric oxide production coupled to ET
B
receptor subtype activation.
Acute Suppression of Muscle Sympathetic Nerve Activity by Hydrocortisone in Humans
Authors: Dodt Christoph , Keyser Barbara , Mölle Matthias , Fehm Horst Lorenz , Elam Mikael
Published: June 2012

Abstract
—In the present study, we examined the acute influence of hydrocortisone on human sympathetic nerve activity and cardiovascular parameters. Muscle sympathetic nerve activity (MSA), heart rate, and blood pressure were monitored in 8 healthy subjects (20 to 37 years old) before and after a bolus injection of 50 mg hydrocortisone followed by a continuous infusion at 50 mg/h during a period of 3 hours in a placebo-controlled, double-blind, crossover protocol. Recordings were performed at rest and during repeated transient sympathoexcitation induced by voluntary apneas. Resting MSA and endogenous serum cortisol concentrations were also measured in a larger study group (49 experiments, 25 subjects). During the experimental period, MSA burst number increased by 56% from the control level in the placebo group. In contrast, MSA was suppressed by 25% at the end of the hydrocortisone infusion, resulting in a significant treatment effect (
P
<0.05). In addition, sympathoexcitation during apnea was significantly reduced with hydrocortisone after 180 minutes. In parallel with the sympathetic outflow, blood pressure decreased in the hydrocortisone-treated group, whereas it rose in the placebo group (
P
<0.05 between groups). No correlation was found between basal MSA and basal cortisol levels. Our results indicate that pharmacological doses of hydrocortisone acutely influence MSA responses to short- and long-lasting environmental stimuli, whereas basal native cortisol levels do not appear to be tonically involved in the regulation of resting MSA. The suppressive hydrocortisone effect is most likely induced via supraspinal autonomic centers and cannot be explained by peripheral steroid mechanisms. The effect of elevated corticosteroid levels on sympathetic nerve discharge may be an important mechanism in cardiovascular adaptations to stress.
Changes of Nocturnal Blood Pressure Dipping Status in Hypertensives by Nighttime Dosing of α-Adrenergic Blocker, Doxazosin
Authors: Kario Kazuomi , Schwartz Joseph E. , Pickering Thomas G.
Published: June 2012

Abstract
—Abnormal nocturnal blood pressure (BP) dipping status may be partly determined by nocturnal sympathetic activity. We studied the effect of nighttime dosing of an α
1
-adrenergic blocker, doxazosin, on the BP dipping status of 118 hypertensives, all of whom underwent 24-hour ambulatory BP monitoring before and after treatment. The mean nighttime/daytime ratio of systolic BP was increased (0.91 after therapy versus 0.89 at baseline,
P
<0.05). The patients were initially divided into 4 groups on the basis of their dipping status at the baseline assessment: 18 (15%) were extreme dippers, with a nighttime systolic BP fall of at least 20% of daytime BP; 46 (39%) were dippers (fall between 10% and 20%); 48 (41%) were nondippers (fall between 0% and 10%); and 6 (5%) were risers (nocturnal increase of systolic BP). A shift in dipping status toward less nocturnal BP dipping was observed after doxazosin therapy (
P
<0.05). Dipping status was determined by nighttime more than by daytime BP, and this was not explained by differences in the number of daytime and nighttime readings. The effects of doxazosin on the mean nocturnal systolic BP changes were an increase of 4.3 mm Hg in extreme dippers and decreases of 0.7 mm Hg in dippers, 12 mm Hg in nondippers, and 18 mm Hg in risers; the reduction was only significant in the latter 2 groups (both
P
<0.01). To estimate the effects of regression to the mean on the changes in dipping status, we also defined dipping status with the average of the BPs before and after doxazosin and found no difference in the degree of nighttime BP reduction among each group. The reduction of daytime BP was now significantly greater in the subgroups with less dipping: 6.4 mm Hg for extreme dippers and 16 mm Hg for risers (
P
<0.05). In conclusion, nighttime dosing with doxazosin markedly affects the nocturnal BP dipping status of hypertensives, but the apparently greater reduction in nighttime pressure in nondippers and risers may be, at least partly, due to the effect of regression to the mean. The most important determinants of the effect of doxazosin were the absolute BP levels, both day and night, rather than dipping status per se.
High-Fat Diet Elevates Blood Pressure and Cerebrovascular Muscle Ca
2+
Current
Authors: Wilde Dixon W. , Massey Kenneth D. , Walker Glenn K. , Vollmer Alan , Grekin Roger J.
Published: June 2012

Abstract
—Dietary fat contributes to the elevation of blood pressure and increases the risk of stroke and coronary artery disease. Previous observations have shown that voltage-gated Ca
2+
current density is significantly increased in hypertension and can be affected by free fatty acids (FAs). We hypothesized that a diet of elevated fat level would lead to an increase in blood pressure, an elevation of L-type Ca
2+
current, and an increase in saturated FA content in vascular smooth muscle cell membranes. Male Osborne-Mendel rats were fed normal rat chow or a high-fat diet (Ob/HT group) for 8 weeks. Blood pressures in the Ob/HT group increased moderately from 122.5±0.7 to 134.4±0.8 mm Hg (
P
<0.05, n=26). Voltage-clamp examination of cerebral arterial cells revealed significantly elevated L-type Ca
2+
current density in the Ob/HT group. Voltage-dependent inactivation of the Ob/HT L-type channels was significantly delayed. Total serum FA contents were significantly elevated in the Ob/HT group, and HPLC analyses of fractional pools of FAs from segments of abdominal aorta revealed that arachidonic acid levels were elevated in the phospholipid fraction in Ob/HT. No differences in vascular membrane cholesterol contents were noted. Plasma cholesterol was significantly elevated in portal venous and cardiac blood samples from Ob/HT rats. These findings suggest that an elevation of plasma FAs may contribute to the development of hypertension via a process involving the elevation of Ca
2+
current density and an alteration of channel kinetics in the vascular smooth muscle membrane.
Cellular Hypertrophy in Subcutaneous Small Arteries of Patients With Renovascular Hypertension
Authors: Rizzoni Damiano , Porteri Enzo , Guefi Daniele , Piccoli Alfonso , Castellano Maurizo , Pasini Giancarlo , Muiesan Maria Lorenza , Mulvany Michael John , Rosei Enrico Agabiti
Published: June 2012

Abstract
—Structural alterations of small arteries in patients with essential hypertension are characterized by inward eutrophic remodeling. However, small arteries in patients with secondary hypertension, as well as in experimental models of hypertension with high circulating renin, are characterized by inward hypertrophic remodeling, which is characterized by smooth muscle cell hypertrophy in animal models. The aim of our study was to determine whether remodeling of subcutaneous small arteries in patients with secondary forms of hypertension is associated with smooth muscle cell hypertrophy and/or alterations in the elastic modulus of the vessel wall. Fifteen patients with renovascular hypertension, 9 with primary aldosteronism, and 13 with essential hypertension and 9 normotensive subjects were included in the study. A biopsy of subcutaneous fat was taken from all subjects. Small arteries were dissected, and morphology was determined on a micromyograph. Unbiased estimates of cell volume and number were made in fixed material. From the resting tension–internal circumference relation of the small arteries, the incremental elastic modulus was calculated and plotted as a function of wall stress. Blood pressure was greater in patients with essential hypertension, renovascular hypertension, or primary aldosteronism than in normotensive subjects, but no significant difference was observed among the 3 groups of hypertensive patients. The media/lumen ratio, the medial cross-sectional area, and the smooth muscle cell volume were significantly greater in patients with renovascular hypertension than in normotensive subjects and patients with essential hypertension. No difference in cell number or in the elastic properties was observed among the 4 groups of subjects. In conclusion, our data demonstrate for the first time that a pronounced activation of the renin-angiotensin-aldosterone system is associated with vascular smooth muscle cell hypertrophy in human hypertension in a manner similar to that found in animal models.
Hypokalemia Associated With Diuretic Use and Cardiovascular Events in the Systolic Hypertension in the Elderly Program
Authors: Franse Lonneke V. , Pahor Marco , Di Bari Mauro , Somes Grant W. , Cushman William C. , Applegate William B.
Published: June 2012

Abstract
—The treatment of hypertension with high-dose thiazide diuretics results in potassium depletion and a limited benefit for preventing coronary events. The clinical relevance of hypokalemia associated with low-dose diuretics has not been assessed. To determine whether hypokalemia that occurs with low-dose diuretics is associated with a reduced benefit on cardiovascular events, we analyzed data of 4126 participants in the Systolic Hypertension in the Elderly Program (SHEP), a 5-year randomized, placebo-controlled clinical trial of chlorthalidone-based treatment of isolated systolic hypertension in older persons. After 1 year of treatment, 7.2% of the participants randomized to active treatment had a serum potassium <3.5 mmol/L compared with 1% of the participants randomized to placebo (
P
<0.001). During the 4 years after the first annual visit, 451 participants experienced a cardiovascular event, 215 experienced a coronary event, 177 experienced stroke, and 323 died. After adjustment for known risk factors and study drug dose, the participants who received active treatment and who experienced hypokalemia had a similar risk of cardiovascular events, coronary events, and stroke as those randomized to placebo. Within the active treatment group, the risk of these events was 51%, 55%, and 72% lower, respectively, among those who had normal serum potassium levels compared with those who experienced hypokalemia (
P
<0.05). The participants who had hypokalemia after 1 year of treatment with a low-dose diuretic did not experience the reduction in cardiovascular events achieved among those who did not have hypokalemia.
Intrinsic Stiffness of the Carotid Arterial Wall Material in Essential Hypertensives
Authors: Bussy Caroline , Boutouyrie Pierre , Lacolley Patrick , Challande Pascal , Laurent Stéphane
Published: June 2012

Abstract
—We have previously shown that the decrease in large artery distensibility observed in patients with essential hypertension (HT group) was primarily due to an increase in distending pressure and not to hypertension-associated structural modifications of the artery, suggesting a functional adaptation of the wall material. To evaluate the elastic properties of the wall material of the common carotid artery, we determined Young’s incremental elastic modulus (Einc) in the HT group and in normotensive subjects (NT group) as a function of blood pressure and circumferential wall stress. In 102 HT patients with never-treated essential hypertension and 40 age- and gender-matched NT subjects, the Einc-pressure and Einc-stress curves were calculated from intima-media thickness and from diameter and pressure waveforms, determined with echo tracking and aplanation tonometry, respectively. The “effective” stiffness of the wall material, determined through Einc calculated at mean blood pressure, was significantly higher in the HT than in the NT group. The “intrinsic” stiffness of the wall material, determined through Einc calculated at a common circumferential wall stress, did not differ between the 2 groups. However, when each group (HT and NT) was analyzed according to tertiles of age, the “intrinsic” stiffness of the arterial wall material was increased only in younger HT patients. In middle-aged and older HT patients, the intrinsic mechanical properties of the carotid arterial wall material were unchanged, and the increased stiffness of the common carotid artery in the HT group was due primarily to the increased level of blood pressure. These results also indicate that the deleterious effects of aging and hypertension on “intrinsic” stiffness are not additive.
Proapoptotic and Growth-Inhibitory Role of Angiotensin II Type 2 Receptor in Vascular Smooth Muscle Cells of Spontaneously Hypertensive Rats In Vivo
Authors: Tea Bun-Seng , Der Sarkissian Shant , Touyz Rhian M. , Hamet Pavel , deBlois Denis
Published: June 2012

Abstract
—Angiotensin type 2 (AT
2
) receptors for angiotensin II suppress cell growth and induce apoptosis in vitro, but their role is poorly defined in vivo. We reported that transient induction of smooth muscle cell (SMC) apoptosis precedes DNA synthesis inhibition and aortic hypertrophy regression in spontaneously hypertensive rats treated with the AT
1
antagonist losartan or the converting-enzyme inhibitor enalapril. Although both drugs are equipotent in reducing SMC number, apoptosis occurs significantly earlier with losartan than enalapril. To examine the role of AT
2
receptors in this model, spontaneously hypertensive rats were given valsartan, an AT
1
antagonist, or enalapril, in combination or not with the AT
2
antagonist PD123319 for 1 or 2 weeks. Control rats received vehicle. Systolic blood pressure was reduced similarly by valsartan and enalapril but it was not significantly affected by PD123319. Angiotensin II plasma levels were increased (6-fold) with valsartan and reduced (80%) with enalapril but unaffected by PD123319. Valsartan significantly increased internucleosomal DNA fragmentation indicative of apoptosis at 1 week only (2.7-fold) and significantly reduced aortic mass (18%), SMC number (33%), and DNA synthesis (24%, measured by
3
H-thymidine incorporation) at 2 weeks. These valsartan-induced changes were prevented by PD123319. In contrast, enalapril-induced DNA fragmentation (2-fold increase at 2 weeks) was not affected by PD123319. PD123319 given alone did not affect growth or apoptosis. AT
1
and AT
2
receptor mRNAs were detected in the aorta by reverse transcription–polymerase chain reaction. Together, these results provide the first evidence that AT
2
receptors mediate vascular mass regression by stimulating SMC apoptosis in vivo, an effect seen during AT
1
receptor blockade but not during converting-enzyme inhibition.
Characterization of Murine Vasopressor and Vasodepressor Prostaglandin E
2
Receptors
Authors: Zhang Yahua , Guan YouFei , Schneider André , Brandon Suzanne , Breyer Richard M. , Breyer Matthew D.
Published: June 2012

Abstract
—Four E-prostanoid (EP) receptors, designated EP
1
, EP
2
, EP
3
, and EP
4
, mediate the cellular effects of prostaglandin E
2
(PGE
2
). The present studies pharmacologically characterize the vasopressor and vasodepressor EP receptors in wild-type mice (EP
2
+/+
mice) and mice with targeted disruption of the EP
2
receptor (EP
2
−/−
mice). Mean arterial pressure (MAP) was measured via a carotid artery catheter in anesthetized male mice. Intravenous infusion of PGE
2
decreased MAP in EP
2
+/+
mice but increased MAP in EP
2
−/−
mice. Infusion of EP
3
-selective agonists, including MB28767, SC46275, and sulprostone, increased MAP in both EP
2
+/+
and EP
2
−/−
mice. Pretreatment with SC46275 desensitized mice to the subsequent pressor effect of sulprostone, but the vasodepressor effect of PGE
2
in EP
2
+/+
mice remained intact. Although PGE
2
alone increased MAP in EP
2
−/−
mice, prior desensitization of the pressor effect with SC46275 allowed a residual vasodepressor effect of PGE
2
to be seen in the EP
2
−/−
mice. An EP
4
-selective agonist (prostaglandin E
1
-OH) functioned also as a vasodepressor in both EP
2
−/−
and EP
2
+/+
mice. High levels of EP
3
receptor mRNA were detected in mouse aortas and rabbit preglomerular arterioles by nuclease protection, with lower expressions of EP
1
, EP
2
, and EP
4
mRNA. The findings suggest that combined vasodepressor effects of EP
2
and EP
4
receptors normally dominate, accounting for the depressor effects of PGE
2
. In contrast, in EP
2
−/−
mice, EP
4
receptor activity alone is insufficient to overcome the EP
3
vasopressor effect. These findings suggest that a balance between pressor and depressor PGE
2
receptors determines its net effect on arterial pressure and that these receptors may be important therapeutic targets.