Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amlodipine is a long acting dihydropyridine calcium antagonist recently introduced for the treatment of angina and hypertension. In order to document its stability in vitro and to develop a pharmacokinetic model in rabbits, a new reversed-phase liquid chromatography (LC) assay with UV detection was developed. The method utilized a C18 column (250 x 4.6 mm i.d.) with a mobile phase composed of a mixture of methanol 0.04 M ammonium acetate-acetonitrile (38:38:24, v/v/v) containing 0.02% triethylamine (final pH 7.1). Under these conditions, the retention times of amlodipine and the internal standard desipramine were 10.6 and 12.9 min, respectively. Using 1 ml of plasma, sensitivity of the assay was 2.5 ng ml-1 at which the RSD was 11%. The standard curve was linear from 2.5 to 100 ng ml-1 (r2 = 0.990), and the mean RSD at this concentration range was 6.8%. The pharmacokinetic model was developed in rabbits which provides results similar to those in dogs, but at less expense. The assay was also applied to a stability study comparing amlodipine and nifedipine in pH 3 and pH 7 ammonium acetate buffers and in methanol. Amlodipine was considerably more stable than nifedipine under all conditions. Finally the assay was applied to a pharmacokinetic study in rabbits (n = 6) after a single 1 mg kg-1 intravenous dose. The mean half-life (t1/2) of amlodipine was 6.5 h, the systemic clearance (CL) was 4.8 l h-1 kg-1 and the apparent volume of distribution at steady state (Vdss) was 30.2 l kg-1.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Liquid chromatography assay for amlodipine: chemical stability and pharmacokinetics in rabbits. 184 Jan 30

We were able to purify two distinct sodium pump inhibitors to homogeneity from human urine based on [3H]ouabain-displacing activity from intact human erythrocytes. The polar and less polar compounds were eluted off the C18 reverse-phase column with 18% and 31% acetonitrile, respectively. The polar compound cross-reacted very weakly with specific antidigoxin antibody and lacked a characteristic ultraviolet absorption peak between 190 and 300 nm. The less polar compound showed a prominent digoxinlike immunoreactivity and had an ultraviolet spectrum similar to that of digoxin. We examined the effects of these compounds on cytosolic free calcium concentration in cultured rat vascular smooth muscle cells (A10 cells) using the fluorescent calcium chelator fura-2. Only the polar ouabain-displacing compound caused a significant increase, from 108 +/- 7 to 162 +/- 8 nM (n = 6, p less than 0.01), in cytosolic free calcium concentration in A10 cells. The rise in cytosolic free calcium concentration induced by the polar ouabain-displacing compound tended to be slower in onset and more sustained than that induced by arginine vasopressin. In contrast, ouabain and bufalin had no appreciable effects on cytosolic free calcium concentration in A10 cells. These results suggest that the polar ouabain-displacing compound we isolated from human urine may possess a vasoactive property and may play an important role in the modulation of vascular tone.
Hypertension 1989 Jun
PMID:Urinary sodium pump inhibitor raises cytosolic free calcium concentration in rat aorta. 254 27

This paper describes a general approach for the therapeutic drug monitoring of 13 different beta blockers in plasma. The chromatographic system contains a cyanopropyl-bonded phase as a stationary phase in combination with a mobile phase composed of acetonitrile and phosphate buffer (pH = 3, mu = 0.05). Two modes of detection are used, namely, UV detection and fluorescence detection. The sample pretreatment is performed with a nitrile-sorbent in combination with methanol-phosphate buffer (pH = 3, mu = 0.05) or with methanol containing 0.1% propylamine as eluent. Acceptable recoveries are obtained for practolol, acebutolol, pindolol, oxprenolol, mepindolol, atenolol, propranolol, prenalterol, alprenolol, metoprolol, sotalol and nadolol. For labetalol, however, the elution recovery has to be improved. Finally, this approach is illustrated by the assay of nadolol in the plasma of patients suffering from hypertension, who had received an oral formulation of the drug.
 ...
PMID:A strategy for the determination of beta blockers in plasma using solid-phase extraction in combination with high-performance liquid chromatography. 257 51

In order to identify a specific endogenous Na+,K+-ATPase inhibitor which could possibly be related to salt-dependent hypertension, we looked for substances in the methanol extract of bovine whole adrenal which show all of the following properties: (i) inhibitory activity for Na+,K+-ATPase; (ii) competitive displacing activity against [3H]ouabain binding to the enzyme; (iii) inhibitory activity for 86Rb uptake into intact human erythrocytes; and (iv) cross-reactivity with sheep anti-digoxin-specific antibody. After stepwise fractionation of the methanol extract of bovine adrenal glands by chromatography on a C18 open column, a 0-15% acetonitrile fraction was fractionated by high-performance liquid chromatography on a Zorbax octadecylsilane column. One of the most active fractions in 0-15% acetonitrile was found to exhibit all of the four types of the activities. It was soluble in water and was distinct from various substances which have been known to inhibit Na+,K+-ATPase such as unsaturated free fatty acids, lysophosphatidylcholines, vanadate, dihydroxyeicosatrienoic acid, dehydroepiandrosterone sulfate, dopamine, lignan, ascorbic acid, etc. This substance was further purified by using an additional five steps of high-performance liquid chromatography with five different types of columns. Molecular mass was estimated as below 350 by fast atom bombardment mass spectroscopy and ultrafiltration. Heat treatment at 250 degrees C for 2 h and acid treatment with 6 N HCl at 115 degrees C for 21 h almost completely destroyed the inhibitory activity of the purified substance for Na+ pump activity. Additionally, alkaline treatment with 0.2 N NaOH at 23 degrees C for 2 h destroyed approximately 70% of the inhibitory activity, whereas boiling for 10 min and various enzyme digestion did not destroy the activity. The dose dependency for the four types of the activities for this substance paralleled those of ouabain, spanning 2 orders of magnitude in concentration range. The inhibitory potencies of the purified substance for Na+,K+-ATPase, Na+ pump, and ouabain binding activities were diminished with increasing K+ concentration, exhibiting a characteristic typical of cardiac glycosides. This substance had no effect on the Ca2+-ATPase activity or the Ca2+ loading rate into the vesicle prepared from skeletal muscle sarcoplasmic reticulum. These results strongly suggest that this water-soluble nonpeptidic Na+,K+-ATPase inhibitor may be a specific endogenous regulator for the ATPase.
 ...
PMID:Isolation and characterization of a specific endogenous Na+,K+-ATPase inhibitor from bovine adrenal. 284 24

The influence of some oral hypoglycaemic sulfonyl ureas on PGI2 release by the rat thoracic aorta in vitro was examined using reversed phase HPLC. The column (Micro Pack MCH-10) (30 cm X 4 mm) was eluted using the solvent mixture:acetonitrile:glacial acetic acid:water (23:0.1:76.9v/v/v). Preincubation of the aortae with the sulfonyl ureas (15 microM) enhanced PGI2 release. The control release (measured as 6-oxo-PGF1 alpha) was 1.15 +/- 0.1 ng/mg wet weight. This was significantly increased to 2.30 +/- 0.20, 2.50 +/- 0.30, 2.90 +/- 0.25, 2.10 +/- 0.20 and 2.40 +/- 0.30 ng/mg by glibenclamide, gliclazide, acetohexamide, glibornuride and chlorpropamide, respectively (P less than 0.01, n = 6). Mepacrine (0.5 mM) abolished both basal and stimulated release. Thus, the enhanced PGI2 release may probably involve activation of the enzyme phospholipase A2. None of the compounds affected ADP-induced rat platelet aggregation even when the platelets were preincubated for 10 min at a concentration of 100-180 microM. The enhanced release of PGI2 may help to delay the development and progression of retinopathy, nephropathy, hypertension and thrombosis in diabetic patients prone to these diseases. Furthermore, the enhanced PGI2 release may partly underly some of the previously observed and poorly explained findings following the administration of some sulfonyl ureas into mammals.
 ...
PMID:The influence of oral hypoglycaemic sulfonyl ureas on prostacyclin release by the rat thoracic aorta. 309 69

17 alpha, 20 alpha-dihydroxy-4-pregnen-3-one (17 alpha, 20 alpha-P) is reportedly a hyper-tensinogenic substance in a model of ACTH induced hypertension in sheep (Scoggins et al). This steroid has not previously been measured in Japan. We have developed a new radioimmunoassay (RIA) system for 17 alpha, 20 alpha-P, and measured this steroid in peripheral blood samples from non-pregnant and pregnant women. In this clinical investigation concentrations of 17 alpha-hydroxyprogesterone (17 alpha-OHP) and progesterone (P) were also measured in the same clinical samples. Specific anti-serum against 17 alpha, 20 alpha-P-3-carboxymethyloxime-BSA was generated in rabbits. Cross-reactions with 5-pregnen-3 beta, 17 alpha 20 alpha-triol (17 alpha, 20 alpha-P5) and 17 alpha-OHP were 42 and 2.4%, respectively. Other steroids showed cross-reactivity of less than 1%. As an internal standard dexamethasone (500 ng/100 microliter) was added to the samples which were extracted twice with 6 volumes of dichloromethane. Separation of the plasma extract was performed by high performance liquid chromatography (HPLC) with the ODS column in the solvent system, acetonitrile:water = 55:45. Eluates of the 17 alpha, 20 alpha-P and 17 alpha-OHP fractions were collected separately and the solvent was evaporated in vacuo. RIA was carried out on each extract with specific anti-sera. RIA of P was performed independently using the anti-P-3-CMO-BSA antiserum; 0.1 ml of serum was extracted with n-hexane and subjected to RIA without chromatography. The coefficient of variation for intra- and interassay (n = 10) were 8.5 and 11.7% for 17 alpha, 20 alpha-P; 7.2 and 12.1% for 17-OHP and 10.5 and 14.0% for P, respectively. The recovery rates of 17 alpha, 20 alpha-P, 17 alpha-OHP and P were 95 +/- 1.5, 93.2 +/- 3.5 and 97.5 +/- 4.2%, respectively. With the use of this method, 17 alpha, 20 alpha-P was measured in the blood samples from the menstrual cycle and normal pregnancy. The mean serum 17 alpha, 20 alpha-P concentrations +/- SD in the follicular, ovulatory and luteal phases, and in the first, second and third trimesters were; 76 +/- 6.0, 100 +/- 31, 101 +/- 6.4, 226 +/- 80, 151 +/- 48 and 367 +/- 99 pg/ml, respectively.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:[Studies on 17 alpha, 20 alpha-dihydroxy-4-pregnen-3-one in non-pregnant and pregnant women by a new radioimmunoassay system]. 360 96

A radioimmunoassay procedure for the measurement of urinary 18-oxocortisol was developed. The antibody was raised against 18-oxocortisol 3-carboxymethyloxime-BSA and had relatively high specificity, except for aldosterone (26.3%). The RIA required a preliminary HPLC purification using a Lichrosorb diol column eluted with toluene:acetonitrile:isopropanol:acetic acid (83:11.9:5.1:0.01). The eluate portion corresponding to 18-oxocortisol was evaporated and subjected to RIA. The RIA procedure had an intraassay variability of 11% when using a pool containing 10.8 micrograms/24 hr (n = 6) and 17% with a pool containing 3.28 micrograms/24 hr. The interassay variability was 11% (n = 4). The recovery of added 18-oxocortisol was 90 +/- 10%. The urinary excretion of 18-oxocortisol in 22 white normal subjects was 3.26 +/- 1.98 (SD) micrograms/24 hr (range 0.8 to 7.1 micrograms/24 hr). The mean excretion of 18-oxocortisol in 4 patients with glucocorticoid-suppressible aldosteronism (GSA) was 38.6 micrograms/24 hr (range 25.5 to 54.6 micrograms/24 hr). The excretion of 18-oxocortisol in 3 patients with adenomas producing primary aldosteronism (APA) varied between 11.1 to 17.3 micrograms/24 hr and in 3 patients with idiopathic aldosteronism (IA) varied between 2.5 to 10.6 micrograms/24 hr. 18-Oxocortisol excretion is increased markedly in the urine of patients with GSA: what role this relatively weak mineralocorticoid plays in the pathogenesis of their hypertension is unknown. Its elevation is probably a reflection of a postulated lack of involution of the 18-methyloxidase in the inner layers of the adrenal.
 ...
PMID:Elevated urinary excretion of 18-oxocortisol in glucocorticoid-suppressible aldosteronism. 648 Aug 7

Nifedipine, (1,4-dihydro-2,6,dimethyl-4-(2-nitrophenyl)-3, 5-pyridinedicarboxylic acid dimethyl ester) a calcium channel blocker widely used in treatment of hypertension, is strongly photolabile. This may represent a problem in patients taking nifedipine and in handling of nifedipine samples. Reactive radical intermediates were determined and characterized in the process of nifedipine illumination using EPR spectroscopy. On illumination of nifedipine by daylight or by a mercury lamp, a nitroxide radical, RIIL-NIFNO.X was observed (in the first step), in various solvents like benzene, cyclohexane, methanol, acetonitrile, dimethylsulphoxide, or aqueous suspensions of liposomes. RIIL-NIF represents the nifedipine skeleton centered with phenyl group, and X is an EPR silent substituent. The generation of RIIL-NIFNO.X is coupled with the formation of nitroso compound, RIIL-NIFNO, as characterized by UV-visible spectroscopy. In a further step, RIIL-NIFNO abstracts hydrogen from nifedipine skeleton under the formation of RIIL-NIFNO.H radical. In addition to this, in system containing RIIL-NIFNO and unsaturated lipids, nitroxide radicals RIIL-NIFNO.RLIPIDS are formed probably via a pseudo Diels-Alder mechanism (RLIPIDS represents lipidic skeleton). The unusually easy photochemical activation of nifedipine is probably stimulated by photosensitization of its nitro group interacting with suitably positioned hydrogen or carboxylic methyl ester group from the pyridinyl ring.
 ...
PMID:Reactive radical intermediates formed from illuminated nifedipine. 786 71

Circulating inhibitors of the transport enzyme, sodium-potassium-activated adenosine triphosphatase (Na(+)-K(+)-ATPase), have been shown to be of possible pathogenetic importance in the mechanism of essential hypertension. Although previous studies have demonstrated the presence of both high molecular weight (HMW) and low molecular weight (LMW) natriuretic plasma Na(+)-K(+)-ATPase inhibitors, no previous attempts have been made to ascertain whether HMW or LMW forms predominate in hypertension. In this study, plasma samples obtained from 26 patients with essential hypertension, 12 normotensive controls, and six normotensives with a family history of hypertension, were separated into HMW and LMW moieties by passage through a 1 kDa Amicon membrane. The LMW moiety was separated on C18 Sep-Pak cartridges, applying a 10% step-wise acetonitrile trifluoroacetic acid gradient. The HMW moiety was further separated on Sephadex G-75. Sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed that the fraction with inhibitory activity contained a distinct 12 kDa protein band, with staining intensity depending on the presence or absence of hypertension. Na(+)-K(+)-ATPase inhibitory activity was found in several LMW fractions, but differences between hypertensives and normotensives were observed in only one fraction (0.29 +/- 0.12 SD v 0.11 +/- .12 mumol/L ouabain equivalents, P < .01). Na(+)-K(+)-ATPase inhibitory activity in the HMW fraction was 38 x the inhibitory activity in the LMW fraction and was significantly increased in hypertensives as compared to normotensive controls (10.9 +/- 8.9 v 1.3 +/- 0.8 mumol/L ouabain equivalents, P < .01). Inhibitory activity in both HMW and LMW fractions correlated positively with mean blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Predominance of high molecular weight plasma Na(+)-K(+)-ATPase inhibitor in essential hypertension. 821 31

Diltiazem (DTZ) is a calcium antagonist widely used in the treatment of angina and hypertension. It is extensively metabolized in humans via N-demethylation, O-demethylation, deacetylation, and oxidative deamination, yielding a host of metabolites, some of which have potent pharmacological properties. After our initial identification of O-desmethyl DTZ (Mx) and N,O-didesmethyl DTZ (MB) as major metabolites of DTZ and our subsequent of identification of their chemical synthesis, an improved high-performance liquid chromatography assay was developed to determine the plasma concentrations of DTZ and seven of its major basic metabolites, including the previously unquantitated Mx and MB. The system consisted of a C18 analytical column protected by a C18 cartridge guard column and a variable wavelength ultraviolet detector set at 237 nm. The mobile phase was a mixture of methanol, 0.04 M ammonium acetate, and acetonitrile (38:36:26) containing 0.08% triethylamine, with final pH of the mobile phase adjusted to 7.5. The system was operated at room temperature isocratically at a flow rate of 1.2 ml/min. Using verapamil as an internal standard, DTZ and the basic metabolites in plasma were determined in young healthy volunteers (n = 21) and in patients with ischemic heart disease (n = 19) at steady state after repeated oral doses of 60 mg DTZ four times daily. Preliminary results show that steady-state plasma concentrations of DTZ and its metabolites were higher in the older patients than in young healthy subjects (p < 0.05).
 ...
PMID:Steady-state plasma concentrations of diltiazem and its metabolites in patients and healthy volunteers. 884 19


1 2 3 4 5 6 7 Next >>