bluuebunny/crossref_metadata_2025 huggingface dataset:
Remission of high blood pressure reverses arterial potassium channel alterations.
Authors: Rusch N J , Runnells A M
Published: June 2012

Rat arterial muscle cells show an elevated Ca(2+)-dependent K+ efflux during the established phase of hypertension. This association of enhanced K+ efflux with high arterial pressure implies that changes of in vivo blood pressure can alter the level of K+ channel current in arterial membranes. We directly tested this hypothesis by comparing K+ current density between patch-clamped aortic muscle membranes of normotensive Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHR), and SHR treated with the angiotensin-converting enzyme inhibitor ramipril (3.5 mg/kg per day PO) to normalize blood pressure. Peak macroscopic K+ current was measured during progressive depolarizing steps (10 mV) from -60 and +60 mV in cells dialyzed with pipette solution containing 10(-6) mol/L calcium to amplify Ca(2+)-dependent K+ current. With the use of this approach, maximum K+ current density in aortic muscle membranes of untreated SHR was 2.6-fold higher than in untreated WKY rats (SHR, 31 +/- 3 pA/pF; WKY, 12 +/- 1 pA/pF) and was predominantly blocked by 2 mmol/L tetraethylammonium. K+ current density in SHR aortic membranes was unchanged after 1 week of ramipril therapy, but it was reduced 42% (to 18 +/- 1 pA/pF) after 2 weeks of treatment. Parallel tension-recording studies showed that untreated SHR aortic segments but not aortic segments from WKY rats or ramipril-treated SHR constricted strongly after block of Ca(2+)-dependent K+ channels by tetraethylammonium. Our findings imply that Ca(2+)-dependent K+ current density in arterial muscle membranes shows a positive correlation with chronic arterial blood pressure levels.(ABSTRACT TRUNCATED AT 250 WORDS)
Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.
Authors: Danser A H , van Kats J P , Admiraal P J , Derkx F H , Lamers J M , Verdouw P D , Saxena P R , Schalekamp M A
Published: June 2012

The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of renin-angiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n = 11) and Ang I (n = 7) and II (n = 7) in the left and right atria were higher than in the corresponding ventricles (P < .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P < .05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n = 11) in cardiac tissue were 10% to 25% of the levels in plasma, which is compatible with its diffusion from plasma into the interstitium. Like angiotensin-converting enzyme, renin was enriched in a purified cardiac membrane fraction prepared from left ventricular tissue, as compared with crude homogenate, and 12 +/- 3% (mean +/- SD, n = 6) of renin in crude homogenate was found in the cardiac membrane fraction and could be solubilized with 1% Triton X-100. Tissue levels of renin and Ang I and II in the atria and ventricles were directly correlated with plasma levels (P < .05), and in both tissue and plasma the levels were undetectably low after nephrectomy. We conclude that most if not all renin in cardiac tissue originates from the kidney. Results support the contentions that in the healthy heart, angiotensin production depends on plasma-derived renin and that plasma-derived angiotensinogen in the interstitial fluid is a potential source of cardiac angiotensins. Binding of renin to cardiac membranes may be part of a mechanism by which renin is taken up from plasma.
Effect of nifedipine on coronary capillary geometry in normotensive and hypertensive rats.
Authors: Rakusan K , Cicutti N , Kazda S , Turek Z
Published: June 2012

The aim of this study was to describe quantitatively changes in the coronary capillary network resulting from hypertrophy in spontaneously hypertensive rats (SHR) and a potential effect of long-term treatment of these animals with nifedipine. Age-matched male SHR and Wistar-Kyoto (WKY) rats were treated for 27 weeks. Four experimental groups were analyzed: (1) untreated SHR, (2) nifedipine-treated SHR, (3) untreated control WKY rats, and (4) nifedipine-treated WKY rats. Treatment significantly decreased systolic blood pressure in SHR, although normotensive pressures were not reached. SHR had significantly higher cardiac weight, which decreased in nifedipine-treated rats, but values remained above those in control animals. Morphometric evaluation revealed lower capillary density and larger capillary domain area in hearts from SHR, which were partially attenuated by treatment with nifedipine. Capillary domain area was also significantly larger at arteriolar portions compared with domains supplied at venular portions. Capillary segment length was consistently shorter on the venular than arteriolar portion of the capillary, whereas no differences were observed between hearts from WKY rats and SHR. Treatment with nifedipine resulted in a prolongation of segment length. Reconstruction of the three-dimensional capillary supply unit (capillary domain area times capillary segment length) revealed significant differences between the amount of tissue supplied by a capillary at its arteriolar portion than more distally, which was detectable in all experimental groups. In hypertrophic hearts from SHR this tissue volume is increased mainly because of longer intercapillary distances and larger domains, especially on arteriolar portions.(ABSTRACT TRUNCATED AT 250 WORDS)
Antihypertensive effect of amlodipine and lack of interference with cyclosporine metabolism in renal transplant recipients.
Authors: Toupance O , Lavaud S , Canivet E , Bernaud C , Hotton J M , Chanard J
Published: June 2012

The catabolism of various calcium channel blockers through cytochrome P-450 is heterogeneous and may be modified by concomitant use of cyclosporin A. In an open study we investigated the antihypertensive effect and clinical tolerance of the dihydropyridine amlodipine and its effects on cyclosporine kinetics in stable hypertensive renal transplant recipients not taking corticosteroids. Ten adult hypertensive patients grafted for 21.4 +/- 8.9 months and well stabilized with normal renal function were included in the study. Renal artery stenosis was ruled out by normal Doppler echography. After 2 weeks of placebo, amlodipine was started at a daily dose of 5 mg. The dose was then adjusted to 10 mg if necessary. Blood and urine chemistries and whole-blood cyclosporine trough levels were measured weekly. Cyclosporine kinetics were determined on a hourly basis before amlodipine administration and after 4 weeks of treatment. Normal blood pressure was obtained with the use of 5 mg/d amlodipine in 7 patients and 10 mg/d in 3, diastolic blood pressure decreasing from 98.7 +/- 3.8 to 81.3 +/- 9.1 mm Hg (P = .0007). Heart rate slightly increased by 10% (P < .02). The drug was well tolerated, and only minor ankle edema was found in 3 patients. Cyclosporine doses were not modified and cyclosporine levels remained unchanged throughout the study. Cyclosporine kinetic parameters were not significantly different at the beginning and end of the study. Bioequivalence was demonstrated indicating that cyclosporine biotransformation was not altered by the concomitant administration of amlodipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Short-term effects of angiotensin II blockade on renal blood flow and sympathetic activity in awake rats.
Authors: Takishita S , Muratani H , Sesoko S , Teruya H , Tozawa M , Fukiyama K , Inada Y
Published: June 2012

To investigate the effects of an angiotensin II type 1 receptor antagonist (CV-11974) on renal blood flow and renal sympathetic nerve activity compared with a calcium antagonist (nicardipine), we measured both parameters in conscious spontaneously hypertensive rats aged 13 to 15 weeks. One to 2 days after surgery, CV-11974 (n = 9) and nicardipine (n = 8) were intravenously administered to decrease arterial pressure in a similar time course and degree of hypotension. CV-11974 increased renal blood flow by 23 +/- 4% at the maximal fall in mean arterial pressure (-32 +/- 1 mm Hg), and renal nerve activity increased by 70 +/- 7%. The maximal increase in renal blood flow (+27 +/- 4%) was observed when mean pressure was reduced by approximately 20 mm Hg. The maximal reduction of renal vascular resistance (-33 +/- 3%) correlated significantly with pretreatment levels of plasma renin concentration (r = -.792). In contrast, nicardipine produced a progressive reduction of renal blood flow and marked increases in heart rate and renal nerve activity. Increases in heart rate and nerve activity were greater than those with CV-11974 treatment (P < .001). At the maximal fall in mean pressure (-32 +/- 1 mm Hg), renal blood flow decreased by 23 +/- 4%, which was significantly correlated with percent changes in renal nerve activity (+150 +/- 11%, r = -.744). Renal denervation in another set of rats (n = 6) improved renal blood flow and renal vascular resistance responses to nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)
Venous distensibility during pregnancy. Comparisons between normal pregnancy and preeclampsia.
Authors: Sakai K , Imaizumi T , Maeda H , Nagata H , Tsukimori K , Takeshita A , Nakano H
Published: June 2012

Preeclampsia is associated with increased peripheral resistance. This study was performed to determine whether an increase of venous distensibility occurs as well in preeclampsia. We obtained venous distensibility by measuring the venous pressure-volume relation in the forearm with a water-filled plethysmograph. Twenty-one women with normal pregnancy, 12 women with severe preeclampsia, and 8 women with mild preeclampsia were studied during the third trimester and/or 6 weeks after the delivery. Ten nonpregnant normotensive women were also studied. Venous distensibility was greater (P < .01) in normal pregnant women and smaller (P < .01) in women with preeclampsia during pregnancy than postpartum. The magnitude of the decrease of venous distensibility correlated with the severity of preeclampsia. Venous distensibility was similar between normotensive nonpregnant women, women with normal pregnancy during the postpartum period, and women with preeclampsia during the postpartum period. Thus, venous distensibility increased during normal pregnancy. In preeclampsia, the decrease of venous distensibility occurred during pregnancy but was reversed postpartum. These results may suggest that a decrease of venous distensibility occurs during preeclampsia. These venous abnormalities may contribute to impaired control of hemodynamics in preeclampsia during pregnancy.
Ouabain is not detectable in human plasma.
Authors: Lewis L K , Yandle T G , Lewis J G , Richards A M , Pidgeon G B , Kaaja R J , Nicholls M G
Published: June 2012

An enzyme-linked immunosorbent assay is described for the measurement of ouabain in human plasma. This assay is specific for ouabain, strophanthidin, and ouabagenin, with other steroids, including digoxin and vasopressor hormones, exhibiting negligible cross-reactivity. Assay sensitivity was 0.06 nmol/L if 1 mL plasma was extracted and less than 0.005 nmol/L when 20 mL plasma was analyzed. Extracted plasma samples showed ouabainlike immunoreactivity that diluted in parallel with the ouabain standard curve. Repeated extraction and assay of single plasma samples, however, did not produce consistent results in the assay. Increased specificity was obtained by high-performance liquid chromatography of sample extracts before assay. When high-performance liquid chromatographic profiles of plasma spiked with ouabain standard or following bolus intravenous injections of ouabain into normal human volunteers were compared with profiles of unspiked plasma, there was no support for the immunoreactive material in the latter samples being ouabain. We propose that if ouabain is present in the human circulation, its concentration is less than 0.005 nmol/L.
Clinical studies on the sites of production and clearance of circulating adrenomedullin in human subjects.
Authors: Nishikimi T , Kitamura K , Saito Y , Shimada K , Ishimitsu T , Takamiya M , Kangawa K , Matsuo H , Eto T , Omae T
Published: June 2012

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67 +/- 10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42 +/- 14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery.(ABSTRACT TRUNCATED AT 250 WORDS)
Association of salt sensitivity in rats with genes of the major histocompatibility complex.
Authors: Kunes J , Zicha J
Published: June 2012

Dietary sodium intake has long been considered an important factor in the genesis and maintenance of hypertension in both humans and experimental animals. To identify the possible association between salt sensitivity and genes of the major histocompatibility complex (RT1 complex), we studied the blood pressure response to an 8% NaCl diet in normotensive Lewis rats, spontaneously hypertensive rats (SHR), and Lewis.1K congenic rats (congenic to Lewis with the SHR main histocompatibility complex RT1). During the first 4 weeks of a high salt diet, the blood pressure increase was the same in SHR and Lewis.1K congenic rats. Thus, the presence of a small segment of SHR chromosome 20 with genes of the RT1 complex (and closely related genes) in the Lewis genome sensitized the blood pressure of these animals to the hypertensive effects of a high salt diet. Genes of the RT1 complex influenced the salt-induced increase of relative kidney weight more than that of relative heart weight. Our results support the hypothesis that some alleles within or close to the RT1 complex might be responsible for the higher sensitivity of hypertensive individuals to certain environmental stressors, including high salt intake.
Sustained Hypertension in Dahl Rats
Authors: Kong Jain-Qiang , Taylor David A. , Fleming William W.
Published: June 2012

Abstract
The perfused mesenteric vasculature of Dahl salt-sensitive rats on a high salt diet for 5 days (prehypertensive or early hypertensive) is selectively supersensitive to norepinephrine. The present goal was to determine whether that supersensitivity was maintained as hypertension developed. Littermates of salt-sensitive and salt-resistant rats (Dahl Brookhaven strain) were followed on low or high salt for up to 6 weeks. Systolic blood pressure was elevated in the salt-sensitive, high salt rats after 3 or 6 weeks but not after 5 days of the diet. The perfused mesenteric vascular beds from salt-sensitive rats were supersensitive to norepinephrine and nerve stimulation but not to potassium chloride when the rats had been maintained for 5 days or 3 weeks on the high salt diet. However, responses to norepinephrine declined after 6 weeks of the high salt diet. To determine whether sustained high blood pressure has a negative effect on mesenteric vascular responses, we conducted additional experiments with perfused mesenteric vascular beds from salt-sensitive Brookhaven (high salt, 5 weeks) and Rapp (high salt, 6 weeks) animals. Both groups exhibited significant negative correlations between in vivo systolic pressure and maximal responses of mesenteric vessels to norepinephrine and potassium chloride. We suggest that sustained hypertension in Dahl rats has a negative effect on the contractility of the mesenteric arterial system that, by 5 to 6 weeks, masks the initial supersensitivity to norepinephrine. No effects of any diet on the dilating responses of the mesenteric vessels to acetylcholine were observed in any group.
Characterization of the Angiotensin II Receptor Antagonist TCV-116 in Healthy Volunteers
Authors: Delacrétaz Etienne , Nussberger Jürg , Biollaz Jerôme , Waeber Bernard , Brunner Hans R.
Published: June 2012

Abstract
The purpose of this study was to assess the inhibitory effect of TCV-116, an orally active angiotensin II (Ang II) antagonist, on the pressor action of exogenous Ang II and to determine the compensatory rise in plasma renin activity and Ang II levels. Twenty-three male volunteers were treated for 8 days in a double-blind fashion with either placebo or TCV-116 (1, 2, or 4 mg PO daily) and challenged on the first, fourth, and eighth days with repeated bolus injections of Ang II. An additional 4 subjects received 8 mg PO daily in a single-blind fashion. The inhibitory effect on the systolic blood pressure response to Ang II was long lasting and clearly dose related. Six hours after 4 mg TCV-116, the systolic blood pressure response to a given dose of Ang II was reduced to 40±4% and 35±8% of baseline value on days 1 and 8, respectively. TCV-116 induced a dose-related increase in plasma renin activity and Ang II levels that was more pronounced on the eighth than on the first day of drug administration. Despite this compensatory mechanism, the relation between the time-integrated systolic blood pressure response to Ang II and the time-integrated CV-11974 levels, the active metabolite of TCV-116, was not different between days 1 and 8. In conclusion, TCV-116 appears to be a well-tolerated, orally active, potent, and long-lasting antagonist of Ang II in men.
Racial Differences in Epinephrine and β
2
-Adrenergic Receptors
Authors: Mills Paul J. , Dimsdale Joel E. , Ziegler Michael G. , Nelesen Richard A.
Published: June 2012

Abstract
This study examined the effects of ethnicity and hypertension on β
2
-adrenergic receptors and on plasma catecholamines in a group of 77 unmedicated mildly hypertensive and normotensive men. Black hypertensive subjects had the most sensitive and white hypertensive subjects the least sensitive β-receptors (as assessed by isoproterenol-stimulated cyclic AMP in lymphocytes [
P
=.02]). In contrast, postreceptor adenylate cyclase activation (as assessed by forskolin stimulation) was similar among groups. As with β-receptor sensitivity, black hypertensive subjects had the highest β-receptor density and white hypertensive subjects the lowest (
P
=.03). Blacks demonstrated lower plasma epinephrine values compared with whites (
P
=.03). Across all subjects, plasma epinephrine was negatively correlated with β-receptor density (
r
=−.26,
P
<.05) and sensitivity (
r
=−.25,
P
<.05). There were no group differences in binding affinity to the β-antagonist iodopindolol. The findings support the notion of increased β-adrenergic receptors in hypertension in blacks.
Hypertension and the Pathogenesis of Atherosclerosis
Authors: Alexander R. Wayne
Published: June 2012

Abstract
Hypertension is a risk factor for the development of atherosclerosis, although the mechanisms have not been well elucidated. As the cellular and molecular mechanisms of the pathogenesis of atherosclerosis and the effects of hypertension are being more clearly defined, it becomes apparent that the two processes have certain common mechanisms. The endothelium is a likely central focus for the effect of both diseases. There is increasing evidence that atherosclerosis should be viewed fundamentally as an inflammatory disease. Atherogenic stimuli such as hyperlipidemia appear to activate the inflammatory response by causing expression of mononuclear leukocyte recruiting mechanisms. The gene for one of these, the vascular cell adhesion molecule-1, is controlled at least in part by transcriptional factors regulated by oxidative stress, which modifies the redox state of the endothelial cell. Alterations in the redox state of the arterial wall also may contribute to vascular smooth muscle cell growth. In a somewhat parallel fashion, there is evidence that hypertension may also exert oxidative stress on the arterial wall. This article reviews evidence that leads to the postulate that hypertension predisposes to and accelerates atherosclerosis at least in part because of synergy between elevated blood pressure and other atherogenic stimuli to induce oxidative stress on the arterial wall.
Inhibition of Endothelial Nitric Oxide Synthase Activity by Protein Kinase C
Authors: Hirata Ken-ichi , Kuroda Ryohei , Sakoda Tsuyoshi , Katayama Masaya , Inoue Nobutaka , Suematsu Masakuni , Kawashima Seinosuke , Yokoyama Mitsuhiro
Published: June 2012

Abstract
Nitric oxide (NO) is an important molecular messenger accounting for endothelium-derived relaxing factor. Recently, NO synthase (NOS) from cultured endothelial cells has been purified and molecularly cloned. To evaluate the effect of phosphorylation by protein kinase C (PKC) and cyclic AMP–dependent protein kinase (PKA) on endothelial constitutive NOS catalytic activity, we incubated purified endothelial NOS with PKC or PKA. Endothelial NOS was stoichiometrically phosphorylated by PKC and PKA. In intact bovine aortic endothelial cells (BAECs), NOS was phosphorylated by stimulation with 12-
O
-tetradecanoylphorbol-13-acetate (TPA). NOS activity measured by the conversion of [
3
H]arginine to [
3
H]citrulline in homogenates of BAECs treated with TPA or phorbol 12,13-dibutyrate was reduced by 30%, whereas dibutylyl cyclic AMP did not affect NOS activity. Moreover, we measured NO release from cultured BAECs by a chemiluminescence method to examine the effect of PKC and PKA on endothelial NOS activity. In cultured BAECs, ATPγS and A23187 induced NO release in time- and dose-dependent manners. Phorbol esters such as TPA and phorbol 12,13-dibutyrate dose dependently inhibited NO release stimulated by A23187 as well as ATPγS. Reduction of NO release by TPA was almost completely prevented by pretreatment with staurosporine, an inhibitor of PKC. NO release by A23187 was increased in PKC-downregulated BAECs. In contrast, dibutylyl cyclic AMP or 8-bromo cyclic GMP had no effect on NO release from BAECs induced by A23187 or ATPγS. These results indicate that phosphorylation of NOS by PKC is associated with a reduction of its catalytic activity in vascular endothelial cells.
Feasibility Study of N-of-1 Trials With Blood Pressure Self-Monitoring in Hypertension
Authors: Chatellier Gilles , Day Martin , Bobrie Guillaume , Menard Joël
Published: June 2012

Abstract
The objective of this study was to assess individual responses to antihypertensive treatment by N-of-1 trials using blood pressure self-monitoring in 79 patients of both sexes referred to a hypertension clinic. Thirty-five patients who remained untreated (study 1) and 44 N-of-1 trial participants (study 2) were consecutively selected if their clinic blood pressure was between 160/95 and 220/115 mm Hg and there were no hypertensive complications. Blood pressure was measured daily at home for 21 days (three consecutive measures, morning and evening). Each N-of-1 trial was a single-blind treatment consisting of two successive 10-day treatment pairs, each pair comprising 5 days of placebo followed by 5 days of 20 mg enalapril once daily in the morning. Study 1 showed no significant blood pressure regression toward the mean over 20 days and justified the choice of 5-day treatment periods in study 2. In study 2, blood pressure fell significantly 12 hours after the first administration of enalapril and rose within 24 hours of the end of the 5-day active treatment period. Using evening blood pressure values (12 hours after enalapril intake) from the first treatment pair, 33 patients were classified as responders (diastolic blood pressure fall ≥6 mm Hg). In 16 of these 33 patients, the fall in blood pressure above 6 mm Hg was not maintained in the morning, 24 hours after drug intake. Response reproducibility was tested by comparison with the second treatment pair: the observed agreement was only 0.71 (chance-corrected agreement: 0.34) when defined according to both evening and morning values. N-of-1 trial methodology can be useful for decision making in the care of individual patients. It can be based on the use of home blood pressure determinations, provided that there are at least 30 readings in each 5-day trial period. The individual agreement between the antihypertensive responses to two successive enalapril treatment periods is only moderate and is not sufficient to justify using this design for performing in individual patients randomized comparison of an angiotensin-converting enzyme inhibitor and another antihypertensive drug.
Association of the α-Adducin Locus With Essential Hypertension
Authors: Casari Giorgio , Barlassina Cristina , Cusi Daniele , Zagato Laura , Muirhead Roslyn , Righetti Marco , Nembri Paola , Amar Karen , Gatti Massimo , Macciardi Fabio , Binelli Giorgio , Bianchi Giuseppe
Published: June 2012

Abstract
Previous studies on genetic rat hypertension have shown that polymorphism within the α-adducin gene may regulate blood pressure. Adducin is a cytoskeletal protein that may be involved in cellular signal transduction and interacts with other membrane-skeleton proteins that affect ion transport across the cell membrane. There is a high homology between rat and human adducin and pathophysiological similarities between the Milan hypertensive rat strain and a subgroup of patients with essential hypertension. Thus, we designed a case-control study to test the possible association between the α-adducin locus and hypertension. One hundred ninety primary hypertensive patients were compared with 126 control subjects. All subjects were white and unrelated. Four multiallelic markers surrounding the α-adducin locus located in 4p16.3 were selected: D4S125 and D4S95 mapping at 680 and 20 kb centromeric, and D4S43 and D4S228/E24 mapping at 660 and 2500 kb telomeric. Alleles for each marker were pooled into groups. Comparisons between control subjects and hypertensive patients were carried out by testing the allele-disease association relative to the marker genotype. The maximal association occurred for D4S95 (χ

1
2

13.33), which maps closest to α-adducin. These data suggest that a polymorphism within the α-adducin gene may affect blood pressure in humans.
Enhanced Na
+
-H
+
Exchanger Activity and NHE-1 mRNA Expression in Lymphocytes From Patients With Essential Hypertension
Authors: Garciandia Ana , López Rafael , Tisaire Javier , Arrázola Arantxa , Fortuño Antonia , Bueno José , Diez Javier
Published: June 2012

Abstract
It has been demonstrated that the activity of the sodium-proton exchanger (NHE-1 isoform) is increased in lymphocytes and other blood cells from patients with essential hypertension. In the present study, we investigated whether an increased level of NHE-1–specific mRNA in lymphocytes from patients with essential hypertension would explain the enhanced transport activity. Twenty-two hypertensive patients and 21 normotensive subjects were studied. Basal cytosolic pH was measured by the pH-sensitive fluorescent probe 2′,7′-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Maximal sodium-proton exchange activity was determined by acidifying cell pH and measuring the initial rate of the net sodium-dependent proton efflux driven by an outward proton gradient. The transcript level of NHE-1 was measured by reverse transcription–polymerase chain reaction in comparison with a constitutively expressed reference gene (β-actin). Intracellular pH was lower in hypertensive patients than normotensive subjects (7.34±0.01 versus 7.39±0.01, mean±SEM,
P
<.001). The maximal activity of the sodium-proton exchanger was higher in hypertensive patients than in normotensive subjects (1262±100 versus 881±56 mmol/L cells per hour,
P
<.01). NHE-1 mRNA was increased in hypertensive patients compared with normotensive subjects (ratio of NHE-1 mRNA to β-actin mRNA, 0.16±0.01 versus 0.12±0.02,
P
<.05). These data suggest that the increased sodium-proton exchange activity in essential hypertension may be related to the de novo synthesis of exchanger protein.
Regulation of Neuronal Nitric Oxide Synthase in Rat Adrenal Medulla
Authors: Iwai Naoharu , Hanai Kazumitsu , Tooyama Ikuo , Kitamura Yoshihisa , Kinoshita Masahiko
Published: June 2012

Abstract
Neuronal nitric oxide synthase (nNOS) has been suggested to be involved in cardiovascular homeostasis. We studied the regulation of nNOS expression, determining nNOS mRNA expression levels in various tissues in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). We also investigated the effects of antihypertensive treatment with the angiotensin II antagonist hydralazine or reserpine on nNOS mRNA expression. The expression levels of nNOS mRNA and nNOS protein were determined by Northern and Western blot analysis, respectively. NADPH-diaphorase histochemistry was used to identify cells in the adrenal medulla that expressed nNOS. No significant differences in expression levels in SHR and WKY were observed in the cerebellum and brain stem. nNOS mRNA expression levels in the decapsular portion of the adrenal gland were developmentally modulated and in a 24-week-old WKY were 2.5 times higher than in an age-matched SHR. This reduced expression of nNOS mRNA in the decapsular portion of the adrenal gland of SHR seemed to be a result of hypertension in the SHR, because administration of either an angiotensin II antagonist (TCV-116) or hydralazine upregulated nNOS mRNA expression in both SHR and WKY. Marked augmentation of nNOS mRNA expression in the decapsular portion of the adrenal gland by reserpine treatment suggested an intimate relation between nNOS in the decapsular portion of the adrenal gland and the sympathoadrenal system. Reserpine treatment also increased the expression of nNOS protein; however, reserpine treatment did not affect the distribution pattern of nNOS-positive cells (NADPH-diaphorase–positive cells) in the adrenal medulla. The present results suggest that nNOS gene expression in the decapsular portion of the adrenal gland is not constitutive and that an intimate relation may exist between nNOS in the decapsular portion of the adrenal gland and the sympathoadrenal system.
Renal Nerves, Renin, and Angiotensinogen Gene Expression in Spontaneously Hypertensive Rats
Authors: Nakamura Akio , Johns Edward J.
Published: June 2012

Abstract
We compared the effect of the renal nerves on renal function, plasma renin activity, and renal renin and angiotensinogen mRNA contents in Wistar rats and spontaneously hypertensive rats (SHR). Rats were anesthetized with sodium pentobarbital, the left kidney was exposed, its nerves were sectioned, the ureter was cannulated, and a flow probe was placed on the renal artery. The renal nerves were stimulated for 1 hour to reduce renal blood flow by 15% and 30%, after which blood was removed for measurement of plasma renin activity, and kidneys were analyzed for renal renin and angiotensinogen mRNA. Frequency-related reductions in filtration rate were similar, from 15% to 50%, as was sodium excretion, from 30% to 70%, in both SHR and Wistar rats. Basal plasma renin activity and responses to nerve stimulation in SHR were approximately half those of Wistar rats (all
P
<.001). SHR renal renin mRNA concentrations were approximately three quarters those of Wistar rats and were unchanged by either low- or high-level renal nerve stimulation, whereas the higher rate increased renin mRNA approximately threefold (
P
<.05) in the Wistar rats. SHR renal angiotensinogen mRNA was one quarter that of the Wistar rats and was unaffected by nerve stimulation, whereas in the Wistar rats it was increased threefold (
P
<.05) by the low but not high level of nerve stimulation. These findings show that whereas the renal nerves are able to modulate hemodynamic and tubular functions relatively normally in SHR, their ability to increase renin release, renal renin, and angiotensinogen mRNA levels is depressed.
Mapping of G Protein Coupling Sites of the Angiotensin II Type 1 Receptor
Authors: Shirai Heigoro , Takahashi Katsunobu , Katada Toshiaki , Inagami Tadashi
Published: June 2012

Abstract
Angiotensin II type 1 (AT
1
) receptors have been identified in a wide variety of tissues, including the kidney, liver, adrenal gland, cardiovascular system, and brain. AT
1
receptors also mediate complex signaling mechanisms that elicit a diversity of specific physiological effects. The rat AT
1A
receptor has seven transmembrane domains and couples with three distinct G proteins: G
q
, G
i
, and G
o
. But it is unknown which domains of AT
1A
couple with and activate each type of G protein. To identify the domains responsible for the activation of various types of G protein, we studied the effect of five different synthetic peptides representing different domains of cytosolic segments of the rat AT
1A
receptor on the binding of the
35
S-labeled stable analogue of GTP, GTPγS. Peptides P-3, which is located in the N-terminal region of the putative third intracellular loop of AT
1A
(residues 216 through 230), and P-5 (residues 306 through 320), corresponding to the N-terminal region of the C-terminal tail, were found to activate purified G
i1
, G
i2
, and G
o
proteins. These results indicate that not only the third cytosolic loop but also the C-terminal cytosolic domain of AT
1A
is important for G
i1
, G
i2
, and G
o
protein coupling and activation.
Antihypertensive Actions of the Novel Nonpeptide Endothelin Receptor Antagonist SB 209670
Authors: Douglas Stephen A. , Gellai Miklos , Ezekiel Mildred , Feuerstein Giora Z. , Elliott John D. , Ohlstein Eliot H.
Published: June 2012

Abstract
Indirect evidence has implicated endothelin-1 in the pathogenesis of hypertension. In the present study we examined such a role directly with SB 209670, a novel nonpeptide endothelin receptor antagonist. The antihypertensive and hemodynamic effects of SB 209670 were examined in conscious, unrestrained spontaneously hypertensive (SHR), normotensive Wistar-Kyoto (WKY), and renin-hypertensive rats. Sustained intravenous infusion of SB 209670 (10 μg · kg
−1
· min
−1
for 6 hours) produced a significant, reversible reduction in mean arterial pressure in SHR but not in WKY rats. The antihypertensive response to 10 μg · kg
−1
· min
−1
SB 209670 (∼25 mm Hg reduction in blood pressure) was associated with bradycardia (16% decrease in heart rate) but only a minimal reduction (3%) in cardiac output, because stroke volume was elevated (by 15%). Therefore, the antihypertensive effect of SB 209670 resulted from a decrease (13%) in total peripheral resistance. A sustained antihypertensive effect could also be observed after intraduodenal administration of SB 209670 (3 mg/kg) in conscious SHR (reduction of ∼35 mm Hg 5 hours after administration). SB 209670 (3 mg/kg intravenous bolus) did not alter the pressor response or tachycardia observed in pithed SHR after stimulation of thoracolumbar sympathetic outflow. SB 209670 was also antihypertensive in renin-hypertensive rats, lowering blood pressure to an extent similar to that observed in SHR. Thus, the data presented provide evidence to support a role for endothelin-1 in the pathophysiology of two animal models of hypertension.
Oscillatory Potentials of the Electroretinogram in Hypertensive Patients
Authors: Bellini Giuseppe , Bocin Elena , Cosenzi Alessandro , Sacerdote Ariela , Molino Rossella , Solimano Nicolò , Ravalico Giuseppe
Published: June 2012

Abstract
Because alteration of oscillatory potentials of the electroretinogram has been described in diabetic patients without signs of diabetic retinopathy as an early marker of changes in microcirculation, we studied the behavior of these potentials in patients with early-onset hypertension. Electroretinograms were recorded in 24 subjects with essential hypertension (blood pressure >140/90 mm Hg) and in 9 age-matched normotensive control subjects (blood pressure <140/90 mm Hg). Diabetes and ocular diseases were considered exclusion criteria. Sitting blood pressure was measured by a single investigator with a mercury sphygmomanometer after each subject had been at rest for 10 minutes. Funduscopic changes in all subjects did not exceed stage I World Health Organization classification. The oscillatory index was calculated by adding waves O1, O2, and O3 within the b wave of the electroretinogram. Statistical analysis was performed with Student’s
t
test for paired and unpaired data and linear regression. The oscillatory index was significantly reduced in hypertensive patients compared with normotensive subjects. An inverse relationship was observed when systolic and diastolic blood pressures were plotted against the oscillatory index. In conclusion, our data demonstrate that the electrical activity of the retina is altered early in the course of hypertension and that the influence of systolic pressure on the oscillatory index is greater than that of diastolic pressure.
Circulating Nitric Oxide (Nitrite/Nitrate) Levels in Postmenopausal Women Substituted With 17β-Estradiol and Norethisterone Acetate
Authors: Rosselli Marinella , Imthurn Bruno , Keller Paul J. , Jackson Edwin K. , Dubey Raghvendra K.
Published: June 2012

Abstract
Postmenopausal women (PMW) have an increased risk of cardiovascular disease that is attenuated by hormone replacement therapy (HRT). Inasmuch as hypertension and atherosclerosis are associated with diminished endothelium-derived nitric oxide (NO), we investigated whether HRT augments NO release in PMW. We determined serum levels of nitrite/nitrate (NO
2
+NO
3
) at baseline and during the 6th, 12th, and 24th months of the study in two groups of PMW. One group (HRT-PMW, n=13) received continuous transdermal administration of 17β-estradiol (Estraderm-TTS-50) supplemented with oral norethisterone acetate (NETA) on days 1 through 12 of each month, and the other group (control PMW, n=13) did not receive HRT. Blood samples in the HRT-PMW group were collected without regard to whether subjects were taking NETA at the time of blood sampling. Serum NO
2
+NO
3
levels increased in HRT-PMW for the duration of the study, whereas serum NO
2
+NO
3
levels remained unchanged in control PMW. When all samples regardless of timing of collection with respect to NETA treatment were included in the statistical analysis, the change in NO
2
+NO
3
levels in HRT-PMW was significantly greater compared with the change in control PMW (
P
=.037). Likewise, when only those samples collected when estradiol-treated subjects were not taking oral NETA were included in the statistical analysis, the change in NO
2
+NO
3
levels in the HRT-PMW group remained significant (
P
=.047) compared with control PMW. In contrast, when only those samples collected when estradiol-treated subjects were taking NETA were included in the analysis, the change in NO
2
+NO
3
levels in the HRT-PMW group was not significant (
P
=.23) compared with control PMW. These results indicate that HRT increases NO levels in PMW, an effect that may contribute to the cardiovascular protection afforded by HRT in PMW. In addition, our data suggest, but do not prove, that concomitant administration of a progestin may attenuate the beneficial effects of estrogen replacement therapy with regard to NO release.
Increased Hyaluronic Acid in the Inner Renal Medulla of Obese Dogs
Authors: Alonso-Galicia Magdalena , Dwyer Terry M. , Herrera Guillermo A. , Hall John E.
Published: June 2012

Abstract
Dogs placed on a high-fat diet develop obesity and hypertension associated with marked sodium retention that is due to increased tubular reabsorption. Previous studies showed that renal interstitial hydrostatic pressure is elevated in obese dogs compared with lean dogs, and histological studies revealed increases in medullary interstitial cells and expansion of the medullary but not the cortical extracellular matrix. This matrix stained intensively with Alcian Blue at pH 2.6, colloidal iron, and periodic acid–Schiff, suggesting increased glycosaminoglycans. The goal of this study was to quantitate medullary glycosaminoglycan content in obese (n=8) compared with lean (n=8) dogs. Measurement of total glycosaminoglycan content, estimated from uronic acid content, and of hyaluronate, the most abundant glycosaminoglycan in canine renal medulla, with an enzyme-linked immunosorbent assay indicated that there were no significant differences in total glycosaminoglycan or hyaluronate contents in the outer medulla of obese dogs compared with those in lean dogs. In contrast, in the inner medulla of obese dogs there was a 140% increase in hyaluronate compared with the content in lean dogs (4.3±0.5 versus 1.8±0.2 mg hyaluronate per gram wet tissue, respectively;
P
<.05); however, total glycosaminoglycan content was not significantly different (6.9±0.7 versus 6.2±0.5 mg uronic acid per gram wet tissue) in obese and lean dogs. These results suggest a change in the relative proportion of the glycosaminoglycan species in the inner medulla of obese dogs, with a selective increase in hyaluronate. These changes in extracellular matrix could contribute to the altered intrarenal physical forces, tubular compression, and increased tubular reabsorption observed in obese dogs.
Angiotensin and Bradykinin Peptides in the TGR(mRen-2)27 Rat
Authors: Campbell Duncan J. , Rong Pei , Kladis Athena , Rees Bronwyn , Ganten Detlev , Skinner Sandford L.
Published: June 2012

Abstract
The transgenic TGR(mRen-2)27 rat, in which the
Ren-2
mouse renin gene is transfected into the genome of the Sprague-Dawley rat, develops severe hypertension at a young age that responds to inhibitors of angiotensin-converting enzyme and to antagonists of the type 1 angiotensin II (Ang II) receptor. Despite this evidence that the hypertension is Ang II dependent, TGR(mRen-2)27 rats have suppressed renal renin and renin mRNA content, and there is controversy concerning the plasma levels of renin and Ang II in these rats. We investigated the effect of the transgene on circulating and tissue levels of angiotensin and bradykinin peptides in 6-week-old male homozygous TGR-(mRen-2)27 rats. Systolic blood pressure of TGR(mRen-2)27 rats was 212±4 mm Hg (mean±SEM, n=25) compared with 108±2 mm Hg (n=29) for age- and sex-matched Sprague-Dawley rats. Compared with control rats, TGR(mRen-2)27 rats had increased plasma levels of active renin (4.5-fold), prorenin (300-fold), and Ang II (fourfold) as well as tissue levels of Ang II (twofold to fourfold in kidney, adrenal, heart, aorta, brown adipose tissue, and lung and 18-fold in brain). Plasma angiotensinogen levels were reduced to 73% of control, and plasma aldosterone levels were increased fourfold. Plasma angiotensin-converting enzyme was reduced to 64% of control. Compared with control rats, TGR-(mRen-2)27 rats had increased bradykinin levels in brown adipose tissue (1.9-fold) and lung (1.6-fold). The elevated circulating and tissue levels of Ang II in TGR(mRen-2)27 rats provide direct support for an Ang II–dependent mechanism of hypertension in these rats.
A Noninvasive Computerized Tail-Cuff System for Measuring Blood Pressure in Mice
Authors: Krege John H. , Hodgin Jeffrey B. , Hagaman John R. , Smithies Oliver
Published: June 2012

Abstract
We have validated a noninvasive computerized tail-cuff system for measuring blood pressure in mice. The system was designed to perform all functions automatically, including a programmable routine of cuff inflation and deflation, analysis and assignment of pulse rate and blood pressure, and recording of data electronically. To evaluate this system over a range of blood pressures, we gave groups of mice enalapril or
N
G
-nitro-
l
-arginine methyl ester in their drinking water. For each of these groups, an equal number of control mice were given nothing in their drinking water. Tail-cuff blood pressures were recorded as the means of blood pressures determined on at least 3 days after at least 7 days of training. Tail-cuff enalapril and control group means were measured both 3 and 4 months after enalapril (or no drug) was begun; the group means at 3 months were not significantly different from the group means at 4 months. These results demonstrate that the system gives reproducible results. After the tail-cuff measurements were completed, intra-arterial blood pressures were attempted in all mice under unrestrained, unanesthetized conditions, and individual mouse (n=22) blood pressures with the use of the two methods were compared. The blood pressures from individual mice by tail-cuff and intra-arterial methods were highly correlated (
r
=.86,
P
<.01). The means for the four mouse groups were also highly correlated (
r
=.98,
P
<.02). These data show that blood pressures measured on trained mice by a computerized noninvasive tail-cuff system are reproducible and correlate well with intra-arterial blood pressures measured on unrestrained, unanesthetized mice.