bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased insulin sensitivity in the high sodium one-kidney, one figure-8 hypertensive rat.
Authors: Frontoni S , Ohman L , Haywood J R , Rossetti L
Published: June 2012

This study examines the relation between sympathetic activity and in vivo insulin-mediated glucose metabolism in a rat model of acquired hypertension. Two groups of conscious, unrestrained rats were studied in the postabsorptive state: sham-operated normotensive rats (n = 10) and renal-wrapped hypertensive rats (n = 10). Mean arterial pressure was increased in the hypertensive compared with the normotensive group in the fed (184 +/- 9 versus 144 +/- 6 mm Hg; p less than 0.01) and in the fasting (147 +/- 8 versus 112 +/- 7 mm Hg; p less than 0.01) state. After a 24-hour fast, hepatic glucose production, plasma glucose, insulin, and norepinephrine concentrations were similar in the two groups. Blood pressure did not change in either group during the 3-milliunits/kg.min euglycemic insulin clamp study; however, plasma norepinephrine concentration rose significantly in hypertensive (207 +/- 24 versus 329 +/- 11 pg/ml; p less than 0.05) but not in normotensive rats (229 +/- 23 versus 267 +/- 27 pg/ml; p = NS). During the insulin clamp study, the hepatic glucose production was similar in the hypertensive (3.8 +/- 0.8 mg/kg.min) compared with the normotensive (4.0 +/- 0.3 mg/kg.min) rats. Insulin-mediated glucose uptake was significantly higher in hypertensive than in normotensive rats (33.0 +/- 0.7 versus 25.8 +/- 0.8; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Salt supplementation does not alter the pressor effect of blocking atrial natriuretic peptide in nucleus tractus solitarii.
Authors: Yang R , Jin H , Wyss J M , Chen Y F , Oparil S
Published: June 2012

We have previously shown that microinjection of monoclonal antibody to atrial natriuretic peptide (ANP) into the caudal nucleus tractus solitarii causes a pressor response in salt-sensitive spontaneously hypertensive rats (SHR) fed a basal (1%) salt diet, suggesting that endogenous ANP in this region may be involved in the centrally mediated regulation of blood pressure in this model. The present study tested the hypothesis that the pressor effect of blocking endogenous ANP in caudal nucleus tractus solitarii is enhanced by dietary salt supplementation in salt-sensitive SHR. Monoclonal antibody to ANP (0.55 micrograms) in 50 nl artificial cerebrospinal fluid or control immunoglobulin G was microinjected into the caudal nucleus tractus solitarii of conscious salt-sensitive SHR, salt-resistant SHR, and Wistar-Kyoto rats fed 1% or 8% salt diets for 3 weeks. Microinjection of the monoclonal antibody into the caudal nucleus tractus solitarii evoked similar increases in mean arterial pressure in salt-sensitive SHR on both 1% and 8% salt diets and in salt-resistant SHR on a 1% salt diet but had no effect in Wistar-Kyoto rats. In contrast, microinjection of control immunoglobulin G into this brain area did not alter mean arterial pressure or heart rate in any experimental group. Thus, endogenous ANP in caudal nucleus tractus solitarii mediates tonic control of blood pressure in both salt-sensitive and salt-resistant SHR but not in Wistar-Kyoto rats, and this effect is independent of the salt sensitivity of hypertension and of dietary salt intake.
Increase in erythrocyte disaggregation shear stress in hypertension.
Authors: Razavian S M , Del Pino M , Simon A , Levenson J
Published: June 2012

The aggregation and disaggregation behaviors of red blood cells were investigated in 17 normotensive and 21 hypertensive subjects with a laser reflectometry technique, and simultaneous measurements were taken of blood viscosity with a coaxial viscometer. Increased red blood cell aggregation (26%, p less than 0.001) and disaggregation shear rate (20%, p less than 0.01) and shear stress (18%, p less than 0.01) were observed in hypertensive subjects when compared with normotensive subjects. Similar elevations in hypertensive subjects were found when the hematocrit was adjusted to 40%. Variation of red blood cell concentration caused the red blood cell disaggregation shear rate to change in an opposite direction but did not modify red blood cell aggregability and disaggregation shear stress. The increase of the reversible aggregation of red blood cells was associated with higher fibrinogen and plasma protein concentrations in hypertension. An increase in red blood cell aggregability and in the shear resistance of red blood cell aggregates may play a role in the development of the cardiovascular complication in hypertension. The quantification of red blood cell disaggregation shear stress, which represents the hydrodynamic force required to disperse the aggregates, may provide a useful parameter for clinical investigations.
Effect of home blood pressure and gender on estimates of the familial aggregation of blood pressure. The Tecumseh Blood Pressure Study.
Authors: Jamerson K A , Schork N , Julius S
Published: June 2012

Blood pressure (BP) readings from a single clinic visit are often used in population studies investigating the genetic basis of BP. We examined first-degree relatives in the Tecumseh Blood Pressure study to compare heritability estimates of BP readings obtained in the clinic-office setting (the average of two seated readings) with self-reported home BP readings (the average of 14 readings) taken over a 1-week period. The hypothesis tested was that repeated BP readings obtained in the home over the 1-week period would have fewer artifacts (i.e., environmentally induced variability in BP) and thus would better estimate the true "basal" BP that, in turn, would improve heritability estimates. We and others assume that the true basal BP level is heritable. We therefore expected that this "true" BP, by reducing BP variability of offspring, would show a stronger between-sibling correlation and that it would correlate better to parental BP as measured in a clinic setting. Correlation coefficients were calculated between siblings in the present Tecumseh study using self-reported home BP and clinic BP readings. Among 380 siblings (average age, 31.4 years), correlation coefficients for the home readings were of the same magnitude as for office readings (home, r = 0.23, p less than 0.01; office, r = 0.24, p less than 0.01). When offspring clinic BP readings were compared with archived BP data on parents, the correlation between offspring clinic and parental clinic BP readings was stronger (r = 0.24, p less than 0.05) than the correlation of offspring home BP readings to parental clinic BP readings (r = 0.17, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Detection of glycyrrhetinic acid-like factors (GALFs) in human urine.
Authors: Morris D J , Semafuko W E , Latif S A , Vogel B , Grimes C A , Sheff M F
Published: June 2012

Patients with the syndrome of apparent mineralocorticoid excess and those who ingest licorice show markedly decreased 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) and 5 beta-reductase activity; both are important for the deactivation of glucocorticoids and other steroid hormones. Glycyrrhetinic acid (GA), present as its glycoside in licorice, is a potent inhibitor of both 11 beta-OHSD and 5 beta-reductase and, as we have also shown, confers Na(+)-retaining properties on glucocorticoids and amplifies those of aldosterone and deoxycorticosterone. We report the results of our initial studies demonstrating the presence of naturally occurring substances, which inhibit both 5 beta-reductase and 11 beta-OHSD as does GA, in partially purified extracts of urine from normotensive men and nonpregnant and pregnant women. Since these substances exhibit GA-like activity, we have termed them GA-like factors (GALFs). This "inhibitory" material is heat stable and does not react with ninhydrin; the majority is not extractable with ethyl acetate and thus is not a "free" steroid. When further purified by high-performance liquid chromatography with a methanol/water gradient, the majority of these GALFs appeared in two regions of inhibitory activity. The chemical nature of this material is currently being investigated. These experiments indicate that normal human urine contains GALFs that may play a role in Na+ homeostasis and regulation of blood pressure.
Dietary sodium chloride increases blood pressure in obese Zucker rats.
Authors: Reddy S R , Kotchen T A
Published: June 2012

In the rat, elevated arterial pressure is not consistently associated with obesity. The purpose of this study was to compare measurements of blood pressure, cardiac output, and total peripheral resistance in obese and lean Zucker rats on different NaCl intakes. Obese and lean rats drank either water or isotonic NaCl for 18 days. Tail systolic blood pressures of saline-drinking obese rats were higher than all other groups (p less than 0.05). NaCl intake did not affect blood pressure in lean rats, and blood pressures of water-drinking obese rats did not differ from those of lean controls. In a subsequent experiment, direct arterial pressures and cardiac outputs (thermodilution) were measured in separate groups of conscious rats that had been maintained on a 1% or 4% NaCl intake for 12 weeks. Arterial pressure was higher (p less than 0.01) in obese rats fed 4% NaCl (130 +/- 4 mm Hg) than in obese rats fed 1% NaCl (118 +/- 2 mm Hg) or than in lean rats fed either NaCl intake (118 +/- 3 mm Hg and 116 +/- 3 mm Hg, respectively). Cardiac output of obese rats was higher than that of lean rats (p less than 0.01); however, the NaCl-induced increase of blood pressure was accounted for by an increase of peripheral resistance (p less than 0.01). Thus, in contrast to the lean Zucker rat, arterial pressure of the obese Zucker rat is increased by a high dietary intake of NaCl.
Trandolapril inhibits atherosclerosis in the Watanabe heritable hyperlipidemic rabbit.
Authors: Chobanian A V , Haudenschild C C , Nickerson C , Hope S
Published: June 2012

The effects of trandolapril (0.25 mg/kg body wt per 48 hours) on aortic atherosclerosis were examined in the Watanabe heritable hyperlipidemic rabbit treated from 3 to 12 months of age. Trandolapril caused a significant decrease in atherosclerotic involvement of the intimal surface of total aorta from 56.3 +/- 5.0% in control Watanabe rabbits to 35.0 +/- 4.1% with treatment (p less than 0.01). The largest reductions were observed in descending thoracic aorta where 21.8 +/- 5.7% of intimal surface was involved in the trandolapril-treated animals versus 54.4 +/- 7.7% in the control group (p less than 0.01). Significant decreases also occurred in ascending aorta/arch and abdominal aortic segments. Cholesterol content of descending thoracic aorta was also significantly reduced in the trandolapril-treated rabbits. The atherosclerotic plaques in aorta from trandolapril-treated rabbits appeared to contain less foam cells and relatively greater amounts of connective tissue than those from control animals. These studies indicate that trandolapril inhibits aortic atherosclerosis in the Watanabe heritable hyperlipidemic rabbit. The similarity in results between the current study and that using captopril suggests that the antiatherosclerotic action of trandolapril and captopril represents a class effect related to angiotensin converting enzyme inhibition.
Phosphoramidon-sensitive effects of big endothelins in the perfused rabbit kidney.
Authors: Télémaque S , Lemaire D , Claing A , D'Orléans-Juste P
Published: June 2012

The enzymatic conversion of human big endothelins (1, 2, and 3) to their respective active metabolites (endothelin-1, -2, and -3) was investigated in the perfused rabbit kidney through the pressor- and eicosanoid-releasing properties of these peptides. Intra-arterial bolus injections of endothelin-1 and -2 (5-50 pmol), endothelin-3 (100-250 pmol), and big endothelin-1 and -2 (100-250 pmol) into the kidney produced dose-dependent increases of perfusion pressure, whereas big endothelin-3 was inactive at doses up to 1,000 pmol. Endothelin-1 and -2 (10 nM), endothelin-3 (100 nM), and big endothelin-1 and -2 (100 nM) are potent enhancers of prostacyclin release without inducing any release of thromboxane B2 in the perfused kidney. In contrast, big endothelin-3 did not trigger the release of eicosanoids. A metalloprotease inhibitor, phosphoramidon (100 microM, 60 minutes), reduced the prostanoid release and pressor responses induced by big endothelin-1 and -2 without affecting the response induced by endothelin-1, -2, and -3. These results suggest the presence of a phosphoramidon-sensitive endothelin converting enzyme that converts the precursors of endothelin-1 and -2, but not of endothelin-3, in the renal vasculature of the rabbit.
Impaired renal vascular reactivity in prehypertensive Dahl salt-sensitive rats.
Authors: Simchon S , Manger W M , Shi G S , Brensilver J
Published: June 2012

We have previously shown that renal vascular resistance is less in Dahl salt-sensitive rats than salt-resistant rats fed 1% NaCl diets; however, renal vascular resistance increases before nonrenal vascular resistance as salt-sensitive rats develop hypertension when fed 8% NaCl diets. When salt-resistant rats are given 8% NaCl diets, renal vascular resistance decreases. The current study reports effects of atrial natriuretic peptide, nitroprusside, norepinephrine, angiotensin II, and endothelin-1 on renal and nonrenal vascular resistance in prehypertensive salt-sensitive and salt-resistant rats given 1% NaCl diets; doses used did not affect blood pressure. Resistance of nonrenal vessels in salt-sensitive and salt-resistant rats responded similarly to dilators or constrictors. However, atrial natriuretic peptide and nitroprusside decreased renal vascular resistance of salt-resistant rats (by 65%, p less than 0.01) but not that of salt-sensitive rats. Norepinephrine, angiotensin II, and endothelin-1 increased renal vascular resistance in salt-sensitive rats by 126%, 135%, and 135%, respectively (p less than 0.01); norepinephrine and angiotensin II did not change renal vascular resistance of salt-resistant rats, but endothelin-1 decreased renal vascular resistance in salt-resistant rats by 30% (p less than 0.01). Reactivity of nonrenal blood vessels in prehypertensive salt-sensitive and salt-resistant rats was similar when infused with dilators or constrictors in doses used. By contrast, renal vessels of salt-sensitive rats did not dilate in response to atrial natriuretic peptide and nitroprusside but were hypersensitive to norepinephrine and angiotensin II. Endothelin-1 caused renal vasoconstriction in salt-sensitive rats and renal vasodilation in salt-resistant rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Sympathetic denervation blocks blood pressure elevation in episodic hypoxia.
Authors: Fletcher E C , Lesske J , Culman J , Miller C C , Unger T
Published: June 2012

We have previously described a rat model that responds to repetitive episodic hypoxia (FiO2 nadir 3-5% for 12 seconds every 30 seconds for 7 hr/day for 35 days) with chronic increase in arterial blood pressure. The purpose of the current study was to determine if peripheral sympathetic nervous system denervation blocks this persistent blood pressure elevation. Chemical sympathetic denervation was achieved and maintained by three intraperitoneal injections (100 mg/kg 6-hydroxydopamine) on days 1, 3, and 27 of a 47-day experiment in two groups of rats. One denervated group was subjected to episodic hypoxia for 40 consecutive days beginning on day 7 and the other remained unhandled in their usual cages. A third group was injected with vehicle only and subjected to the same episodic hypoxia while a fourth group remained unhandled for 40 days. The vehicle-treated, episodic hypoxia-exposed group showed a 7.7 mm Hg increase in mean arterial blood pressure (conscious, unrestrained) over the 40-day period, whereas all other groups showed a decrease in mean arterial pressure. The left ventricle and septum/whole body weight ratio was higher in both episodic hypoxia-exposed groups at the end of the study. Plasma epinephrine in both groups administered 6-hydroxydopamine was higher on day 6 than in the vehicle-injected rats. Measurement of catecholamines in cardiac muscle homogenate confirmed denervation in 6-hydroxydopamine animals. These results indicate that the peripheral sympathetic nervous system is necessary for the persistent increase in blood pressure in response to repetitive episodic hypoxia.
Angiotensin II-induced protein phosphorylation in the hypertrophic heart of the Dahl rat.
Authors: Sunga P S , Rabkin S W
Published: June 2012

Angiotensin II-induced phosphorylation of proteins was examined in isolated myocytes from hearts of Dahl rats. A high salt diet induced cardiac hypertrophy in Dahl salt-sensitive rats. Angiotensin II-induced phosphorylation of a 42-kd protein (pp42) was detected by two-dimensional electrophoresis in hypertrophic but not normal ventricular myocytes. Angiotensin II stimulation was time-dependent, with a peak effect at 30 minutes. The half-maximal and maximal concentrations of angiotensin II that stimulated pp42 phosphorylation were 1 and 10 nM, respectively. Phosphorylation of pp42 was a function of cardiac hypertrophy. Phorbol 12-myristate 13-acetate-induced phosphorylation of pp42 indicates the possibility of an association between protein kinase C and the signal transduction pathway of angiotensin II-induced pp42 phosphorylation. Ionomycin and A23187 (both at 1 microM) did not stimulate phosphorylation of pp42. Angiotensin II produced a small increase in the synthesis of myocyte proteins in both normal and hypertrophic cells as shown by [35S]methionine incorporation. However, this increase could not account for the increase in the phosphate content of pp42. This protein was not an isoform of actin nor was it of platelet origin. These results raise the possibility that angiotensin II may play a role in the activation of factors in hypertrophic myocytes; however, further study is required to define a link between phosphorylation of pp42 and the hypertrophic process.
Alterations in renal endothelin-1 production in the spontaneously hypertensive rat.
Authors: Hughes A K , Cline R C , Kohan D E
Published: June 2012

Endothelin-1 inhibits sodium and water transport systems in the inner medullary collecting duct. Endothelin-1 levels are reduced in the medulla of spontaneously hypertensive rats (SHR), raising the possibility that decreased inner medullary collecting duct production of endothelin-1 could contribute to inappropriate sodium and water retention. In the current study, immunoreactive endothelin-1 was measured in the urine, blood, and eluates from cortex and outer and inner medulla of SHR before (age 3-4 weeks) and after (age 8-9 weeks) the development of hypertension and in age-matched Wistar-Kyoto (WKY) controls. There was no difference in endothelin-1 levels between prehypertensive SHR and WKY rats. In contrast, 8-9-week-old SHR had significantly reduced endothelin-1 in the urine and outer and inner medulla, but not in the cortex or serum compared with those of WKY controls. Furthermore, inner medullary collecting duct cells from 8-9-week-old SHR, either acutely isolated or cultured, released less endothelin-1 than did those from WKY rats. Finally, the level of endothelin-1 messenger RNA was only reduced in the inner medulla and in inner medullary collecting duct cells from 8-9-week-old SHR. In summary, renal medullary, and in particular terminal collecting duct, endothelin-1 production is reduced in SHR only after the development of hypertension. Such decreases in inner medullary collecting duct endothelin-1 production may contribute to the hypertensive state in SHR.
Pharmacology of smooth muscle cell replication.
Authors: Jackson C L , Schwartz S M
Published: June 2012

The suggestion that smooth muscle cell proliferation contributes to hypertension, atherosclerosis, and restenosis after angioplasty has led to a growing interest in the use of drugs to inhibit this process. This review summarizes pharmacological studies of smooth muscle cell proliferation in vitro and in vivo and identifies specific mediators of proliferation that are implicated by drugs binding with high affinity to enzymes or receptors.
Regulation of renin gene expression in rat adrenal zona glomerulosa cells.
Authors: Wang Y , Yamaguchi T , Franco-Saenz R , Mulrow P J
Published: June 2012

Our previous studies indicated that the amount of renin present in cultured adrenal zona glomerulosa cells increased after stimulation with adrenocorticotropic hormone or potassium. In the present study, we investigated the effects of adrenocorticotropic hormone or potassium on renin gene expression in cultured rat adrenal zona glomerulosa cells. The amount of rat renin messenger RNA (mRNA) was measured by complementary DNA synthesis and the competitive polymerase chain reaction method. The effects of adrenocorticotropic hormone or potassium on adrenal zona glomerulosa cell renin activity and renin mRNA content were compared with the activity and content of control cells. After 1 and 4 hours of stimulation by adrenocorticotropic hormone or potassium, total renin in the medium increased slightly; at the same time, the percent change in the amount of renin mRNA was 281% and 291%, respectively, in the adrenocorticotropic hormone-stimulated group and 218% and 348%, respectively, in the potassium-stimulated group. Twenty-four hours after adrenocorticotropic hormone or potassium stimulation, total renin in the medium increased significantly, by 689% and 220%, respectively; percent change in the renin mRNA content was 754% and 278%, respectively. These results demonstrate that adrenocorticotropic hormone and potassium increased the activity of adrenal renin through an increase in the level of renin mRNA.
Molecular determinants of human prorenin processing.
Authors: Chu W N , Mercure C , Baxter J D , Reudelhuber T L
Published: June 2012

In humans, active renin is generated by the removal of a 43-amino acid prosegment from the zymogen prorenin. This cleavage event is highly specific, occurring at only one of the seven pairs of basic amino acids in the body of preprorenin. This cleavage site selectivity is also displayed by a number of other proteases in vitro and in mouse pituitary AtT-20 cells transfected with a human preprorenin expression vector, suggesting that specificity of cleavage is directed in part by the primary sequence, the higher order structure, or both of prorenin itself. To test this hypothesis, single amino acid mutations were introduced in the region of human preprorenin surrounding the natural cleavage site, and the resultant recombinant proteins were expressed in cultured Chinese hamster ovary and AtT-20 cells. The results suggest that amino acids in addition to the pair of basic amino acids surrounding the cleavage site affect the ability of both trypsin and the endogenous AtT-20 processing enzyme to cleave prorenin. Notably, although a proline at position -4 is essential for processing of prorenin in AtT-20 cells and is correlated with predicted formation of a beta-turn at this position, site-directed mutations suggest that this structural feature in addition to a pair of basic amino acids is not sufficient to lead to proteolytic activation of prorenin. Displacement of sequences surrounding the cleavage site to a position 10 amino acids toward the amino terminus led to partial processing of a mutated prorenin.(ABSTRACT TRUNCATED AT 250 WORDS)
Time course of stimulation of renal renin messenger RNA by furosemide.
Authors: Chen M , Schnermann J , Malvin R L , Killen P D , Briggs J P
Published: June 2012

Renin secretion responds rapidly to a variety of stimuli; however, reported changes in renal renin messenger RNA (mRNA) levels in vivo have been observed only after prolonged stimulation. Studies were designed to test whether rapid changes in renin mRNA levels can be produced in vivo. In the first series, Sprague-Dawley rats received furosemide (10 mg/kg) intraperitoneally and a low sodium diet (0.05% sodium); renin secretion was significantly stimulated at 8 or 16 hours after treatment, but renin mRNA levels did not change. In a second series, rats were pretreated with deoxycorticosterone acetate (200 mg/kg) and saline drinking water for 3 days and then killed 0, 2, 4, 8, or 48 hours after furosemide administration. The renin mRNA level was unchanged at 2 hours but was stimulated twofold at 4 and 8 hours and threefold at 48 hours. In additional animals, the response of renin mRNA 4 hours after furosemide was found not to be potentiated by the converting enzyme inhibitor quinapril (5 mg/kg). The results demonstrate that with acute stimulation, renin mRNA levels lag 2-4 hours behind the change in plasma renin levels.
Studies on the peptides encoded by rat and human angiotensin II complementary RNA.
Authors: Jackson E K , Prakash C , Blair I A
Published: June 2012

Some evidence suggests that RNA complementary to the messenger RNA encoding a peptide hormone encodes a complementary peptide that binds the original peptide hormone. The objective of this investigation was to assess in vivo the ability of complementary angiotensin II (II Ang) peptides to block the biological effects of angiotensin II (Ang II). Increasing concentrations of rat or human II Ang were preincubated with Ang II for 2 hours, and this solution was then infused intra-arterially into the superior mesenteric artery. Human, but not rat, II Ang dose-dependently inhibited Ang II-induced mesenteric vasoconstriction. The in vivo inhibitory potencies of human II Ang and [Sar1,Ile8]Ang II, with respect to inhibition of the pressor response to Ang II, were compared by infusing intravenously increasing doses of each blocker and determining their effects on a fixed intravenous dose of Ang II. Although human II Ang could abolish the pressor response to Ang II, [Sar1,Ile8]Ang II was approximately 100 times more potent in this regard. A fixed dose of human II Ang (150 micrograms/min i.v.) inhibited the effects of increasing doses of Ang II on mesenteric vascular resistance, arterial blood pressure, and aldosterone secretion. The 1H nuclear magnetic resonance spectra of human II Ang and Ang II were determined both separately and when combined in the same cuvette. The spectrum obtained by overlaying the separate spectra for these two peptides was the same as the spectrum obtained from the mixture of these two peptides in the same cuvette.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of endothelium in endothelin-evoked contractions in the rat aorta.
Authors: Taddei S , Vanhoutte P M
Published: June 2012

We designed experiments to determine the role of endothelium-derived contracting factor or factors in the response to endothelin-1 and endothelin-3 in the aorta of normotensive and hypertensive rats. Rings of thoracic aortas, with and without endothelium, from normotensive and spontaneously hypertensive rats were suspended in organ chambers for recording of isometric tension in the presence of nitro-L-arginine, an inhibitor of nitric oxide synthase. The removal of endothelium decreased the contractions evoked by both endothelins in the aorta of spontaneously hypertensive but not of normotensive rats. Indomethacin (inhibitor of cyclooxygenase), dazoxiben (inhibitor of thromboxane synthase), and SQ-29,548 (antagonist of thromboxane A2 receptors) reduced, in aortic rings of spontaneously hypertensive rats, the contractions to endothelins in rings with but not in those without endothelium, whereas their effect was not endothelium-dependent in tissues of normotensive rats. BQ-123, a selective endothelin-A receptor antagonist, shifted the concentration-response curve to endothelin-1 to the right in a concentration-dependent manner and abolished the endothelium-dependent component of the contractions evoked by the peptide. The presence of the endothelium increased the basal and endothelin-stimulated release of thromboxane B2, the stable metabolite of thromboxane A2, in aortas of spontaneously hypertensive rats but not in those of normotensive rats. These data suggest that endothelium-derived thromboxane A2 contributes to contractions evoked by endothelin-1 and endothelin-3 in the aorta of the spontaneously hypertensive rat but not in that of the normotensive rat. Both the receptors on the endothelial cells (mediating the release of thromboxane A2) and those on vascular smooth muscle belong to the endothelin-A subtype.
Mechanism of hypertriglyceridemia in Dahl rats.
Authors: Mondon C E , Plato P A , Dall'Aglio E , Sztalryd C , Reaven G
Published: June 2012

Plasma triglyceride concentrations were shown to be higher in hypertensive (153 +/- 2 mm Hg) male Dahl salt-sensitive rats than in control Sprague-Dawley rats (122 +/- 2 mm Hg). These differences in triglyceride concentrations were seen when blood was drawn at 9 AM from unfasted animals (229 +/- 27 versus 111 +/- 8 mg/dL), at 1 PM after a 4-hour fast (186 +/- 13 versus 88 +/- 4 mg/dL), or at 9 AM after a 13-hour fast (151 +/- 6 versus 90 +/- 6 mg/dL), all p < 0.001. Total triglyceride secretion was also compared in groups of rats by determining the increment in plasma triglyceride concentration for 2 hours after blocking triglyceride removal from plasma by injecting Triton. Studies performed at 1 PM and 9 AM, after the 4- and 13-hour fast, demonstrated that total triglyceride secretion was greater (p < 0.05) in Dahl rats only when studied at 1 PM. Direct estimates of hepatic triglyceride secretion at 1 PM also demonstrated a significant (p < 0.02) increase in secretion rate by perfused livers from Dahl rats, due in part to their increased liver size. In addition, removal of prelabeled very low density lipoprotein-triglyceride in the intact rat was significantly (p < 0.05) decreased in Dahl rats. Lipoprotein lipase activity measured in skeletal muscle, heart, and adipose tissue was also significantly decreased at 9 AM and 1 PM (after 0 and 4 hours of fasting) in tissue from Dahl rats. These data confirm that Dahl rats have higher plasma triglyceride concentrations than Sprague-Dawley rats. Since both total and hepatic triglyceride secretion were somewhat greater in Dahl rats, in association with a decrease in both removal of very low density lipoprotein from plasma and decreased muscle and adipose tissue lipoprotein lipase activity, it seems likely that hypertriglyceridemia in Dahl rats results from a combination of increased triglyceride secretion and decreased triglyceride removal.
Circadian rhythms of blood pressure after liver transplantation.
Authors: van de Borne P , Gelin M , Van de Stadt J , Degaute J P
Published: June 2012

Twenty-four-hour systolic blood pressure, diastolic blood pressure, and heart rate profiles were recorded in 17 liver-transplanted patients by noninvasive ambulatory monitoring and were analyzed with the periodogram method. These recordings were compared with those of control subjects matched for age, sex, and daytime ambulatory blood pressure. Abnormal blood pressure patterns were found in seven of the 17 patients, whereas the other 10 patients had circadian blood pressure profiles that were not different from those of control subjects. These two groups of liver-transplanted patients did not differ in age, sex, oral dose of cyclosporine, specific serum cyclosporine level, and proportion of patients receiving azathioprine and antihypertensive medications. In contrast, the daily oral dose of prednisolone was significantly higher (p < 0.001) in the seven patients with abnormal circadian blood pressure patterns. Moreover, only the daily oral dose of prednisolone was inversely correlated with the magnitude of the nighttime systolic and diastolic blood pressure decrease (r = -0.64 and r = -0.66, p < 0.01). In contrast to blood pressure, patients and control subjects had similar circadian heart rate variations. We conclude that exogenous glucocorticoid administration may have a dose-dependent effect on the nighttime blood pressure fall and may play an important role in the pathogenesis of the abnormal circadian blood pressure profiles observed in liver-transplanted patients.
Glucocorticoid hypertension and nonadrenal phenylethanolamine N-methyltransferase.
Authors: Kennedy B , Elayan H , Ziegler M G
Published: June 2012

Several drugs that block epinephrine synthesis by inhibiting phenylethanolamine N-methyltransferase (PNMT) lower blood pressure in hypertensive rats. We investigated the mechanism by which these drugs lower blood pressure in rats made hypertensive with the glucocorticoid dexamethasone. We performed adrenalectomy or sham operation on several rats and then gave them either dexamethasone chronically or vehicle. The dexamethasone-treated adrenalectomized rats also received either the centrally acting PNMT inhibitor SKF 64139 chronically or an equal dose of the primarily peripherally acting PNMT inhibitor SKF 29661. Both SKF 64139 and SKF 29661 reduced blood pressure by more than 25 mm Hg. SKF 64139 also reduced PNMT activity in hypothalamus, medulla oblongata, skeletal muscle, and cardiac atria and ventricles; SKF 29661 inhibited PNMT in muscle and heart tissue by 40-75%, did not inhibit PNMT in hypothalamus, and inhibited PNMT by only 29% in medulla oblongata. PNMT activity in peripheral tissues was also more highly correlated with blood pressure than was PNMT activity in the brain areas studied. Neither drug reduced tissue epinephrine levels, but SKF 64139 elevated dopamine or norepinephrine levels or both in several tissues. We conclude that the blood pressure-lowering action of PNMT-inhibiting drugs in glucocorticoid hypertensive rats may be due to inhibition of peripheral nonadrenal PNMT. We speculate that elevations in nonadrenal PNMT may mediate glucocorticoid hypertension.
The angiotensin I converting enzyme gene and predisposition to high blood pressure.
Authors: Harrap S B , Davidson H R , Connor J M , Soubrier F , Corvol P , Fraser R , Foy C J , Watt G C
Published: June 2012

Phenotypic abnormalities of the renin-angiotensin system have been associated with the predisposition to high blood pressure. The angiotensin I converting enzyme (ACE) gene has been implicated as a candidate gene. We examined the distribution of common alleles of the ACE gene and measured circulating components of the renin-angiotensin system and urinary sodium excretion in 170 young Caucasian adults with contrasting genetic predisposition to high blood pressure. Predisposition was defined on the basis of personal and parental blood pressure levels by using the four corners sampling method. Young adults with greatest predisposition who had high blood pressure and two parents with high blood pressure did not show any significant difference in the distribution of the markers of the ACE gene, either as genotype or allele frequencies, when compared with young adults with least predisposition who had low blood pressure and two parents with low blood pressure. Offspring with urinary sodium excretion above the median (143.4 mmol per day) also showed no significant differences in the distribution of ACE alleles or genotype between groups. Different genotypes were associated with different average serum ACE concentrations (p < 0.0001), but plasma angiotensin II and aldosterone showed no significant variation with ACE genotype. These results suggest that in a group of Caucasians selected from the general population, the ACE gene is not associated with genetic predisposition to high blood pressure. In this population common ACE gene allelic markers would not be useful indexes of susceptibility to hypertension.
Characteristics of arterial myosin in experimental renal hypertension in the dog.
Authors: Upadhya A , Samuel M , Cox R H , Bagshaw R J , Chacko S
Published: June 2012

We compared myosin samples isolated from iliac-femoral arteries of control and renal (stenosis) hypertensive dogs to determine the effects of increased blood pressure on the characteristics of the myosin. The ratio of 204-kd (SM-1) to 200-kd (SM-2) myosin heavy chains was approximately 1:0.75 for myosin from the iliac-femoral artery of normotensive dogs. This was not altered significantly in response to hypertension. Both SM-1 and SM-2 myosin heavy chains cross-reacted with antibody against smooth muscle myosin on Western blot analysis. In addition to these heavy chains, purified myosin from both groups showed a very faint protein band slightly below the 200-kd myosin heavy chain on electrophoresis on a highly porous sodium dodecyl sulfate-polyacrylamide gel. This protein band cross-reacted with antibody against nonmuscle myosin but not with smooth muscle myosin antibody. The 20- and 17-kd light chains of myosin isolated from normotensive and hypertensive dogs gave similar results on isoelectric focusing. Peptide maps of tryptic digests of heavy chains revealed both quantitative and qualitative differences. The Ca(2+)-activated myosin ATPase activity measured in high salt (0.5 mol/L KCl) was similar for myosin from both groups, whereas the potassium (ethylenedinitrilo)tetraacetic acid-stimulated ATPase of myosin from hypertensive animals was higher than that from normotensive animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Properties of the random zero sphygmomanometer.
Authors: Kronmal R A , Rutan G H , Manolio T A , Borhani N O
Published: June 2012

The random zero sphygmomanometer is widely used in studies involving blood pressure measurement because it is believed to eliminate digit preference and reduce measurement error. We performed blood pressure measurements sequentially using random zero and standard sphygmomanometers in random order in 1,356 participants in the Cardiovascular Health Study. Despite adherence to the manufacturer's instructions, we observed a substantially nonuniform distribution of zero levels generated by the random zero sphygmomanometer and a disturbing correlation between the zero level and blood pressures taken with the standard sphygmomanometer. With the random zero device, the pooled estimated slopes for the regression of standard systolic and diastolic pressures on the zero level were -0.71 and -0.17, respectively (both p < 0.0001). The only plausible explanation for this relation between the random zero device and the standard device is that by some unknown mechanism the subject's blood pressure is influencing the zero level. Systolic and diastolic blood pressures measured with the random zero device were, respectively, 1.65 and 1.84 mm Hg lower (both p < 0.0001) than standard blood pressures. Digit preference was detectable in the uncorrected blood pressure and zero level measured with the random zero device but was eliminated after calculation of the corrected blood pressure. For most epidemiological studies, the random zero sphygmomanometer offers no significant advantage over the standard sphygmomanometer. It may still be useful in those epidemiological studies and clinical trials where blinding is important.
Autonomic modulation of contractions to endothelin-1 in canine coronary arteries.
Authors: Aarnio P , McGregor C G , Miller V
Published: June 2012

Endothelin-1 contracts vascular smooth muscle and inhibits release of neurotransmitter from adrenergic and cholinergic neurons. Experiments were designed to investigate the interaction of these mechanisms in a blood vessel that receives both adrenergic and cholinergic innervation. Rings cut from canine left anterior descending coronary arteries were suspended in organ chambers for the measurement of isometric force. In some rings, the endothelium was removed. Endothelin-1 caused concentration-dependent increases in tension in all rings. During electrical stimulation (1 Hz, 9 V, 2 msec), the contractions to endothelin-1 were reduced significantly. In rings without endothelium, this decrease was greater in the presence of atropine (10(-6) M) and was eliminated by a combination of phentolamine (10(-5) M) and propranolol (5 x 10(-6) M). Contractions to endothelin-1 during electrical stimulation in rings with endothelium were significantly less than those without endothelium. This difference was eliminated by atropine and NG-monomethyl L-arginine (10(-4) M). The presynaptic effects of endothelin-1 were studied by measurement of tritium-labeled norepinephrine. Phasic electrical stimulation induced release of norepinephrine; this was inhibited by endothelin-1 at high concentrations (4 x 10(-7) M) in the presence of atropine. These results suggest that the major effect of endothelin-1 is postsynaptic in canine coronary arteries. However, contractions to endothelin-1 may be modulated by the level of sympathetic and parasympathetic tone. In situations in which innervation to the coronary arteries is altered, for example, in hearts used for transplantation, the contractile effects of endothelin-1 would prevail.
Altered beta-receptor control of in situ membrane potential in hypertensive rats.
Authors: Stekiel W J , Contney S J , Rusch N J
Published: June 2012

Sympathetic neural activation of vascular smooth muscle beta-receptors induces membrane hyperpolarization and arterial relaxation. This response, which likely is mediated by the Gs protein-adenylyl cyclase-cyclic AMP signaling cascade, is reduced in some hypertensive animal models and in human essential hypertension. Since reduced beta-receptor-mediated vasodilation is a potential mechanism for enhanced arterial resistance, this study was designed to identify which step (or steps) in the beta-receptor signaling cascade is altered in hypertension. Transmembrane potentials were recorded in situ in small first-order arterioles and venules of cremaster muscle from hypertensive, reduced renal mass rats and normotensive, sham-operated controls. Vascular muscle cells in arterioles and venules of hypertensive rats were 5-7 mV more depolarized than in respective vessels of control rats during superfusion with physiological salt solution. Hyperpolarization and depolarization responses were reduced in hypertensive rats during superfusion with a beta-receptor agonist and antagonist, respectively, suggesting attenuated beta-receptor responsiveness compared with normotensive rats. Furthermore, direct activation of Gs protein by 10 ng/mL cholera toxin did not affect arterial or venous transmembrane potential in hypertensive rats, but hyperpolarized arterial and venous vascular muscle in normotensive controls by 17 mV. However, when the Gs protein-adenylate cyclase coupling step of the beta-receptor cascade was bypassed by using 10(-5) M forskolin to directly activate adenylate cyclase, arterial and venous vascular muscle of hypertensive rats hyperpolarized by 25-27 mV.(ABSTRACT TRUNCATED AT 250 WORDS)
A novel angiotensin receptor subtype in rat mesangium. Coupling to adenylyl cyclase.
Authors: Zhou J , Ernsberger P , Douglas J G
Published: June 2012

The diversity of angiotensin II (Ang II) actions implies multiple receptor subtypes. To characterize these subtypes in rat mesangial cells, we used the angiotensin subtype 1A (AT1A) antagonist losartan (DuP 753), the subtype 2/1B (AT2/AT1B) antagonist PD 123319, and the AT2 antagonist CGP 42112A in radioreceptor and adenylyl cyclase assays. In radioligand binding competition experiments, approximately 25% of the specific binding sites labeled by 125I-[Sar1]Ang II were inhibited by low concentrations of PD 123319 (0.1 to 10 nM), whereas the AT2 antagonist CGP 42112A was inactive at concentrations less than 0.1 microM. Conversely, losartan inhibited 75% of the binding at low concentrations (0.1 nM to 0.1 microM), but higher concentrations (up to 10 microM) were required to inhibit the second component of 125I-[Sar1]Ang II binding. The effects of the different antagonists on the inhibition by Ang II of forskolin-stimulated cyclic AMP production were also analyzed. Ang II inhibited forskolin-stimulated adenylyl cyclase in a concentration-dependent fashion (IC50, 35 +/- 7 nM), and the maximal inhibition of adenylyl cyclase was 44 +/- 2%. In the radioligand binding experiments, both losartan and PD 123319 antagonized the inhibition of adenylyl cyclase elicited by 0.1 microM Ang II (IC50, 0.5 +/- 0.2 and 1.2 +/- 0.4 microM, respectively), whereas CGP 42112A was less potent (IC50, 5.7 +/- 1.6 microM). Comparison of binding affinities at AT1B receptor sites with antagonist potencies in the adenylyl cyclase assay show good agreement for losartan and CGP 42112A, whereas PD 123319 is less potent than expected from membrane binding assays, possibly because of partial agonist properties.(ABSTRACT TRUNCATED AT 250 WORDS)
The hypertensive Y chromosome elevates blood pressure in F11 normotensive rats.
Authors: Ely D L , Daneshvar H , Turner M E , Johnson M L , Salisbury R L
Published: June 2012

Our laboratory has shown that the Y chromosome has a significant effect on blood pressure in the spontaneously hypertensive rat (SHR) model of hypertension and that the testes and androgen receptor contribute to the blood pressure rise. As an extension of our research, we have developed two new rat strains, SHR/a and SHR/y (F11) to study the Y chromosome. The objectives of the following research were 1) to study the blood pressure of rats with an SHR Y chromosome in a normotensive genetic background (SHR/y) or a normotensive Y chromosome in an SHR genetic background (SHR/a), 2) to determine the effect of male sex phenotype on the blood pressure of these rats, 3) to determine if testosterone replacement in castrated rats would restore blood pressure, and 4) to determine whether the Y chromosome from the SHR/y strain when crossed with a normotensive female can induce hypertension in androgen receptor-deficient male offspring. Blood pressure of male SHR/y rats was significantly higher than that of normotensive Wistar-Kyoto males (p < 0.01), and SHR/a males had significantly lower blood pressure compared with that of the parent SHR strain (p = 0.05). Testosterone replacement in castrated rats of both strains (SHR/a and SHR/y) restored blood pressure to control levels. Normotensive female King-Holtzman rats heterozygous for the testicular feminization gene were crossed with F11 SHR/a and SHR/y males.(ABSTRACT TRUNCATED AT 250 WORDS)
Increased expression of endothelin-1 gene in blood vessels of deoxycorticosterone acetate-salt hypertensive rats.
Authors: Larivière R , Day R , Schiffrin E L
Published: June 2012

We have recently shown that the content of immunoreactive endothelin-1 is increased in acid extracts from blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats compared with uninephrectomized control rats. We have also found by immunohistochemistry a significant increase in immunoreactive endothelin-1 in endothelial cells of aorta and mesenteric arteries of DOCA-salt hypertensive rats. In the present study, we investigated preproendothelin-1 gene expression in blood vessels of DOCA-salt hypertensive rats and uninephrectomized control rats. Northern blot analysis using a specific 32P-labeled complementary RNA probe for rat preproendothelin-1 of 319 base pairs revealed a fourfold to fivefold increase in abundance of preproendothelin-1 messenger RNA transcripts in both aorta and mesenteric arteries from DOCA-salt hypertensive rats. Thus, increased immunoreactive endothelin-1 content in blood vessels of DOCA-salt hypertensive rats is secondary to increased preproendothelin-1 gene expression. Exaggerated expression of the preproendothelin-1 gene in mineralocorticoid hypertension may contribute to the maintenance of elevated blood pressure.