bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular biology of adrenergic receptors in the rat and frog central nervous system.
Authors: Caron M G , Leeb-Lundberg L M , Strader C D , Dickinson K E , Pickel V M , Joh T , Lefkowitz R J
Published: September 2013

Recent developments in the characterization of the adrenergic receptors have led to the identification and purification of the binding subunits of the various catecholamine receptors. beta-Adrenergic receptors have been identified in a wide variety of tissues by photoaffinity labeling with the antagonist [125I]p-azidobenzylcrazolol and have been purified to apparent homogeneity from several of these tissues. Thus, beta 1- and beta 2-adrenergic receptor binding sites appear to reside on peptides with molecular weights of 60,000 to 65,000. The alpha 1-adrenergic receptor binding subunit has been identified in several peripheral tissues by photoaffinity labeling with a newly developed probe (4-amino-6,7-dimethoxy-2[4(5(3-[125I]-iodo-4-azidophenyl) pentanoyl)-1-piperazinyl]-quinazoline, or [125I]APDQ). This binding site resides on a peptide with a molecular weight of 80,000. These techniques have been applied to the elucidation of the binding subunit structure of these receptors in the rat central nervous system with the result that beta 1-, beta 2-, and alpha 1-adrenergic binding sites appear to reside on peptides of similar molecular weight to those identified in peripheral tissues (i.e., 60,000-65,000 and 80,000). Using immunocytochemical techniques with antibodies raised to the frog erythrocyte, beta 2-adrenergic receptor, beta-adrenergic receptors were identified at the light microscopic level in regions of the rat and frog brain previously found by ligand binding and autoradiography to be richest in beta-adrenergic receptors. At the electron microscopic level, beta-receptor immunoreactivity was found throughout dendritic processes with local accumulations at certain postsynaptic sites. This finding is consistent with the idea that the density of the receptors might be significantly increased at postsynaptic junctions of adrenergic neurons.
Effects of methyldopa metabolites on amine transmitters and adrenergic receptors in rat brain.
Authors: Louis W J , Conway E , Summers R , Beart P , Jarrott B
Published: September 2013

Studies of catecholamine concentrations in defined nuclei from the anterior hypothalamic-preoptic regions and the medulla oblongata, known to contribute to cardiovascular control, were measured following acute or chronic methyldopa administration. These studies indicated that methyldopa was enzymatically converted to methyldopamine and methylnorepinephrine, and in some areas to methylepinephrine which replaced endogenous epinephrine. The predominant metabolite was methylnorepinephrine, which accumulated in concentrations higher than endogenous norepinephrine levels. (-)Methylnorepinephrine was found to be 6 times more potent and 75 times more selective for alpha 2-adrenergic receptors than (-) norepinephrine, and it is suggested that this alpha 2-adrenergic receptor action, particularly in the nucleus tractus solitarius, contributes to a major part of the antihypertensive effect of methyldopa.
Hemodynamic and cardiac effects of centrally acting antihypertensive drugs.
Authors: Frohlich E D , Messerli F H , Pegram B L , Kardon M B
Published: September 2013

The centrally acting alpha-adrenergic receptor agonist compounds have been available for treatment of hypertension for more than 25 years. Through studies of these compounds during this time, new knowledge has been made available not only on their mechanisms of antihypertensive action but also on the role of the adrenergic nervous system in essential hypertension. This discussion primarily reviews work from this laboratory on the cardiovascular actions of these compounds but reflects the general information from other quarters. In general, reduction of arterial pressure induced by these agents is associated with a cardiac output that remains relatively unchanged and with organ blood flows that are preserved. As a result of the reduced pressure, cardiac function is improved; and in recent studies, cardiac mass may be reduced. Associated with the reduced arterial pressure is an expanded plasma volume that is associated with a reduced blood viscosity, hematocrit, and plasma renin activity, but which may be at the expense of some return of arterial pressure toward pretreatment levels. The latter usually requires the addition of diuretic therapy. Current studies in our laboratory concern the performance of the heart following regression of ventricular hypertrophy both at reduced as well as increased ventricular afterloads.
Differential modulation of the baroreceptor reflex by brain and plasma vasopressin.
Authors: Unger T , Rohmeiss P , Demmert G , Ganten D , Lang R E , Luft F C
Published: September 2013

Plasma vasopressin sensitizes the baroreceptor reflex, whereas vasopressin given into the cerebral ventricle overrides the baroreceptor reflex by means of sympathetic stimulation. To test the hypothesis that arginine vasopressin stimulates two different receptor subtypes (V1 and V2) in the central nervous system, we measured the baroreceptor reflex (change in pulse interval vs change in blood pressure) after administering methoxamine (10-300 micrograms/kg i.v.) in conscious rats. Animals were pretreated either with a V1 vasopressin receptor antagonist administered intravenously or intracerebroventricularly, or with a V2 receptor antagonist administered intravenously. The central V1 antagonist caused sensitization of the baroreceptor reflex, whereas the intravenous V2 antagonist attenuated it. The intravenous V1 vasopressin antagonist had no effect on baroreceptor reflex sensitivity. When the experiments were repeated in rats with hereditary diabetes insipidus, neither antagonist influenced the baroreceptor reflex. Volume expansion lowered circulating vasopressin levels and also attenuated the baroreceptor reflex--effects similar to those observed with the intravenous V2 antagonist. We conclude that vasopressin sensitizes the baroreceptor reflex through V2 receptors accessible from the blood and inhibits the reflex through V1 receptors in the brain that cannot be reached from the blood. These observations suggest a direct interaction between hormonal and neuronal vasopressin in cardiovascular control.
Immunoreactive atrial natriuretic hormone levels increase in deoxycorticosterone acetate-treated pigs.
Authors: Grekin R J , Ling W D , Shenker Y , Bohr D F
Published: September 2013

Extensive evidence reported here and elsewhere indicates a hormonal role for atrial natriuretic factor. In the light of this evidence, it appears that atrial natriuretic hormone is a more appropriate term for these peptides than atrial natriuretic factor. Plasma levels of immunoreactive atrial natriuretic hormone were measured daily in seven pigs before and 1 week after subcutaneous implantation of deoxycorticosterone acetate (DOCA). Nine other animals underwent daily measurements of mean arterial pressure and central venous pressure during similar treatments. Plasma immunoreactive atrial natriuretic hormone levels rose progressively during the first 3 days after implantation, from a basal level of 60 +/- 9 pmol/L to a peak level of 159 +/- 21 pmol/L (p less than 0.05), and they remained significantly elevated throughout the rest of the 7-day observation period. In two animals that were restudied 6 weeks after DOCA implantation, plasma immunoreactive atrial natriuretic hormone had returned to preimplantation levels. The rise in plasma hormone levels after DOCA implantation closely paralleled the previously reported time course of mineralocorticoid escape. Whether atrial natriuretic hormone plays an important part in the escape phenomenon remains to be determined.
The adrenergic system and the release and pressor action of vasopressin.
Authors: Gavras I , Hatinoglou S , Gavras H
Published: September 2013

We studied the effect of various adrenergic components on vasopressin in groups of anephric rats. Pharmacological interventions included alpha 1-, alpha 2-, and beta-adrenergic receptor blockade and infusions of sodium nitroprusside to achieve a baseline blood pressure fall similar to that obtained by alpha 1-blockade, followed by hypertonic saline infusion to stimulate vasopressin release and administration of a specific V1 vascular vasopressin inhibitor to test the degree of blood pressure dependency on vasopressin. The combined hypotensive and osmolar stimuli of nitroprusside followed by hypertonic saline led to the highest level of plasma vasopressin (104 +/- 17 pg/ml, p less than 0.01) but only a 7 +/- 1 mm Hg fall in blood pressure in response to the vasopressin inhibitor. Rats subjected to alpha 1-blockade and saline infusion had the largest blood pressure reduction in response to the vasopressin inhibitor (43 +/- 5 mm Hg, p less than 0.001), despite a modest rise in vasopressin levels (18 +/- 2 pg/ml). Other pharmacological maneuvers produced intermediate responses in terms of vasopressin release and blood pressure response to the vasopressin inhibitor. There was no correlation between vasopressin levels achieved by each maneuver and the magnitude of blood pressure reduction in response to the vasopressin inhibitor. We conclude that 1) plasma levels of vasopressin under these conditions do not permit an accurate estimate of the magnitude of its pressor contribution to the maintenance of a given blood pressure level, which can be demonstrated only by the depressor response to a vasopressin inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Biochemical and immunochemical studies of supraoptic and paraventricular cultures.
Authors: Morris M , Sundberg D K , Bennett B A
Published: September 2013

A tissue culture model was established for the study of hypothalamic peptide synthesis and secretion. Microdissected explants of the paraventricular and supraoptic regions from Sprague-Dawley rats (neonates or young rats) were maintained in culture for up to 3 weeks. Studies were performed to evaluate vasopressin and oxytocin content (medium and tissue levels), immunocytochemical localization, and biosynthetic activity. Immunocytochemical staining for oxytocin, neurophysin, and neuron-specific enolase showed positive neurons in both the paraventricular and supraoptic cultures. In many cases, the neurons were large (30-40 microns) and bipolar, resembling the classic magnocellular neuron. Measurement of tissue and medium content showed the continued presence of vasopressin and oxytocin in the cultured explants. Even after 3 weeks, there were significant amounts of vasopressin present. Biosynthesis was evaluated by determining the incorporation of 35S-labeled cystine or cysteine into proteins and peptides. The medium and tissue extracts were separated by reverse-phase high-performance liquid chromatography. Results showed that most of the labeled peptides were released into the medium rather than stored. There were two labeled peaks in the medium, which chromatographically resembled native vasopressin and oxytocin. Treatment with a protein synthesis inhibitor, either puromycin or cycloheximide, resulted in a decrease in labeled peptides. A comparison of 35S-labeled cystine and cysteine showed that the latter was the label of choice, with significantly greater incorporation.
Preliminary observations on abnormalities of membrane structure and function in essential hypertension.
Authors: Naftilan A J , Dzau V J , Loscalzo J
Published: September 2013

To test the hypothesis that structural abnormalities exist in the cell membrane in persons with essential hypertension and that these abnormalities affect membrane-related cellular functions, we examined several membrane-dependent phenomena and membrane lipid composition in the blood cells of subjects with essential hypertension. We analyzed platelet aggregability, membrane fluidity, membrane fatty acid composition, and erythrocyte deformability in four normolipidemic subjects with untreated essential hypertension and in five age-matched normotensive controls. As compared with the controls, the subjects with essential hypertension had platelets that aggregated at lower concentrations of adenosine 5'-diphosphate, platelet membranes that were less fluid, and erythrocytes that were more deformable. Lipid analysis of the membranes of platelets from the two study groups showed that although the cholesterol content was identical, the membranes from the essential hypertension group contained significantly less linoleic acid (18:2) than did those from the normotensive controls. Given the known effects of cis-unsaturated fatty acyl composition on membrane fluidity and membrane-related cellular functions, these data suggest that one factor contributing to essential hypertension is an inherent structural membrane abnormality that alters the physical and functional properties of the cell membrane.
Renal mechanisms for suppression of renin secretion by atrial natriuretic factor.
Authors: Villarreal D , Freeman R H , Davis J O , Verburg K M , Vari R C
Published: September 2013

The effects of synthetic atrial natriuretic factor on renin secretion were examined in anesthetized dogs with either a single filtering kidney or a single denervated nonfiltering kidney. In dogs with a single filtering kidney (Series 1, n = 6), a priming dose of atrial natriuretic factor (2 micrograms/kg, i.v.) followed by sustained intravenous infusions at doses of 200 and 400 ng/kg/min for 20 minutes each produced striking decrements (p less than 0.05) in renin secretion, from 1083 +/- 322 to 205 +/- 120 and 286 +/- 168 ng of angiotensin I per minute. This fall in renin secretion was associated with significant increases (p less than 0.05) in creatinine clearance, urine flow, sodium excretion, and the filtered load of sodium. Renal blood flow increased only transiently. In dogs with a single denervated nonfiltering kidney (Series 2, n = 6), infusion of atrial natriuretic factor at these doses also produced marked inhibition (p less than 0.05) of renin secretion, from 311 +/- 98 to 72 +/- 22 and 91 +/- 37 ng of angiotensin I per minute. Renal blood flow remained significantly elevated (p less than 0.05) throughout the infusion, in contrast to renal blood flow in Series I. Similar results were obtained in a third series of dogs (n = 6) with a single denervated nonfiltering kidney, during sustained intrarenal arterial infusions of atrial natriuretic factor. These results suggest that an increase in the sodium load delivered to the macula suppression of renin secretion by atrial natriuretic factor is mediated through its interactions with the two intrarenal receptor mechanisms, the renal vascular receptor and the macula densa.(ABSTRACT TRUNCATED AT 250 WORDS)
Decreased venous distensibility and reduced renin responsiveness in hypertension.
Authors: Fitzpatrick M A , Hinderliter A L , Egan B M , Julius S
Published: September 2013

Abnormalities of renin release and of venous distensibility have been described in essential hypertension. We have postulated that decreased venous distensibility could contribute to the blunted renin response to upright posture in hypertension. Stiffer veins might prevent venous pooling in the lower extremities, which in turn might affect the stretch on cardiopulmonary mechanoreceptors, thereby influencing the reflex release of renin. We investigated this hypothesis in the present study of 47 patients with mild hypertension and 26 (male) healthy volunteers of similar age and race. To induce isolated changes in the stretch of cardiopulmonary mechanoreceptors, systemic hemodynamics were measured before and after thigh cuff inflation at 60 mm Hg for 30 minutes. Cardiac output was determined by dye dilution. Before the intervention, variable thigh cuff pressures were used to measure venous pressure volume with mercury-in-Silastic strain gauge plethysmography. Venous distensibility was diminished in hypertension, as evidenced by a shift in the calf venous volume/pressure curve toward the pressure axis. During the 30-minute experiment, the hypertensive subjects had less blood pooling in their legs in response to thigh cuff inflation, as compared with the control subjects. The hemodynamic and renin responses reflected this diminished effect of thigh cuff inflation on venous return. The smaller increase of renin in the hypertensive group was associated with a smaller fall in the stroke index and right atrial pressure; the reflex rise in the heart rate was also decreased. By pooling blood in the lower extremities, thigh cuff inflation simulates upright posture. It is customary to classify the renin status of hypertensive patients according to the renin response to upright posture.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of deoxycorticosterone-salt hypertension on cell ploidy in the rat aorta.
Authors: Lichtenstein A H , Brecher P , Chobanian A V
Published: September 2013

We investigated the effect of deoxycorticosterone-salt hypertension and its reversal on nuclear ploidy in rat aortic smooth muscle cells, using flow cytometry. Systolic blood pressure and the percentage of cells with tetraploid nuclei increased over a 4-week period and then remained constant. In control rats 6.0 +/- 0.6% of aortic cells had tetraploid nuclei, and this increased to 27.0 +/- 1.1 and 26.6 +/- 2.4% after 4 and 8 weeks of deoxycorticosterone-salt treatment, respectively. Computer analysis of the forward light scatter data obtained from the cell sorter indicated that the average tetraploid cell was approximately 1.6-fold larger than the average diploid cell in both normotensive and hypertensive animals. Analysis of the DNA content of intact cells and isolated nuclei indicated that the increased DNA content per cell was predominantly attributable to tetraploid nuclei rather than binucleated cells. Reversal of hypertension with either a low sodium diet for 8 to 13 weeks or chlorothiazide administration failed to reverse the abnormalities seen in arterial smooth muscle cell ploidy, despite normalization of the blood pressure and the ratio of heart to body weight.
Platelet binding sites for atrial natriuretic factor in humans. Characterization and effects of sodium intake.
Authors: Schiffrin E L , Deslongchamps M , Thibault G
Published: September 2013

Platelets bear receptors for vasoactive peptides such as angiotensin II and vasopressin. The presence of binding sites for another vasoactive peptide, atrial natriuretic factor, was therefore investigated in human platelets. 125I-labeled synthetic atrial natriuretic factor bound specifically to human platelets. Steady-state and kinetic experiments demonstrated the existence of one class of high-affinity low-capacity binding sites for atrial natriuretic factor in platelets with a dissociation constant of 30 pM. The order of potency of atrial natriuretic factor fragments showed that the structural requirements of the high-affinity binding site detected were similar to those of receptors for atrial natriuretic factor in rat blood vessels and adrenal zona glomerulosa. To study the regulation of these binding sites by sodium, normal young men were subjected successively in random order to a low-sodium (40 mmol per day) and high-sodium (300 mmol per day) diet for 4 days. Binding of atrial natriuretic factor to platelets was higher with the low-sodium diet (10.3 +/- 1.0 sites per cell) than with the high-sodium diet (7.1 +/- 0.7 sites per cell). In conclusion, human platelets bear binding sites for atrial natriuretic factor, the density of which may be modulated by sodium intake. The platelet is a useful model for investigating atrial natriuretic factor receptors in different physiopathological conditions in humans.
Biochemical similarity of expressed human prorenin and native inactive renin.
Authors: Hsueh W A , Do Y S , Shinagawa T , Tam H , Ponte P A , Baxter J D , Shine J , Fritz L C
Published: September 2013

Prorenin is secreted by mammalian cells transfected with a human preprorenin expression construct. The purpose of this investigation was to compare the physicochemical properties of expressed prorenin in culture medium with the known characteristics of human inactive renin, which accounts for nearly half the renin in plasma and kidney. We found that expressed human prorenin strongly resembles human renal and plasma inactive renin. The expressed prorenin was inactive and could be equally activated by acid (dialysis to pH 3.3) or trypsin. Acid activation was completely reversible; reexposure to acid could reactivate the expressed inactive renin. Exposure to cold (-5 degrees C for 3 days) could also activate expressed renin. The Michaelis-Menten constant of acid-activated expressed renin with sheep substrate was 0.29 microM, and the pH optimum was 7.8. Expressed inactive renin bound to a cibacron-blue affinity column and could be eluted with 0.5M NaCl. All the above characteristics resemble those of human renal and plasma inactive renin. In addition, the molecular weight of expressed prorenin and human chorionic renin was 47,000, as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and 46,000, as measured by high-performance liquid chromatography. These data, taken together with the published observation that native human inactive renin cross-reacts with antibodies generated against amino acid sequences in the prosegment of renin, provide strong support for the hypothesis that human inactive renin is prorenin.
Detection of left ventricular hypertrophy by M-mode echocardiography. Anatomic validation, standardization, and comparison to other methods.
Authors: Devereux R B
Published: September 2013

Because of its simplicity, widespread availability, relatively low cost, and lack of adverse effects, M-mode echocardiography has become the most widely used technique for measurement of human left ventricular mass. Necropsy comparison studies have yielded formulas for anatomically accurate estimation of left ventricular mass in patients with normally shaped ventricles using left ventricular measurements by either Penn or American Society of Echocardiography conventions, but M-mode methods are less accurate in abnormally shaped ventricles. The standard error of M-mode echocardiographic left ventricular mass measurements is approximately 40 g under difficult clinical recording conditions and 30 g or less for research studies of stable subjects. Interstudy variability of mass estimates appeared somewhat lower, resulting in 95% confidence limits for serial change up to 58 g for individual subjects and up to 10 g for study populations of 34 patients or more. The accuracy of M-mode echocardiography for measurement of left ventricular mass is similar to that of contrast angiography but may be exceeded by newer methods with greater cost or radiation exposure, including magnetic resonance imaging, cine-computed tomography, and three-dimensional echocardiographic reconstruction. Identification of left ventricular hypertrophy needs to take into account the influence of sex and body size, the variables that most influence normal ventricular mass, with provisional criteria for recognition of hypertrophy being left ventricular mass index over 134 g/m2 in men and above 110 g/m2 in women.
Standardization in the measurement of left ventricular wall mass. M-mode echocardiography.
Authors: Reichek N
Published: September 2013

A wide variety of approaches to M-mode echocardiographic methods for estimation of left ventricular mass have been proposed and employed in hypertensive heart disease. The cube function geometry, which assumes an ellipsoid of revolution with a length twice the minor axis, appears to be optimal provided left ventricular shape is relatively normal. The Penn measurement technique for wall thickness and diameter is best validated, but American Society of Echocardiography measurements can be used with appropriate regression correction. Changes in instrumentation may warrant reexamination of measurement techniques as well as the relative value of M-mode and two-dimensional echocardiographic techniques for estimation of left ventricular mass.
Disparate relationships between blood pressure and left ventricular mass in patients with and without left ventricular hypertrophy.
Authors: Drayer J I , Gardin J M , Brewer D D , Weber M A
Published: September 2013

The relationship between casual blood pressure and left ventricular (LV) mass has been reported to be fairly weak in hypertensive patients. In this study we analyzed this relationship using noninvasive devices to monitor blood pressure for 24 hours in ambulatory patients and M-mode echocardiography to determine LV mass. Among the 33 patients with hypertension, 21 had echocardiographic LV hypertrophy (LV mass greater than 250 g). Patients with LV hypertrophy did not differ significantly from patients without hypertrophy with respect to age or casual systolic or diastolic blood pressure. The averages of whole-day systolic and diastolic blood pressures were 146 +/- 17 (SD) over 90 +/- 12 and 136 +/- 16 over 89 +/- 12 mm Hg, respectively. The relationship between whole-day average systolic blood pressure and LV mass was significantly positive (r = 0.66, p less than 0.05) in patients without hypertrophy but was not significant in patients with LV hypertrophy (r = -0.24). Similarly, the relationship between whole-day average diastolic blood pressure and LV mass was significantly positive in the former group (r = 0.64, p less than 0.05) but significantly negative in hypertensive patients with LV hypertrophy (r = -0.67, p less than 0.01). Thus, blood pressure correlates positively with LV mass only in patients without cardiac hypertrophy. In hypertensive patients with LV hypertrophy, factors additional to the high blood pressure itself must participate in the regulation of LV mass.
Echocardiographic studies of regression of left ventricular hypertrophy in hypertension.
Authors: Fouad-Tarazi F M , Liebson P R
Published: September 2013

The availability of echocardiography has allowed direct determinations of left ventricular wall thickness and calculation of left ventricular mass. As a result, the past decade has witnessed a remarkable evolution in our understanding of structural changes in the heart. Moreover, cardiac hypertrophy was found to be reversible by some forms of therapy. In general, reduction of left ventricular mass became evident after 8 to 12 weeks of antihypertensive therapy. Sympatholytics (including methyldopa and reserpine), converting enzyme inhibitors (captopril and enalapril), and calcium entry blockers led to significant regression of left ventricular hypertrophy. On the other hand, arteriolar vasodilators (hydralazine, trimazosin, and minoxidil) were not associated with regression of hypertrophy despite adequate blood pressure control. Finally, data regarding diuretics and beta-blockers are controversial. These differences in results among various antihypertensive drugs reflect the multiplicity of factors modulating left ventricular hypertrophy.
Future directions in the use of echocardiography.
Authors: Frohlich E D
Published: September 2013

The heart may play an active, passive, or incidental role in the pathogenesis of hypertension. Echocardiography probably contributes little to understanding of active mechanisms, although it may provide important information relative to structural and functional adaptive changes associated with development of left ventricular hypertrophy. Moreover, because other clinical conditions frequently coexist with hypertensive heart disease, echocardiography may provide another dimension in the assessment of obesity, coronary heart disease, mitral valve prolapse, idiopathic hypertrophic subaortic stenosis, and asymmetric septal hypertrophy in the overall problem. Critical in this understanding are the subtle changes that occur in the individual patient, reflecting the natural history of the disease or response to its treatment. Since technical problems preclude echocardiographic evaluation in all patients with hypertension, particular care must be exercised in making epidemiologic generalizations.
Conversion of B1 kinin receptor-mediated vascular relaxation to contraction.
Authors: Churchill L , Ward P E
Published: September 2013

We have previously reported that des-Arg9-bradykinin can relax the phenylephrine-precontracted rabbit mesenteric artery through B1 kinin receptor stimulation and the subsequent release of prostaglandins. In the present study, we have found that this relaxant response can be converted to a contractile response by the cyclooxygenase inhibitor indomethacin. Contraction was dose-dependent and was blocked by the B1 receptor antagonist [Leu8]des-Arg9-bradykinin, with a pA2 value obtained by Schild regression similar to that reported for relaxation in the absence of indomethacin. Des-Arg10-kallidin (ED50 = 5.0 +/- 0.9 X 10(-9) M) was 16 times more potent than des-Arg9-bradykinin (ED50 = 8.1 +/- 0.8 X 10(-8) M) in contracting the indomethacin-treated artery and was also blocked by [Leu8]des-Arg9-bradykinin. In contrast, only 13 out of 24 indomethacin-treated vessels contracted in response to bradykinin, which had only one tenth and one 160th the potency (ED50 = 9.9 +/- 1.8 X 10(-7) M) of des-Arg9-bradykinin and des-Arg10-kallidin, respectively. B1 kinin receptor-mediated contraction in the presence of indomethacin was unaffected by the dual cyclooxygenase-lipoxygenase inhibitor BW 755c. These results indicate that des-Arg-kinins can stimulate both relaxation and contraction of the phenylephrine-precontracted rabbit mesenteric artery through stimulation of B1 kinin receptors. The relaxation is dependent on the release of prostaglandins, while the contraction may represent a direct effect.
Mechanisms of protection of the blood-brain barrier during acute hypertension in chronically hypertensive rats.
Authors: Mayhan W G , Faraci F M , Heistad D D
Published: September 2013

Spontaneously hypertensive rats are less susceptible than normotensive rats to disruption of the blood-brain barrier during acute hypertension. The purpose of this study was to examine mechanisms that protect the blood-brain barrier from disruption in chronically hypertensive rats during acute hypertension. Normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) were studied using intravital fluorescent microscopy and fluorescein-labeled dextran. Disruption of the blood-brain barrier was characterized by the appearance of microvascular leaky sites and quantitated by the clearance of fluorescein-labeled dextran. We measured pressure (servo null) in pial arterioles and venules 40 to 60 micron in diameter. In WKY, acute, phenylephrine-induced hypertension increased pial arteriolar pressure by 47 +/- 7 mm Hg (mean +/- SE) and pial venous pressure by 20 +/- 2 mm Hg. Leaky sites increased from 0 to 28 +/- 2. In SHRSP, acute hypertension increased pial arteriolar pressure 44 +/- 8 mm Hg, but pial venous pressure increased only 6 +/- 1 mm Hg and leaky sites increased from 0 to only 6 +/- 1. All leaky sites were venular. In another group of WKY and SHRSP, we increased pial venous pressure passively with a neck cuff. In WKY, venous pressure increased by 22 +/- 2 mm Hg, and leaky sites increased from 0 to 23 +/- 2. In SHRSP, venous pressure increased by 19 +/- 1 mm Hg, and leaky sites increased from 0 to 24 +/- 2. Thus, when venous pressure is increased to the same level in WKY and SHRSP, disruption of the blood-brain barrier is similar. We conclude that protection of the blood-brain barrier during acute hypertension in SHRSP is related to attenuation of increases in pial venous pressure, not pial arteriolar pressure, and the blood-brain barrier in venules of SHRSP probably is not inherently resistant to disruption.
Responsiveness of locus ceruleus neurons in hypertensive rats to vasopressin.
Authors: Berecek K H , Olpe H R , Hofbauer K G
Published: September 2013

We studied the actions of vasopressin administered microiontophoretically onto neurons of the locus ceruleus in rats with deoxycorticosterone-acetate (DOCA)-salt hypertension and in control (normotensive) rats. Rats were studied at 3 days (prehypertensive stage) and 4 to 6 weeks after DOCA-salt treatment (chronic hypertensive stage). Experiments were performed in anesthetized rats using conventional microiontophoretic and single-cell recording techniques. Three days after DOCA-salt administration, the treated rats showed no rise in arterial pressure in comparison with control rats, but 4 to 6 weeks later, the treated rats had significantly greater pressures (p less than 0.01) than controls. Vasopressin administered with currents of 10 to 90 nA for 1 minute produced a current-dependent increase in the firing rate of noradrenergic neurons in all rats. Increases in the firing rate of noradrenergic neurons in DOCA-salt-treated rats, whether in the prehypertensive or the chronic stage, were significantly greater than increases in control rats. These findings indicate that 1) vasopressin can affect neuronal activity in the locus ceruleus and 2) noradrenergic neurons in the locus ceruleus of DOCA-salt-treated rats have an increased responsiveness to the excitatory effects of vasopressin in both prehypertensive and chronic stages of hypertension.
Reduced sodium concentration and increased sodium-potassium pump activity of erythrocytes in human hypertension.
Authors: Simon G , Engel C R
Published: September 2013

Erythrocyte Nai, Nai/Ki and ouabain-sensitive and ouabain-insensitive 86Rb uptake (K transport) were measured in whole blood of 16 normotensive and 19 hypertensive white male subjects, within seconds or minutes after withdrawal of blood. Erythrocyte Nai and Nai/Ki were reduced (p less than 0.05), and ouabain-sensitive 86Rb uptake was increased (p less than 0.01) in hypertensive subjects. In a separate group of hypertensive white male subjects, an inverse correlation was found between erythrocyte Nai/Ki and ouabain-binding sites per erythrocyte (r = 0.85, p less than 0.01, n = 9). The abnormalities of erythrocyte cation fluxes in hypertensive subjects are similar to those induced by aldosterone in vascular smooth muscle cells and by glucocorticoid administration in the erythrocytes of human subjects, suggesting similarities in pathogenesis.
Altered pressure-natriuresis relationship in young spontaneously hypertensive rats.
Authors: Roman R J
Published: September 2013

In the present study, the pressure-natriuretic responses of 3- to 5- and 6- to 9-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were characterized to determine whether the relationship between sodium excretion and renal perfusion pressure is altered during the development of hypertension. Differences in the neural tone and renal hormone levels in SHR and WKY were minimized by denervating the kidney and fixing plasma concentrations of aldosterone, vasopressin, norepinephrine, and cortisol by intravenous infusion. Renal perfusion pressure was varied using adjustable occluders on the lower aorta. The slopes of the relationships between sodium excretion and renal perfusion pressure were not significantly different in 3- to 5-week-old SHR and WKY (0.31 +/- 0.05 vs 0.42 +/- 0.06 microEq/min/g kidney weight); however, the x-intercept of this relationship was significantly shifted to the right by 15 mm Hg in SHR compared to WKY. Blood pressure was moderately elevated even in the 3- to 5-week-old SHR in comparison to WKY (98 +/- 5 vs 81 +/- 6 mm Hg). As the degree of hypertension became more severe, the slope of the pressure-natriuresis relationship became significantly lower in 6- to 9-week-old SHR compared to the corresponding slope observed in age-matched WKY (0.16 +/- 0.02 vs 0.31 +/- 0.04 microEq/min/g kidney weight). These results indicate that the relationship between sodium excretion and renal perfusion pressure is altered even in very young SHR. Thus, the resetting of kidney function occurs very early and may be necessary for the development of hypertension in SHR.
Prevention or attenuation of baroreceptor resetting by pulsatility during elevated pressure.
Authors: Chapleau M W , Heesch C M , Abboud F M
Published: September 2013

Acute static elevation of arterial pressure increases the pressure threshold for activation of baroreceptors (acute resetting). The purpose of this study was to test the hypothesis that pulsatility during acute elevation of pressure modifies this acute resetting. Activity was recorded in 21 single baroreceptor units from the isolated carotid sinuses of dogs anesthetized with chloralose. Single-unit pressure thresholds were determined with a slow ramp increase in pressure. After a control period of static pressure at 25 to 50 mm Hg, the pressure threshold averaged 69 +/- 4 (SE) mm Hg. Three graded levels of static pressure were held for 5 to 15 minutes. The levels averaged 76 +/- 4, 115 +/- 6, and 170 +/- 5 mm Hg. The corresponding nerve activity during these periods was 0, 44 +/- 6, and 63 +/- 6 spikes per second, and the resulting increases in pressure threshold averaged 10 +/- 1, 17 +/- 2, and 26 +/- 3 mm Hg, respectively. In contrast, during equivalent elevations of pulsatile pressure, nerve activity averaged 20 +/- 3, 37 +/- 4, and 61 +/- 5 spikes per second, and the increases in pressure threshold averaged 0 +/- 4, 14 +/- 2, and 24 +/- 2 mm Hg, respectively. In some units, the pressure threshold decreased following elevation of pulsatile pressure. The results indicate that: pulsatility during elevation in pressure prevents or attenuates the acute baroreceptor resetting except at maximal pressure; upward resetting occurs with elevation of static pressure even when there is no nerve activity during the period of elevated pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Enhanced vascular reactivity to protein kinase C activators in genetically hypertensive rats.
Authors: Turla M B , Webb R C
Published: September 2013

Recent studies suggest that phospholipid-sensitive, Ca2+-dependent protein kinase C participates in contractile responses of vascular smooth muscle. This study characterizes vascular reactivity to protein kinase C activators in stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY). Helical strips of mesenteric arteries were mounted in organ chambers for measurement of isometric contractions (responses were normalized as a percentage of maximal force in response to 100 mM KCl; in SHRSP, 350 +/- 16 mg; in WKY, 335 +/- 21 mg). Arteries from SHRSP contracted faster and developed greater force than arteries from WKY (168 +/- 9% vs 143 +/- 3%) in response to the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Arteries from SHRSP (0.6 X 10(-8) M) were more sensitive to the phorbol ester than those from WKY (2.2 X 10(-8) M), as indicated by the dose of the phorbol ester required to produce 50% of the maximal response to KCl. Additionally, SHRSP arteries were more sensitive to the contractile effects of mezerein, a non-phorbol ester activator of protein kinase C. Ca2+-free solution (1.0 mM EGTA) and verapamil (10(-7) M) caused relaxation (approximately -60%) of contractions in response to the phorbol ester (10(-6) M). Addition of 10(-6) M of the phorbol ester to arteries that were preincubated in Ca2+-free solution (1.0 mM EGTA for 30 minutes) elicited submaximal contractions (in SHRSP, 26 +/- 4%; in WKY, 38 +/- 7%). Upon addition of 1.6 mM Ca2+, arteries from SHRSP contracted faster (t1/2 = 2.7 +/- 0.6 minutes) than those from WKY (8.2 +/- 0.5 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)
Changes in hemodynamics and myocardial contractility during chronic sodium depletion in conscious dogs.
Authors: Nii T , Fouad-Tarazi F M , Ferrario C M , Bravo E L , Czerska B
Published: September 2013

Chronic sodium depletion has been reported to decrease ejection fraction in anesthetized dogs. We tested the hypothesis that this reduction in cardiac performance is due to either hemodynamic or humoral factors. Seven mongrel dogs were fed a low sodium diet (less than 2 mEq Na+ per day) for 5 weeks. Echocardiographic and radionuclide techniques were used to monitor cardiac function. There was a gradual but significant (p less than 0.01) decrease in ejection fraction from 61 +/- 7% (SD) at baseline to 47 +/- 8% after 5 weeks of sodium depletion in association with a fall in left ventricular end-diastolic volume. Ejection fraction did not change in five control dogs fed 55 mEq Na+ per day throughout the 5-week follow-up period. Myocardial contractility did not change in either salt-depleted or control dogs. Plasma norepinephrine levels in the coronary sinus were twice as high in salt-depleted as in control dogs, but there were no significant differences in arterial norepinephrine concentration between the two groups. Therefore, we concluded that reduced ejection fraction during sodium depletion resulted from hemodynamic changes (decreased preload). The excess available norepinephrine failed to increase myocardial contractility, suggesting a dysfunction at the cardiac adrenergic neuroeffector junction.
Angiotensin II stimulation of vascular smooth muscle phosphoinositide metabolism. State of the art lecture.
Authors: Griendling K K , Berk B C , Ganz P , Gimbrone M A , Alexander R W
Published: September 2013

Phosphoinositide hydrolysis is an integral step in the activation of vascular smooth muscle by angiotensin II. Sequential phospholipase C-mediated hydrolysis of the polyphosphoinositides and phosphatidylinositol in cultured vascular smooth muscle cells stimulated with angiotensin II results in a coordinated series of biochemical events: a transient formation of inositol trisphosphate associated with calcium mobilization, and a biphasic, sustained formation of diacylglycerol associated with activation of protein kinase C and cytosolic alkalinization. The initial, rapid phase and the sustained phase of the angiotensin II response appear to be differentially controlled. Formation of inositol trisphosphate and mobilization of calcium are attenuated by activation of protein kinase C. Sustained diacylglycerol formation is promoted by cytosolic alkalinization, and appears to require cellular processing of the angiotensin II-receptor complex. Calcium and cyclic guanosine 3',5'-monophosphate do not appear to regulate phospholipase C-mediated phosphoinositide hydrolysis in vascular smooth muscle. Thus, regulation of angiotensin II-stimulated second messenger generation in vascular smooth muscle is complex, perhaps involving protein kinase C activation, changes in intracellular pH, and processing of the angiotensin II-receptor complex.
Tissue-specific regulation of renin expression in the mouse.
Authors: Dzau V J , Brody T , Ellison K E , Pratt R E , Ingelfinger J R
Published: September 2013

Increasing biochemical evidence suggests that the renin-angiotensin system may be present in may extrarenal tissues. We have employed the mouse submandibular gland renin complementary DNA (pDD-1D2) and the rat liver angiotensinogen complementary DNA (pRang 3) to demonstrate that renin and angiotensinogen messenger RNAs are expressed in the mouse kidney, submandibular gland, heart, adrenal, brain, and testis. To elucidate the factors that influence local tissue renin-angiotensin expressions, we studied tissue renin messenger RNA and enzymatic levels of male mice in response to sodium depletion and castration. Sodium depletion resulted in increased renin expression in the kidney, heart, and adrenal, but not in the submandibular gland and testis. Castration lowered renin levels in all extrarenal tissues but appeared to increase renin level in the kidney. Taken together, the above data demonstrate tissue-specific regulation of renin expression and imply different functions for the sodium responsive and nonresponsive systems.
Obesity-induced hypertension in the dog.
Authors: Rocchini A P , Moorehead C , Wentz E , Deremer S
Published: September 2013

To study the relationship between body weight and blood pressure, we have developed an animal model of obesity-induced hypertension. Nine adult mongrel dogs were chronically instrumented with aortic and vena caval catheters. After a 2-week control period, all dogs were made to gain weight by adding 2 lb/day of beef fat to their diet for 5 weeks. Blood pressure, heart rate, and body weight were measured daily before the addition of dietary fat, during the 5 weeks of the high fat diet, and for 6 weeks after the fat supplement was stopped. Plasma volume and cardiac output were measured prior to and after 5 weeks of the fat diet. During the 5-week high fat diet, the dogs' body weight increased from 22.2 +/- 2.1 to 27.4 +/- 3 kg (p less than 0.001); mean blood pressure increased from 90 +/- 5 to 112 +/- 6 mm Hg (p less than 0.01); and heart rate increased from 70 +/- 7 to 85 +/- 5 beats/min (p less than 0.05). Blood pressure, heart rate, and body weight returned to near control values after the fat diet was stopped. Over the 5-week fat diet, the dogs' plasma volume increased from 920 +/- 130 to 1059 +/- 195 ml (p less than 0.05); cardiac output increased from 2.5 +/- 0.4 to 3.1 +/- 0.3 L/min (p less than 0.05); and systemic vascular resistance increased from 35.3 +/- 8 to 38.9 +/- 9 mm Hg/L/min (p less than 0.1). Weight gain in the dogs was also associated with hyperinsulinemia and insulin resistance.(ABSTRACT TRUNCATED AT 250 WORDS)
Electrocardiographic changes during antihypertensive therapy in the International Prospective Primary Prevention Study in Hypertension.
Authors: Bolli P , Burkart F , Vesanen K , Baker J L , Pinto M , Buhler F R
Published: September 2013

In the International Prospective Primary Prevention Study in Hypertension, electrocardiographic changes before and during 3- to 5-year antihypertensive treatment were investigated in a cohort of 5819 men and women aged 40 to 64 years with entry diastolic blood pressures of 100 to 125 mm Hg. They were randomly allocated to treatment regimens that either included or excluded the slow-release beta-blocker oxprenolol. Electrocardiograms (ECGs) were assessed using the Minnesota Code and assigned to groups of normal ECGs or ECGs with pressure-related, ischemic, "intermediate," or "other" abnormalities. Antihypertensive treatment was associated with a decrease (mainly in men) of pressure-related and (mainly in women) of intermediate abnormalities. Ischemic abnormalities increased, particularly in men. Inclusion of the beta-blocker resulted in a greater reduction in intermediate abnormalities and in a lesser increase in ischemic abnormalities. Better blood pressure control was associated with a lesser increase in ischemic abnormalities and in a regression of pressure-related abnormalities. The presence of ST segment depression and of a complete left bundle branch block in the entry ECG was associated with a significant risk for sudden death and myocardial infarction. Optimal blood pressure control prevents pressure-induced cardiac target organ damage and, hence, heart failure, and may delay the progression of ischemic abnormalities. This tallies with the lower critical cardiac event rate associated with lower blood pressure that was observed in the same study.