bluuebunny/crossref_metadata_2025 huggingface dataset:
Cardiac and aortic effects of angiotensin converting enzyme inhibitors.
Authors: Frohlich E D , Horinaka S
Published: August 2012

The effects of six angiotensin converting enzyme inhibitors (captopril, CGS-16617, cilazapril, enalapril, utibapril, and quinapril) on cardiovascular structure, systemic hemodynamics, left ventricular end-diastolic pressure, left ventricular pumping ability, and aortic distensibility were assessed in male normotensive Wistar-Kyoto and spontaneously hypertensive rats 16-19 weeks of age. Rats (10 in each group) were treated for 3 weeks with drugs or control diluents administered daily by gavage. The agents, in general, had similar hemodynamic effects, although these effects on cardiac mass were variable; some agents reduced left ventricular mass and some produced no change. These effects occurred in hypertrophied as well as nonhypertrophied chambers. Furthermore, changes in left ventricular pumping ability were not necessarily related to the ability of these agents to change left ventricular mass; this dissociation in performance was neither related to change in structure nor to changes in aortic distensibility. Thus, even within a same class of antihypertensive agents (i.e., angiotensin converting enzyme inhibitors), similarly induced hemodynamic alterations were associated with inconsistent changes in left ventricular pumping ability or aortic distensibility regardless of whether the structure was hypertrophied before therapy. These dissociated responses in cardiovascular structure and function may be related to pharmacodynamic or pharmacokinetic differences; alternatively, they also may be related to these differences in action on local myocytic renin-angiotensin systems or in intramyocytic biological responses.
Effects of saralasin on arterial compliance in normotensive and hypertensive rats. Role of endothelium.
Authors: Stefas L , Levy B I
Published: August 2012

We used an experimental model of in situ isolated carotid arteries to clarify the participation of angiotensin II (Ang II) in the mechanical properties of the arterial wall in 12-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs). The effects of local incubation with saralasin ([Sar1,Thr8]Ang II, 10(-6) M) on carotid compliance were compared with the effects of endothelium removal and with those of total abolition of vasomotor tone with potassium cyanide (0.1 mg/ml). Operating carotid compliance measured for pressure values close to the mean arterial pressure of each group was (mean +/- SD) 12.6 +/- 2.9 x 10(-3) microliters/mm Hg.mm vessel in WKY rats and 8.2 +/- 1.6 x 10(-3) microliters/mm Hg.mm vessel in SHRs (p less than 0.001). With intact endothelium, local incubation with saralasin increased carotid compliance by 24% in WKY rats and 23% in SHRs relative to control values (p less than 0.05 and p less than 0.001, respectively). Endothelium removal induced significant increases in carotid compliance in WKY rats (17%, p less than 0.01) and in SHRs (33%, p less than 0.001). After endothelium removal, saralasin induced significant further carotid compliance increases in both strains (+18%, p less than 0.001, and +11%, p less than 0.01, in WKY rats and SHRs, respectively). After potassium cyanide poisoning, carotid compliance did not increase further relative to saralasin values in both strains with or without endothelium. These findings suggest that Ang II receptors play a major role in the control of the basal vasomotor tone of large arteries in both normotensive and hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Cilazapril inhibits wall thickening of vein bypass graft in the rat.
Authors: Roux S P , Clozel J P , Kuhn H
Published: August 2012

Venous grafts implanted in the systemic circulation progressively undergo wall thickening, a phenomenon thought to be responsible for late saphenous graft disease after bypass surgery. Angiotensin converting enzyme (ACE) inhibitors recently have been shown to prevent myointimal thickening after arterial injury. Thus, the goal of the present study was to test the effects of ACE inhibition in a rat model of venous graft. For this purpose, a segment of jugular vein was interposed in the right carotid artery of normotensive rats that received either placebo or 10 mg/kg/day cilazapril, a long-acting ACE inhibitor. Three weeks later, the venous grafts and the implanted carotid arteries were fixed under perfusion and embedded for morphometric analysis. In the control group, the wall of the venous graft thickened dramatically compared with the nonimplanted contralateral jugular vein (up to 20 times increase in total cross-sectional area). On the arterial side, thickening of the wall and a neointima also were observed, most likely because of the surgical arterial injury. Cilazapril decreased by 33% (p less than 0.05) and 26% (p less than 0.01) the total cross-sectional area of the wall of the venous grafts and of the carotid arteries, respectively. Thus, these results suggest a role of the renin-angiotensin system in the early process of venous graft thickening. This study also suggests that ACE inhibitors could be a new therapeutic means to prevent late saphenous graft disease.
Role of angiotensin II in injury-induced neointima formation in rats.
Authors: Osterrieder W , Müller R K , Powell J S , Clozel J P , Hefti F , Baumgartner H R
Published: August 2012

Angiotensin converting enzyme inhibition markedly suppresses neointima formation in response to balloon catheter-induced vascular injury of the rat carotid artery. To determine whether this effect was mediated through the vasoactive peptide angiotensin II (Ang II), two approaches were followed. First, the balloon model was used to compare the effects of continuous infusion of Ang II, with and without concurrent converting enzyme inhibition by cilazapril; second, the effects of the orally active nonpeptidic Ang II receptor antagonist DuP 753 were analyzed. Morphometric analysis was performed at 14 days after balloon injury. Animals that received continuous infusion of Ang II (0.3 micrograms/min/rat) were found to have significantly greater neointima formation in response to balloon injury than controls. Animals treated with cilazapril (10 mg/kg/day) had markedly reduced neointima formation, but in animals receiving infusion of Ang II, treatment with cilazapril did not suppress development of neointimal lesions. In the second group of experiments, DuP 753 (10 mg/kg twice daily) was as effective to prevent neointima formation as cilazapril. These data support the conclusions that converting enzyme inhibition prevents neointima formation after vascular injury through inhibition of Ang II generation.
Angiotensin II receptor antagonists. From discovery to antihypertensive drugs.
Authors: Timmermans P B , Carini D J , Chiu A T , Duncia J V , Price W A , Wells G J , Wong P C , Wexler R R , Johnson A L
Published: August 2012

Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)
The immune system and hypertension.
Authors: Dzielak D J
Published: August 2012

Primary or secondary activation of immune mechanisms has been implicated in the pathogenesis of many forms of hypertension. Changes in serum immunoglobulin levels, alterations in both humoral and cellular immune functions, and inherited abnormalities of the complement system have been identified in patients with essential hypertension. In addition, many models of spontaneous hypertension (such as the Okamoto and Lyon strains of hypertensive rats and the hypertensive New Zealand Black mouse) have identifiable abnormalities in immune function that are associated with their hypertensive disease. Other models (such as partial renal infarct hypertension, post-mineralocorticoid-salt hypertension, and hypertension induced by repeated injections of angiotensin II) also may have primary or secondary immunologic factors contributing to their etiology. Although there is a strong association between alterations in immune function and hypertension, the specific immunologic mechanisms that contribute to the pathogenesis of hypertension are not known. Therefore, further investigation will be necessary to elucidate these mechanisms.
Obese Zucker rats are normotensive on normal and increased sodium intake.
Authors: Pawloski C M , Kanagy N L , Mortensen L H , Fink G D
Published: August 2012

The purpose of this study was to determine whether genetically obese Zucker rats have higher arterial pressures than lean littermates on normal and high sodium intakes. Mean arterial pressure was directly measured in chronically instrumented Zucker rats (six lean [weight, 345.8 +/- 8.0 g] and five obese [529.0 +/- 6.2 g]) for 2 weeks on both a normal (2 meq sodium/day) and high (6 meq sodium/day) sodium intake (7 days each). In addition, daily heart rate, water intake, urine output, urinary sodium excretion, urinary potassium excretion, and weekly fasting plasma insulin levels were measured. Obese rats exhibited significantly lower heart rate and greater water intake and urine output compared with lean rats whether maintained on control or high sodium intakes. Urinary sodium excretion, however, was identical in lean and obese rats throughout the experiment. Fasting plasma insulin levels in obese rats were seven times greater than those in lean rats. When the rats were maintained on a 2 meq/day sodium intake, mean arterial pressures obtained from the two groups were similar: 103 +/- 1 versus 106 +/- 1 mm Hg (lean versus obese). An increase in sodium intake did not significantly affect mean arterial pressure in either group: 101 +/- 1 versus 105 +/- 1 mm Hg (lean versus obese). These results indicate that at 12-14 weeks of age, male obese Zucker rats do not exhibit higher resting arterial pressures than lean littermates when maintained on normal or high sodium intake.
Reactivity of small blood vessels in hypertension: relation with structural changes. State of the art lecture.
Authors: Schiffrin E L
Published: August 2012

Small blood vessels, particularly small arteries of 150-300 microns in lumen diameter and larger arterioles of 50-150 microns in lumen diameter, are the most important location of the arterial bed that undergoes changes resulting in the increased peripheral resistance that characterizes elevated blood pressure. This article reviews these morphological and functional alterations of small blood vessels. Study of mesenteric small arteries with a lumen diameter of 220-260 microns revealed consistently a reduced external and lumen diameter in renal and deoxycorticosterone acetate-salt hypertensive rats early in the evolution of hypertension. The media of the vessel wall was significantly thickened in the hypertensive rats, and the media/lumen ratio was increased. Although the tension that developed in response to different vasoconstrictors was not elevated or was even decreased in hypertensive rats, exaggerated transmural pressures resulted in the isolated blood vessels as a consequence of the law of Laplace because of the narrowed lumen. Similar findings were obtained in small resistance arteries from subcutaneous gluteal biopsies of hypertensive humans. In arterioles, on the other hand, decreases in the density of blood vessels (rarefaction) and in vasomotion amplitude may play a more important role than reductions in lumen diameter. As a consequence of the design of small resistance blood vessels and as a result of functional and structural alterations, which may be primary to or a consequence of high blood pressure, the pressor effect of vasoconstrictors is amplified and interacts with other factors to contribute to the maintenance of elevated blood pressure even if the intrinsic response of vascular smooth muscle to these agents is not exaggerated.
Insulin enhances pressor responses to norepinephrine in rat mesenteric vasculature.
Authors: Townsend R R , Yamamoto R , Nickols M , DiPette D J , Nickols G A
Published: August 2012

Hyperinsulinemia and insulin resistance have been proposed to play a role in human and experimental hypertension. To characterize this relation further, we examined the pressor responses to periarterial nerve stimulation (PNS) and norepinephrine infusion in the isolated mesenteric vasculature of the normal rat before and after insulin (10, 100, and 1,000 microunits/ml) infusion. The pressor responses to PNS were similar before and after insulin, except at the highest dose of insulin (1,000 microunits/ml) and the highest frequency of PNS (10 Hz). However, insulin significantly increased the pressor responses to norepinephrine. This increase in responsiveness was evident at all doses of insulin studied. In contrast, insulin did not affect the pressor responses to either angiotension II or serotonin administration. The mechanism or mechanisms for the augmented pressor response to norepinephrine after insulin infusion remain to be determined. However, the selectivity of the response for norepinephrine and the absence of a marked pressor increase after PNS indicate that the mechanism probably involves either the alpha-receptor itself or an amplification of the postreceptor signal transduction. The role of chronic hyperinsulinemia and insulin resistance in the pathogenesis of essential hypertension requires further study.
Actions of cromakalim in isolated human saphenous vein.
Authors: de Moura R S , Jasbik W
Published: August 2012

The present study was performed to evaluate the effect of cromakalim on human vein in vitro. Branches of human saphenous vein (leftovers), obtained from patients undergoing heart revascularization surgery, were cut into rings and suspended in an organ chamber filled with Krebs-Ringer solution for the measurement of isometric contractile force. Concentration-response curves to norepinephrine and serotonin were constructed before and after pretreatment with cromakalim. The concentration-response curves to norepinephrine and serotonin were displaced to the right, and the maximal responses to both agonists were significantly inhibited by cromakalim in a concentration-dependent manner. Following sustained contraction induced by prostaglandin F2 alpha or 20 mM KCl, the cumulative addition of cromakalim to the organ chamber produced a concentration-dependent relaxation. However, in veins precontracted with 60 mM KCl the addition of cromakalim in concentrations of up to 10(-5) M did not induce relaxation. The relaxation induced by cromakalim in veins precontracted with prostaglandin F2 alpha was significantly inhibited by glibenclamide. These results indicate that cromakalim has a dilator effect in human vein that may play a helpful role in the treatment of angina. The venodilator effect of cromakalim in human saphenous vein probably involves activation of adenosine triphosphate-regulated potassium channels.
Effect of enalapril on the inotropic response to isoproterenol in renal hypertensive rats.
Authors: Gómez Llambí H , Mazzadi A , Fontán M , Taquini C M
Published: August 2012

It is not clear whether regression of cardiac hypertrophy normalizes cardiac contractility. We studied the effect of enalapril treatment on the contractile response to beta-adrenergic stimulation with isoproterenol in renal hypertension. Male Wistar rats (n = 28) were divided into a clipped group (n = 14) and control group (n = 14). Three weeks after surgery, half of the animals from each group received for 21 days either enalapril (2.5 mg/kg) twice a day or vehicle by gastric intubation. Arterial pressure and body weight were measured twice a week. At the end of the experimental period, the hearts were excised, the ventricles were weighed, and the left ventricular papillary muscle was mounted in a bath. Myocardial contractility was characterized by the maximal developed tension, the maximal rate of rise of tension (+T), and the maximal velocity of relaxation (-T), which were measured at basal conditions and after cumulative doses of isoproterenol (10(-11) to 10(-4) M). The ratio of ventricular weight to body weight increased in hypertensive rats. Enalapril induced a decrease in arterial pressure and in the cardiac mass in both treated groups (p less than 0.05). The basal values of maximal developed tension, +T, and -T were similar in the four groups. The increment in +T and -T in response to isoproterenol (10(-4) M) was depressed in the hypertensive animals and in both treated groups (p less than 0.05). There was no significant difference in the +T/-T ratio or in the ED50 among the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Baroreceptor reflex control of heart rate during development of coarctation hypertension.
Authors: Michelini L C , de Oliveira M , dos Santos M
Published: August 2012

To study whether resetting of the baroreceptors is accompanied by normal reflex activity to the heart, we analyzed time-course changes of pressure, heart rate, baroreceptor reflex sensitivity, and plasma renin activity during the development of coarctation hypertension. Baseline heart rate was measured daily, and plasma renin activity and reflex changes in heart rate (bolus injections of either phenylephrine or nitroprusside, 0.2-25.6 micrograms/kg i.v.) were recorded at different times in coarcted and sham-coarcted rats. Hypertension was stable (approximately 39% from baseline mean arterial pressure of 112 +/- 3 mm Hg), whereas heart rate (333 +/- 4 beats per minute) showed a biphasic behavior: bradycardia at 6 hours (264 +/- 7 beats per minute) and tachycardia at 5 days (418 +/- 14 beats per minute). On day 10 of hypertension, heart rate was normal. Plasma renin activity was markedly increased only after 6 hours (4.9 times). Reflex bradycardia exhibited a progressive impairment: The slopes of the regression lines between changes in heart rate and changes in mean arterial pressure were not significantly reduced at 6 and 48 hours when the resetting was in development (changes of 17% and 28% from a control of -1.89 +/- 0.20 beats per minute/mm Hg) but were significantly depressed after the resetting had been completed (-51% and -56% at 5 and 10 days, respectively). Reflex tachycardia was significantly reduced in all periods studied (75%, 78%, 52%, and 61% at 6 hours and 2, 5, and 10 days, respectively; -3.92 +/- 0.42 beats per minute/mm Hg in sham rats).(ABSTRACT TRUNCATED AT 250 WORDS)
Doppler ultrasonography for the detection of renal artery stenosis in transplanted kidneys.
Authors: Maia C R , Bittar A E , Goldani J C , Keitel E , Deboni L M , Garcia V D
Published: August 2012

The objective of this study was to evaluate the importance of Doppler ultrasonography in diagnosing renal artery stenosis in transplanted kidneys using angiography as the accepted gold standard. Fourteen kidney graft recipients with clinical severe hypertension, impaired renal function, or both had their renal artery blood flow studied by Doppler ultrasonography before angiography. Seven patients had renal artery stenosis diagnosed by angiography. In six of them, the same diagnosis was achieved by Doppler ultrasonography, and in one patient, Doppler ultrasonography and angiography showed total occlusion of the renal artery. In six patients, both exams were normal. The only false-negative result was in an 8-year-old patient whose graft was placed in the left flank. The Doppler ultrasonography specificity was 100% and its sensitivity was 87.5%. The predictive value of a positive test was 100%; the predictive value of a negative test was 85.7%. Doppler ultrasonography of the renal artery in transplanted kidneys showed an accuracy of 92.86% in diagnosing renal artery stenosis. Because the technique is noninvasive, it should be considered as a first-line screening test.
Ventricular function by radionuclide ventriculography in malignant hypertension.
Authors: Silva H B , Bortolotto L A , Giorgi D M , Frimm C de C , Giorgi M C , Bellotti G , Pileggi F
Published: August 2012

Malignant hypertension is a unique and natural model for the study of abnormalities of left ventricular function due to arterial hypertension, because the development and regression of these abnormalities can be observed in a short period. Studies of ventricular function by radionuclide ventriculography, either before or after therapy, have not been previously reported in malignant hypertensive patients. We used this methodology to study left ventricular function in 17 malignant/accelerated hypertensive patients at the time of admission to the hospital and 3, 6, and 9 months after discharge. Seventy percent of patients (12 of 17) had symptoms of congestive heart failure at admission. We compared these data with those obtained in 12 normotensive subjects and 13 mild-to-moderate untreated hypertensive patients. Blood pressure of malignant hypertensive patients was 213 +/- 26/140 +/- 17 mm Hg at admission and 165 +/- 23/101 +/- 15 after 9 months of therapy. Radionuclide ventriculography at admission showed that peak filling rates of malignant hypertensive patients (2.13 +/- 0.21 end-diastolic volume [counts] [EDV]/sec) were significantly lower than those in normotensive subjects (2.40 +/- 0.41) and in mild-to-moderate hypertensive patients (2.46 +/- 0.21). In contrast, peak ejection rates were significantly higher in malignant hypertensive patients (3.44 +/- 0.38 EDV/sec) than in the two control groups (3.01 +/- 0.32 and 3.10 +/- 0.43, respectively). Ejection fractions were similar in the three groups of patients. After 9 months of therapy, peak filling rates of malignant hypertensive patients increased to 2.38 +/- 0.35 EDV/sec, whereas peak ejection rates decreased to 2.89 +/- 0.43 EDV/sec, both not significantly different from data in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of upright tilt on nifedipine-induced natriuresis.
Authors: Juncos L I , Villafane C , Escalante R , Cornejo J C
Published: August 2012

Calcium channel blockers are antihypertensive agents with diuretic actions. Yet edema occurs in some patients receiving long-term treatment with these drugs. As with other vasodilators, stimulation for fluid retention could result from systemic vasodilation. We speculated that the upright posture could enhance sodium retention. To test this hypothesis, we studied the effect of upright tilt in 10 patients before and after the oral administration of 20 mg nifedipine. Before nifedipine upright tilt caused a 41% drop in the sodium excretion rate, from 0.27 +/- 0.04 to 0.16 +/- 0.03 meq/min (p less than 0.05). Fractional sodium excretion decreased by 46%, from 2.4 +/- 0.5 to 1.3 +/- 0.3% (p less than 0.01). Urinary volume and renal plasma flow also decreased (p less than 0.05). Plasma renin activity (PRA) rose by 46% (p less than 0.005). With the patients in the supine posture nifedipine increased the sodium excretion rate to 0.49 +/- 0.09 meq/min (p less than 0.05). Fractional sodium excretion was 3.1 +/- 0.6 meq/min (p = 0.2). The natriuresis took place despite a fall in mean blood pressure and a significant rise in PRA (up 115% from prenifedipine supine values, p less than 0.005). Renal plasma flow also increased (p less than 0.01). The upright tilt caused a reversal of the nifedipine-induced natriuresis. The sodium excretion rate dropped to 0.23 +/- 0.05 meq/min and fractional sodium excretion to 1.3 +/- 0.2% (both not different from control). This drop in natriuresis occurred while mean blood pressure was at its lowest and PRA was 254% above the initial levels (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
Comparisons of blood pressure measurements by auscultation and Physiometrics Infrasonde recording techniques.
Authors: van den Berg B J
Published: August 2012

The levels of blood pressures measured by a Physiometrics Infrasonde recorder (model SR-2) were compared with the levels simultaneously measured byt auscultation utilizing a standard mercury sphygmomanometer (Baumanometer). The measurements were made on 1530 adult women and their 1760 adolescent children 15-17 years old. Two sets of blood pressures were taken about 3 minutes apart, each with an occluding cuff connected to the Physiometrics recorder as well as to the mercury sphygmomanometer. The reproducibility of the Physiometrics method was similar to that of the auscultation method. The means of the systolic pressures measured by the Physiometrics method were virtually equal to those of the auscultation method for women and girls; for boys, the means of the former method surpassed those of the latter by about 3 mm. The mean diastolic pressures by the Physiometric method were very close to the Korotkoff sound 5 (K5) pressure by the auscultation method for all three groups. The correlation coefficients between both methods were 0.98 for the systolic and 0.93 for the diastolic pressure of the adult women, and 0.94 for the systolic pressure of the adolescents. The correlations between the two diastolic pressures of adolescents were much less (0.69). The Physiometrics measurements were consistent with the measurements by auscultation for systolic and diastolic pressures of women and systolic pressure of adolescents, but the consistency was low for diastolic pressure of adolescents. An effort has been made to relate differences between the two methods with other anthropometric variables, but the correlations with these variables were of low level.
Does plasma immunoreactive ouabain originate from the adrenal gland?
Authors: Naruse K , Naruse M , Tanabe A , Yoshimoto T , Watanabe Y , Kurimoto F , Horiba N , Tamura M , Inagami T , Demura H
Published: August 2012

It was reported recently that the endogenous digitalis-like factor ouabain may mainly originate from the adrenal gland. To ascertain the pathophysiological significance of endogenous ouabain and to examine if it originates in the adrenal gland, we determined plasma immunoreactive ouabain levels in patients with various cardiovascular and endocrine diseases. Plasma immunoreactive ouabain levels were also determined in the adrenal venous blood by adrenal venous sampling. Plasma immunoreactive ouabain levels were significantly increased in patients with essential hypertension, primary aldosteronism, Cushing's syndrome, pheochromocytoma, acromegaly, and chronic renal failure. Plasma immunoreactive ouabain levels were decreased in patients with primary aldosteronism after unilateral adrenalectomy, acromegaly after pituitary adenomectomy, and chronic renal failure after hemodialysis. Plasma immunoreactive ouabain levels in patients after bilateral adrenalectomy were similar to those in healthy subjects. There was no significant step-up of immunoreactive ouabain levels in the adrenal vein from the peripheral vein in three patients, whereas one patient with hypertension and right adrenal tumor but without any known adrenal hormone excess showed higher plasma immunoreactive ouabain levels in the right adrenal vein than those in the peripheral vein. These results suggest an important pathophysiological significance of endogenous ouabain in various cardiovascular and endocrine diseases. It is unlikely that the adrenal gland is a major source of plasma ouabain, although a possible excess production of ouabain by the adrenal tumor remains to be elucidated.
Mechanism by which angiotensin II stabilizes messenger RNA for angiotensinogen.
Authors: Klett C , Bader M , Ganten D , Hackenthal E
Published: August 2012

The most important specific regulatory mechanism for hepatic angiotensinogen synthesis and secretion is its stimulation by angiotensin II, the effector peptide of the renin-angiotensin system. In the circulating system, this octapeptide is thought to stimulate hepatic angiotensinogen synthesis through a positive feedback loop. In the present study, we have identified the intracellular mechanisms leading to an increase in angiotensinogen messenger RNA (mRNA) and secretion. In a [3H]uridine-dependent pulse and chase system as well as in hepatocytes in which de novo synthesis of mRNA has been blocked by actinomycin D or 5,6-dichlorobenzimidazole riboside, angiotensin II significantly increased the half-life of angiotensinogen mRNA. In contrast, no effect of angiotensin II on the transcription of angiotensinogen mRNA could be observed in a nuclear run-on assay with nuclei from pretreated hepatocytes, whereas dexamethasone, as a positive control, increased the transcription fivefold to sevenfold. We have isolated a 12-kD protein from the polysomal fraction of isolated hepatocytes, which has an affinity to the nontranslated 3' tail of angiotensinogen mRNA. For in vitro transcription of this mRNA fragment, the DNA sequence coding for the nontranslated 3' tail was excised from the vector pRAG 16 and cloned into the transcription vector pGEM 5zf+. Molecular weight and isoelectric point of the mRNA-binding protein correspond to the parameters of a cytosolic protein that becomes phosphorylated by decreased cyclic AMP concentrations as analyzed in [32P]orthophosphate-loaded hepatocytes. In a cytosolic incubation system in which the polysomal fraction was integrated, the mRNA-binding protein increased the half-life of angiotensinogen mRNA significantly.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of sarcoplasmic reticulum calcium pump inhibitors on vascular smooth muscle.
Authors: Kwan C Y , Chaudhary R , Zheng X F , Ni J , Lee R M
Published: August 2012

A dysfunctioning of Ca2+ pump ATPase in the sarcoplasmic reticulum in vascular smooth muscle has been proposed as a contributing factor for the development of genetic hypertension. In this study, we determined whether in vitro inhibition of the sarcoplasmic reticulum Ca2+ pump in vascular smooth muscle tissues and cultured cells isolated from aortas of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats would elicit the known alterations of contractile function and cell growth. We found the following common vascular effects of thapsigargin and cyclopiazonic acid, which are known to be selective inhibitors of sarcoplasmic reticulum Ca(2+)-ATPase in a number of tissues including smooth muscle: (1) Both sarcoplasmic reticulum Ca2+ pump inhibitors diminished agonist-induced transient contraction in Ca(2+)-free medium (ie, contraction due to intracellular release of Ca2+) and enhanced nifedipine-sensitive contraction on readmission of Ca2+ (ie, Ca2+ influx via L-type channels); and (2) thapsigargin and cyclopiazonic acid inhibited the attachment of cultured aortic muscle cells to the substrate in a similar degree in both SHR and WKY cells, but SHR cells were more sensitive than WKY cells to the inhibition of cell proliferation by these two agents. The first effect may provide an explanation for several contractile abnormalities known to be associated with elevated cytosolic Ca2+ concentration, whereas the second effect suggests that elevation of cytosolic Ca2+ in aortic smooth muscle cells is not necessarily associated with or sufficient to account for the accelerated cellular proliferation in SHR. These results, however, further stress the functional importance of impairment of Ca2+ regulation in vascular smooth muscle cells in genetic hypertension.
Left ventricular mass and cardiovascular reactivity in young men.
Authors: Rostrup M , Smith G , Bjørnstad H , Westheim A , Stokland O , Eide I
Published: August 2012

The relation between left ventricular wall thickness and mass, arterial plasma catecholamines, and blood pressure at rest and during a mental arithmetic challenge and a cold pressor test was examined in 69 healthy men 19 years of age. The subjects were recruited from the 1st (n = 21), 50th (n = 26), and 99th (n = 22) percentiles in mean blood pressure. All underwent echocardiography to determine mean wall thickness and left ventricular mass. Continuous intra-arterial blood pressure, electrocardiogram, and arterial sampling of plasma catecholamines were performed after 30 minutes of supine rest, during a 5-minute mental arithmetic challenge, and during a 1-minute cold pressor test. Stepwise multiple-regression analyses considering mean wall thickness and left ventricular mass as the dependent variables were applied. Intra-arterial systolic blood pressure (r = .54, P < .0001) and arterial plasma epinephrine (r = .31, P = .009) after 30 minutes of supine rest were the only independent explanatory variables of mean wall thickness (multiple R2 = .33, P < .0001). Blood pressure at screening and during mental stress and cold pressor tests were not independent explanatory variables. The present study suggests that resting arterial blood pressure and plasma epinephrine may be of importance for development of left ventricular hypertrophy.
Vascular kallikrein in deoxycorticosterone acetate-salt hypertensive rats.
Authors: Nolly H , Carretero O A , Lama M C , Miatello R , Scicli A G
Published: August 2012

We determined the status of vascular kallikrein in rats with severe hypertension caused by treatment with deoxycorticosterone acetate (DOCA) and drinking of 1% NaCl for 6 weeks. We assayed active and total kininogenase (kallikrein) activity in the perfusate and in arterial and venous tissue. DOCA-salt rats had higher systolic blood pressure at 6 weeks (214 +/- 5 mm Hg) than rats drinking tap water (135 +/- 4 mm Hg) or saline (145 +/- 8 mm Hg). Kininogenase in the perfusate (nanograms bradykinin per minute per kilogram body weight) increased significantly at 2 weeks, from 5.8 +/- 2.1 to 8.9 +/- 1.4 for active kallikrein and from 28.7 +/- 0.4 to 48.7 +/- 2.9 for total kallikrein. Total kallikrein returned to control values at 4 weeks, whereas it was significantly reduced at 6 weeks (20.9 +/- 0.7). Active kallikrein was significantly depressed at 4 and 6 weeks (1.08 +/- 0.1 and 0.85 +/- 0.1, respectively [P < .05]). Active kallikrein in arterial tissue (picograms bradykinin per milligram per minute) showed a small but significant increase at 2 weeks, from 156 +/- 7 to 201 +/- 10 (P < .05), finally decreasing significantly by 6 weeks to 64 +/- 3; however, total kallikrein showed a significant decrease only at 6 weeks, from 844 +/- 17 to 427 +/- 27. Both active and total kallikrein in the veins were higher than control values at 2 weeks, changing from 437 +/- 7 to 541 +/- 19 and from 1619 +/- 17 to 2062 +/- 86, respectively. Venous kallikrein remained elevated until the end of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial and brain natriuretic peptides in cardiovascular diseases.
Authors: Naruse M , Takeyama Y , Tanabe A , Hiroshige J , Naruse K , Yoshimoto T , Tanaka M , Katagiri T , Demura H
Published: August 2012

The human heart secretes both atrial natriuretic peptide and brain natriuretic peptide. This study attempts to clarify the pathophysiological significance of the peptides in cardiovascular diseases. Using immunoradiometric assay, plasma brain natriuretic peptide and atrial natriuretic peptide levels in essential hypertension, various secondary hypertension, chronic renal failure, chronic heart failure during cardiac pacing, and acute myocardial infarction were determined. Mean plasma brain natriuretic peptide and atrial natriuretic peptide levels in healthy subjects were 3.7 +/- 0.3 and 5.7 +/- 0.3 pmol/L, respectively, and increased as a function of age. Plasma brain natriuretic peptide levels showed a larger increase than atrial natriuretic peptide levels in various cardiovascular diseases. In chronic renal failure, whereas plasma atrial natriuretic peptide levels decreased significantly after hemodialysis and were correlated with the changes in body weight, changes in plasma brain natriuretic peptide levels were less prominent and did not show such a correlation. In chronic heart failure, both basal plasma brain natriuretic peptide and atrial natriuretic peptide levels were also significantly elevated. However, in response to acute ventricular or atrial pacing, brain natriuretic peptide levels did not show any increase in contrast to the marked increase of atrial natriuretic peptide levels. In acute myocardial infarction, brain natriuretic peptide levels showed more prominent changes than atrial natriuretic peptide levels and were correlated with serum levels of creatine kinase and cardiac myosin light chain I in most patients. These results suggest that both brain and atrial natriuretic peptides play an important role in the regulation of cardiovascular homeostasis.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of a metalloendopeptidase-24.15. Inhibitor on renal hemodynamics and function in rats.
Authors: Yang X P , Saitoh S , Scicli A G , Mascha E , Orlowski M , Carretero O A
Published: August 2012

N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (cFP-AAF-pAB), an active-site-directed inhibitor of metalloendopeptidase-24.15, has been shown to lower blood pressure, increase cardiac output and renal blood flow, and potentiate the intravenous bradykinin-induced vasodepressor response. Because in vivo cFP-AAF-pAB can be converted to N-[1-(R,S)-carboxyl-3-phenylpropyl]-Ala-Ala (a compound with angiotensin converting enzyme inhibitory activity) by metalloendopeptidase-24.11, it is possible that some of its effects are due to angiotensin converting enzyme inhibition. In the present study, we questioned (1) whether cFP-AAF-pAB inhibits angiotensin converting enzyme in vivo and (2) whether cFP-AAF-pAB has renal effects that are independent of its conversion to an angiotensin converting enzyme inhibitor. cFP-AAF-pAB alone (3 mumol in 300 microL per rat) almost abolished the blood pressure response to angiotensin I, suggesting that in vivo it inhibits angiotensin converting enzyme. In rats pretreated with a high dose of enalaprilat (1 mg/kg), cFP-AAF-pAB had no further effect on blood pressure, renal blood flow, or potentiation of the vasodepressor response to bradykinin but still increased glomerular filtration rate by 44 +/- 9% (P < .01); urine volume increased by 118 +/- 10% (P < .001), urinary sodium excretion by 230 +/- 31% (P < .001), urinary potassium excretion by 68 +/- 14% (P < .01), and urinary cyclic GMP by 55 +/- 18% (P < .01). All of these changes were significant compared with enalaprilat/vehicle-treated rats. Fractional excretion of sodium and potassium did not differ from controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Dopaminergic abnormalities in hypertension associated with moderate renal insufficiency.
Authors: Kuchel O G , Shigetomi S
Published: August 2012

To evaluate the additive effect of moderate chronic renal failure to the abnormal dopamine generation and action observed in stable hypertension, we investigated 22 age-matched patients with a comparable degree of hypertension with and without chronic renal failure. Both groups were compared with each other and with an age-matched control group after a single oral dose of dihydroxyphenylalanine (DOPA) while cardiorenal responses and DOPA, dopamine, and their metabolites were measured. The hypertensive patients with chronic renal failure shared with their hypertensive counterparts without chronic renal failure an impaired DOPA decarboxylation to dopamine. However, patients with chronic renal failure had decreased hemodynamic and normal natriuretic responses compared with the hypernatriuresis of hypertensive patients with normal renal function; patients with chronic renal failure had elevated basal plasma concentrations of DOPA and dopamine sulfates as well as increased plasma and urinary DOPA sulfate but blunted urinary dopamine sulfate increases after DOPA administration; they presented augmented plasma atrial natriuretic factor concentrations. Thus, hypertensive patients with moderate chronic renal failure exhibit a decreased hemodynamic responsiveness to DOPA administration-induced dopamine elevation but with the natriuretic effect of dopamine maintained (possibly because of its permissive interaction with increased atrial natriuretic factor levels). Hypertensive patients with chronic renal failure have a heightened DOPA and dopamine sulfoconjugating propensity. Dopamine sulfate attenuates the biologic action of free dopamine. This may contribute (possibly via glomerular hypertension and hyperfiltration due to decreased postglomerular vasodilation) to progressive hypertensive renal damage, particularly in groups predisposed to dopamine deficiency, such as diabetics, blacks, and the elderly.
Insulin sensitivity and the effects of insulin on renal sodium handling and pressor systems in essential hypertensive patients.
Authors: Shimamoto K , Hirata A , Fukuoka M , Higashiura K , Miyazaki Y , Shiiki M , Masuda A , Nakagawa M , Iimura O
Published: August 2012

Insulin resistance and hyperinsulinemia are linked with essential hypertension. To clarify insulin sensitivity in Japanese essential hypertensive patients and the role of insulin resistance in these patients, a euglycemic hyperinsulinemic glucose clamp was applied in 17 essential hypertensive patients and 12 normotensive subjects. The mean glucose infusion rate was used as an indicator of insulin sensitivity (M value). This study revealed a significantly lower M value in essential hypertensive patients than in normotensive subjects. Increased plasma norepinephrine, renin activity, and aldosterone levels were observed after hyperinsulinemia for 120 minutes after glucose clamp in normotensive subjects and essential hypertensive patients. Urinary sodium excretion and fractional excretion of sodium were decreased in essential hypertensive patients as well as normotensive subjects during glucose clamp compared with the period before glucose clamp. No difference in the percent change was observed between essential hypertensive patients and normotensive subjects. These results indicate that selective insulin resistance with respect to glucose metabolism exists in essential hypertensive patients and that insulin action on renal sodium handling and pressor systems was maintained in these patients.
Time course of changes in sigmoidal-fitting baroreceptor curves in one-kidney, one clip hypertensive rats.
Authors: Moyses M R , Cabral A M , Bissoli N , Vasquez E C
Published: August 2012

The present study examined the time course of changes in baroreceptor reflex function by means of sigmoidal curve-fitting analysis in conscious, unrestrained renovascular one-kidney, one clip (1K1C) rats at 1, 3, 7, 15, 30, and 60 days after renal artery clipping. The reflex heart rate responses were elicited by alternate intravenous bolus injections of phenylephrine (change, +5 to +50 mm Hg) and sodium nitroprusside (change, -5 to -50 mmHg). Atropine methylnitrate and atenolol were given to evaluate the responses mediated by the cardiac sympathetic or vagal component, respectively. The average baroreceptor reflex gain (sensitivity) decreased progressively (day 1, 3.35 +/- 0.3 beats per minute [bpm] per millimeter of mercury), reaching a maximal attenuation in the 30-day 1K1C group (1.83 +/- 0.5 bpm/mm Hg) compared with sham rats (approximately 4.60 bpm/mm Hg). The data showed a decreased vagal activity contributing to the attenuation of the baroreceptor gain only in the 30-day 1K1C group. In contrast, the cardiac sympathetic component of the baroreceptor reflex was significantly decreased in all 1K1C groups (from 2.10 +/- 0.4 to 0.50 +/- 0.2 bpm/mm Hg) compared with the respective sham groups (from 3.80 +/- 0.3 to 3.10 +/- 0.4 bpm/mm Hg). These results suggest that a reduced contribution of the sympathetic component to the baroreceptor heart rate reflex may be the main cause of the progressive attenuation of the baroreceptor reflex sensitivity observed in conscious 1K1C hypertensive rats.
Renal prostaglandins and the control of renin release.
Authors: Freeman R H , Davis J O , Dietz J R , Villarreal D , Seymour A A , Echtenkamp S F
Published: August 2012

This study examines the hypothesis that the renal prostaglandins function as essential mediators in stimulus-secretion coupling for one or more of the basic receptor mechanisms in the control of renin release. Changes in plasma renin activity (PRA) were evaluated in response to suprarenal aortic constriction before and after indomethacin administration in conscious dogs with either a single denervated nonfiltering kidney or with intact filtering kidneys. Suprarenal aortic constriction was adjusted to reduce renal perfusion pressure below the autoregulatory range in both groups of dogs. Inhibition of cyclooxygenase with indomethacin significantly decreased urinary prostaglandin E2 (PGE2) excretion, but indomethacin failed to block or attenuate the increase in PRA in response to a decrease in renal perfusion pressure in either group of dogs. These results fail to support the hypothesis that the renal prostaglandins function as essential mediators of the intrarenal receptor mechanisms for renin release which are activated by a decrease in renal perfusion pressure below the autoregulatory range.
Low renin in young mothers and their children following hypertension in pregnancy.
Authors: Cottrill C M , Kotchen J M , Guthrie G P , Kotchen T A
Published: August 2012

Young women who became pregnant as adolescents and developed hypertension during their first pregnancies had higher blood pressures than women who had remained normotensive throughout pregnancy. These young mothers served as subjects for a study to evaluate the relationship between different levels of "normal" blood pressure and renin-aldosterone. Overall, plasma renin activity (PRA), but not plasma aldosterone, was inversely related to systolic blood pressure both before (r = -0.28; p less than 0.003) and after (r = -0.24, p less than 1.01) treadmill exercise. Unrelated to blood pressure, PRA was also lower in blacks and in women using oral contraceptive agents (p less than 0.01). Of women with a history of hypertension in pregnancy, 30% (9 of 30) had low PRA after exercise. Low renin was associated with higher blood pressures. At the time of a second exercise test 3 years later, these women still showed elevated arterial pressure and low renin. PRA was also suppressed in the children of mothers with low renin, and there were significant correlations between maternal and child PRA (r = +0.55; p less than 0.003) and between maternal and child aldosterone (r = +0.60; p less than 0.001). In conclusion, low renin may be an appropriate response to higher arterial pressures, and within families may be a marker of "pre-hypertension."