bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of nitric oxide in long-term angiotensin II-induced renal vasoconstriction.
Authors: Manning R D , Hu L , Mizelle H L , Granger J P
Published: June 2012

In vitro studies have indicated that nitric oxide may play an important role in modulating the renal vascular actions of angiotensin II (Ang II). However, the physiological importance of this interaction in the long-term regulation of renal hemodynamics is unknown. Therefore, the goal of this study was to determine if long-term Ang II-induced renal vasoconstriction was potentiated by nitric oxide synthesis inhibition. The intrarenal effects of Ang II were examined in eight unilaterally nephrectomized, conscious dogs before and after systemic inhibition of nitric oxide synthesis. Ang II infusion into the renal artery at 0.5 ng/kg per minute resulted in decreases in renal plasma flow of 15% and 9% after 3 and 5 days, respectively. During this time, glomerular filtration rate decreased 12% after 3 days of angiotensin but was not significantly changed after 5 days. After 4 days of recovery from Ang II, nitric oxide synthesis was inhibited with intravenous NG-nitro-L-arginine-methyl ester (L-NAME) at 10 micrograms/kg per minute for 5 days, and this caused a significant decrease in renal plasma flow but no change in glomerular filtration rate. Infusion of Ang II into L-NAME-pretreated dogs for an additional 5 days further decreased renal plasma flow and glomerular filtration 14% and 11%, respectively. However, the effects of Ang II and L-NAME on renal plasma flow were only additive on days 3 and 5 of this period, and the effects on glomerular filtration were additive on day 3 but were potentiated on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)
Bradykinin does not modulate the natriuretic response to atrial natriuretic factor in rats with aortocaval fistula.
Authors: Abassi Z A , Klein H , Cox J , Keiser H R
Published: June 2012

Rats with aortocaval fistula, an experimental model of congestive heart failure (CHF), display two distinct patterns of sodium excretion: some rats develop marked sodium retention and worsening edema with urinary excretion of sodium (UNaV) < 200 microEq per 24 hours, i.e., uncompensated CHF, whereas in others sodium balance rapidly returns to normal (UNaV > 1,400 microEq per 24 hours), i.e., compensated CHF. Similar patterns of sodium excretion are found in patients with CHF. The mechanisms underlying these responses are not fully understood. The present study was designed to assess whether bradykinin plays a role in the compensatory response to CHF. Infusions of either 10 or 50 micrograms/kg per minute of synthetic atrial natriuretic factor (ANF)8-33 into sham-operated control animals produced significant increases in urine flow and fractional excretion of sodium (FENa). Infusions of ANF at the same doses into rats with compensated CHF increased FENa from 0.11 +/- 0.03% to a maximum of 6.10 +/- 1.30%, whereas the rise in FENa in animals with uncompensated CHF was significantly reduced (0.05 +/- 0.01% to 0.59 +/- 0.18%) compared with sham-operated controls (0.23 +/- 0.05% to 8.32 +/- 1.0%) or the group with compensated CHF. Treatment of the compensated rats with the bradykinin antagonist HOE-140 (D-Arg,[Hyp3, Thi5, D-Tic7, Oic8]-bradykinin) given at a rate of 100 nmol/kg per hour did not affect their renal response to the ANF. In addition, infusion of the bradykinin antagonist alone into compensated rats with aortocaval fistula had no significant effect on their basal urinary flow rate or sodium excretion during the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Low calorie unrestricted protein diet attenuates renal injury in hypertensive rats.
Authors: Reisin E , Azar S , DeBoisblanc B P , Guzman M A , Lohmann T
Published: June 2012

In the present investigation we researched the effects of low calorie diet without protein restriction on the renal function and glomerular injury of uninephrectomized spontaneously hypertensive rats. We compared the findings with those that occurred in two different groups of uninephrectomized spontaneously hypertensive rats: one treated with oral hydralazine (10 mg/kg per day) and a second fed regular food. The low calorie diet and hydralazine treatment significantly reduced intra-arterial blood pressure in each group (p < 0.05 and p < 0.001, respectively). The control group showed at the end of the experiment a slight but not significantly different increase in the intra-arterial blood pressure. Low calorie diet was more effective in protecting the kidney function. Creatinine clearance after treatment was significantly higher in uninephrectomized spontaneously hypertensive rats on a low calorie diet than in either the hydralazine-treated or control groups (p < 0.01). The 24-hour urinary protein excretion in the low calorie diet group was significantly lower than in the control group (p < 0.05) and lower but not statistically different from the hydralazine-treated group. The mean glomerular injury index of the remaining kidney in the low calorie diet group was lower than in either the hydralazine-treated or control groups (p < 0.05), and the mean mesangial expansion index in the low calorie diet group was significantly lower than in the control group (p < 0.05). The favorable effect of low calorie diet on renal function was independent of protein restriction or sodium and potassium content.(ABSTRACT TRUNCATED AT 250 WORDS)
Salt-sensitive hypertension caused by long-term alpha-adrenergic blockade in the rat.
Authors: Osborn J W , Provo B J , Montana J S , Trostel K A
Published: June 2012

We conducted the present study to test the hypothesis that sympathetic responsiveness, rather than its absolute level of activity, is a determinant of salt-sensitive hypertension. Sprague-Dawley rats were instrumented for computerized recordings of arterial pressure and placed in metabolic cages. In one group (n = 10), the alpha 1-adrenergic antagonist prazosin was chronically infused throughout the experiment. A second group served as a vehicle control (n = 9). Mean arterial pressure, sodium and water intake, urine output, and urinary sodium excretion were measured for 3 control days (0.4% NaCl diet), followed by 10 days of increased dietary NaCl (8.0% NaCl) and a subsequent 3-day recovery period (0.4% NaCl). Plasma renin activity was measured on day 2 of 0.4% NaCl, days 2 and 9 of 8.0% NaCl, and day 2 of the recovery period. Control values for all variables were similar between groups. Increased dietary NaCl resulted in a gradually developing hypertension in prazosin-treated rats. By day 10 of the 8% NaCl diet, arterial pressure had increased significantly more in prazosin-treated (41 +/- 6 mm Hg) compared with vehicle (8 +/- 4 mm Hg) rats. There were no differences between groups for daily or cumulative sodium or water balances throughout the study. During 0.4% NaCl, plasma renin activity was similar in prazosin (2.9 +/- 0.8 ng/mL per hour) and vehicle (4.1 +/- 0.7 ng/mL per hour) groups and was equally suppressed during 8.0% NaCl. These results are consistent with the hypothesis that impaired adrenergic responsiveness, caused by prazosin infusion, is a determinant of salt-sensitive hypertension in the rat.
Role of pressure natriuresis in long-term control of renal electrolyte excretion.
Authors: Mizelle H L , Montani J P , Hester R L , Didlake R H , Hall J E
Published: June 2012

If pressure natriuresis is to play an important role in arterial pressure control, renal perfusion pressure must have a long-term effect on urinary sodium excretion. The aim of this study was to quantitate the importance of renal perfusion pressure per se in controlling renal hemodynamics and electrolyte excretion chronically. Female mongrel dogs (n = 6) were instrumented with bilateral renal artery catheters for measurement of renal perfusion pressure and occluders on both renal arteries for servo-control of renal perfusion pressure at different levels; the urinary bladder was split for determination of renal clearances and electrolyte excretion from each kidney separately. Because both kidneys were exposed to the same neurohumoral influences, any changes in renal function could be attributed to differences in renal perfusion pressure between the two kidneys. After 5 days of control, renal perfusion pressure to one kidney was reduced from 86.7 +/- 0.2 to 74.2 +/- 0.6 mm Hg for 12 days, and pressure in the contralateral kidney increased to 91.5 +/- 0.4 mm Hg. Sodium excretion decreased from 41 +/- 2 to 25 +/- 1 mmol/d in the servo-controlled kidney and increased from 41 +/- 1 to 55 +/- 1 mmol/d in the contralateral kidney during 12 days of servo-control. Urine volume, chloride excretion, and potassium excretion exhibited similar patterns during servo-control. In addition, autoregulation of effective renal plasma flow and glomerular filtration rate was relatively well maintained; however, in the low-pressure kidney, glomerular filtration rate was slightly but significantly lower (approximately 8%) than in the contralateral kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Evidence for in vivo carotid and femoral wall thickening in human hypertension. Groupe de Prévention Cardio-vasculaire en Médecine du Travail.
Authors: Gariepy J , Massonneau M , Levenson J , Heudes D , Simon A
Published: June 2012

Little is known of the in vivo structural changes of large arteries in uncomplicated hypertension. Therefore, we measured the intima-media thickness and lumen diameter of common carotid and femoral arteries by a computerized ultrasonographic technique in 25 normotensive and 25 never treated hypertensive men of similar age (from 25 to 72 years). The intraobserver variability of carotid and femoral wall thicknesses was 4.3% and 5.6%, respectively. Moreover, an in vitro study of 13 human arterial segments removed at autopsy demonstrated a strong correlation (r = .989, P < .001) between computerized ultrasonic and histological intima-media thickness measurements. Compared with control subjects, hypertensive patients had similar arterial diameters but higher carotid and femoral intima-media thicknesses (P < .001) as well as higher ratios of carotid and femoral intima-media thickness to lumen (P < .001, P < .01). The carotid thickness was correlated with age in control subjects (r = .48, P < .05) but not in hypertensive patients. The femoral thickness was correlated with age both in control subjects (r = .55, P < .01) and in hypertensive patients (r = .46, P < .05). Thus, carotid and femoral arterial walls of hypertensive patients were thickened. This thickening was not due to age, although aging also thickened both vessels in control subjects and the femoral artery only in hypertensive patients. Such a wall thickening associated with a normal diameter provides direct evidence of vascular growth and represents a new target to monitor noninvasively in vivo for large artery changes in human hypertension.
Insulin-stimulated glucose utilization and borderline hypertension in young adult blacks.
Authors: Falkner B , Hulman S , Kushner H
Published: June 2012

The purpose of this investigation was to determine whether there is a relation between impaired insulin-stimulated glucose utilization, or insulin resistance, and blood pressure (BP) in a young adult black population. Clinically well, young black men and women, including normotensive (BP < 135/85 mm Hg, n = 23) and borderline hypertensive (BP > or = 135/85 mm Hg, n = 27) individuals, were studied. Each subject had an oral glucose tolerance test (OGTT) and underwent a euglycemic hyperinsulinemic clamp procedure. A two-way analysis of variance demonstrated a significantly greater fasting insulin plasma concentration (P < .02) and sum of insulin levels during the OGTT (P = .04) in the borderline hypertensive compared with normotensive subjects. In both BP groups, women had significantly higher fasting plasma insulin levels than men (P < .02 and P = .009). Body mass index was a significantly covariate of the plasma insulin concentration. Data obtained from the clamp demonstrated significant insulin resistance in borderline hypertensive compared with normotensive subjects (4.69 +/- 0.50 versus 6.57 +/- 0.63 mg/kg per minute, P = .002). A stepwise multiple linear regression analysis demonstrated that there are significant multiple correlations of insulin resistance with body mass index, clamped insulin level, BP group, and systolic BP (multiple R = .7862, P < .001). Application of this analysis to the nonobese sample (n = 33) found significant correlations of insulin resistance with sex, BP group, and systolic BP (multiple R = .6817, P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)
Thromboxane A2 receptor antagonism and synthase inhibition in essential hypertension.
Authors: Ritter J M , Barrow S E , Doktor H S , Stratton P D , Edwards J S , Henry J A , Gould S
Published: June 2012

Short-term effects of ridogrel, a combined thromboxane synthase inhibitor and receptor antagonist, were investigated in 16 patients with uncomplicated essential hypertension. After a 2-week placebo period without antihypertensive medication, patients were admitted to the hospital overnight on two occasions 3 weeks apart. On each occasion, they received two doses of either placebo or ridogrel (300 mg) 12 hours apart according to a double-blind crossover protocol. Renal and systemic thromboxane A2 and prostacyclin biosynthesis were investigated by measuring urinary excretion of thromboxane B2, 6-oxo-prostaglandin F1 alpha, and their respective 2,3-dinor metabolites using gas chromatography/mass spectrometry. Responses of platelets to a thromboxane A2 mimetic and to adenosine diphosphate were studied turbidometrically. Blood pressure was measured automatically at 20-minute intervals. Ridogrel reduced excretion of 2,3-dinor-thromboxane B2 and thromboxane B2 compared with placebo (21 +/- 6 versus 279 +/- 28 and 14 +/- 4 versus 39 +/- 9 ng/g creatinine, respectively; P < .0001 and P < .05). Excretion of 2,3-dinor-6-oxoprostaglandin F1 alpha and 6-oxoprostaglandin F1 alpha was increased by ridogrel compared with placebo (184 +/- 20 versus 146 +/- 11 and 86 +/- 9 versus 58 +/- 6 ng/g creatinine, respectively; P < .05). Ridogrel selectively antagonized platelet aggregation to the thromboxane mimetic (P < .0001). Blood pressure did not differ significantly between ridogrel and placebo treatment periods. Thus, in patients with essential hypertension, acute administration of ridogrel reduces renal and extrarenal thromboxane A2 biosynthesis, increases renal and extrarenal prostacyclin biosynthesis, inhibits thromboxane receptor-activated platelet aggregation, but has no effect on systemic arterial pressure.
Plasma brain natriuretic peptide and endopeptidase 24.11 inhibition in hypertension.
Authors: Richards A M , Crozier I G , Espiner E A , Yandle T G , Nicholls M G
Published: June 2012

In contrast to the wealth of information available concerning the response of plasma atrial natriuretic peptide to changes in pressure and volume status and to inhibition of endopeptidase 24.11, very little is known of possible concomitant effects on brain natriuretic peptide. The effects of change in posture, pressor infusions of angiotensin II, or inhibition of endopeptidase 24.11 were documented in two groups of patients with essential hypertension receiving one of two orally active inhibitors (SCH 42495 or UK 79300) in double-blind, placebo-controlled, random-order crossover studies. Sustained (4 days) inhibition of endopeptidase 24.11 with either inhibitor significantly enhanced plasma atrial natriuretic peptide (P < .05, both groups) but suppressed plasma brain natriuretic peptide (P < .01, both groups) in association with significant falls in arterial pressure (P < .05, both groups). Assumption of the recumbent posture increased plasma atrial natriuretic peptide (20 +/- 5 vs 13 +/- 3 pmol/L, P < .05), whereas brain natriuretic peptide was unchanged (7 +/- 0.3 vs 7 +/- 0.4 pmol/L, NS). Pressor infusions of angiotensin II increased plasma levels of both atrial natriuretic peptide and brain natriuretic peptide (33 +/- 11 vs 17 +/- 4 pmol/L, P < .05, and 7.5 +/- 0.6 vs 5.5 +/- 0.4 pmol/L, P < .05, respectively). In contrast to atrial natriuretic peptide, brain natriuretic peptide probably is primarily regulated by left ventricular load rather than by atrial distending pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Excitatory sympathetic reflex in NaCl-sensitive spontaneously hypertensive rats.
Authors: Nakamura Y , Calhoun D A , Chen Y F , Wyss J M , Oparil S
Published: June 2012

We have previously demonstrated blunted reflex responses of lumbar sympathetic nerve activity during volume expansion in NaCl-sensitive spontaneously hypertensive rats maintained on basal (1% NaCl) diets compared with NaCl-resistant spontaneously hypertensive rats, Wistar-Kyoto rats, and Sprague-Dawley rats. The current study tested the hypothesis that chronic ingestion of a high (8%) NaCl diet further blunts cardiopulmonary reflex function in the NaCl-sensitive spontaneously hypertensive rat. After 3 weeks of a 1% or 8% NaCl diet, male rats of all four strains were instrumented with femoral arterial and venous cannulas and lumbar nerve recording electrodes at 10 weeks of age. Two days later, conscious rats were infused with whole blood to expand blood volume. NaCl-sensitive spontaneously hypertensive rats maintained on a 1% NaCl diet had blunted responses of nerve activity to acute volume expansion compared with control strains. NaCl-sensitive spontaneously hypertensive rats maintained on an 8% NaCl diet had increases in nerve activity responses to volume expansion. In a second experiment, the volume expansion protocol was repeated in anesthetized NaCl-sensitive spontaneously hypertensive rats that had been subjected to sinoaortic denervation after 3 weeks of a 1% or 8% NaCl diet. After sinoaortic denervation, an increase in nerve activity was again observed during volume expansion in animals fed the 8% NaCl diet. In animals fed the 1% NaCl diet, changes in nerve activity were variable. The excitatory response was significantly reduced after bilateral vagotomy. These studies suggest that blood pressure regulation in NaCl-sensitive spontaneously hypertensive rats is a complex interaction of excitatory and inhibitory sympathetic reflex systems that is altered by high dietary NaCl exposure.
Erythrocyte anion exchanger activity and intracellular pH in essential hypertension.
Authors: Alonso A , Arrázola A , Garciandía A , Esparza N , Gómez-Alamillo C , Díez J
Published: June 2012

The present study was designed to examine the activity of the sodium-independent chloride-bicarbonate anion exchanger and the sodium-proton exchanger in erythrocytes of 30 normotensive and 35 hypertensive subjects and its relation to the previously reported decrease in erythrocyte pH. Erythrocyte cytosolic pH was measured by the pH-sensitive fluorescent probe 2'-7'-bis(2-carboxyethyl)- 5(6)-carboxyfluorescein. The activity of the anion exchanger was determined by acidifying cell pH and measuring the initial rate of the net sodium-independent, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-sensitive, bicarbonate influx driven by an outward proton gradient. The activity of the sodium-proton exchanger 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 activity of the anion exchanger was higher in hypertensive than control individuals (18,863 +/- 1081 vs 15,629 +/- 897 mmol/L cells per hour, P < .05). The activity of the sodium-proton exchanger was higher in hypertensive than control individuals (301 +/- 45 vs 162 +/- 23 mmol/L cells per hour, P < .005). Basal erythrocyte pH was lower in hypertensive than control individuals (7.27 +/- 0.02 vs 7.33 +/- 0.01, mean +/- SEM, P < .05). With the 100% confidence (lower) limit of the normotensive population as a cutoff point, a subgroup of 11 hypertensive patients had an abnormally low erythrocyte pH (< 7.19).(ABSTRACT TRUNCATED AT 250 WORDS)
Alcohol use and blood pressure in an unacculturated society.
Authors: Klag M J , He J , Whelton P K , Chen J Y , Qian M C , He G Q
Published: June 2012

Alcohol intake has been associated with higher blood pressure in acculturated populations but not in unacculturated societies. We performed a cross-sectional survey of a random community sample of 5023 male Yi rural farmers and 1656 Yi and 2173 Han men living in an urban setting. Average alcohol intake among drinkers was 36.4 g/d in Yi farmers, 56.5 g/d in Yi migrants, and 38.7 g/d in Han men. Age-adjusted mean diastolic blood pressure was 66.9, 70.5, and 71.7 mm Hg, respectively. Diastolic blood pressure was higher at higher alcohol intakes in all three groups (all P < .001). After adjustment for age, body mass index, heart rate, smoking, and physical activity, the change (95% confidence interval) in diastolic blood pressure for each standard drink was 0.50 (0.38-0.62), 0.31 (0.18-0.43), and 0.24 (0.07-0.40) mm Hg for Yi farmers, Yi migrants, and Han men, respectively. The percentage of variance in diastolic blood pressure explained by alcohol intake was 5% for Yi farmers, 4% for Yi migrants, and 2% for Han men. In a random sample of 831 men, these associations were independent of urinary sodium, potassium, calcium, and magnesium and sodium-potassium ratio. In the Yi farmers, associations were less strong for systolic blood pressure and no longer significant after adjustment. Approximately 33% of hypertension could be attributed to daily alcohol use in the Yi groups compared with 9.5% in the Han people.(ABSTRACT TRUNCATED AT 250 WORDS)
Major approaches for generating and analyzing transgenic mice. An overview.
Authors: Sigmund C D
Published: June 2012

Over the past decade, the development of gene-transfer technology in whole animals has afforded unprecedented opportunities for investigators to probe complex regulatory systems in vivo. Important advances in our understanding of the mechanisms of gene expression and regulation and the development of animal models of human diseases are but two examples of how this technology has affected medical science. Transgenic animals are defined as animals in which a segment of DNA has been physically integrated into the genome of all cells, including the germ line, so that it can be transmitted to offspring as a simple Mendelian trait. The DNA segment generally consists of a whole cloned gene, cDNA, or a novel gene modified by recombinant DNA methodologies. Whole genomic clones of genes are often used to study tissue- and cell-specific expression and regulation or can be used to overexpress a gene product. Alternatively, the coding region of one gene can be fused to the transcriptional regulatory region of another gene, causing it to be expressed in a new spectrum of tissues and cell types. A number of methods can be used to introduce the DNA segment, including direct microinjection of one-cell fertilized embryos, retroviral-mediated transfer, or gene transfer in embryonic stem cells. The technique most often used to generate transgenic animals and perform "gene addition" experiments is direct microinjection. Alternatively, gene deletions or "knockouts" are performed by gene transfer in embryonic stem cells by specifically targeting the site of integration in the genome.(ABSTRACT TRUNCATED AT 250 WORDS)
Embryonic stem cell model systems for vascular morphogenesis and cardiac disorders.
Authors: Doetschman T , Shull M , Kier A , Coffin J D
Published: June 2012

To better understand the formation of the cardiovascular system and its disease states, models amenable to manipulation must be developed. In this article we present two models. One is a small animal model for an inflammatory disorder that can lead to heart failure. Production of this model is based on the ability of blastocyst-derived embryonic stem cells, which can be genetically altered in vitro by a technique called gene targeting, to reconstitute an entire animal when reintroduced into a blastocyst and allowed to colonize the germ line of the resulting chimeric embryo. The other model is based on the capacity of embryonic stem cells to differentiate in culture into embryo-like structures called embryoid bodies. Embryoid bodies contain angioblasts, or prevascular endothelial cells, which can be induced to undergo aspects of vascular development by manipulation of culture conditions.
ATP-sensitive potassium channels in the basilar artery during chronic hypertension.
Authors: Kitazono T , Heistad D D , Faraci F M
Published: June 2012

We examined the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive potassium channels is impaired in stroke-prone spontaneously hypertensive rats (SHRSP). Changes in basilar artery diameter in response to aprikalim, a direct activator of ATP-sensitive potassium channels, were measured in anesthetized SHRSP and normotensive Wistar-Kyoto (WKY) rats through a cranial window. Topical application of aprikalim increased basilar artery diameter in WKY rats. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, abolished aprikalim-induced vasodilatation. Thus, ATP-sensitive potassium channels are functional in the basilar artery of WKY rats in vivo. Aprikalim (10(-6) mol/L) dilated the basilar artery by 31 +/- 5% (mean +/- SEM) in WKY rats but only 5 +/- 1% in SHRSP. The concentration-response curve to aprikalim in SHRSP was significantly shifted to the right, but the response to the highest concentration of aprikalim (10(-5.5) mol/L) was similar in SHRSP and WKY rats. Vasodilatation in response to norepinephrine was also impaired in SHRSP. Dilator responses of the basilar artery to forskolin, a direct activator of adenylate cyclase, and nitroprusside, a direct activator of guanylate cyclase, were normal in SHRSP. The findings suggest that dilatation of the basilar artery in response to direct activation of ATP-sensitive potassium channels is impaired in SHRSP compared with WKY rats in vivo.
High sensitivity to salt in kininogen-deficient brown Norway Katholiek rats.
Authors: Majima M , Yoshida O , Mihara H , Muto T , Mizogami S , Kuribayashi Y , Katori M , Oh-ishi S
Published: June 2012

Brown Norway Katholiek rats, which have very low levels of plasma kininogens, excreted a much smaller amount of kinin in the urine than normal rats of the same strain. The systolic blood pressure of 7-week-old kininogen-deficient rats fed low (0.3%) NaCl diets (131 +/- 4 mm Hg, n = 12) was not different from that in normal rats. Two percent NaCl diets given from 7 weeks of age for 4 weeks caused rapid increases in blood pressure (167 +/- 4 mm Hg, n = 12, 9 weeks old) in deficient rats, although the same diets induced no blood pressure increase in normal rats. Urinary excretion of active kallikrein and prokallikrein remained constant in both rat groups throughout NaCl loading. During this period, the deficient rats secreted less urine (9 weeks old, P < .05) and less urinary sodium (11 weeks old, P < .05). Serum levels of sodium in deficient rats were higher (P < .05) than in normal rats at 9 weeks of age. Intracellular concentrations of sodium in the erythrocytes of deficient rats were higher (P < .05) than in normal rats throughout NaCl loading. Subcutaneous infusion of bovine low molecular weight kininogen with an osmotic pump in NaCl-loaded deficient rats induced a reduction (P < .01) in blood pressure and increases (P < .05) in urine volume and urinary sodium and kinin levels. By contrast, subcutaneous infusion of the bradykinin antagonist Hoe 140 or of aprotinin in NaCl-loaded normal rats induced a hypertensive response. This antagonist treatment reduced urine volume and urinary sodium. These results indicate that the lack of kinin generation observed in the kininogen-deficient rats was related through sodium retention to the hypertensive response to NaCl loading.
Pregnancy restores the renal vasodilator response to glycine in Dahl salt-sensitive rats.
Authors: Whitescarver S A , Heesch C M
Published: June 2012

To determine if pregnancy alters the impaired renal vasodilator responses in hypertensive Dahl salt-sensitive (Dahl S) rats, we measured glomerular filtration rate and effective renal plasma flow and calculated renal vascular resistance before, during, and after renal vasodilation with glycine (0.17 mmol/kg per minute IV). Conscious, midterm (day 11 to 14) pregnant and age-matched virgin Dahl S and Dahl salt-resistant (Dahl R) rats were fed an 8% NaCl diet for 4 weeks (n = 6 per group). Mean arterial pressure was elevated (P < .05) in Dahl S compared with Dahl R rats, with no significant difference between pregnant and virgin animals in either group. Pregnancy resulted in significant increases in plasma volume, baseline glomerular filtration rate, and renal plasma flow and a significant decrease in renal vascular resistance. The glycine-induced increase in filtration rate in virgin Dahl S rats (27 +/- 4%) was less (P < or = .01) than pregnant Dahl S (60 +/- 4%) and either group of Dahl R (virgin, 43 +/- 3%; pregnant, 45 +/- 5%) rats. Similarly, the 21 +/- 4% increase in renal plasma flow in virgin Dahl S rats was less (P < or = .01) than the pregnant Dahl S (45 +/- 4%) and either pregnant (45 +/- 5%) or virgin (45 +/- 5%) Dahl R rats. Glycine decreased renal vascular resistance only 12 +/- 2% in the virgin Dahl S compared with 31 +/- 3% in the pregnant Dahl S rats and 30 +/- 4% and 28 +/- 3% in pregnant and virgin Dahl R rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Neurogenic component of ouabain-evoked contractions is modulated by the endothelium.
Authors: Rodríguez-Mañas L , Sánchez-Ferrer C F , Pareja A , Casado M A , Arribas S , Salaices M , Marín J
Published: June 2012

The influence of endothelium on the neurogenic component of ouabain-induced contractions in isolated perfused guinea pig carotid arteries was analyzed. Ouabain (0.1 mumol/L to 0.1 mmol/L) evoked concentration-dependent increases of perfusion pressure. Phentolamine (0.3 to 10 mumol/L) and prazosin (30 nmol/L to 10 mumol/L) (nonselective antagonist of alpha-adrenergic receptors and selective antagonist of alpha 1-adrenergic receptors, respectively) induced a concentration-dependent relaxation in segments precontracted with ouabain (0.1 mmol/L). When the arteries were preincubated with those blockers (both at 3 mumol/L) or the animals were pretreated with reserpine, the contractions to the glycoside were diminished, indicating that they are partially mediated by norepinephrine release from adrenergic nerve endings. De-endothelialization abolished the effect of adrenergic blockade on ouabain-induced contractions. On the other hand, de-endothelialization did not modify significantly the effect of the adrenergic blockade on norepinephrine-induced contractions. The nitric oxide blocker oxyhemoglobin, at concentrations (10 mumol/L) that abolished endothelium-dependent relaxations induced by 3 mumol/L acetylcholine; or the cyclooxygenase blocker indomethacin (10 mumol/L) did not modify the relaxation caused by phentolamine. In bioassay experiments, 30 mumol/L phentolamine induced a relaxation on the ouabain-elicited contraction only when the glycoside was added through a donor segment with endothelium. Ouabain-induced tritiated norepinephrine release was significantly reduced by the removal of endothelium but not by 1 mumol/L oxyhemoglobin or 1 mumol/L indomethacin. These results suggest that the endothelium modulates the neurogenic component involved in contractions evoked by the glycoside by a diffusible factor (or factors) whose nature is unknown; however, the factor is neither nitric oxide nor a cyclooxygenase-related compound.
Rostral ventrolateral medulla as a site for the central hypertensive action of kinins.
Authors: Privitera P J , Thibodeaux H , Yates P
Published: June 2012

In the present study, we focused on the rostral ventrolateral medulla as a possible site of action for kinins because of its established importance in the central regulation of the cardiovascular system. Unilateral microinjections of 100 pmol to 4 nmol bradykinin into the rostral ventrolateral medulla produced dose-dependent increases in mean arterial pressure in Sprague-Dawley (SD) rats, Wistar-Kyoto (WKY) rats, and spontaneously hypertensive rats (SHR). The dose-response curves for the hypertensive responses to bradykinin in SD and WKY rats were essentially the same, whereas the hypertensive effect of bradykinin was significantly greater in SHR than in either SD or WKY rats. The kinin B2 receptor antagonists D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin and Hoe 140 inhibited the hypertensive responses to bradykinin in both SHR and WKY rats. The hypertensive effect of 500 pmol bradykinin was reduced 65 +/- 5% after 4 nmol of D-Arg0, Hyp3,Thi5,8,D-Phe7-bradykinin in SHR and 50 +/- 16% in WKY rats, whereas 1 nmol Hoe 140 abolished the hypertensive effect of 500 pmol bradykinin injected into the rostral ventrolateral medulla. Microinjection of D-Arg0,Hyp3,Thi5,8,D-Phe7-bradykinin produced prolonged dose-dependent decreases in mean arterial pressure and heart rate. Blood pressure decreased 70 +/- 8 mm Hg and heart rate decreased 49 +/- 9 beats per minute in SHR, whereas in WKY rats mean arterial pressure decreased 12 +/- 4 mm Hg, with no change in heart rate. In a similar fashion, Hoe 140 caused a 51 +/- 7 and 17 +/- 3 mm Hg reduction in blood pressure in SHR and WKY rats, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Regulation of aldosterone secretion in hypertensive blacks.
Authors: Fisher N D , Gleason R E , Moore T J , Williams G H , Hollenberg N K
Published: June 2012

Hypertension in blacks is common, often severe, and largely unexplained. Recent studies have suggested that aldosterone secretion in blacks may be reduced, whereas older data demonstrate no racial differences in aldosterone excretion. We performed this study to examine adrenal responsiveness in black hypertensive patients under controlled metabolic conditions. Thirty-one black hypertensive patients and 7 black normotensive subjects were studied on intakes of 10 mmol/d sodium and 100 mmol/d potassium, with the renin-angiotensin-aldosterone system further stimulated by upright posture or infusion of angiotensin II (Ang II). Forty-six hypertensive and 14 normotensive whites underwent the same protocol as a comparison group. Hypertensive blacks and whites had similar mean basal plasma aldosterone levels on a low salt diet, lower in both groups than in normotensive subjects. In the black patients, however, plasma aldosterone responses were significantly lower than responses in white hypertensive patients when further stimulated by either posture (1451 +/- 216 versus 2571 +/- 225 pmol/L [52.3 +/- 7.8 versus 92.7 +/- 8.1 ng/dL], P < .002) or Ang II infusion (843 +/- 122 versus 1617 +/- 189 pmol/L [30.4 +/- 4.4 versus 58.3 +/- 6.8 ng/dL], P < .001). Renin status did not account for the difference. Basal and stimulated plasma aldosterone concentrations, on the other hand, were similar in normotensive white and black subjects. Blunted adrenal responses to upright posture and Ang II infusion are common among black hypertensive patients. These abnormalities may be part of a larger constellation of abnormalities in blacks, reflecting perhaps a greater, more frequent underlying disturbance in salt handling than in whites.
Inhibition of vasopressin action in vascular smooth muscle by the V1 antagonist OPC-21268.
Authors: Li X , Kribben A , Wieder E D , Tsai P , Nemenoff R A , Schrier R W
Published: June 2012

In vascular smooth muscle cells arginine vasopressin acting through the V1 receptor increases intracellular Ca2+, leading to vasoconstriction. Recent studies have also shown that vasopressin activates mitogen-activated protein kinase (MAP kinase), which may contribute to vasopressin-induced hypertrophy of vascular smooth muscle cells. We examined the ability of an orally active, nonpeptide selective V1 antagonist (OPC-21268) to block vasopressin binding and postreceptor signaling in these cells. [3H]Vasopressin binding at 2 x 10(-9) mol/L was half-maximally blocked at 10(-9) mol/L OPC-21268. To compare effects of OPC-21268 on binding and postreceptor signaling, we stimulated cells with 10(-8) mol/L vasopressin. At this vasopressin concentration, half-maximal inhibition of binding occurred at 5 x 10(-9) mol/L OPC-21268. Half-maximal inhibition of Ca2+ efflux or increases in intracellular free Ca2+ required higher concentrations of antagonist (10(-7) mol/L), and half-maximal inhibition of vasopressin-stimulated MAP kinase was observed only at 10(-6) mol/L OPC-21268. These results indicate that this agent selectively blocks both vasopressin binding and postreceptor signaling in vascular smooth muscle cells. The requirement of higher concentrations of OPC-21268 for blocking increases in intracellular Ca2+ and activation of MAP kinase suggests that binding to a fraction of V1 receptors generates maximal levels of second messengers or the existence of subtypes of the V1 receptor with differential affinity for this antagonist. These data have implications for the clinical use of this compound.
Human tissue kallikrein induces hypotension in transgenic mice.
Authors: Wang J , Xiong W , Yang Z , Davis T , Dewey M J , Chao J , Chao L
Published: June 2012

We investigated the role of the kallikrein-kinin system in blood pressure control by developing transgenic mice overexpressing human tissue kallikrein. Two lines of transgenic mice carrying the human tissue kallikrein gene under the control of the mouse metallothionein metal-responsive promoter were established. Human tissue kallikrein was identified in pancreas, salivary gland, kidney, liver, and spleen of the transgenic mice by a specific radioimmunoassay for human tissue kallikrein. The immunoreactive human tissue kallikrein reached high levels in the circulation. The linear displacement curves for the transgenic product were parallel with the human tissue kallikrein standard curve, indicating their immunologic identity. The expression of human tissue kallikrein transcript in the transgenic mice was further confirmed by Northern blot analysis and by reverse transcription-polymerase chain reaction followed by Southern blot. Both lines of transgenic mice had significantly lowered blood pressure (86.4 +/- 13.5 mm Hg [mean +/- SD], n = 8 and 78.9 +/- 12.4 mm Hg, n = 8) compared with control mice (100.9 +/- 5.0 mm Hg, n = 8). Induction with zinc did not lower the blood pressure further despite elevated expression of the transgene. Administration of aprotinin, a potent tissue kallikrein inhibitor, restored the blood pressure of the transgenic mice but had no significant effect on control littermates. Our findings raise the possibility of tissue kallikrein being a powerful modulator of blood pressure and provide a new animal model for the study of blood pressure regulation.
Insulin and renal sodium retention in hypertension-prone men.
Authors: Endre T , Mattiasson I , Berglund G , Hulthén U L
Published: June 2012

Insulin-stimulated peripheral glucose uptake and insulin-induced renal tubular sodium reabsorption were investigated in normotensive men with a family history of hypertension (relatives, n = 35) compared with age- and body mass index-matched normotensive men with no family history of hypertension (controls, n = 23). The effect of insulin on the renin-aldosterone system was also studied. The euglycemic hyperinsulinemic clamp technique was used to measure peripheral glucose uptake (insulin sensitivity index). Renal clearance of 51Cr-labeled EDTA, sodium, and lithium was used to calculate fractional excretion of sodium and fractional proximal and distal tubular reabsorption of sodium before and during insulin infusion. The insulin sensitivity index was lower in relatives than in controls. Fractional excretion of sodium was reduced, and fractional proximal and distal tubular reabsorption of sodium were increased to the same extent in both groups during insulin infusion. Fractional distal tubular reabsorption of sodium was positively correlated to the reduction of serum potassium in all individuals. Plasma renin activity increased to the same extent in both groups, whereas plasma aldosterone was reduced only in controls. In conclusion, the impaired insulin-stimulated glucose uptake in peripheral tissues in normotensive sons of hypertensive families was accompanied by retained insulin-induced tubular sodium reabsorption. The lack of suppression of aldosterone secretion in these individuals may enhance sodium retention.
Perindopril changes the mesenteric pressure profile of conscious hypertensive and normotensive rats.
Authors: Christensen K L , Mulvany M J
Published: June 2012

Information about how antihypertensive therapy affects the arterial blood pressure profile in conscious animals is at present not available. Here we report measurements of part of the pressure profile in conscious spontaneously hypertensive rats (SHR, n = 7) and Wistar-Kyoto (WKY, n = 7) rats before and after treatment with the angiotensin-converting enzyme inhibitor perindopril. The previously developed technique that we used, provided simultaneous measurements of the undisturbed arterial blood pressure at the base of mesenteric arcades (P(arc); diameter, approximately 100 microns) and systemic mean blood pressure (MBP). The ratio P(arc)/MBP was 63 +/- 2% (mean +/- SEM) in SHR and 64 +/- 3% in WKY rats. When a bolus of perindopril (0.8 mg/kg) was injected into the aorta, P(arc)/MBP fell within 2 minutes to 51 +/- 2% (P < .05) for SHR and 56 +/- 2% (P < .05) for WKY rats, and these levels were maintained for the next hour. In contrast, MBP did not change for approximately 5 minutes in either strain, whereas after 1 hour MBP still had not changed significantly in WKY rats, but MBP had fallen by 16 +/- 2% (P < .05) in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)
Renal atrophy and arterial stenosis. A prospective study with duplex ultrasound.
Authors: Guzman R P , Zierler R E , Isaacson J A , Bergelin R O , Strandness D E
Published: June 2012

Renal artery disease is an important cause of both renal failure and hypertension. Duplex ultrasound is a reliable noninvasive method for classifying the severity of renal artery lesions and can be repeated to follow the course of the disease over time. The purpose of this study was to determine the changes in kidney size associated with various degrees of renal artery disease. Serial kidney lengths were measured as part of a prospective duplex ultrasound study of patients with renal artery narrowing. Fifty-four patients (22 men, 32 women; mean age, 65.8 years) with 101 renal artery and kidney sides eligible for follow-up were evaluated at 6-month intervals for an average of 14.4 months (range, 4 to 24 months). No kidneys with renal arteries classified as normal or less than 60% diameter stenosis by duplex criteria were found to have a decrease in length of greater than 1 cm during follow-up. In kidneys with a high-grade renal artery stenosis (> or = 60% diameter reduction), 26% (13 of 49 sides) were found to have a decrease in length of greater than 1 cm. The average decrease in length was 1.9 cm (range, 1.2 to 3.4 cm). By life table analysis, the estimated risk of a decrease in length of greater than 1 cm for kidneys with 60% stenosis or greater was 19% at 1 year. Loss of renal mass, as documented by ultrasound measurement of kidney length, is an important consequence of high-grade renal artery stenosis.
Molecular mechanism of adipogenic activation of the angiotensinogen gene.
Authors: Tamura K , Umemura S , Iwamoto T , Yamaguchi S , Kobayashi S , Takeda K , Tokita Y , Takagi N , Murakami K , Fukamizu A
Published: June 2012

Angiotensinogen gene expression is controlled in a tissue- and development-specific manner. Interestingly, the angiotensinogen gene is abundantly expressed in adipose tissues other than the liver, where it is mainly produced. We investigated the molecular mechanism of angiotensinogen gene expression in a 3T3-L1 preadipocyte-adipocyte system. Although angiotensinogen mRNA was barely detectable in preadipocytes, its levels increased significantly during differentiation. As a whole, the pattern of the change in transcriptional activity of the angiotensinogen promoter was similar to that of the angiotensinogen mRNA levels during adipogenic differentiation, indicating that the activation of the angiotensinogen promoter might be involved in the adipogenic differentiation-coupled gene expression. The proximal promoter region, from -96 to +22 of the transcriptional start site, was sufficient to confer adipogenic activation, and the proximal element from -96 to -52 of the transcriptional start site was necessary for this promoter stimulation. DNA-protein binding experiments showed that this proximal element specifically bound to a nuclear factor induced by adipogenic differentiation. These results suggest that the proximal promoter element from -96 to -52 plays a role in adipogenic activation of the angiotensinogen promoter.
Hypertension in the transgenic rat TGR(mRen-2)27 may be due to enhanced kinetics of the reaction between mouse renin and rat angiotensinogen.
Authors: Tokita Y , Franco-Saenz R , Reimann E M , Mulrow P J
Published: June 2012

The transgenic rat TGR(mRen-2)27, in which the Ren-2 mouse renin gene is transfected into the genome of the rat, develops severe hypertension with high adrenal renin and low kidney renin. These animals express both mouse and rat renin. To investigate the cause of hypertension in the TGR rat, we compared the kinetics of mouse renin acting on mouse and rat angiotensinogens. The optimum pH of the renin reaction in the Sprague-Dawley rat was 6.5, whereas the optimum pH of the reaction in the TGR rat was approximately 8.5. The optimum pH of the renin reaction in the DBA mouse was 6.0. Purified mouse Ren-2 renin acting on rat angiotensinogen showed a pH profile similar to that for the renin reaction in the TGR rat. The angiotensinogen concentration in pooled plasma from eight DBA mice was 104.5 ng angiotensin I/mL and was clearly lower than that in Sprague-Dawley rats (772.4 +/- 37.3 ng angiotensin I/mL, n = 4). The reaction of purified mouse Ren-2 renin with rat angiotensinogen was 10 times faster than with mouse angiotensinogen. Plasma renin activity in DBA mice increased dramatically on addition of rat angiotensinogen (from 253.4 +/- 66.7 to 225,000 +/- 48,000 ng angiotensin I/mL per hour). Intravenous injection of 2 or 10 microL of DBA mouse plasma into the nephrectomized Sprague-Dawley rat increased the mean arterial pressure of the rat by 27.7 +/- 4.7 and 61.8 +/- 2.7 mmHg, respectively, whereas injection of 200 microL of Sprague-Dawley rat plasma did not change the mean arterial pressure of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Nitrendipine improves glucose tolerance and deoxyglucose uptake in hypertensive rats.
Authors: Bursztyn M , Raz I , Mekler J , Ben-Ishay D
Published: June 2012

We assessed the effect of the vasodilating calcium channel blocker nitrendipine on glucose tolerance in young spontaneously hypertensive rats (SHR) (n = 15). The nitrendipine group received 1 g/kg chow for 3 weeks. Untreated SHR (n = 14) served as controls. At 3 weeks body weight was comparable, whereas systolic blood pressure was 157 +/- 9 mm Hg in nitrendipine-treated rats versus 191 +/- 10 mm Hg in controls (mean +/- SD, P < .00001). Fasting glucose was 6.8 +/- 2.7 mmol/L in nitrendipine-treated versus 8.9 +/- 1.5 mmol/L in control rats (P < .03). An intravenous glucose tolerance test (300 mg/kg) showed plasma glucose levels at 2, 5, 15, and 30 minutes to be significantly lower in the nitrendipine-treated group versus controls (two-way ANOVA, P < .03). Glucose utilization was estimated by the uptake of [3H]deoxyglucose after its intravenous administration (2 microCi/100 g body wt) to instrumented awake animals. Heart and striated muscle uptake was, respectively, 7983 +/- 5812 and 951 +/- 731 cpm.microL/g.min in the nitrendipine-treated group versus 3532 +/- 2316 and 424 +/- 201 cpm.microL/g.min in controls (P < .02 and P < .04, respectively). [3H]Deoxyglucose plasma half-life and fasting and post-glucose load insulin levels were comparable in the two groups. The results show that nitrendipine improves glucose tolerance by increasing muscle glucose uptake. We suggest that glucose tolerance in SHR is influenced by muscle blood flow and can be improved by vasodilation.