bluuebunny/crossref_metadata_2025 huggingface dataset:
Vasopressor hyperresponsiveness in New Zealand genetically hypertensive rats.
Authors: Baer P G
Published: June 2012

The relationship of blood pressure (BP) to vascular hyperresponsiveness to norepinephrine (NE) in New Zealand genetically hypertensive (NZGH) rats was studied with an isolated, perfused hindquarters preparation. Four separate studies were conducted, and the findings were as follows. 1) Compared with New Zealand normotensive rats (NZNR), NZGH rats by 3 weeks of age clearly showed hyperresponsiveness, although the BP difference had not yet fully developed. 2) Bilateral renal denervation of NZGH at 3 weeks of age delayed the development of hypertension for 4 weeks, but did not lessen the vascular hyperresponsiveness. 3) In one-kidney, one clip renal hypertensive NZNR, vascular responsiveness was increased but remained less than that of age-matched NZGH. 4) In an F2 generation of NZGH-NZNR cross-bred rats, the average adult systolic BP was 163 mm Hg, similar to that of the NZGH parent strain; however, vascular responsiveness was reduced to an intermediate level, lower than that of NZGH but higher than that of NZNR. It is concluded that the vascular hyperresponsiveness of NZGH rats to NE is a primary characteristic that can be largely dissociated from elevated BP.
Is the hypertensive rat really hyperreactive?
Authors: Sutterer J R , Stoney C M , Sanfillipo M
Published: June 2012

This study investigated the behavior of hypertensive-prone and nonhypertensive-prone rat strains to see whether there are differences in behavioral reactivity to environmental stimulation. Of primary interest was general activity, because investigators have assumed it to be an index of reactivity to environmental stimulation and to be correlated with the elevation of blood pressure in spontaneously hypertensive rats (SHR) but not in normotensive Wistar-Kyoto (WKY) rats. Therefore, general activity was assessed in SHRs and WKYs as a function of walking and rearing in an open field (Experiments 1 and 2) and crossings in a shuttlebox test (Experiments 3, 4, and 5). Activity was assessed under a constant level of environmental stimulation in the open field (Experiment 1) and shuttlebox (Experiment 3) or under varying degrees of stimulation in the open field (Experiment 2) and shuttlebox (Experiments 4 and 5). In the open field and the shuttlebox, SHR activity was above WKY activity when the degree of environmental stimulation was constant. However, when stimulation was manipulated, the SHR activity level was similar for all intensity levels, while the WKY activity was inversely related to stimulus intensity. These results suggest that while the SHRs may generally be more active than WKYs, WKYs display a greater behavioral reactivity to environmental stimulation than SHRs.
Microvascular pressure, flow, and resistance in spontaneously hypertensive rats.
Authors: Roy J W , Mayrovitz H N
Published: June 2012

Microvascular resistance (MVR), determined as the ratio of the second-order arteriolar blood pressure (servo-null method) to blood flow (dual-slit), was assessed in the cremaster muscle preparation of 7- to 8-week-old normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The MVR was used as an index of resistance during 1) control conditions; 2) superfusion of graded concentrations of the catecholamine norepinephrine (NE; WKY n = 8, SHR n = 8); 3) superfusion with NE and in the presence of a fixed concentration of the vasodilator sodium nitroprusside (NP; 10(-5) M); and 4) superfusion with the noncatecholamine phenylephrine (PE; WKY n = 8, SHR n = 9). The vasoconstrictor challenges were carried out to determine if there was any differential vascular sensitivity between the hypertensive and nonhypertensive rats to the exposure of an endogenous-like constrictor possessing a catechol nucleus as opposed to a strictly synthetic analog. The presence of NP was employed to assess the degree of vasoconstriction normally present under control conditions. The combination of NE and NP was used to test for a differential vasoconstrictor sensitivity, beginning from maximally dilated conditions. The MVR, assessed at the second-order arteriolar level, represents approximately 35% of the total resistance of the skeletal muscle and is intimately involved in maintaining proper end-organ perfusion pressure. The microvascular resistance of the SHR group was almost four times greater than that of the WKY group under control conditions. Maximum vasodilation with topical NP reduced the MVR in both groups, but the SHR microvascular resistance remained two times greater than that found in the WKY. The SHR had greater MVR responses following challenge with both NE and PE and also in the presence of NP during NE challenge. The conclusions are: 1) the microvascular resistance of the SHR is elevated under control conditions due to structural modifications of the vasculature and exacerbated following constrictor challenge as a result of heightened vasoconstrictor sensitivity; and 2) the elevated MVR in the SHR is not due to a simple arterial vasoconstriction that can be totally eliminated with vasodilation.
Role of dopamine in the development of spontaneous hypertension.
Authors: van den Buuse M , Versteeg D H , de Jong W
Published: June 2012

To investigate the role of brain catecholamines in the development of spontaneous hypertension, rats were treated with different doses of the neurotoxins 6-hydroxydopamine (6-OHDA) or DSP-4 (N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine hydrochloride). Intracerebroventricular (i.c.v.) 6-OHDA attenuated the development of hypertension in spontaneously hypertensive rats (SHR) and also lowered the systolic blood pressure (BP) in Wistar-Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Norepinephrine was markedly and dose-dependently depleted in brain areas of all three substrains. Dopamine was affected also, although to a lesser extent. Pretreatment with the norepinephrine-uptake inhibitor desmethylimipramine (DMI) did not influence the effect of 6-OHDA on the development of hypertension in SHR. DMI largely antagonized the 6-OHDA-induced depletion of brain norepinephrine, while dopamine depletion was not affected. Specific depletion of brain norepinephrine by treatment with DSP-4 did not alter the rise in BP in SHR. These results suggest that the effect of 6-OHDA on the development of hypertension in SHR may not be mediated through destruction of brain norepinephrine neurons, but that interruption of brain dopaminergic mechanisms is a possibility in this respect.
Sympathetic vasoconstriction sensitive to alpha 2-adrenergic receptor blockade. No evidence for preferential innervation of alpha 1-adrenergic receptors in the canine femoral bed.
Authors: Elsner D , Saeed M , Sommer O , Holtz J , Bassenge E
Published: June 2012

In the canine femoral bed, we studied the involvement of vascular alpha 2-adrenergic receptors in vasoconstriction by stimulating the sympathetic nerve during different degrees of activation of metabolic counterregulation (constant pressure and constant flow perfusion). In chloralose-anesthetized, despinalized dogs under beta-blockade (2 mg/kg nadolol) and under a constant femoral perfusion pressure, cumulative doses of rauwolscine (0.03, 0.3, and 3.0 mg/kg i.v., n = 8) or of prazosin (0.012, 0.12, and 1.2 mg/kg i.v., n = 8) caused dose-dependent shifts to the right of the dose-response curve of intraarterial norepinephrine (NE) infusions. These cumulative doses also caused attenuations of the vasoconstriction initiated by lumbar sympathetic stimulation (0.1, 0.3, 1.0, and 3.0 Hz). Sham treatment (n = 8) had no such results. In experiments with constant flow perfusion (n = 6 for each antagonist), rauwolscine shifted the NE dose-response curve significantly more compared to the experiments with constant pressure perfusion, while prazosin was similarly effective under both conditions. Under constant flow perfusion, both antagonists dose-dependently attenuated the vasoconstrictions caused by sympathetic stimulation. While prazosin and sham treatment did not modify the overflow of NE from the femoral bed during stimulation, this overflow was augmented by rauwolscine during stimulation at 3 Hz, which indicated presynaptic modulation of NE release. Under both experimental conditions, no significant difference could be observed in the attenuation of low-frequency sympathetic vasoconstriction by the two antagonists, when dosages were compared on the basis of their action against infused NE. It is concluded that both a rauwolscine-sensitive component and a prazosin-sensitive component are involved in the competition between sympathetic vasoconstriction and metabolic dilation. The vascular alpha-adrenergic receptors activated by these two components have a similar postsynaptic localization relative to the nerve endings.
Chronic arterial and venous catheterization of conscious, unrestrained rats.
Authors: Fejes-Tóth G , Náray-Fejes-Tóth A , Ratge D , Frölich J C
Published: June 2012

A method is described for implanting arterial and venous cannulas in rats that requires only minor surgery. Catheters are introduced into the abdominal aorta through the ventral tail artery and into the vena cava through a lateral tail vein. The wounds are covered with an acrylic cuff and the catheters are brought out through a stainless steel spiral connected to the cuff and then attached to top of a metabolism cage used to house the rat. This method makes possible continuous access to the catheters in undisturbed, mobile animals. Using this model we compared mean arterial pressure, heart rate, plasma renin activity, and plasma catecholamine levels in freely moving Long-Evans rats and in Brattleboro homozygous rats.
Three-dimensional structure of human renin.
Authors: Akahane K , Umeyama H , Nakagawa S , Moriguchi I , Hirose S , Iizuka K , Murakami K
Published: June 2012

A three-dimensional model of human renin has been constructed based on the assumption that the overall folding of the aspartyl proteases is very similar. As a reference, we used penicillopepsin, the structure of which has been reported at a resolution of 1.8 A, and its main chain was traced to build a model of renin. The resulting structure seems to be stable from the hydrophobic and hydrophilic viewpoints. Comparison of the tertiary structure of human renin with that of penicillopepsin and mouse renin suggests the existence of a high structural homology as well as differences in the molecular geometry of the active sites that may influence the substrate specificity. The asparagine side chains in the glycosidation signal of Asn-X-Thr are exposed on the surface. Moreover, the site in human renin that corresponds to the proteolytic cleavage site in mouse renin also appears to be exposed on the surface so as to be easily scissored during the maturation process. The insertions and deletions of amino acid residues were found to arise on the surface, and in some places they occurred in complementary manners. Models of molecular complexes between human renin and renin inhibitor were constructed to understand the interacting modes that indicate how new renin inhibitors develop. Inhibitor-binding sites were directly assigned based on the models of the inhibitor-enzyme complex.
Sodium and volume depletion activates neurogenic mechanisms in renal hypertensive dogs.
Authors: Sweet W D , Freeman R H , Davis J O , Villarreal D
Published: June 2012

The acute response to ganglionic blockade (hexamethonium bromide, 30 mg/kg, i.v.) was used to evaluate the neurogenic contributions to mean arterial pressure maintenance in the conscious one-kidney, one clip hypertensive dog. Approximately 2 hours (112 minutes) after ganglionic blockade, captopril (10 mg/kg, i.v.) was given to block the renin-angiotensin system. Hypertensive animals were studied 3 days after clipping (group 2) or 2 to 4 weeks after clipping (groups 3 and 4). Groups 2 and 3 were fed a regular sodium diet, but group 4 animals were sodium and volume depleted. Normotensive control animals (group 1) were fed a regular sodium diet. On the day of the acute experiment the baseline blood pressures measured in group 2 (151 +/- 10 mm Hg, n = 5), group 3 (154 +/- 5 mm Hg, n = 7), and group 4 (160 +/- 8 mm Hg, n = 7) were not different (p greater than 0.05) from each other, but all were elevated (p less than 0.05) compared with the group 1 animals (106 +/- 3 mm Hg, n = 8). Also, there were no significant differences (p greater than 0.05) in the baseline plasma catecholamine levels among the three hypertensive groups. Ganglionic blockade produced a greater fall in blood pressure (p less than 0.05) in the sodium/volume-depleted dogs of group 4 (-35 mm Hg) than in group 1 (-10 mm Hg), group 2 (-3 mm Hg), or group 3 (-12 mm Hg) animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction of vasopressin and prostaglandins through calcium ion in the renal circulation.
Authors: Seino M , Abe K , Tsunoda K , Yoshinaga K
Published: June 2012

To determine whether the effects of arginine vasopressin (AVP) on the renal and systemic vessels are modulated by prostaglandins (PGs), AVP (10, 20, and 50 mU/kg/min) was infused into the renal artery before and after treatment with indomethacin (8 mg/kg) in anesthetized rabbits. Arginine vasopressin elicited a dose-dependent increase in systemic arterial pressure and renal vasoconstriction. However, after cessation of the infusion, significant renal vasodilation was observed. Indomethacin potentiated the systemic and renal vasoconstrictor actions and attenuated the renal vasodilator reaction induced by AVP. These results suggest that endogenously produced PGs buffer the vasoconstrictor action of AVP, and the renal vasodilator reaction induced by AVP could be mediated through PGs. Further, to investigate whether the effects of AVP on the systemic and renal vessels are mediated by calcium ion (Ca++), the Ca++ entry blocker nifedipine was used. Intravenous administration of nifedipine (50 micrograms/kg) attenuated the systemic and renal vasoconstrictor action of AVP. The renal vasodilator reaction induced by AVP was also diminished after treatment with nifedipine. These results indicate that the systemic and renal vasoconstrictor actions of AVP are mediated through Ca++ influx into the vascular smooth muscle cells. The present study suggests that Ca++ participates in the AVP-induced vasodilator reaction, itself probably mediated by PGs.
Does renin determine the blood pressure response to calcium entry blockers?
Authors: Waeber B , Nussberger J , Brunner H R
Published: June 2012

Male Wistar rats with one-kidney, one clip renal hypertension were maintained on either a regular or a low salt diet for 3 weeks after clipping. At that time mean blood pressure in the unanesthetized rats was equally elevated in sodium-depleted (n = 17) and in sodium-replete rats (n = 19), but plasma renin activity was significantly higher in the former (p less than 0.05). Infusion of the calcium entry blocker verapamil at a rate of 0.05 mg/kg/minute decreased blood pressure within 60 minutes to a similar extent in rats kept on a salt-deficient diet and in rats fed a regular salt diet. In all rats taken as a group, there was a close, direct correlation (r = 0.87, p less than 0.001) between the magnitude of the blood pressure response to verapamil and the pretreatment blood pressure levels. Verapamil markedly accelerated heart rate and stimulated renin release in all rats. In additional groups of sodium-depleted (n = 8) and sodium-replete renal hypertensive rats (n = 7), nifedipine administration (4 micrograms/kg/min i.v.) within a 45-minute observation period caused a blood pressure fall (p less than 0.001) and heart rate acceleration (p less than 0.001) that were comparable in both groups. These findings suggest that in the rat with renal hypertension the short-term blood pressure response to the calcium antagonists verapamil and nifedipine is not influenced by the state of sodium balance and plasma renin activity. In this experimental model of hypertension, the magnitude of the blood pressure lowering effect of calcium entry blockers appears to be proportional to pretreatment blood pressure levels.
Loss of accommodation in sympathetic neurons from spontaneously hypertensive rats.
Authors: Yarowsky P , Weinreich D
Published: June 2012

Synaptic transmission and membrane properties of sympathetic neurons in superior cervical ganglia of spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) were investigated in vitro by extracellular and intracellular recording. The sympathetic neurons of SHR showed an atypical loss of spike accommodation. The spike discharge was insensitive to the sodium channel blocker tetrodotoxin, but it was reversibly blocked by a variety of calcium antagonists. The loss of accommodation in the neurons of SHR was not due to a loss of M-current, a potassium current involved in controlling spike frequency adaptation in sympathetic neurons. Superfusion of ganglia of SHR with muscarine (10 microM), which suppresses M-current and leads to a loss of accommodation, potentiated the repetitive discharge. In the presence of muscarine the current-voltage curves in neurons of SHR and SD were shifted to similar extents. Resting membrane potentials of neurons of SHR and WKY were consistently depolarized as compared with neurons of SD. Synaptic efficacy through the ganglia of SHR, assessed by extracellular recordings of presynaptic and postsynaptic compound action potentials at 0.25 Hz stimulation, was elevated when compared with the ganglia of WKY, but was similar to that of the ganglia of SD. These results indicate that strain differences should be considered when attempting to attribute changes in sympathetic neuron membrane properties to hypertension. The sympathetic neurons of SHR appear to have lost their accommodative properties and might possess an exaggerated calcium conductance. This calcium conductance may explain the augmented calcium-dependent release of norepinephrine during sympathetic nerve stimulation in the SHR.
Onset and dose relationships of ACTH effects on blood pressure in sheep.
Authors: Scoggins B A , Allen K J , Coghlan J P , Denton D A , Fei D T , Tresham J J , Wang X M , Whitworth J A
Published: June 2012

The threshold and dose-response relationships for the blood pressure and metabolic effects of adrenocorticotropic hormone (corticotropin, ACTH) were examined in conscious sheep. Corticotropin was infused at five rates (0.5 micrograms/kg/day, n = 4; 1 micrograms/kg/day, n = 4;2 micrograms/kg/day, n = 6; 5 micrograms/kg/day, n = 5; and 10 micrograms/kg/day, n = 5) for 3 days, and the time of onset of the rise in blood pressure was assessed with a computer-based system. The effects of equimolar infusion of beta-endorphin and ACTH at 5 micrograms/kg/hour also were examined. Corticotropin infusion at 0.5 microgram/kg/day had no effect on mean arterial pressure. An ACTH infusion of 1.0 microgram/kg/day significantly increased mean arterial pressure (p less than 0.001), but the rise was less than that at the three higher doses, all of which produced similar effects. Changes in heart rate were significant at the 10 micrograms/kg/day level only (p less than 0.01). Initial urinary sodium retention was present at the three higher but not the two lower rates of infusion. Corticotropin infusion had no effect on urinary potassium excretion at any rate but produced hypokalemia at rates of 1.0 microgram/kg/day and above, which appeared to be dose related. Plasma sodium concentration was increased significantly only at the three higher rates (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Increased membrane permeability of skin fibroblasts from the spontaneously hypertensive rat.
Authors: Tamura H , Kino M , Tokushige A , Searle B M , Aviv A
Published: June 2012

Recently, we have demonstrated several abnormalities in Na+ and K+ homeostasis in cultured vascular smooth muscle cells derived from spontaneously hypertensive rats (SHR). To study whether similar defects can be identified in other cells of this rat strain, 86Rb and 22Na flux experiments as well as measurements of intracellular Na+ and K+ levels were performed in cultured skin fibroblasts of SHR and normotensive Wistar-Kyoto rats (WKY). The efflux rate constant (ke) for Rb+ (K+ analogue) was higher (p less than 0.001) in fibroblasts of SHR than in those of WKY (2.11 +/- 0.03 and 1.66 +/- 0.02 X 10-2/min; mean +/- SEM). The ouabain-insensitive influx rate constant (ki) for Rb+ was also higher (p less than 0.001) in fibroblasts of SHR than in those of WKY (13.26 +/- 0.41 and 10.71 +/- 0.27 X 10-2/min. On the other hand, the activity of the Na+-K+ pump of cells of SHR (44.81 +/- 0.81 X 10-2/min) was not different from that of cells of WKY (44.72 +/- 0.47 X 10-2/min). This parameter was obtained by calculating the ouabain-sensitive Rb+ influx rate constant. There was also no difference in the Na+ uptake (in the presence of ouabain) between cells of the two rat strains. Although there was no statistically significant difference in the measured intracellular total K+ levels between the two groups, on the basis of equilibrium distribution of 86Rb+, we calculated a significantly lower (p less than 0.001) level of exchangeable intracellular K+ in fibroblasts of SHR (98.2 +/- 1.2 mEq/L) as compared with cells of WKY (115.3 +/- 1.5 mEq/L). These findings indicate increased membrane permeability to K+ in fibroblasts of SHR and that this defect is likely to be innate to their membrane structure.
Red blood cell abnormalities and spontaneous hypertension in the rat. A genetically determined link.
Authors: Bianchi G , Ferrari P , Trizio D , Ferrandi M , Torielli L , Barber B R , Polli E
Published: June 2012

The significance of the erythrocyte abnormalities described in rats and humans with spontaneous hypertension is far from clear. This study, in two highly inbred strains of rats, was designed to evaluate whether these abnormalities are primary and thus genetically related to hypertension. The Milan hypertensive strain (MHS) and its normotensive control strain (MNS) were used to carry out two types of experiments. In two groups of lethally irradiated (MHS X MNS) F1 hybrids, bone marrow from MHS or MNS was transplanted. The differences in red cell function between the recipients of bone marrow from MHS and recipients of bone marrow from MNS were similar to those existing between the parental donor MHS and MNS: Na+-K+ cotransport was increased (p less than 0.02) and intracellular Na+ content (p less than 0.05) and cell volume (p less than 0.02) were decreased in MHS. The same pattern was observed when this experiment was repeated in different groups of F1 hybrids. In individuals of the segregating F2 population, obtained by crossing the (MHS X MNS) F1 hybrids, there was a positive correlation (p less than 0.001) between the red blood cell Na+-K+ cotransport and the mean blood pressure. These results indicate that the erythrocyte abnormalities may well be genetically associated with the primary cause of spontaneous hypertension in rats. Because of the many similarities demonstrated when young prehypertensive MHS or humans prone to develop hypertension are compared with their respective controls, it is possible that the findings described here in rats are relevant to human essential hypertension.
Body size, composition, and fitness in adolescents with elevated blood pressures.
Authors: Wilson S L , Gaffney F A , Laird W P , Fixler D E
Published: June 2012

Increased body size is often found in children with elevated blood pressures, but it is not clear whether this is a result of obesity or early maturity. Similarly, levels of activity and fitness have marked effects on blood pressure and body composition. To study these interrelated factors, we measured height, weight, and body composition (skinfold thickness and total body water) as well as heart rate, blood pressure, and oxygen consumption at rest and during exercise in 192 ninth grade boys and girls, 102 with persistently elevated blood pressures at or above the 95th percentile and 90 matched controls with blood pressures below the 50th percentile for the entire population of 10,641 Dallas County ninth graders tested. Differences in resting blood pressures also were present during maximal exercise and recovery periods. Boys with persistently elevated blood pressures were characterized by increased supine and recovery heart rates, normal fitness, excess size for age in the absence of obesity, and early maturation. Girls with persistently elevated blood pressures had increased heart rates, decreased fitness, and obesity.
Aortic endothelial junctions in developing hypertension.
Authors: McGuire P G , Twietmeyer T A
Published: June 2012

The morphology of the intercellular pathway of aortic endothelium was investigated in spontaneously hypertensive rats (SHR) at three different stages in the hypertensive process. Aortic endothelial cells of the SHR, in contrast to those of the normotensive Wistar-Kyoto rats exhibited an increased length and complexity of tight junctions, at all ages studied. That this finding was seen in young SHR, before the elevation of arterial pressure, suggests that other factors (genetic, humoral, neurogenic) may be influencing the morphology of aortic endothelium in the SHR. The area of lateral endothelial membrane occupied by gap junctions also was increased in the SHR, especially at 10 weeks of age, and corresponded to the greatest increase in tight junction strand length and the most rapid and dramatic rise in arterial pressure. The results indicate that aortic endothelium of the SHR can anticipate or respond, and partially adapt, to the abnormal influence of elevated arterial pressure.
Erythrocyte lithium transport changes induced by deoxycorticosterone acetate treatment in pigs.
Authors: Weder A B , Torretti B A
Published: June 2012

Ouabain-insensitive lithium efflux from lithium-loaded pig erythrocytes has sodium-dependent and sodium-independent components. Lithium effluxes into sodium (total efflux) and sodium-free (leak) media, sodium-dependent lithium efflux, defined as the difference between total and leak fluxes, and changes in red cell cation and water contents as well as blood pressure were assessed serially for 3 weeks in pigs implanted with Silastic strips impregnated with deoxycorticosterone acetate or with Silastic alone and maintained on a high salt diet (200 mEq/day). Significant differences developed between the groups in blood pressure, red cell sodium content, red cell water content, leak flux, and sodium-dependent lithium efflux (maximal difference: 648 +/- 60 vs 256 +/- 81 mumoles of lithium per liter of cells per hour, deoxycorticosterone acetate vs controls; p less than 0.01). Increased sodium-dependent lithium efflux paralleled a decrease of the diffusional leak component of lithium efflux; total lithium efflux was unchanged. Deoxycorticosterone acetate hypertension in pigs is a useful model in which to study factors modulating erythrocyte cation content and lithium transport in vivo. Changes in lithium transport characterized in red blood cells in this form of experimental hypertension may reflect generalized membrane phenomena.
Effects of baroreceptor denervation on volume loading hypertension in anephric dogs.
Authors: Manning R D , Cowley A W , Coleman T G
Published: June 2012

The role of the baroreceptor mechanism in determining the relationship between fluid volume and arterial pressure is not clear. Therefore, the effects of the baroreflex on the arterial pressure and fluid volume of conscious, anephric dogs were studied after a sustained 10% increase in blood volume. The animals were equipped with long-term indwelling arterial and venous catheters, and arterial pressure was monitored 24 hours a day. The increase in blood volume was achieved by intravenous infusion of 50 ml/kg of lactated Ringer's solution in 30 minutes. After volume loading arterial pressure increased rapidly to hypertensive levels (130.8 +/- 7.5% of control) in a baroreceptor denervated group. The initial increase in arterial pressure in a group of normally innervated dogs was smaller (118.8 +/- 1.8% of control), but by 24 hours postinfusion the arterial pressure of both groups had reached the same level. The innervated group had probably experienced baroreceptor resetting by this time. Blood volume both before and after infusion was not different in the denervated and innervated groups; however, sodium space was markedly higher before the infusion in the denervated dogs (431.8 +/- 13.8 ml/kg vs 344.8 +/- 19.0 ml/kg in the innervated dogs), and the volume load caused parallel increases in this space in the denervated and innervated groups. The present study shows that the blood volume of anephric dogs was unchanged after baroreceptor denervation while the extracellular fluid volume of denervated dogs was elevated. Furthermore, a small sustained increase in blood volume in either conscious, innervated dogs or conscious, baroreceptor denervated dogs, in contradistinction to the effects in anesthetized dogs, resulted in significant increases in arterial pressure (p less than 0.05).
Chronic dietary tyrosine supplements do not affect mild essential hypertension.
Authors: Sole M J , Benedict C R , Myers M G , Leenen F H , Anderson G H
Published: June 2012

The blood pressure and plasma norepinephrine response to oral tyrosine, the precursor of norepinephrine, supplementation (2.5 g t.i.d.) of regular meals was examined in 13 untreated patients with mild essential hypertension. Using a randomized double-blind crossover design, each 2-week treatment was followed by a 2-week supplement-free interval. Supine and standing blood pressure and plasma norepinephrine levels were measured at the beginning and end of each 2-week treatment. Plasma tyrosine levels increased (p less than 0.001) from 71.2 +/- 8.0 nM/ml at baseline to 152.8 +/- 17.4 nM/ml 2 hours after the tyrosine supplement. Blood pressure under control conditions was 144 +/- 3 Hg systolic, 91 +/- 2 mm Hg diastolic (109 +/- 2 mm Hg mean) after 30 minutes in the supine position and 148 +/- 4 mm Hg systolic, 102 +/- 3 mm Hg diastolic (117 +/- 3 mm Hg mean) after 5 minutes of standing. Plasma norepinephrine levels were 191 +/- 18 pg/ml in the supine subjects and 390 +/- 33 pg/ml in the standing subjects. No difference in systolic, diastolic, or mean blood pressure, heart rate, or plasma norepinephrine levels were seen between the beginning and end of each period or between groups. Individual changes in blood pressure showed no correlation with individual changes in norepinephrine levels. These results indicate that the addition of a tyrosine supplement to the usual diet of mild hypertensive subjects has no beneficial effect on blood pressure.
Endogenous angiotensin-aldosterone-pressure relationships during sodium restriction.
Authors: Richards A M , Nicholls M G , Espiner E A , Ikram H , Hamilton E J , Wells J E , Maslowski A H , Yandle T G
Published: June 2012

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.
Monitoring 24-hour blood pressure in a drug trial. Evaluation of a noninvasive device.
Authors: Berglund G , De Faire U , Castenfors J , Andersson G , Hartford M , Liedholm H , Ljungman S , Thulin T , Wikstrand J
Published: June 2012

To test the usefulness of noninvasive ambulatory 24-hour blood pressure recording, the Del Mar Avionics system was used in a double-blind clinical trial in which 31 hypertensive patients were randomly allocated to receive placebo or pafenolol (25 mg or 50 mg), a novel, long-acting, highly selective beta-blocker, once daily. The results of 24-hour blood pressure and heart rate recording after 4 weeks of treatment were compared with a previous 24-hour recording performed after a 4-week placebo run-in period using the 3-hour mean of recordings performed every 7.5 minutes both day and night. Furthermore, 24-hour means were analyzed in each patient before and after 4 weeks. The system was easy to use and, judging from two placebo periods in the same patients, the reproducibility was good. The 24-hour blood pressure and heart rate recordings showed a clear dose-response relationship for pafenolol that could not be detected by ordinary casual readings. A daily dose of 25 mg of pafenolol significantly reduced blood pressure during the 9 hours after tablet intake (p less than 0.01), while 50 mg per day of pafenolol resulted in a significant reduction throughout the 24-hour period (p less than 0.01). The same pattern was seen for heart rate, which indicates a greater degree of beta-blockade during treatment with the higher dose. These results indicate that the tested noninvasive equipment is a useful tool for monitoring ambulatory 24-hour blood pressure. It gives important information impossible to obtain from single casual readings. This noninvasive method should be further evaluated to define its place in clinical work and as a research tool.
Effects of a specific and long-acting renin inhibitor in the marmoset.
Authors: Wood J M , Gulati N , Forgiarini P , Fuhrer W , Hofbauer K G
Published: June 2012

Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-Arg-Pro-Phe-His-Sta-Ile-His-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 X 10(-9) M; marmoset = 5 X 10(-9) M) and less potent against dog (2 X 10(-7) M) or rat (3 X 10(-5) M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 X 10(-5) M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)
Evidence for endothelium-derived relaxing factor in cultured cells.
Authors: Loeb A L , Owens G K , Peach M J
Published: June 2012

Intracellular cyclic GMP concentration was used as a biochemical indicator of endothelium-dependent and organonitrate-induced responses to these vasodilators in cultured porcine aortic smooth muscle and endothelial cells. Sodium nitroprusside (10(-6) M) caused a rapid increase in cyclic GMP levels in confluent smooth muscle cell cultures but not in confluent endothelial monolayers. Adenosine triphosphate (10(-4) M) and methacholine (10(-5) M), two agents that elicit endothelium-dependent relaxation in intact vessels, failed to raise cyclic GMP concentrations in muscle or endothelial cultures alone. When the cell types were grown together in mixed culture, however, treatment with adenosine triphosphate or methacholine induced an elevation in intracellular cyclic GMP levels. These findings suggest that mixed cultures of arterial smooth muscle and endothelial cells can be used to study the phenomenon of endothelium-dependent responses in arterial smooth muscle.
Inhibition of the kallikrein-kinin system and vascular reactivity in Bartter's syndrome.
Authors: Rodriguez-Portales J A , Lopez-Moreno J M , Mahana D
Published: June 2012

To study the significance of the increased activity of the kallikrein-kinin system described in patients with Bartter's syndrome, we investigated the pressor response to infused angiotensin II in four patients with the syndrome receiving no treatment and during the administration of aprotinin and of indomethacin. Five normal subjects served as controls. Aprotinin is a proteolytic enzyme that inhibits the formation of kinins by inhibiting plasma and glandular kallikrein. Indomethacin, a prostaglandin-synthesis inhibitor, can also inhibit the kallikrein-kinin system and normalizes vascular responsiveness to angiotensin II in Bartter's syndrome. All patients had increased urinary kallikrein and prostaglandin E2 concentrations. Aprotinin significantly decreased the dose of infused angiotensin II required to induce a 20 mm Hg increase in diastolic blood pressure, from 11 +/- 4 ng/kg/min to 7.0 +/- 2.0 ng/kg/min (mean +/- SD; p less than 0.05) in normal subjects and from 135 +/- 57 ng/kg/min to 70 +/- 26 ng/kg/min (p less than 0.05) in the patients with Bartter's syndrome, without significantly changing plasma renin activity, mean control blood pressure, or urinary prostaglandin E2 concentration. Indomethacin normalized the pressor response to angiotensin II in three patients who had been pretreated for 4 days (pressor dose, 10 ng/kg/min) but not in one patient who received a single oral dose of indomethacin 5 hours before the test. Our results suggest that inhibition of the kallikrein-kinin system alone accounts for approximately a 50% decrease in vascular resistance to the pressor effect of angiotensin II in Bartter's syndrome, while additional suppression of prostaglandins entirely normalizes the vascular response to angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)
Changes in prostanoid synthesis in response to diet and hypertension in one-kidney, one clip rats.
Authors: Codde J P , McGowan H M , Vandongen R , Beilin L J
Published: June 2012

This study was designed to examine the effects of diets that alter prostaglandin biosynthesis on the blood pressure in one-kidney, one clip rats with established hypertension and to compare the prostanoid generating capacity of hypertensive animals with those that remained normotensive. Rats attaining blood pressures of at least 180 mm Hg within 8 weeks of nephrectomy and renal artery stenosis were paired by weight and blood pressure and then placed on either a safflower oil or a prostaglandin I2 inhibitory diet (cod liver oil-linseed oil mix) for 4 weeks. Animals with blood pressures of less than 150 mm Hg were also paired for the same two dietary regimens. Comparison between the two blood pressure groups revealed that on both dietary regimens hypertensive rats produced significantly more aortic 6-keto-prostaglandin F1 alpha and serum thromboxane B2. Rats on the cod liver oil-linseed oil diet incorporated eicosapentaenoic acid into tissue stores with a corresponding decrease in arachidonic acid and significantly impaired ability to generate serum thromboxane B2 (36%), aortic 6-keto-prostaglandin F1 alpha (65%), renal homogenate 6-keto-prostaglandin F1 alpha (64%) and prostaglandin E2 (58%), and urinary prostaglandin E2 (70%) and 6-keto-prostaglandin F1 alpha (52%). Despite these differences in prostanoid synthesizing capacity, no differences in blood pressure were observed between the safflower oil-fed rats and rats fed cod liver oil-linseed oil within either the hypertensive or normotensive groups. These results suggest that prostanoids do not play a major role in maintaining blood pressure in established one-kidney, one clip hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
Presence of cytochrome P-450-dependent monooxygenase in intimal cells of the hog aorta.
Authors: Abraham N G , Pinto A , Mullane K M , Levere R D , Spokas E
Published: June 2012

Cytochrome P-450-dependent mixed function oxidase activity is present in vascular tissue; however, as far as we could determine, the distribution of monooxygenase activity across the blood vessel wall has not previously been assessed. The aryl-hydrocarbon hydroxylase activity was examined by metabolism of benzo[a]pyrene in microsomes prepared from intimal and smooth muscle cell scrapings of the hog thoracic aorta. Microsomes of intimal cells comprising 95% endothelial cells showed an approximately 2.5-fold increase in aryl-hydrocarbon hydroxylase activity compared with that in microsomes prepared from medial smooth muscle cells. Michaelis-Mentin kinetics for the intimal enzyme yielded an apparent Km value of 11.11 microM and an apparent Vmax of 3-OH benzo[a]pyrene of 40 pmol/mg protein/10 min. Aryl-hydrocarbon hydroxylase activity was dependent on nicotinamide adenine dinucleotide phosphate and was inhibited by 7,8 benzoflavone, SKF 525A, and carbon monoxide. The localization of cytochrome P-450-dependent mixed function oxidase primarily to the intimal surface of the aorta may indicate a role for this enzyme system in vasoregulation and the pathogenesis of atherosclerosis.
Characterization of monoclonal and polyclonal antibodies to human tissue kallikrein.
Authors: Chao J , Chao L , Tillman D M , Woodley C M , Margolius H S
Published: June 2012

Monoclonal antibodies to purified human urinary kallikrein have been developed. Selection of antibody producing clones was based on 125I-kallikrein binding activity of hybridoma media in both radioimmunoassay and enzyme-linked immunosorbent assay. Three clones (2 IgG1, 1 IgG2b) were subcloned, characterized, and compared with the polyclonal antiserum generated in rabbits immunized with the purified kallikrein. With radioimmunoassay, mouse ascitic fluids or rabbit antisera dilutions showing 50% binding to 125I-kallikrein were 1:1.2 X 10(6) (E7A9), 1:1.2 X 10(5) (H6A6), 1:8.0 X 10(4) (E12H1), and 1:1.4 X 10(6) (the rabbit antisera). With enzyme-linked immunosorbent assay, mouse ascitic fluids from clones E7A9 and H6A6 showed half-maximal absorbance at dilutions of 1:2.1 X 10(5) and 1:1.0 X 10(5) respectively, and the polyclonal antiserum showed half-maximal absorbance at a dilution of 1:2.0 X 10(4). These monoclonal antibodies showed no cross-reactivity with rat tissue kallikrein, rat urinary plasminogen activator, or dog pancreatic kallikrein, while the polyclonal antiserum showed some cross-reactivity. The binding of monoclonal or polyclonal antibodies to 125I-human urinary kallikrein was not affected by human plasma kallikrein, thrombin, or urokinase in a competitive radioimmunoassay. By using purified human urinary kallikrein immobilized to agarose, antibodies produced by clones E7A9 and H6A6 and in the rabbit antisera were purified to homogeneity. Each of these affinity-purified antibodies inhibited the esterase activity, and two of the three inhibited the kininogenase activity, of human urinary kallikrein. A sandwich immunosorbent assay was developed to measure this kallikrein using monoclonal antibody from the clone E7A9 in conjunction with the polyclonal antibodies.(ABSTRACT TRUNCATED AT 250 WORDS)
Sodium-lithium countertransport and blood pressure in healthy blood donors.
Authors: Turner S T , Johnson M , Boerwinkle E , Richelson E , Taswell H F , Sing C F
Published: June 2012

Studies finding an increased maximal rate of Na-Li countertransport in red blood cells from persons with essential hypertension and their normotensive offspring have raised the possibility that Na-Li countertransport may serve as a marker for the genetic predisposition to hypertension. We studied Na-Li countertransport in 238 randomly selected blood donors representative of the population of Rochester, Minnesota. The mean value (+/- SD) for Na-Li countertransport in units of mmoles of lithium efflux per liter of red blood cells per hour was 0.29 +/- 0.12. The distribution of Na-Li countertransport values among the donors was continuous. An analysis for multimodality, however, detected significant evidence of bimodality with 72% of the population predicted to belong to the lower mode with a mean of 0.24 mmol/L red blood cells per hour and 28% of the population to belong to the upper mode with a mean of 0.42 mmol/L red blood cells per hour. There was a positive association between Na-Li countertransport and blood pressure; after adjustment for weight and age, Na-Li countertransport predicted approximately 3% of the variation in blood pressure. Persons belonging to the upper mode of the Na-Li countertransport distribution may be at increased risk of acquiring elevated blood pressure as they age.
Cardiovascular and metabolic profile during intervention with urapidil in humans.
Authors: Gerber A , Weidmann P , Marone C , Uehlinger D , Riesen W
Published: June 2012

Increased sympathetic activity or vascular reactivity to norepinephrine or both may play a complementary role in the pathogenesis of essential hypertension. Therefore, blood pressure regulation and metabolic correlates of cardiovascular risk were evaluated in 19 normal subjects and in 13 subjects with essential hypertension receiving placebo and after 4 weeks of intervention with urapidil, an agent that was found experimentally to exert a combined central sympathetic and peripheral alpha-adrenergic receptor inhibition. In hypertensive patients, urapidil normalized the initially low norepinephrine pressor dose (+ 106%), mildly increased basal plasma norepinephrine levels (+36%), and markedly shifted the plasma norepinephrine concentration-blood pressure response curve (p less than 0.01). Blood pressure was decreased (p less than 0.001). In normal subjects, urapidil produced only mild increases in norepinephrine plasma levels (+22%) and norepinephrine pressor dose (+38%) and no change in blood pressure. Body weight, exchangeable sodium, and blood volume were unaltered or increased slightly. Heart rate; plasma epinephrine, renin, angiotensin II, basal aldosterone, and electrolyte levels; plasma clearances of norepinephrine and angiotensin II; pressor effects of angiotensin II; chronotropic responses to isoproterenol or a norepinephrine-induced rise in blood pressure; and urinary prostaglandin F2 alpha excretion, as well as serum lipoprotein fractions and glucose, insulin, and uric acid levels, were not significantly modified by urapidil. Prostaglandin E2 excretion tended to be increased. Aldosterone responsiveness to angiotensin II was increased by urapidil in normal (p less than 0.05) but not in hypertensive subjects.(ABSTRACT TRUNCATED AT 250 WORDS)