bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased transcripts for B-type natriuretic peptide in spontaneously hypertensive rats. Quantitative polymerase chain reaction for atrial and brain natriuretic peptide transcripts.
Authors: Dagnino L , Lavigne J P , Nemer M
Published: June 2012

The cardiac natriuretic peptide family includes atrial natriuretic factor and brain or B-type natriuretic peptide, also known as iso-atrial natriuretic factor (isoANF). Although these peptides contribute to cardiovascular homeostasis, their respective roles remain unclear. To study regulation of atrial natriuretic factor and isoANF gene expression during progression of hypertension, we developed a quantitative polymerase chain reaction protocol to measure their transcript level in spontaneously hypertensive rat (SHR) hearts. At the onset of hypertension, atrial natriuretic factor transcripts in 5-week-old SHR were 50% of those of age-matched Wistar-Kyoto (WKY) rats, whereas the level of isoANF transcripts was similar in atria and twofold higher in ventricles. Because atria are the major sites of atrial natriuretic factor gene expression and ventricles contribute predominantly to cardiac isoANF synthesis, total atrial natriuretic factor messenger RNA (mRNA) in the hearts of 5-week-old SHR was about 50% of that in WKY rats, and total isoANF mRNA content was already higher than in control rats. In left ventricles and ventricular septa, progression of hypertension led to a maximal increase of twofold and fourfold in atrial natriuretic factor and isoANF mRNA levels, respectively, with no detectable change in right ventricles. In the atria of older SHR, atrial natriuretic factor and isoANF mRNA levels were comparable to those of age-matched controls. These data indicate that, although increased blood pressure stimulates both atrial natriuretic factor and isoANF gene expression, regulation of the two natriuretic peptide genes is not temporally coordinated in all cardiac compartments. Furthermore, isoANF mRNA is already induced in the ventricles at the onset of the hypertensive stage, and in older SHR, the isoANF gene is hyperresponsive to progression of hypertension compared with atrial natriuretic factor. Thus, isoANF might represent a very sensitive marker of cardiac changes in hypertension.
Blocking hypothalamic AT1 receptors lowers blood pressure in salt-sensitive rats.
Authors: Yang R H , Jin H , Chen S J , Wyss J M , Oparil S
Published: June 2012

Previous studies from our laboratory have shown that microinjection of DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist of type 1 angiotensin II receptors, into the anterior hypothalamic area produces a dose-related depressor response in salt-sensitive spontaneously hypertensive rats fed a basal (1%) salt diet. The current study tested the hypothesis that the depressor response to anterior hypothalamic type 1 angiotensin II receptor blockade with DuP 753 or its metabolite EXP 3174 is enhanced by high (8%) salt feeding in this model. DuP 753 or EXP 3174 (40 micrograms in 100 nl artificial cerebrospinal fluid vehicle) or vehicle alone was microinjected into the anterior hypothalamic area of conscious salt-sensitive spontaneously hypertensive and Wistar-Kyoto rats that had been fed 1% or 8% salt diets for 3 weeks. Both DuP 753 and EXP 3174 caused significant decreases in mean arterial pressure in spontaneously hypertensive but not in Wistar-Kyoto rats fed either diet. The magnitude and duration of the depressor responses to DuP 753 and EXP 3174 were significantly greater in the 8% salt-fed spontaneously hypertensive rats than in 1% salt-fed rats. Vehicle injections had no effect on blood pressure in either strain-diet group. Microinjection of angiotensin II (2 micrograms in 100 nl artificial cerebrospinal fluid vehicle) into the anterior hypothalamic area caused significant pressor and bradycardiac responses in all strain-diet groups; dietary salt supplementation enhanced these effects in salt-sensitive spontaneously hypertensive rats but not in Wistar-Kyoto rats. These responses were blocked by pretreatment with EXP 3174.(ABSTRACT TRUNCATED AT 250 WORDS)
Non-modulation as an intermediate phenotype in essential hypertension.
Authors: Williams G H , Dluhy R G , Lifton R P , Moore T J , Gleason R , Williams R , Hunt S C , Hopkins P N , Hollenberg N K
Published: June 2012

Non-modulation is a trait characterized by abnormal angiotensin-mediated control of aldosterone release and the renal blood supply. To determine whether non-modulation defines a specific subgroup of the hypertensive population and its utility as an intermediate phenotype, we have studied the distribution of this quantitative trait, whether its features are reproducible on repeated testing, and whether there is concordance of its multiple features. Essential hypertensive patients (224) and normotensive subjects (119) received an infusion of angiotensin II (Ang II) at 3 ng.kg-1.min-1 for 30-45 minutes. p-Aminohippurate (PAH) clearance was assessed as an index of renal plasma flow while the subjects were on a 200 meq sodium diet; plasma aldosterone levels were measured while the subjects were on a 10 meq sodium diet. In 54 subjects, diuretic-induced volume depletion superimposed on a low salt diet was substituted for the Ang II infusion. The results of each study were submitted to maximum likelihood analysis to assess bimodality. In response to both diuretic-induced volume depletion (p < 0.000023) and Ang II infusion (p < 0.0009), aldosterone responses were bimodally distributed in the essential hypertensive but not in the normotensive subjects, suggesting that this trait identifies a discrete subgroup. In the 59 subjects who had both an adrenal and renal study, 50 (85%) were concordant. Finally, in 27 subjects studied two to six times over a span of 1-60 months, the intraclass correlations of the adrenal, PAH, or both responses were highly significant (p values between 0.001 and 0.00007), indicating high reproducibility of results on repeated testing.(ABSTRACT TRUNCATED AT 250 WORDS)
Marine oils dose-dependently inhibit vasoconstriction of forearm resistance vessels in humans.
Authors: Chin J P , Gust A P , Nestel P J , Dart A M
Published: June 2012

The effects of dietary supplementation with marine oils on vascular reactivity in human forearm resistance arteries were studied. Healthy male adults (six to nine subjects per group) were given either maxEPA capsules (content: eicosapentaenoic acid, 0.178 g/g; docosahexaenoic acid, 0.116 g/g) at doses of 20, 10, or 5 g/day or placebo capsules at 20 g/day for 28 days. Capsule compliance was confirmed by measurement of platelet membrane incorporation of n-3 fatty acids. Blood pressure was not affected by either maxEPA or placebo. The influence of treatment interventions on forearm vasoconstrictive responses to local infusions of angiotensin II and norepinephrine was examined using venous occlusion plethysmography before and after treatment. Responses to both agonists were significantly suppressed by 20 g/day maxEPA (slopes before and after maxEPA, respectively: angiotensin II, 3.34 and 0.89; norepinephrine, 0.91 and 0.41). When analyzed as difference in area under the dose-response curves, the suppressive effects of maxEPA were clearly dose dependent (angiotensin II: 20 g area reduced by 72%, 10 g by 67%, 5 g by 33%). Similarly, responses to norepinephrine were dose-dependently suppressed by maxEPA (20 g area reduced by 61%, 10 g by 63%, and 5 g by 33%). Placebo had no effect on the responses to either constrictor. The responses to both agonists returned to preoil levels after 2 months' discontinuation of 20 g/day maxEPA. We conclude that the suppressive effects of marine oils on vascular reactivity may, in part, contribute to their cardioprotective influence in humans.
Doxazosin and captopril in mildly hypercholesterolemic hypertensive patients. The Doxazosin-Captopril in Hypercholesterolemic Hypertensives Study.
Authors: Ferrara L A , Di Marino L , Russo O , Marotta T , Mancini M
Published: June 2012

The evidence linking hypertension and hypercholesterolemia is strong and has fueled research into possible adverse effects of some antihypertensive agents on serum lipid profile. This multicenter, open, parallel study compares the effects of doxazosin and captopril on blood pressure, serum lipid levels, and quality of life in 224 hypercholesterolemic hypertensive patients. Blood pressure was significantly reduced in both treatment groups (p < 0.001) and was normalized (standing diastolic pressure < or = 90 mm Hg) in 73% of the doxazosin patients and 67% of the captopril group. Serum total cholesterol level was favorably reduced by both doxazosin (from 238 to 223 mg/dl, p < 0.001) and captopril (from 245 to 233 mg/dl, p < 0.001), whereas high density lipoprotein cholesterol concentration increased only in the doxazosin group (from 33 to 36 mg/dl, p < 0.001). The calculated 10-year risk for the development of coronary heart disease was reduced significantly (p < 0.001) by 28% in the doxazosin group and by 19% in the captopril group. The quality of life evaluation showed beneficial changes in both treatment groups. As a result of proven antihypertensive efficacy and a lack of unfavorable effects on lipid parameters and health status measures, these findings support the use of both doxazosin and captopril as agents of first choice in the treatment of hypertensive patients with associated lipid abnormalities.
Alterations in calcium metabolism in young people at risk for primary hypertension. The Dutch Hypertension and Offspring Study.
Authors: van Hooft I M , Grobbee D E , Frölich M , Pols H A , Hofman A
Published: June 2012

Several disturbances in calcium metabolism have been reported in primary hypertensive subjects. It is, however, not clear whether these alterations predate the development of hypertension or occur as a consequence of high blood pressure. We studied indexes of calcium metabolism in three groups of normotensive children with different familial predispositions for hypertension, based on parental blood pressure levels, with two, one, or no hypertensive parents. Plasma intact parathyroid hormone [1-84] was higher in the offspring of hypertensive parents compared with offspring of normotensive parents (difference, 0.58 pmol/L; standard error of the difference [SED], 0.24; p = 0.02). Mean serum calcium levels were slightly reduced in the offspring of two hypertensive parents (-0.019 mmol/L, SED = 0.013, p = 0.17). Plasma magnesium and phosphate levels were lower in the offspring of hypertensive parents (-0.032 mmol/L [SED = 0.016, p = 0.05] and -0.045 mmol/L [SED = 0.024, p = 0.05], respectively). Mean 1.25-dihydroxyvitamin D3 levels were similar among the groups. No differences in dietary intake of calcium, phosphate, or fiber were found. Urinary calcium excretion per 24 hours and the ratio of 24-hour urinary calcium excretion to daily calcium intake were somewhat higher in the offspring of hypertensive parents. Renal fractional excretion of calcium was similar in the offspring of two hypertensive parents, and renal fractional excretion of phosphate was lower in the offspring of two hypertensive parents compared with offspring of two normotensive parents (-1.50%, SED = 0.74, p = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Insulin resistance in young salt-sensitive normotensive subjects.
Authors: Sharma A M , Schorr U , Distler A
Published: June 2012

Insulin resistance has been demonstrated in patients with essential hypertension, and insulin-mediated sodium retention is believed to contribute to hypertension in these individuals. Recently, a hyperinsulinemic response to an oral glucose load has been found in salt-sensitive normotensive subjects, suggesting that insulin resistance may be present in these hypertension-prone individuals before the development of hypertension. In the present study, we examined the relation between insulin sensitivity and blood pressure response to salt intake in young, lean normotensive subjects on a high and a low salt diet. Insulin sensitivity was estimated by the "insulin suppression test," i.e., by measuring the plasma glucose and insulin concentrations achieved during a 180-minute infusion of somatostatin, insulin, and glucose in 18 healthy male volunteers (age, 21-28 years) given a standardized low salt diet (20 mmol/day) for 2 weeks, supplemented by either 220 mmol of NaCl per day or placebo in a single-blind randomized order for 1 week each. We defined salt sensitivity as a significant decrease in mean arterial blood pressure (> 3 mm Hg [p < 0.05]) measured for 60 minutes at 1-minute intervals on the low salt diet. By this definition, seven of the 18 subjects were salt sensitive. Although insulin infusion resulted in similar plasma insulin levels (approximately 50 milliunits/L) in both groups, concomitant glucose infusion resulted in plasma glucose levels that were more than 50% higher in the salt-sensitive than in the salt-resistant group (p < 0.005 by two-way analysis of variance).(ABSTRACT TRUNCATED AT 250 WORDS)
Endothelium-derived contracting factors in resistance arteries of young spontaneously hypertensive rats before development of overt hypertension.
Authors: Jameson M , Dai F X , Lüscher T , Skopec J , Diederich A , Diederich D
Published: June 2012

Vascular relaxations are impaired in adult spontaneously hypertensive rats (SHRs) because of increased production of an endothelium-derived, cyclooxygenase-dependent contractile factor or factors. To test the hypothesis that alterations in endothelial function precede and contribute to the development of overt hypertension in SHRs, we compared in myographs endothelium-mediated relaxations of mesenteric resistance arteries from 4-week-old SHRs and Wistar-Kyoto (WKY) rats. Acetylcholine (10(-9) to 10(-4) M) induced comparable relaxations in SHR and WKY arteries precontracted (ED50) with norepinephrine. In arteries obtained from SHRs but not from WKY rats, relaxations were replaced by contractile responses with higher concentrations of acetylcholine (10(-6) to 10(-5) M). The contractile responses were endothelium dependent, were augmented by nitro L-arginine (10(-4) M), and were prevented by pretreatment with indomethacin (10(-5) M) or 3-amino-1,2,4-triazole (10(-3) M), an inhibitor of superoxide anion production via the cyclooxygenase pathway. Inhibition of thromboxane synthetase (CGS-13080, 5 x 10(-5) M) and antagonism of prostaglandin H2/thromboxane A2 receptors (SQ-29,548, 5 x 10(-5) M) failed to block the contractile response to acetylcholine in SHR arteries. Acetylcholine-mediated relaxations were significantly impaired in mesenteric arteries from 16-week-old SHRs but not from WKY rats. Endothelium-independent relaxations produced by sodium nitroprusside and contractile responses to norepinephrine and endothelin were comparable in arteries from SHRs and WKY rats of all ages. In summary, endothelium-dependent relaxations of mesenteric arteries from "prehypertensive" SHR rats were impaired by the production of a contractile factor (or factors) that appears to be superoxide anions.
Cyclosporine and oxidized lipoproteins affect vascular reactivity. Influence of the endothelium.
Authors: Galle J , Schenck I , Schollmeyer P , Wanner C
Published: June 2012

Cyclosporine and in particular oxidatively modified low density lipoproteins can both exert direct vasoconstricting effects. We hypothesized that coincubation of arteries with low density lipoproteins and cyclosporine would enhance their respective influence on vascular tone. Therefore, we investigated vascular reactivity of isolated intact rabbit renal arteries preincubated with cyclosporine in the presence of native and oxidized low density lipoproteins. After preincubation of the arteries with cyclosporine (10 micrograms/ml, 90 minutes), unstimulated vascular tone as well as norepinephrine-induced vasoconstrictions remained unchanged compared with controls preincubated with the cyclosporine solvent dimethyl sulfoxide. Oxidized low density lipoproteins (100 micrograms/ml) in the absence of cyclosporine significantly enhanced vasoconstrictions to threshold concentrations of norepinephrine (78 +/- 10 microns at 30 nM). However, after cyclosporine treatment, the oxidized low density lipoprotein-induced potentiation of contractile responses to norepinephrine was further enhanced (157 +/- 19 versus 71 +/- 11 microns). Native low density lipoproteins had no influence on vascular tone. Potentiation of norepinephrine-induced vasoconstriction by oxidized low density lipoproteins took place in either endothelium-denuded or endothelium-intact arteries, whereas the further enhancement of vascular tone after cyclosporine treatment was seen only in endothelium-intact segments. Endothelium-dependent dilations to acetylcholine were fully preserved after treatment with oxidized low density lipoproteins and cyclosporine. Indomethacin, saralasin, and the thromboxane A2 antagonist daltroban had no influence, but the Ca2+ antagonist verapamil prevented the potentiation of vasoconstrictions by cyclosporine and oxidized low density lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Heparin has an inhibitory effect on endothelin-1 synthesis and release by endothelial cells.
Authors: Imai T , Hirata Y , Emori T , Marumo F
Published: June 2012

We studied the inhibitory effects of heparin on basal and agonist-induced endothelin-1 biosynthesis and release from cultured bovine endothelial cells. Heparin dose-dependently and similarly inhibited endothelin-1 release, inositol trisphosphate production, and intracellular free Ca2+ levels stimulated by thrombin. Hirudin fragment had an inhibitory effect on thrombin-induced endothelin-1 release, whereas anti-thrombomodulin antibody had no effect. Heparin completely blocked phorbol ester-induced endothelin-1 release, whereas it had a partial inhibitory effect on endothelin-1 release stimulated by angiotensin and vasopressin. Northern blot analysis using complementary DNA for bovine preproendothelin-1 as a probe revealed that heparin reduced not only the basal but also the stimulated expression of preproendothelin-1 messenger RNA by thrombin and phorbol ester. These data suggest that heparin, in addition to its antithrombin effect, has an inhibitory effect on the biosynthesis and release of endothelin-1, possibly by inhibiting protein kinase C-dependent pathway.
Urodilatin binds to and activates renal receptors for atrial natriuretic peptide.
Authors: Valentin J P , Sechi L A , Qui C , Schambelan M , Humphreys M H
Published: June 2012

Urodilatin is a recently described member of the atrial natriuretic peptide family, thought possibly to be synthesized in the kidney. To determine if urodilatin binding sites are present in rat and human kidney, we evaluated the effect of urodilatin on iodine-125-labeled atrial natriuretic peptide (ANP) (100 pM) binding to tissue sections using an in situ autoradiographic technique. 125I-ANP binding occurred primarily in glomeruli and medullary structures of both rat and human kidney. Increasing concentrations of urodilatin yielded a monophasic displacement of 125I-ANP binding with an IC50 of 4.2 nM, a value nearly identical to that achieved with unlabeled ANP (7.2 nM). In additional experiments, rat glomeruli and inner medullary collecting duct cells were isolated and incubated in vitro with either ANP or urodilatin (10(-11) to 10(-6) M) and cyclic guanosine-3',5'-monophosphate accumulation measured by radioimmunoassay. Dose-response curves for the two peptides were superimposable in each tissue; at 10(-6) M, ANP generated 613 +/- 41 and urodilatin 603 +/- 55 fmol cyclic guanosine monophosphate per 10 minutes per milligram protein in inner medullary collecting duct cells (p = NS). Thus, urodilatin is as effective as ANP in displacing 125I-ANP binding to both rat and human renal tissue and in generating cyclic guanosine monophosphate in renal target cells in the rat, suggesting that its physiological effects may occur through the same receptors and signaling pathways that mediate the actions of ANP.
Regulation of vascular angiotensin release.
Authors: Kato H , Iwai N , Inui H , Kimoto K , Uchiyama Y , Inagami T
Published: June 2012

To investigate the regulatory mechanism of the vascular renin-angiotensin system, we perfused isolated rat hind legs with plasma-free buffer and quantified angiotensin peptides in the perfusate. Angiotensin release from hind legs was increased in rats pretreated with losartan (DuP 753) and rats fed a low sodium diet with subsequent furosemide and was decreased in nephrectomized rats and rats given dexamethasone, ethynylestradiol, and triiodothyronine. Using these models, we have attempted to identify which step or component of angiotensin metabolism determines angiotensin release level. Changes caused by these manipulations in plasma renin concentration and basal angiotensin release from hind legs were almost parallel, whereas plasma angiotensinogen concentration and the angiotensin release changed in opposite directions. Infusion of renin in hind legs caused a marked increase in angiotensin release and continued even 1 hour after cessation of renin infusion. Infusion of angiotensinogen did not alter the angiotensin release. Angiotensin clearance and angiotensin I conversion were not affected by either nephrectomy or losartan pretreatment. Aortic renin messenger RNA level was extremely low and not increased by nephrectomy or losartan pretreatment, although kidney renin messenger RNA level was increased by losartan pretreatment. These results provide evidence that plasma renin of kidney origin is the major source of vascular functional renin and plays the determining role in the regulation of vascular angiotensin release. Plasma-derived or locally produced angiotensinogen, locally produced renin, converting enzyme, and angiotensin clearance are not considered to be the primary determinant in the regulation of vascular angiotensin release in these acute and subacute experimental models.
Arteriolar constriction and local renin-angiotensin system in rat microcirculation.
Authors: Vicaut E , Hou X
Published: June 2012

Intravital microscopy was used in a preparation of rat cremaster muscle that was isolated from its normal blood supply and externally perfused with a physiological solution, thus allowing exclusion of circulating converting enzyme, renin, and angiotensinogen. The arterioles studied were classified as second-, third-, and fourth-order arterioles with mean diameters of 60.5, 29.9, and 14.8 microns, respectively. Topical administration of 1 nmol/mL angiotensin I or 1 nmol/mL tetradecapeptide renin substrate induced marked vasoconstrictions (i.e., 38.5%, 61.5%, and 90.1% and 25%, 34%, and 88% for second-, third-, and fourth-order arterioles with angiotensin I and tetradecapeptide renin substrate, respectively). The angiotensin converting enzyme inhibitor quinapril significantly inhibited the vasoconstrictions caused by either angiotensin I or tetradecapeptide renin substrate. Almost no vasoconstriction was found when angiotensinogen-rich renin-free plasma containing either 2.45 nmol/mL of angiotensinogen or 1.2 micrograms/mL renin was administered. Conversely, these two compounds induced significant constrictions in cremaster muscle preparations in which normal blood perfusion (and thus circulating renin and angiotensinogen) was left in place. We concluded that, in skeletal muscle, 1) the microvascular network is a very effective site of local angiotensin converting enzyme activity and consequently an important target site of angiotensin converting enzyme inhibitors; 2) the effects of tetradecapeptide renin substrate are very different from those of angiotensinogen from plasma and suggest that a large part of the effect of tetradecapeptide renin substrate was due to its nonspecific hydrolysis; and 3) at the microvascular level, circulating renin and angiotensinogen are more effective in inducing arteriolar constriction, in the presence of their substrate or associated enzyme, than local renin and angiotensinogen.
Hydrochlorothiazide improves ventricular compliance and thus performance without reducing hypertrophy in renal artery stenosis in rats.
Authors: Norton G R , Tsotetsi O J , Woodiwiss A J
Published: June 2012

The effect of hydrochlorothiazide (1 mg/kg per day) on left ventricular (LV) mass and systolic and diastolic function was investigated in two-kidney, one clip (2K1C) renovascular hypertensive rats. Hydrochlorothiazide was administered from 8 weeks, and LV mass and function were measured at 16 weeks after surgery to induce hypertension. Cardiac performance was determined from cardiac output, stroke volume (per 100 g of body weight), and stroke work (per gram of LV weight) versus LV end-diastolic pressure (LVEDP) and versus LV strain relations in anesthetized open-chest, ventilated rats. LV compliance was determined from the LVEDP versus strain relation. Strain was calculated from LV end-diastolic short-axis diameter values. Hydrochlorothiazide reduced systolic blood pressure in 2K1C rats to levels similar to those in sham-operated controls (sham) at 12 weeks after surgery. A reduced afterload failed to influence LV mass, as left LV hypertrophy developed to the same extent in treated 2K1C rats. 2K1C hypertension produced abnormal cardiac performance with altered cardiac output, stroke volume, and stroke work versus LVEDP relations (stroke work versus LVEDP, intercept of 2K1C versus sham, p < 0.001). This was attributed to a decreased ventricular compliance (strain versus LVEDP, slope of 2K1C versus sham, p < 0.001). In contrast, hydrochlorothiazide improved ventricular compliance (strain versus LVEDP, slope of 2K1C versus 2K1C hydrochlorothiazide, p < 0.01) and thus returned the stroke work versus LVEDP relation to sham values (intercept of 2K1C versus 2K1C hydrochlorothiazide, p < 0.001). We conclude that hydrochlorothiazide reduces blood pressure but not the development of ventricular hypertrophy in 2K1C rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of endogenous angiotensin on the renovascular response to norepinephrine.
Authors: Yang H M , Lohmeier T E
Published: June 2012

The purpose of this study was to elucidate the role of endogenous angiotensin II in mediating the renovascular effects of renal adrenergic stimulation. Six conscious dogs instrumented for monitoring of renal blood flow were subjected to step increases every 10 minutes in the rate of norepinephrine infusion into the renal artery. Under control conditions, infusion of norepinephrine (10-40 ng/min per milliliter per minute of control renal blood flow) increased plasma renin activity and decreased renal blood flow progressively by approximately 10-75%. When increments in angiotensin II during norepinephrine infusion were abolished by fixing plasma levels of angiotensin II at either normal or high concentrations by chronic infusion of captopril plus angiotensin II, renal blood flow responses to adrenergic stimulation were greatly attenuated at rates of norepinephrine infusion that decreased renal blood flow up to approximately 40% under control conditions. Thus, acutely generated angiotensin II appeared to contribute to the renovascular effects of norepinephrine. However, when endogenous levels of angiotensin II were suppressed to low levels by chronic infusion of captopril alone, norepinephrine induced severe renal ischemia at much lower rates of infusion than occurred when the renin-angiotensin system was intact. Since this enhanced sensitivity to norepinephrine did not occur during chronic captopril infusion when angiotensin II was given simultaneously at rates that restored mean arterial pressure to normotensive levels or higher, low arterial pressure during chronic captopril administration may predispose the kidneys to excessive renal vasoconstriction during renal adrenergic stimulation.
Sodium retention and hypertension after kidney transplantation in rats.
Authors: Graf C , Maser-Gluth C , de Muinck Keizer W , Rettig R
Published: June 2012

The present study was designed to investigate the development of blood pressure and renal sodium handling in recipients of renal grafts from adult stroke-prone spontaneously hypertensive rats (SHRSP), normotensive Wistar-Kyoto (WKY) rats, and borderline hypertensive F1 hybrids bred from SHRSP and WKY rats. Unilaterally nephrectomized F1 hybrids served as renal graft recipients. The second native kidney was removed 7 days after transplantation. Starting on the day of transplantation, renal graft recipients were put on a standard diet for 7 days followed by a low salt diet (0.18% salt) for 10 days and a high salt diet (1.8% salt) for another 14 days. In recipients of a renal graft from SHRSP donors, systolic blood pressure rose progressively from 140 +/- 4 mm Hg before to 190 +/- 7 mm Hg 4 weeks after transplantation. In contrast, in recipients of a renal graft from WKY rat donors, blood pressure fell during the same time from 139 +/- 7 mm Hg to 120 +/- 4 mm Hg. Blood pressure did not change significantly in recipients of a renal graft from F1 hybrid donors (132 +/- 4 versus 138 +/- 7 mm Hg). With transition from a low salt to high salt diet, all rats exhibited renal sodium retention. The accumulating amount of sodium retained by the renal graft was significantly higher in recipients of an SHRSP kidney than in recipients of a WKY rat kidney at all days on the high salt diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Metabotropic glutamate receptors in the ventrolateral medulla of rats.
Authors: Tsuchihashi T , Averill D B
Published: June 2012

We investigated the hypothesis that stimulation of metabotropic excitatory amino acid receptors in the ventrolateral medulla evokes cardiovascular responses. Thus, (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD], a selective agonist of metabotropic excitatory amino acid receptors, was microinjected into the rostral or caudal ventrolateral medulla of halothane-anesthetized Sprague-Dawley rats. Microinjections of (1S,3R)-ACPD (100 pmol-1 nmol) into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure (+20 +/- 4 mm Hg by 100 pmol and +35 +/- 2 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and integrated splanchnic sympathetic nerve activity (+17 +/- 3% and +46 +/- 4%, respectively, p < 0.01), whereas (1S,3+)-ACPD microinjected into the caudal ventrolateral medulla decreased mean arterial pressure (-28 +/- 2 mm Hg by 100 pmol and -48 +/- 6 mm Hg by 1 nmol, p < 0.01 versus artificial cerebrospinal fluid) and splanchnic sympathetic nerve activity (-24 +/- 4% and -49 +/- 5%, p < 0.01). The blockade of ionotropic excitatory amino acid receptors by the combined injection of 2-amino-7-phosphonoheptanoic acid (200 pmol) and 6,7-dinitroquinoxaline-2,3-dione (200 pmol), which effectively blocked the responses elicited by either N-methyl-D-aspartate (20 pmol) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (5 pmol), failed to affect the responses evoked by either (1S,3R)-ACPD (100 pmol) or L-glutamate (2 nmol) microinjected in the rostral and caudal ventrolateral medulla. These results suggest that metabotropic receptors are present and mediate cardiovascular responses evoked by L-glutamate injections into the rostral and caudal ventrolateral medulla.
Inhibition of central angiotensin responses by angiotensin type-1 receptor antibody.
Authors: Richards E M , Lu D , Zelezna B , Phillips M I , Trolliet M , Sumners C , Raizada M K
Published: June 2012

Angiotensin type-1 receptor subtypes (AT1) are implicated in the physiological actions of angiotensin II in the brain. In the present study we used an AT1 receptor antibody and a polymerase chain reaction--synthesized AT1 receptor complementary DNA to show that the hypothalamus expresses significantly higher levels of AT1 receptor messenger RNA and protein compared with the brain stem. Intracerebroventricular injections of AT1-specific antibody blocks the dipsogenic and blood pressure responses induced by centrally injected angiotensin II. These results demonstrate the expression of AT1 receptor gene in the brain and that the AT1 receptor antibody is able to inhibit the physiological responses of angiotensin II mediated by the brain.
Captopril or conventional therapy in hypertensive type II diabetics. Three-year analysis.
Authors: Lacourcière Y , Nadeau A , Poirier L , Tancrède G
Published: June 2012

The effects of long-term treatment with captopril and conventional therapy on albuminuria and metabolic parameters were compared in 74 hypertensive type II diabetics with normal serum creatinine. Patients were treated double-blind with either captopril monotherapy or combined with hydrochlorothiazide or therapy with metoprolol, hydrochlorothiazide, or both for 36 months. The treatment was titrated to achieve goal diastolic blood pressure of < or = 85 mm Hg. The reductions in blood pressures during treatment were similar in patients with (n = 21) and without (n = 53) microalbuminuria treated with either captopril or conventional therapy. No significant changes in albuminuria occurred in normoalbuminuric patients with either therapy. Although albuminuria fell in nearly all patients with microalbuminuria treated with captopril, it rose in eight of 12 patients on conventional therapy, with macroalbuminuria developing in two of them. Renal function was preserved by both types of treatment in both patient groups. Long-term treatment with either conventional therapy or captopril did not alter metabolic variables. We conclude that captopril alone or in combination decreases albuminuria and prevents the development of macroalbuminuria in hypertensive type II diabetics with persistent microalbuminuria. The renoprotective effect of this agent, however, remains to be demonstrated with longer term data on renal function. Aggressive antihypertensive treatment with either captopril or conventional therapy appears to be effective in preventing the onset of microalbuminuria in most normoalbuminuric patients. In contrast, with previous short-term studies, the use of converting enzyme inhibitors or conventional therapy did not cause adverse metabolic effects.
Atrial natriuretic peptide in non-modulating essential hypertension.
Authors: Luparini R L , Ferri C , Santucci A , Balsano F
Published: June 2012

To evaluate the atrial natriuretic peptide response to angiotensin II (Ang II) infusion in non-modulating hypertension, we studied 31 men with essential hypertension. These patients were subdivided into groups of low renin patients (n = 8), non-modulators (n = 11), and modulators (n = 12) according to their renin profile and ability to modulate renin and aldosterone responses to a graded infusion of Ang II (1.0 and 3.0 ng/kg per minute) on a low Na+ intake (10 mmol Na+ per day). During basal conditions, plasma atrial natriuretic peptide was higher (p < 0.05) in low renin patients (16.34 +/- 2.67 fmol/mL) than in both modulators (10.59 +/- 4.29 fmol/mL) and non-modulators (9.85 +/- 2.64 fmol/mL). During Ang II infusion, plasma atrial natriuretic peptide significantly increased in both low renin (27.67 +/- 2.61 fmol/mL at 60 minutes, p < 0.01) and modulating (20.36 +/- 3.07 fmol/mL at 60 minutes, p < 0.05) patients, whereas it did not change in non-modulators (13.94 +/- 4.39 fmol/mL, NS). After 5 days on a high sodium intake (200 mmol Na+ per day), plasma atrial natriuretic peptide rose in modulating (20.61 +/- 2.31 fmol/mL, p < 0.01 versus low sodium intake), non-modulating (20.11 +/- 6.48 fmol/mL, p < 0.01 versus low sodium intake), and low renin (26.13 +/- 3.81 fmol/mL, p < 0.001 versus low sodium intake) hypertensive patients. When the Ang II infusion was repeated with a high sodium intake, plasma atrial natriuretic peptide increased again in low renin and modulating patients, whereas it did not change in non-modulators.(ABSTRACT TRUNCATED AT 250 WORDS)
Psychophysiological reactivity and cardiac end-organ changes in white coat hypertension.
Authors: Cardillo C , De Felice F , Campia U , Folli G
Published: June 2012

This study aimed 1) to assess whether patients with an exaggerated blood pressure response to the doctor's presence ("white coat" effect) also display a pattern of enhanced blood pressure reactivity to mental stress and physical exercise and 2) to determine the presence of left ventricular structural and filling abnormalities in patients with white coat hypertension. We studied 56 (40 men) consecutive patients (mean [SD] age, 46.4 [9.1] years) whose clinic blood pressure was repeatedly high. Patients were classified as having white coat hypertension (n = 20) if both their mean daytime (from 7 AM to 11 PM) ambulatory systolic and diastolic blood pressures were less than 134 and 90 mm Hg, respectively. Patients were considered to have persistent hypertension (n = 36) if daytime systolic blood pressure was 134 mm Hg or more or diastolic blood pressure was 90 mm Hg or more. Eighteen subjects with clinic blood pressure lower than 140/90 mm Hg served as a normotensive control group. Blood pressure reactivity from baseline to mental arithmetic, isometric handgrip, and cycle ergometry did not display any difference among the three groups. The white coat hypertensive group had left ventricular mass index lower than the persistent hypertensive group but higher than the normotensive group. Doppler indexes of left ventricular diastolic filling displayed similar abnormalities in the white coat and persistent hypertensive groups compared with the normotensive group.(ABSTRACT TRUNCATED AT 250 WORDS)
Effect of endothelin-1 on glomerular hydraulic pressure and renin release in dogs.
Authors: Lin H , Sangmal M , Smith M J , Young D B
Published: June 2012

The present study was designed to analyze quantitatively the effects of a wide range of endothelin-1 levels on renal hemodynamics and renin release in the canine nonfiltering kidney, including their effects on glomerular hydraulic pressure. Intrarenal infusion of endothelin-1 produced dose-dependent reductions in renal blood flow, but it did not affect glomerular hydraulic pressure until the infused dose reached high rates. At the rate of 1.0 ng/kg per minute, endothelin-1 reduced renal blood flow by 23% (p < 0.01), whereas glomerular hydraulic pressure was not significantly changed from 68.1 +/- 1.3 to 67.4 +/- 1.2 mm Hg. However, with a higher rate of endothelin-1 infusion (5.0 and 10.0 ng/kg per minute), glomerular hydraulic pressure fell to 59.5 +/- 1.3 and 51.5 +/- 1.8 mm Hg (p < 0.01), whereas renal blood flow was reduced from 154.5 +/- 15 to 83.0 +/- 9.5 and 53.5 +/- 9.9 mL/min, respectively. Endothelin-1 infusion also produced an inhibitory effect on renin release. With infusion at 1.0 ng/kg per minute, renin release fell from the control level of 47.9 +/- 5.6 to 26.6 +/- 4.9 units/min per gram kidney weight (p < 0.01), and it fell further to 16.1 +/- 4.3 units/min per gram kidney weight with infusion at 10.0 ng/kg per minute. In summary, endothelin-1 infusion did not affect glomerular hydraulic pressure despite a fall in renal blood flow at low doses, but at high doses it reduced both, suggesting that endothelin-1 exerts separate, dose-dependent effects on preglomerular and postglomerular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)
Resting and ambulatory blood pressure differences in Afro-Caribbeans and Europeans.
Authors: Chaturvedi N , McKeigue P M , Marmot M G
Published: June 2012

To investigate why mortality from stroke in people of Afro-Caribbean origin is twice the average for England and Wales, we examined 1166 European and Afro-Caribbean people in London. Age-standardized median systolic blood pressure was 6 mm Hg higher (128 versus 122 mm Hg) in Afro-Caribbean than European men and 17 mm Hg higher (135 versus 118 mm Hg) in Afro-Caribbean than European women. Migrants from West Africa and the Caribbean had similar blood pressures. Body mass index was higher in Afro-Caribbean than European women, accounting for 4 mm Hg of the systolic difference. Diabetes prevalence was 16% in Afro-Caribbeans and 5% in Europeans (P < .001), accounting for 1 mm Hg of the difference in systolic pressure in men and 2 mm Hg in women. In participants not taking antihypertensive medication, mean fall in ambulatory systolic pressure between daytime and nighttime, adjusted for resting blood pressures, was 24 mm Hg in Europeans and 18 mm Hg in Afro-Caribbeans (P = .05), and percent day-night fall in systolic blood pressure adjusted for resting systolic pressure was 17% in Europeans and 12% in Afro-Caribbeans (P < .05). This difference persisted when men and women and normotensive and hypertensive individuals were examined separately. We estimate that the differences in blood pressure between Afro-Caribbeans and Europeans may be enough to account for ethnic differences in stroke mortality in women but not men. The reasons for the high prevalence of hypertension and related morbidity in this and other populations of African descent remain to be established.
Sulfhydryl group donors potentiate the hypotensive effect of acetylcholine in rats.
Authors: Lahera V , Khraibi A A , Romero J C
Published: June 2012

Nitric oxide mediates the vasodilator and hypotensive responses of acetylcholine infusion. It has been reported that nitric oxide could be protected from free radical destruction by forming an S-nitrosothiol compound. Furthermore, sulfhydryl donors such as N-acetylcysteine or thiosalicylic acid enhance nitric oxide production from nitroglycerin. Consequently, the hypotensive effect of intravenous acetylcholine infusion might be potentiated during the simultaneous administration of sulfhydryl donors. The objective of the present study was to test in Okamoto spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats (1) whether the hypotensive effect of acetylcholine (10 micrograms/kg per minute) was affected by the simultaneous administration of N-acetylcysteine (10 micrograms/kg per minute) or thiosalicylic acid (10 micrograms/kg per minute), and (2) whether NG-nitro-L-arginine-methyl ester (100 micrograms/kg per minute) administration was able to reverse the changes induced by acetylcholine plus N-acetylcysteine or acetylcholine plus thiosalicylic acid. The administration of acetylcholine reduced (P < .05) mean arterial pressure in WKY rats (13 +/- 2%) and SHR (14 +/- 2%) without affecting urine flow rate, urinary sodium excretion, and glomerular filtration rate. In the presence of N-acetylcysteine, the acetylcholine-induced reduction in mean arterial pressure was potentiated (P < .05) in WKY rats (24 +/- 4%) and SHR (20 +/- 2%). These changes in mean arterial pressure were accompanied by significant reductions in urine flow rate and urinary sodium excretion in WKY rats, as well as in glomerular filtration rate in SHR.2
Sex-specific effects of an insulin secretagogue in stroke-prone hypertensive rats.
Authors: Peuler J D , Johnson B A , Phare S M , Sowers J R
Published: June 2012

Glyburide, an insulin secretagogue and an insulin-sensitizing agent, lowers blood pressure in normal male and female dogs when administered acutely. Because insulin resistance may contribute to spontaneous hypertension in rats, we sought to determine if long-term administration of glyburide (5 mg/kg per day by diet, age 5 weeks to 5 months) would lower blood pressure in male and female stroke-prone spontaneously hypertensive rats. Arterial (aortic) rings from these rats were incubated with insulin in vitro (100 mU/mL) 1 hour before and during phenylephrine-induced contraction to determine if long-term glyburide administration improves vascular sensitivity to the intrinsic vasodilator action of insulin. Glyburide, however, significantly increased blood pressures and ratios of heart weight to body weight in 5-month-old female rats (+20 mm Hg diastolic, P < .05), with no significant change noted in male rats (+4 mm Hg diastolic). Glyburide increased plasma insulin levels (twofold, P < .04) in female but not in male rats. Glyburide did not affect plasma glucose or catecholamine levels. After incubation with insulin, aortic to rings from glyburide-treated female rats demonstrated more than 40% greater contractile responsiveness the phenylephrine compared with aortic rings from control female rats (P < .04). This insulin-dependent increase in phenylephrine-induced contraction consisted of a reversal in the in vitro action of insulin, from attenuation to accentuation of such contraction (P < .05). This change was not seen in male rats. Neither gender, glyburide, nor insulin influenced acetylcholine-induced relaxation of phenylephrine-induced contraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Sympathoadrenal system is critical for structural changes in genetic hypertension.
Authors: Korner P , Bobik A , Oddie C , Friberg P
Published: June 2012

In spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, we examined tissue and adrenal norepinephrine concentrations, left ventricular (LV) weight, LV weight/body weight ratio (LV/BW), hindquarter resistance properties, ie, perfusion pressures at maximum dilatation and constriction (PPmax, PPmin), and the slope of the methoxamine log dose-PP curve. In series 1, we studied 4-week-old controls (SHRc, WKYc), sympathectomized rats (SX; SHRsx, WKYsx), and SX rats also given prazosin (SXP; SHRsxp, WKYsxp). With SX and SXP, adrenal norepinephrine concentrations increased in both strains, but tissue (LV, muscle, kidney) norepinephrine was depleted. At 4 weeks, LV/BW, PPmin, and PPmax were all greater in SHRc than in WKYc. With SX, these differences between strains remained unchanged, but SXP abolished them completely, indicating the importance of blockade of alpha-adrenergic receptor stimuli of adrenal origin. In SHRc (but not in WKYc), there was evidence of reinnervation after 4 weeks of SX. Hence, in series 2, the SXP period was extended to 8 weeks, and we studied SHRc, WKYc, SHRsxp, and WKYsxp. Systolic blood pressure was already elevated at 4 weeks in SHRc, and by 35 weeks it was 64 mm Hg greater than in WKYc. At 21 and 35 weeks, LV/BW, PPmax, PPmin, and slopes were all greater in SHRc than in WKYc, and the findings suggested greater LV and vascular hypertrophy than at 4 weeks. In SHRsxp hypertension, LV hypertrophy and the vascular changes were completely prevented over the entire 35-week observation period. SXP mainly affected SHR and had few effects on WKY rats. The sympathetic nerves and adrenals are probably the sources of alpha-adrenergic receptor stimulation in young SHR. They account for the development of hypertension and for most of the cardiovascular structural differences between SHR and WKY rats.
Enhancement of intracellular sodium by vasopressin in spontaneously hypertensive rats.
Authors: Okada K , Ishikawa S , Saito T
Published: June 2012

The arginine vasopressin-induced increase in intracellular sodium concentration was augmented in cultured rat vascular smooth muscle cells derived from 12-week-old spontaneously hypertensive rats (SHR) compared with those from 12-week-old normotensive Wistar-Kyoto (WKY) rats. This difference was enhanced by treatment with a Na+,K(+)-ATPase inhibitor, ouabain. The calcium-free state did not affect the basal intracellular sodium concentration but completely blocked the arginine vasopressin-induced increase in intracellular sodium concentration in both cell groups. The arginine vasopressin-mobilized cytosolic free calcium was enhanced in SHR compared with WKY rats. This enhancement was diminished but not completely inhibited in the calcium-free state. Also, arginine vasopressin-produced intracellular alkalinization was augmented in SHR. Pretreatment of both cell groups with a calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, completely blocked arginine vasopressin-induced intracellular alkalinization and increased intracellular sodium concentration. Scatchard analysis showed that the V1 receptor number of either quiescent or proliferative cells of SHR was five to seven times greater than that of WKY rats, without any change in receptor affinity. These findings therefore indicate that the arginine vasopressin-induced increase in intracellular sodium concentration is augmented in vascular smooth muscle cells of SHR mediated through the enhancement of the mobilization of cytosolic free calcium and the activity of sodium-hydrogen exchange, which depends on an increase in V1 receptor number.