bluuebunny/crossref_metadata_2025 huggingface dataset:
Pressor response to small elevations of cerebroventricular pressure in conscious rats.
Authors: Nakamura K , Osborn J W , Cowley A W
Published: June 2012

Acute relationships between cerebrospinal fluid hydrostatic pressure and arterial pressure were quantified in conscious rats. The rats were catheterized with a left femoral artery catheter, and a double set of catheters was implanted into the third cerebral ventricle. In three groups of rats, artificial cerebrospinal fluid with various sodium concentrations (142, 152, and 162 mM) was infused into the third ventricle for 3 hours at 1.0 microliter/min. Mean arterial pressure (MAP) and third ventricular pressure were monitored simultaneously, and both increased progressively over the 3-hour infusion period; the rate of rise was significantly greater with infusion of the hypertonic solution. There were no significant differences between the rat groups infused with low, normal, or high artificial cerebrospinal fluid sodium in either the slope or the intercept of the regression equation relating cerebrospinal fluid pressure and MAP: a 1 cm H2O rise of cerebrospinal fluid pressure was always associated with nearly a 1 mm Hg rise in MAP. In other rats, changes in both cerebrospinal fluid pressure and MAP were shown to be highly dependent on the rate of ventricular infusion. We conclude that elevations of systemic arterial pressure are associated with only small elevations of cerebrospinal fluid pressure and that physiological changes of cerebrospinal sodium (+/- 10 mM) influence arterial pressure by altering intravascular hydrostatic pressure rather than sodium or osmosensitive receptors in the cerebral ventricles.
High NaCl diet reduces hypothalamic norepinephrine turnover in hypertensive rats.
Authors: Chen Y F , Meng Q C , Wyss J M , Jin H , Oparil S
Published: June 2012

The current study tested the hypothesis that high NaCl diets elevate blood pressure in NaCl-sensitive spontaneously hypertensive rats (SHR-S) by reducing noradrenergic input to depressor neurons in the anterior hypothalamus. SHR-S were studied at 7 weeks of age, and age-matched salt resistant SHR (SHR-R) and normotensive Wistar-Kyoto rats (WKY) were controls. Rats were fed either high (8%) NaCl or control (1% NaCl) diets for 2 weeks, following which norepinephrine turnover in hypothalamus (anterior, posterior, and ventral regions), brainstem (pons and medulla), and thoracic spinal cord was assessed using the dopamine beta-hydroxylase inhibitor 1-cyclohexyl-2-mercapto-imidazole (CHMI). Regional brain catecholamines were measured by high performance liquid chromatography with electrochemical detection following intraperitoneal injection of CHMI or vehicle. Disappearance of norepinephrine following CHMI was used as an index of noradrenergic neuronal activity. The 8% NaCl diet caused a significant elevation in blood pressure in SHR-S but not in SHR-R or WKY. Endogenous norepinephrine levels and turnover were lower in the anterior hypothalamus of SHR-S fed 8% NaCl than in those fed 1% NaCl but were not significantly different in other groups. Endogenous norepinephrine levels and turnover were greater in pons of 8% NaCl--fed SHR-S than in those fed 1% NaCl but were not significantly different in other groups. These observations support the hypothesis that reduced noradrenergic input to depressor neurons in the anterior hypothalamus and increased noradrenergic input to neurons in the pons are related to NaCl sensitivity in the SHR-S.
Hemodynamics of the carotid artery after vasodilation in essential hypertension.
Authors: Laurent S , Lacolley P , London G , Safar M
Published: June 2012

We performed simultaneous noninvasive measurements of common carotid artery and brachial artery hemodynamics in nine normal subjects and 10 subjects with sustained essential hypertension. In hypertensive subjects, brachial artery blood flow and forearm vascular resistance were in the normal range while carotid artery blood flow and carotid artery resistance were decreased and increased, respectively. The most important findings were the changes in the internal caliber of large arteries. Although the brachial and carotid artery diameters of hypertensive subjects were measured for the same level of mean arterial pressure, brachial artery diameter was significantly increased and carotid artery diameter was strictly normal as compared with values found in normal subjects. To assess whether carotid artery circulation could influence the baroreceptor reflex response to arteriolar vasodilation, carotid artery and brachial artery hemodynamics were measured in immediate succession in normotensive and hypertensive subjects before and after oral administration of cadralazine, a dihydralazine derivative. After cadralazine treatment, carotid artery tangential tension decreased in hypertensive subjects, and the changes were significantly correlated to the increase in heart rate. A similar correlation was found in normal subjects, but it was reset toward higher heart rates. These results indicate that the carotid artery does not behave like the brachial artery in response to a chronic increase in blood pressure. This behavior indicates intrinsic alterations of the arterial wall and might be involved in the resetting of the carotid baroreceptor reflex. Carotid artery circulation could play a role in hypertension by modulating the carotid baroreceptor mechanisms involved in the response to drug-induced arteriolar vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension.
Authors: Kudo K , Abe K , Chiba S , Sato M , Yasujima M , Kohzuki M , Omata K , Tanno M , Tsunoda K , Yoshinaga K
Published: June 2012

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.
Papillary collecting tubule synthesis of prostaglandin E2 in Dahl rats.
Authors: Reid G M , Appel R G , Dunn M J
Published: June 2012

Isolated kidneys of Dahl salt-sensitive rats (DS) excrete sodium less readily than those of Dahl salt-resistant rats (DR). The collecting tubule is an important source of papillary prostaglandin E2 and is a site of significant sodium reabsorption. We cultured renal papillary collecting tubule cells from 5-week-old, prehypertensive DS and DR on a low salt diet and also after 14 weeks of high salt feeding, and we measured prostaglandin E2 synthetic capacity. Unstimulated renal papillary collecting tubule cells from 5-week-old DS produced 62 +/- 5% less prostaglandin E2 than did comparable cells from DR (p less than 0.001). The cells from DS also synthesized less prostaglandin E2 after stimulation with the calcium ionophore A23187 (67 +/- 6% of control; p less than 0.001) or the addition of exogenous arachidonate (74 +/- 7% of control; p less than 0.01). Urinary prostaglandin E2 excretion was also diminished in the 5-week-old DS compared with their salt-resistant counterparts (18.1 +/- 1.3 vs 23.9 +/- 1.7 ng/24 hr; p less than 0.025). After high salt feeding, the DS became hypertensive but the DR remained normotensive. Renal papillary collecting tubule cells cultured from these DS continued to produce less prostaglandin E2 than those from control rats, both in the basal state (60 +/- 12% of control; p less than 0.09) and after stimulation with ionophore (62 +/- 2% of control; p less than 0.002). In these older animals, the DS continued to underexcrete prostaglandin E2 compared with the DR (29.7 +/- 3.2 vs 42.2 +/- 6.1 ng/24 hr; p less than 0.08). The underproduction of prostaglandin E2 in the papillary collecting tubule of DS may play a role in their inadequate renal natriuretic capacity and contribute to the onset and maintenance of salt-induced hypertension in this strain.
Purinergic receptors in the brainstem mediate hypotension and bradycardia.
Authors: Tseng C J , Biaggioni I , Appalsamy M , Robertson D
Published: June 2012

Adenosine acts at many sites to modulate neuronal activity. The purpose of this study was to investigate a possible role for adenosine as a neuromodulator of brainstem cardiovascular control. Microinjections of adenosine (0-2.3 nmol) were made stereotaxically into various brainstem sites. Injection of adenosine into the nucleus tractus solitarii (NTS) produced dose-related decreases in heart rate and systolic and diastolic blood pressures. Maximal changes occurred 90 seconds after injection. Injection into the area postrema also produced decreased heart rate and systolic and diastolic blood pressures. No significant effect occurred following injection into the C1 area. Adenosine 5'-triphosphate and its analogue, beta, gamma-methylene adenosine 5'-triphosphate also produced dose-related and potent vasodepressor and bradycardia effects in the NTS. Injection of 1,3-dipropyl-8-p-sulfophenylxanthine (0.92 nmol), a potent adenosine receptor antagonist, produced no effect itself, but abolished for 45 minutes the actions of further injections of adenosine and adenosine 5'-triphosphate (but not L-glutamate) in both the NTS and area postrema. Thus, NTS and area postrema injections of adenosine decrease blood pressure and heart rate in anesthetized normotensive rats through adenosine receptors located in these areas. These findings support a role for endogenous adenosine as a central modulator in cardiovascular control.
Evaluation of medial hypertrophy in resistance vessels of spontaneously hypertensive rats.
Authors: Owens G K , Schwartz S M , McCanna M
Published: June 2012

The role of smooth muscle cell hypertrophy, hyperploidy, and hyperplasia in medial hypertrophy of mesenteric resistance vessels of 107- to 111-day-old spontaneously hypertensive rats (SHR) was examined using a combination of morphometric, biochemical, and immunological techniques. Mesenteric arteries were classified on the basis of branching order for comparative purposes. Branch level I vessels were those that directly enter the jejunal wall, while Branches II to IV represented more proximal vessels; Branch IV vessels were those that branch from the superior mesenteric artery. Medial hypertrophy was assessed in perfusion-fixed vessels by morphometric evaluation of medial cross-sectional area and smooth muscle content. Medial cross-sectional area and smooth muscle content were significantly increased in larger (Branches III and IV) but not smaller (Branches I and II) mesenteric resistance vessels of SHR compared with control normotensive Wistar-Kyoto rats (WKY). Smooth muscle cell hypertrophy and hyperploidy were evaluated in isolated cells obtained by enzymatic dissociation of mesenteric resistance vessels. Approximately 80% of the cells in these preparations were identified as smooth muscle cells using a smooth muscle-specific isoactin antibody. Feulgen-DNA microdensitometric evaluation of isolated cells showed that polyploid cells were present in mesenteric resistance vessels but at very low frequencies, and no differences were apparent between SHR and WKY. Likewise, no differences in cellular protein content or relative smooth muscle cell size (i.e., area profile) were observed between cells obtained from SHR and WKY vessels. These results demonstrate that the increase in medial smooth muscle content observed in larger mesenteric resistance vessels of SHR cannot be accounted for by smooth muscle hypertrophy and hyperploidy, inferring that hyperplasia must be present. Results indicate that studies of the initiating mechanisms for medial smooth muscle hypertrophy in SHR resistance vessels, at least relatively early in hypertension, should focus on examination of factors that induce true cellular proliferation rather than hypertrophy and hyperploidy.
A comparison of the random-zero and standard mercury sphygmomanometers.
Authors: Parker D , Liu K , Dyer A R , Giumetti D , Liao Y L , Stamler J
Published: June 2012

Both the standard mercury sphygmomanometer and the random-zero sphygmomanometer have been used in epidemiological studies and clinical trials. Problems arise in comparing studies since, in addition to other methodological differences, the readings obtained with the random-zero sphygmomanometer have been found to be lower than those obtained with the standard mercury sphygmomanometer. In the present study, blood pressures were measured in 66 subjects to examine the comparability of findings with the two instruments. Trained observers measured blood pressures simultaneously using a double-headed stethoscope and one cuff connected to the two sphygmomanometers. Use of instrument was randomly assigned for each blood pressure measurement; each observer was unaware of the other's blood pressure reading. Readings were lower with the random-zero sphygmomanometer; mean difference ranged from 2.5 to 3.3 mm Hg for systolic pressure and 1.9 to 2.7 mm Hg for diastolic pressure. Digit distributions recorded by the two observers for the standard mercury sphygmomanometer and the random-zero sphygmomanometer were not significantly different for either systolic or diastolic blood pressure. Intraindividual variation was greater with the random-zero sphygmomanometer than with the standard mercury sphygmomanometer. These data do not indicate that one instrument is clearly superior to the other, although in studies where the observer seeks to reduce the bias of multiple readings per person, the random-zero sphygmomanometer may be the more appropriate instrument. Critical to the use of either instrument are careful training, standardization, certification, and periodic recertification of observers.
Race and cardiovascular reactivity. A replication.
Authors: Murphy J K , Alpert B S , Walker S S , Willey E S
Published: June 2012

In a previous study, we reported that black children demonstrated greater cardiovascular reactivity than did white children to the psychological stress of a television video game. Reliance on urban volunteers and the wide age range of the children may have limited conclusions concerning the generalizability of those results. In the present study, 481 of 484 children enrolled in the third grade of the public schools of an entire rural county in Tennessee were examined with the same video game procedure used previously. Results indicated greater heart rate and blood pressure reactivity among black children than among white children. Thus, the previous results were replicated. The greater prevalence of hypertension among black adults may relate to the greater reactivity among black children; reactivity may be either a marker or a mechanism in the development of hypertension.
Effects of arterial vasodilators on cardiac hypertrophy and sympathetic activity in rats.
Authors: Tsoporis J , Leenen F H
Published: June 2012

In spontaneously hypertensive rats (SHR), the progression (or absence of regression) of cardiac hypertrophy despite adequate blood pressure (BP) control by arterial vasodilators has been attributed to increased cardiac sympathetic activity. We evaluated changes in indices of general and cardiac sympathetic tone in relation to changes in cardiac anatomy during treatment of normotensive rats and SHR with hydralazine, 120 mg/L, or minoxidil, 120 mg/L of drinking water. In SHR, both vasodilators reduced BP rapidly and consistently. Significant increases in heart rate and plasma norepinephrine were observed only in the initial 2 days of arterial vasodilator treatment. After 5 weeks of treatment, marked increases in left and right ventricular sympathetic activity (as assessed by norepinephrine turnover rates) were present, but no increase was seen in heart rate and plasma norepinephrine. Intravascular volume expansion was observed on Day 14 of minoxidil and Day 35 of hydralazine treatment. Prolonged treatment with minoxidil induced significant increases in left ventricular internal diameter, as well as in left and right ventricular weights, but not in the wall thickness of the left ventricle. Treatment with hydralazine did not affect left ventricular weight and caused a small increase in the weight of the right ventricle. In normotensive rats, both vasodilators initially decreased BP, but tolerance developed within 1 to 2 weeks of treatment. Plasma norepinephrine and heart rate showed increases only at Day 1 of either treatment, whereas cardiac sympathetic hyperactivity persisted at 2 and 5 weeks of treatment. Changes in cardiac anatomy were qualitatively similar to those observed in SHR. We conclude that, during treatment of normotensive rats and SHR with arterial vasodilators, cardiac sympathetic hyperactivity persists and may be involved in the cardiac effects of arterial vasodilators. However, other mechanisms, such as chronic cardiac volume overload, may also play an important role, particularly with minoxidil.
Sympathetic stimulation and hypertension in the pyridoxine-deficient adult rat.
Authors: Paulose C S , Dakshinamurti K , Packer S , Stephens N L
Published: June 2012

Pyridoxal phosphate is the coenzyme of various decarboxylases involved in the formation of monoamine neurotransmitters such as gamma-aminobutyric acid, serotonin, dopamine, and norepinephrine. Adult male Sprague-Dawley rats placed on a pyridoxine-deficient diet for 8 weeks showed significant hypertension compared with pyridoxine-supplemented controls. Hypothalamic contents of pyridoxal phosphate, gamma-aminobutyric acid, and serotonin in the pyridoxine-deficient rats were significantly lower than those in pyridoxine-supplemented controls. Hypertension was associated with sympathetic stimulation. Treatment of pyridoxine-deficient rats with a single dose of pyridoxine (10 mg/kg body weight) reversed the blood pressure to normal levels within 24 hours, with concomitant restorations of hypothalamic serotonin and gamma-aminobutyric acid as well as the return of plasma norepinephrine and epinephrine to normal levels. Also, pyridoxine treatment reversed the hypothalamic hypothyroidism observed in pyridoxine-deficient rats. These results indicate an association between pyridoxine deficiency and sympathetic stimulation leading to hypertension.
Effect of 6-iodoamiloride in various models of experimental hypertension.
Authors: Pamnani M B , Rinaudo M S , Haddy F J , Cragoe E J
Published: June 2012

6-Iodoamiloride, an analogue of the sodium channel blocker amiloride, is a vasodilator-depressor, diuretic-natriuretic, and antikaliuretic agent. In these experiments we intravenously infused 6-iodamiloride (0.38 mg/100 g body weight) over a 10- to 11-minute period into rats with reduced renal mass-saline hypertension or one-kidney, one clip hypertension. The infusion produced a prompt but transient fall in blood pressure. These findings are in contrast to those in spontaneously hypertensive rats (SHR), in which the same infusion of 6-iodoamiloride produced a prompt, pronounced, and sustained fall in blood pressure. Studies from a number of laboratories suggest that vascular smooth muscle cells from the SHR have increased permeability to sodium whereas vascular smooth muscle cells from the other two models do not. Thus, 6-iodoamiloride may have potential both as a diagnostic probe and a therapeutic agent for hypertension characterized by increased vascular smooth muscle cell permeability to sodium.
Dietary salt produces abnormal renal vasoconstrictor responses to upright posture in borderline hypertensive subjects.
Authors: Lawton W J , Sinkey C A , Fitz A E , Mark A L
Published: June 2012

We studied the effect of high and low NaCl diets in normotensive and borderline hypertensive subjects to determine if a high NaCl diet produces abnormal renal vasoconstriction during the stress of upright posture in borderline hypertensive subjects. We studied 13 normotensive young men with diastolic blood pressures below 85 mm Hg and nine borderline hypertensive young men defined by diastolic blood pressures intermittently above 90 mm Hg. The subjects achieved comparable sodium balance during 6 days of low NaCl (10 mEq Na, 40 mEq Cl, 100 mEq K) and high NaCl (400 mEq Na, 400 mEq Cl, 100 mEq K) diets. In the normotensive subjects, standing for 30 minutes resulted in a tendency for diastolic blood pressure to fall during both diets. In contrast, during standing borderline hypertensive subjects showed no change in diastolic blood pressure during the low salt diet and a tendency for diastolic blood pressure to increase after the high salt diet. Standing reduced renal plasma flow in both groups during both diets. However, only during the high NaCl diet did the absolute decrease and percent decrease in renal plasma flow during standing differ significantly (p less than 0.05 and p less than 0.01, respectively) between the borderline hypertensive (-151 +/- 24 ml/min/1.73m2; -29 +/- 4%) and normotensive subjects (-79 +/- 17 ml/min/1.73m2; -15 +/- 3%). The resultant increase in the renal vascular resistance index with standing did not differ between the two groups during the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)
High potassium diets protect against dysfunction of endothelial cells in stroke-prone spontaneously hypertensive rats.
Authors: Sugimoto T , Tobian L , Ganguli M C
Published: June 2012

Two lines of evidence strongly support the hypothesis that high potassium diets protect arterial endothelial cells from hypertensive damage. Stroke-prone spontaneously hypertensive rats (SHRSP) fed normal (0.75%) K or high (2.1%) K and normotensive Wistar-Kyoto rats (WKY) were examined in an endothelial function study and a histological study. In the endothelial function study, aortic rings were suspended in tissue baths to monitor isometric tension. Rings contracted with norepinephrine were tested with acetylcholine and sodium nitroprusside. In normal K SHRSP (blood pressure, 156 mm Hg), endothelium-dependent acetylcholine relaxation was severely depressed by 49% (p less than 0.001), whereas in high K SHRSP (blood pressure, 155 mm Hg), normal values were preserved. Endothelium-independent nitroprusside relaxation was virtually the same in both the SHRSP groups (high K vs normal K diet). Since indomethacin did not improve the impaired acetylcholine relaxation in normal K SHRSP, the cyclooxygenase products do not appear to have affected the endothelium-dependent relaxation in the normal K SHRSP. Thus, the endothelium-dependent relaxation response was much decreased in the normal K SHRSP and was preserved in the high K SHRSP. Thus, a high K diet appears to protect the aortic endothelium from a hypertension-induced dysfunction. In the histological study, aortic and mesenteric intimal lesions were assessed blindly under the microscope and graded from 0 to 60 for aortic and from 0 to 40 for mesenteric lesions. Aortic intimal lesion scores were 28 in normal K SHRSP (blood pressure, 209 mm Hg) and 13 in high K SHRSP (blood pressure, 207 mm Hg; -54%; p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Vascular smooth muscle calponin. A novel troponin T-like protein.
Authors: Takahashi K , Hiwada K , Kokubu T
Published: June 2012

In a search for additional Ca2+ regulatory components in vascular smooth muscle, a novel troponin T-like protein was purified from bovine aorta smooth muscle. The isolated protein was separated into several isoforms on isoelectric focusing. The major isoelectric variants were focused in the pH region of 8.4 to 9.1. The protein had slightly different molecular masses in the Mr range of 35,000 on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its molar ratio relative to tropomyosin in the muscle extract was estimated to be 0.9:1.0. The novel protein bound to the immobilized calmodulin and exhibited a number of common physicochemical properties with gizzard (Mr = 34,000) calmodulin-binding and F-actin-binding protein. The aorta and gizzard proteins were immunologically cross-reactive. Both proteins shared a common antigenic determinant with COOH-terminal segments of rabbit skeletal and bovine cardiac troponin T and bound to the immobilized smooth muscle tropomyosin. Both proteins interacted with rabbit skeletal troponin C in the presence and absence of Ca2+, but they did not interact with troponin I. These results suggest that the novel protein, which is designated calponin, may be a specialized component of smooth muscle thin filament involved in the regulation of contractile apparatus.
Atrial natriuretic polypeptide in bovine adrenal medulla.
Authors: Mukoyama M , Nakao K , Morii N , Shiono S , Itoh H , Sugawara A , Yamada T , Saito Y , Arai H , Imura H
Published: June 2012

Two radioimmunoassays for alpha-human atrial natriuretic polypeptide (alpha-hANP) with different specificities were used to study the tissue level and the nature of alpha-hANP-like immunoreactivity in the bovine adrenal gland. A considerable amount of alpha-hANP-like immunoreactivity was detected in the adrenal medulla (90.8 +/- 21.1 and 90.0 +/- 23.1 ng/g with the two radioimmunoassays), while no detectable amount (less than 1.0 ng/g) was present in the cortex. Gel permeation chromatographic analysis showed that ANP in the medulla is composed of two components of alpha-hANP-like immunoreactivity with high and low molecular weights in the approximate ratio of 2:1, eluting at the elution positions of gamma-hANP and alpha-hANP, respectively. Reverse-phase high performance liquid chromatographic analysis revealed that alpha-hANP-like immunoreactivity with a low molecular weight in the medulla consists of two major components, which comigrate with synthetic alpha-hANP(5-28) and alpha-hANP. When cultured bovine adrenal chromaffin cells were incubated in the presence of nicotine (10(-5) M), alpha-hANP-like immunoreactivity was released into the medium concomitantly with catecholamines from chromaffin cells. These findings indicate that a discrete ANP system is present in the adrenal medulla and that ANP is cosecreted with catecholamines from chromaffin cells, suggesting the possible involvement of ANP in the adrenomedullary function.
A highly potent and long-acting oral inhibitor of human renin.
Authors: Hiwada K , Kokubu T , Murakami E , Muneta S , Morisawa Y , Yabe Y , Koike H , Iijima Y
Published: June 2012

An orally active renin inhibitor, ES 6864 (N-[(2R)-3-morpholinocarbonyl-2-(1-naphthylmethyl)propionyl]-(4- thiazolyl)-L-alanyl-cyclostatine-(2-morpholinoethyl)amide), was synthesized. ES 6864 was found to be a highly potent inhibitor of human renin with a Ki value of 7.3 x 10(-9) M. The compound competitively inhibited human renin. The inhibitor was also potent against monkey renin but was less effective against renins from pig, goat, dog, rabbit, and rat. ES 6864 did not inhibit cathepsin D, pepsin, trypsin, chymotrypsin, angiotensin converting enzyme, and urinary kallikrein at a concentration of 10(-5) M. ES 6864 was resistant to proteolytic actions of the enzymes in rat tissue homogenates (liver, kidney, pancreas, and small intestine). Oral administration of ES 6864 at 30 mg/kg to conscious, sodium-depleted marmosets produced a significant blood pressure reduction and almost complete inhibition of plasma renin activity, which persisted for 5 hours. Oral administration of ES 6864 also produced dose-related decreases of blood pressure in hog renin-infused rats, but the duration of action was much shorter than that in conscious marmosets. The parent compound in the blood following oral administration of ES 6864 to marmosets was confirmed directly by measuring the plasma concentration of ES 6864. These results enhance the possibility of developing renin inhibitors that can be used clinically.
Effect of vasopressors on atrial natriuretic factor and hemodynamic function in humans.
Authors: Shenker Y , Bates E R , Egan B H , Hammoud J , Grekin R J
Published: June 2012

To assess the effects of vasopressors on plasma levels of immunoreactive atrial natriuretic factor (ANF), 13 normal men were studied on two occasions. On the experimental day, subjects received sequential 15-minute intravenous infusions of angiotensin II in doses of 4, 8, and 16 pmol/kg/min. Following a 30-minute recovery period, subjects received sequential 15-minute infusions of phenylephrine in doses of 0.4 and 0.8 micrograms/kg/min. Right atrial pressure, mean pulmonary capillary wedge pressure, pulmonary artery pressure, mean systemic arterial pressure, and plasma levels of renin activity, aldosterone, angiotensin II, and immunoreactive ANF were obtained sequentially throughout the protocol. During the control day, vehicle was infused and plasma samples were obtained for hormone measurements. Infusion of angiotensin II and phenylephrine increased mean systemic arterial pressure in a stepwise fashion. Both right atrial pressure and pulmonary capillary wedge pressure increased significantly during both doses of phenylephrine, but only the highest dose of angiotensin II significantly increased atrial pressures. Plasma levels of immunoreactive ANF increased parallel with the changes in right atrial pressure and pulmonary capillary wedge pressure, with significant increases occurring only at the highest dose of both pressors. Angiotensin II and aldosterone levels increased and renin activity decreased during infusion of angiotensin II. There were no significant changes in plasma levels of immunoreactive ANF during the control day. These studies demonstrate that infusion of vasopressors increases plasma levels of ANF, but only when the vasopressor effect is associated with significant increases in right atrial and pulmonary capillary wedge pressures. Atrial stretch is the most likely mediator of the increase in plasma levels of immunoreactive ANF during vasoconstriction.
The renin response to aortic occlusion is enhanced by stimulation of the hypothalamus.
Authors: Porter J P
Published: June 2012

The sympathetic nervous system is an important factor that can induce increased renin secretion by the kidney. In recent years, the notion has arisen that the sympathetic nervous system may also function to set the level of responsiveness of the kidney to nonneural stimuli for renin secretion. However, evidence in favor of this possibility has come primarily from studies employing direct electrical stimulation of renal nerves, and no attempt has been made to determine if central neural sites can also influence the responsiveness of the kidney. In the present study, the ability of hypothalamic activation to enhance the renin response to suprarenal aortic occlusion was investigated. Conscious, freely moving rats with an inflatable cuff placed around the aorta were used to determine the relationship between renal-perfusion pressure and plasma renin activity in the control state and during continuous low-level stimulation of the paraventricular nucleus. The stimulation resulted in a rightward shift in the curve that related renal perfusion pressure to plasma renin activity; that is, for any given decrease in renal perfusion pressure, the plasma renin activity was greater during the ongoing stimulation. This rightward shift appeared to be mediated by increased renal nerve activity, since renal denervation prevented the shift. These data indicate that the hypothalamus, which plays an important role in regulating sympathetic activity, is capable of increasing the sensitivity of the kidney to a nonneural stimulus for renin secretion. This effect may become important in certain hypertensive and prehypertensive states where central neural activity is thought to be enhanced.
A monoclonal antibody to alpha-human atrial natriuretic polypeptide.
Authors: Mukoyama M , Nakao K , Sugawa H , Morii N , Sugawara A , Yamada T , Itoh H , Shiono S , Saito Y , Arai H
Published: June 2012

A monoclonal antibody to alpha-human atrial natriuretic polypeptide (alpha-hANP), KY-ANP-I, has been produced by fusion of a nonproducing mouse myeloma cell line, X63-Ag8.653, with spleen cells from BALB/c mice immunized with synthetic alpha-hANP conjugated to bovine thyroglobulin using the carbodiimide coupling procedure. Hybridomas were screened for antibody production by radioimmunoassay using culture media and 125I-alpha-hANP. They were cloned by the limiting dilution technique, expanded in culture, and injected intraperitoneally into BALB/c mice. The obtained antibody belonged to the immunoglobulin G1 subclass. Analysis by a Scatchard plot revealed a high affinity for alpha-hANP, with an association constant of 3.1 x 10(10) M-1. With this monoclonal antibody, a specific radioimmunoassay for alpha-hANP has been established. The antibody in mouse ascites was available for radioimmunoassay at a final dilution of 1:10(6). Values of IC10 and IC50 in this radioimmunoassay were 3 and 30 fmol/tube, respectively. The radioimmunoassay showed a cross-reactivity of 0.9% with alpha-rat ANP. alpha-hANP-(8-22) and alpha-ANP-(1-6) exhibited less cross-reactivity than alpha-rat ANP on a molar basis. There was no cross-reaction with alpha-ANP-(17-28). Thus, the recognized epitope must be located in the N-terminal half of the ring structure of alpha-hANP including Met12 residue. This radioimmunoassay could detect gamma-hANP and beta-hANP as well as alpha-hANP. The monoclonal antibody was also useful for immunohistochemical studies. ANP-positive cells were finely stained in the human atrium using the avidin-biotin-peroxidase complex technique.(ABSTRACT TRUNCATED AT 250 WORDS)
Pressure-diuresis in volume-expanded rats. Cortical and medullary hemodynamics.
Authors: Roman R J , Cowley A W , Garcia-Estañ J , Lombard J H
Published: June 2012

This study evaluated whether pressure-diuretic and pressure-natriuretic responses are associated with alterations in vasa recta hemodynamics. Autoregulation of cortical and papillary blood flow was studied using a laser-Doppler flowmeter in volume-expanded and hydropenic rats. Superficial cortical flow and whole kidney renal blood flow were autoregulated in volume-expanded rats and decreased by less than 10% after renal perfusion pressure was lowered from 150 to 100 mm Hg. In contrast, papillary blood flow was not autoregulated and fell by 24 +/- 2%. The failure of papillary blood flow to autoregulate was due to changes in the number of perfused vessels as well as to alterations in blood flow in individual ascending and descending vasa recta. Pressure in vasa recta capillaries increased from 6.8 +/- 0.8 to 13.8 +/- 1.2 mm Hg after renal perfusion pressure was elevated from 100 to 150 mm Hg, and renal interstitial pressure rose from 7.4 +/- 0.8 to 12.3 +/- 1.4 mm Hg. In hydropenic rats, papillary blood flow was autoregulated to a significant extent, but it still decreased by 19% after renal perfusion pressure was lowered from 150 to 100 mm Hg. The pressure-diuretic and pressure-natriuretic responses in hydropenic rats were blunted in comparison to those observed in volume-expanded rats. These findings indicate that the pressure-diuretic and pressure-natriuretic responses are associated with changes in vasa recta hemodynamics and renal interstitial pressure.
Evaluation of the baroreceptor-heart rate reflex by 24-hour intra-arterial blood pressure monitoring in humans.
Authors: Parati G , Di Rienzo M , Bertinieri G , Pomidossi G , Casadei R , Groppelli A , Pedotti A , Zanchetti A , Mancia G
Published: June 2012

The baroreceptor control of the sinus node was evaluated in 10 normotensive and 10 age-matched essential hypertensive subjects in whom ambulatory blood pressure was recorded intra-arterially for 24 hours and scanned by a computer to identify the sequences of three or more consecutive beats in which systolic blood pressure (SBP) and pulse interval (PI) progressively rose (+PI/+SBP) or fell (-PI/-SBP) in a linear fashion, according to a method validated in cats. In normotensive subjects, several hundred +PI/+SBP and -PI/-SBP sequences of 3 beats were found whereas the number of sequences of 4, 5, and more than 5 beats showed a progressive drastic reduction. The mean slopes of +PI/+SBP (7.6 +/- 2.0 msec/mm Hg) and -PI/-SBP (6.4 +/- 1.5 msec/mm Hg) sequences were similar, but in both instances there was a large scattering of the values around the mean (variation coefficients: 64.2 +/- 4.7 and 62.6 +/- 2.4%). The slopes decreased as a function of the sequence length and baseline heart rate and increased to a marked extent during the night as compared with daytime values. All sequences were more rare (-33.2% for +PI/+SBP and -31.7% for -PI/-SBP) and less steep in hypertensive subjects (-40.3 and -36.2%, respectively), who failed to show the marked nighttime increase in slope observed in normotensive subjects. To our knowledge, these observations provide the first description in humans of the baroreceptor-heart rate reflex in daily life. This reflex is characterized by marked within-subject variations in sensitivity due in part to hemodynamic, temporal, and behavioral factors.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of eicosanoids on renal function of DOCA-salt hypertensive rats.
Authors: Roman R J , Kaldunski M L , Mattson D L , Mistry M , Nasjletti A
Published: June 2012

The present study examined the contribution of changes in the synthesis or degradation (or both) of renal eicosanoids to the alterations in renal hemodynamics observed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Renal blood flow and glomerular filtration rate were markedly reduced in DOCA-salt hypertensive rats compared with values observed in control rats given water or saline to drink. The abnormalities in renal hemodynamics in the hypertensive rats were associated with an increase in the excretion of thromboxane B2, an increase in the release of thromboxane B2 from renal cortical tissue slices, and a diminished release of prostaglandin E2 (PGE2) from renal medullary tissue. Additionally, the urinary excretion of PGE2 and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) and the release of 6-keto-PGF1 alpha from renal cortical and medullary tissue were elevated in rats with DOCA-salt hypertension. Since the excretion of PGE2 and 6-keto-PGF1 alpha and the release of 6-keto-PGF1 alpha by medullary tissue were also elevated in normotensive rats given 1% NaCl solution to drink, these latter changes probably were related to an elevation of sodium intake rather than to the development of hypertension. The functional significance of the alterations in the renal production of thromboxane in DOCA-salt hypertensive rats was evaluated by comparing the effects of a thromboxane synthesis inhibitor and a receptor antagonist on renal function in normotensive and DOCA-salt hypertensive rats. The administration of the thromboxane synthetase inhibitor furegrelate and the thromboxane receptor blocker SQ 29548 had no effect on renal hemodynamics in either group.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of hypertension and its reversal on canine arterial wall properties.
Authors: Cox R H , Bagshaw R J
Published: June 2012

Segments of carotid, femoral, saphenous, and left circumflex coronary arteries were obtained from control, renal hypertensive, and nephrectomized hypertensive dogs for in vitro study of mechanical properties. Hypertension was produced in two-kidney dogs by unilateral renal artery constriction. After 3 months, the compromised kidney was removed in half of the dogs. Mean arterial pressure was significantly elevated in the hypertensive dogs after 3 months (127 +/- 2 vs 94 +/- 1 mm Hg for controls) and partially returned toward normal 3 months after nephrectomy (105 +/- 2 mm Hg). Pressure-diameter relations were determined under conditions of maximum active and passive smooth muscle activation. Contiguous segments were used for the determination of water and connective tissue content. Hypertension was associated with increased passive arterial wall stiffness at most sites, with a partial return toward normal after nephrectomy. Maximum responses to smooth muscle activation (active stress and constriction response) were augmented in arteries from hypertensive dogs and partially returned toward normal in the nephrectomized hypertensive group. The elastin content of these arteries was unchanged, while collagen content was nonuniformly decreased in renal hypertensive dogs. Small decreases were found in the radius-wall thickness ratio of some arteries. No significant mechanical changes occurred in the saphenous artery. The largest hypertension-related changes were found in the coronary arteries, which also exhibited the smallest recovery toward normal properties after nephrectomy. Considerable regional variability of changes in arterial wall in renal hypertensive and nephrectomized hypertensive dogs was found. Incomplete resolution of the hypertension and arterial wall changes by nephrectomy was found in this animal model.
Angiotensin converting enzyme inhibition improves diagnostic procedures for renovascular hypertension in dogs.
Authors: Jonker G J , de Zeeuw D , Huisman R M , Piers D B , Beekhuis H , van der Hem G K
Published: June 2012

In renovascular hypertension adaptive mechanisms in the poststenotic kidney are a probable cause of the 20 to 25% false-negative findings during rapid sequence urography or [123I]o-iodohippurate renography. We blocked the renin-angiotensin system in an effort to increase the yield of these diagnostic procedures. Chronically instrumented, salt-depleted conscious dogs were used in which a light (n = 5), moderate (n = 4), or severe (n = 2) renal artery stenosis was induced. Before stenosis 10 of the dogs showed no left-right differences with either diagnostic procedure, and angiotensin converting enzyme (ACE) inhibition did not change this result. Two to 3 weeks after induction of a renal artery stenosis, all dogs showed signs of renovascular hypertension. However, only 50% of the renograms and 22% of the urograms showed differences between the two kidneys indicative of the presence of stenosis. After ACE inhibition, all previously negative test results became positive (abnormal) and previously existing left-right differences became more evidence. Electromagnetically measured renal blood flow on the stenotic side did not change during ACE inhibition (146 +/- 13 vs 145 +/- 21 ml/min), whereas contralateral blood flow showed a distinct increase (207 +/- 18 vs 282 +/- 20 ml/min, p less than 0.01). In conclusion, ACE inhibition markedly improves the sensitivity of rapid sequence urography and hippurate renography in the diagnosis of renovascular hypertension in the two-kidney, one clip Goldblatt hypertensive dog. The effects of ACE inhibition on the handling of the different tracers do not appear to be related to its effects on renal blood flow or systemic blood pressure.
Arterial hypertension is associated with hypalgesia in humans.
Authors: Ghione S , Rosa C , Mezzasalma L , Panattoni E
Published: June 2012

An association between increased blood pressure and hypalgesia has been reported in several studies in animals and in a few reports in humans. We investigated the relationship between hypertension and pain perception by comparing the response to graded electrical stimulation of the tooth pulp, which is thought to represent an exclusively nociceptive system. The test was performed with a commercial tooth pulp tester in a large series of subjects with borderline or established hypertension and in three groups of normotensive controls: volunteers, nonhypertensive patients, and medical students with a well-established or no family history of hypertension. Subjects had to report when they started to feel pulp stimulation (sensory threshold) and when this became painful (pain threshold). Sensory and pain thresholds were obtained as means of the measurements on four healthy, unfilled teeth. Sensory thresholds were significantly higher in subjects with borderline or established hypertension than in two of the three normotensive groups (volunteers and normotensive patients), whereas no significant difference was observed between the two hypertensive groups. The results for the pain threshold were qualitatively similar but less clear and less amenable to statistical analysis because this parameter could not be determined with accuracy in a number of subjects in whom the subjective pain threshold was above the upper range of stimulation of the instrument. The association between blood pressure levels and pain perception was further confirmed by the highly significant correlation found for the overall data between mean arterial blood pressure and both thresholds.(ABSTRACT TRUNCATED AT 250 WORDS)
Abnormal renal responses to calcium entry blockade in normotensive offspring of hypertensive parents.
Authors: Montanari A , Vallisa D , Ragni G , Guerra A , Colla R , Novarini A , Coruzzi P
Published: June 2012

In nine young normotensive subjects with no family history of hypertension and nine age-matched normotensive subjects with one parent with essential hypertension, effective renal plasma flow (p-aminohippuric acid clearance), glomerular filtration rate (inulin clearance), and excretion of sodium and exogenously administered lithium were measured for 90 minutes before and after administration of a single 20-mg oral dose of the calcium entry blocker nifedipine. Segmental tubular handling of fluid and sodium was estimated using lithium clearance as a marker of proximal tubular reabsorption. Nifedipine did not cause any change in subjects with no family history of hypertension, but in those with one hypertensive parent there was a marked increase in effective renal plasma flow (from 644 +/- 39 to 847 +/- 42 [SEM] ml/min x 1.73 m2; p less than 0.001) and a decrease in filtration fraction (from 17.6 +/- 1.0 to 12.6 +/- 0.4%; p less than 0.001), while the glomerular filtration rate was unchanged, thus suggesting a prevailing efferent vasodilation. Sodium excretion rate (p less than 0.02) and fractional sodium excretion (p less than 0.025) increased slightly but significantly in subjects with one hypertensive parent, but not in normotensive subjects with no family history of hypertension. Lithium clearance also rose (from 29.0 +/- 2.0 to 32.8 +/- 1.9 ml/min, p less than 0.001), and the derived value of fractional proximal reabsorption diminished (from 75.8 +/- 1.0 to 71.3 +/- 1.2%, p less than 0.001). Estimated distal delivery of sodium and absolute distal sodium reabsorption both increased significantly (p less than 0.005), while fractional distal sodium reabsorption was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)