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Biomedical subjects

M Winn

Publications and source records attributed to M Winn.

36 records · Page 2Linked to original sources
PubMed1993

Antihypertensive activity of ABBOTT-81282, a nonpeptide angiotensin II antagonist, in the renal hypertensive rat.

ABBOTT-81282, 4-(N-butyl-N-[(2-'-[1H-tetrazol-5yl]biphenyl-4-yl)methyl]ami no) pyrimidine-5-carboxylic acid is a novel nonpeptide angiotensin II (AII) antagonist. In vivo studies were performed to evaluate ABBOTT-81282 for its antihypertensive effect, pharmacological mechanism(s) of action, and cardiovascular safety. In the conscious renal artery-ligated (RAL) hypertensive rat, a model of high renin hypertension, ABBOTT-81282 (1-10 mg/kg p.o. and 0.1-1.0 mg/kg i.v.) lowered mean arterial pressure (MAP) in a dose-dependent manner with the ED30 values of 2.2 mg/kg for p.o. administration and 0.08 mg/kg for i.v. administration. At 10 mg/kg p.o., ABBOTT-81282 lowered blood pressure in the RAL rat (delta MAP 66 +/- 9 mm Hg from control MAP 167 +/- 7 mm Hg, n = 6) to a normotensive level (MAP, 115 +/- 5 mm Hg) for greater than 24 h and did not change heart rate. The i.v. administration of 1 mg/kg of ABBOTT-81282 also produced a sustained, long-lasting decrease (delta MAP 27-52 mm Hg) in blood pressure that was significantly different from the vehicle group at 8 h postdosing (143 +/- 3 mm Hg, n = 4 for ABBOTT-81282 vs. 181 +/- 3 mm Hg, n = 6 for vehicle group, p < 0.01). When blood pressure in the renal hypertensive rat was maximally lowered (delta MAP 72 +/- 9 mm Hg, n = 4) following the 1 mg/kg i.v. dose (cumulative) of ABBOTT-81282, additional administration of captopril (3 mg/kg i.v.) produced no further decline in blood pressure. In the conscious normotensive rat, 10 mg/kg p.o. of ABBOTT-81282 had no effect on basal MAP (119 +/- 3 vs. 115 +/- 4 mm Hg, pre- vs. 3.5 h postdosing, n = 4) and heart rate (364 +/- 18 vs. 363 +/- 14 beats/min, pre- vs. 3.5 h postdosing, n = 4) but inhibited the AII (0.1 micrograms/kg i.v.)-induced increase in MAP by 64-70%, while the MAP responses to norepinephrine (0.3 micrograms/kg i.v.), vasopressin (0.03 IU/kg i.v.) and bradykinin (3 micrograms/kg i.v.) remained intact. ABBOTT-81282 was also administered to conscious normotensive rats (n = 4) instrumented with ECG telemetry transmitters. At an i.v. dose of 10 mg/kg, which is 125 times greater than the i.v. ED30, ABBOTT-81282 caused a minimal decrease (< 14%) in MAP and had no effect on ECG waveforms. These data demonstrate that ABBOTT-81282 is a safe and efficacious antihypertensive agent with selective AII antagonism.(ABSTRACT TRUNCATED AT 400 WORDS)

Administration, Oral↗
PubMed1990

Black health care in America: a political perspective.

Despite recent improvements in the health status of blacks, significant disparities continue to exist between blacks and whites in nearly every health status index. Contributing to these disparities are biases in the health system; economic bias being the most significant. This article assesses the competitive market strategy, the most recent federal initiative to promote equity in the access to health services in terms of the consequences for black health. Several policy actions are recommended to improve the health status of the black population.

Adolescent↗
PubMed1987

A new nasal decongestant, A-57219: a comparison with oxymetazoline.

2-(4-Amino-3,5-dichlorobenzyl)imidazoline hydrochloride (A-57219), has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Adrenergic alpha-Agonists↗
PubMed1986

Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.

The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).

Adrenergic alpha-Agonists↗
PubMed1986

Conformationally defined adrenergic agents. 3. Modifications to the carbocyclic ring of 5,6-dihydroxy-1-(2-imidazolinyl)tetralin: improved separation of alpha 1 and alpha 2 adrenergic activities.

A series of modifications to positions 1, 2, and 4 of the tetralin ring of 5,6-dihydroxy-1-(2-imidazolinyl)tetralin (1, A-54741) succeeded in improving the separation of the potent alpha 1 and alpha 2 adrenergic agonism observed for the parent compound 1. In particular 5,6-dihydroxy-4,4-dimethyl-1-(2-imidazolinyl)tetralin (7) was found to be a specific alpha 1 adrenergic agonist, and 7,8-dihydroxy-4-(2-imidazolinyl)chroman (2) was found to have improved alpha 2 adrenergic agonistic selectivity relative to the parent compound 1.

Animals↗
PubMed1985

Conformationally defined adrenergic agents. 1. Design and synthesis of novel alpha 2 selective adrenergic agents: electrostatic repulsion based conformational prototypes.

A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).

Adrenergic alpha-Agonists↗
PubMed1984

Photoaffinity labeling of mammalian alpha 1-adrenergic receptors. Identification of the ligand binding subunit with a high affinity radioiodinated probe.

We have synthesized and characterized a novel high affinity radioiodinated alpha 1-adrenergic receptor photoaffinity probe, 4-amino-6,7-dimethoxy-2-[4-[5-(4-azido - 3 - [125I]iodophenyl) pentanoyl] - 1 - piperazinyl] quinazoline. In the absence of light, this ligand binds with high affinity (KD = 130 pM) in a reversible and saturable manner to sites in rat hepatic plasma membranes. The binding is stereoselective and competitively inhibited by adrenergic agonists and antagonists with an alpha 1-adrenergic specificity. Upon photolysis, this ligand incorporates irreversibly into plasma membranes prepared from several mammalian tissues including rat liver, rat, guinea pig, and rabbit spleen, rabbit lung, and rabbit aorta vascular smooth muscle cells, also with typical alpha 1-adrenergic specificity. Autoradiograms of such membrane samples subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveal a major specifically labeled polypeptide at Mr = 78,000-85,000, depending on the tissue used, in addition to some lower molecular weight peptides. Protease inhibitors, in particular EDTA, a metalloprotease inhibitor, dramatically increases the predominance of the Mr = 78,000-85,000 polypeptide while attenuating the labeling of the lower molecular weight bands. This new high affinity radioiodinated photoaffinity probe should be of great value for the molecular characterization of the alpha 1-adrenergic receptor.

Affinity Labels↗
PubMed1983

Covalent labeling of the cerebral cortex alpha 1-adrenergic receptor with a new high affinity radioiodinated photoaffinity probe.

A novel high affinity radioiodinated photoaffinity probe, 4-amino-6,7-dimethoxy-2[4-[5(3-[125I]iodo-4-azidophenyl)pentanoyl]-1- piperazinyl]-quinazoline, structurally related to the potent alpha 1-adrenergic antagonist prazosin, was developed and used to covalently label the rat cerebral cortex alpha 1-adrenergic receptor. In the absence of light, this ligand binds to cortex plasma membranes with a dissociation constant of 308 pM and with a maximal number of binding sites of 200 fmol/mg protein. Upon photolysis, the ligand incorporates irreversibly into plasma membrane proteins. Autoradiograms of such membrane samples subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis reveal a major specifically labeled polypeptide at Mr = 79,000. The covalent incorporation into the peptide at Mr = 79,000 can be inhibited by several adrenergic receptor ligands with a typical alpha 1-adrenergic receptor specificity and stereoselectivity.

Affinity Labels↗
PubMed1983

The radionuclide detection of lower gastrointestinal bleeding sites.

A retrospective review of two years' experience with radionuclide screening to detect lower gastrointestinal bleeding sites was conducted at New York's Montefiore Medical Center. Of 82 studies performed in 63 patients, 13 identified active bleeding sites. Only three of eight angiograms obtained in these 13 patients were positive. Thirteen contrast angiograms were performed in the group of 50 patients with negative radionuclide studies of which ten were negative and one was equivocal. The results of this study suggest that the Tc-99m sulfur colloid study for active lower gastrointestinal (GI) bleeding is an effective screening procedure. Positive studies help determine which vessel to catheterize selectively if an angiogram is to be performed. If vascular ectasis is still suspected following a negative radionuclide study, contrast angiography can be more efficaciously performed on a nonemergent basis.

Adult↗
PubMed1981

Strain differences in kidney function of inbred rats: 1. Glomerular filtration rate and renal plasma flow.

Bodyweight, kidney weight and glomerular filtration rate showed significant differences between strains--70% of the total variance was ascribed to the between-strain variance component--while the renal plasma flow showed only a slight strain difference due to a high within-strain variance component (63%). Heritability in the broad sense was 0.78 for bodyweight, 0.85 for kidney weight, 0.66 for glomerular filtration rate and 0.35 for renal plasma flow. There were significant genetic correlations between bodyweight and kidney weight (0.90), bodyweight and glomerular filtration rate (0.73), and between glomerular filtration rate and renal plasma flow (0.71), but not between kidney weight and kidney functions. Significant environmental correlations could be calculated only between bodyweight and all other variables, so that for comparison between strains it seems better to correct renal functions for bodyweight than for kidney weight, which would increase the variation of glomerular filtration rate.

Animals↗
PubMed1976

Drugs derived from cannabinoids. 5. delta6a,10a-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains.

Ten new delta6a,10a-THC analogs with arylalkyl side chains, one with a dimethylaminoalkyl side chain, and six heterocyclic delta6a,10a-THC analogs [8-substituted 5,5-dimethyl-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H-[1]benzo-pyrano[4,3-c]pyridines] were prepared. They showed pharmacological activity as analgesics, tranquilizers, antihypertensives, and hypnotics and as antisecretory, antiulcer, and antidiarrheal agents. The most potent compounds had either a 1-methyl-4-(4-fluorophenyl)butyl or a 1,2-dimethyl-4-(4-fluorophenyl)butyl side chain.

Aggression↗
PubMed1976

Drugs derived from cannabinoids. 4. Effect of alkyl substitution in sulfur and carbocyclic analogs.

Various CNS-active cannabinoids in which the alicyclic ring was thiopheno, cyclopenteno, or cyclohexeno with the alkyl substituent in various positions (structural types 1-6) were synthesized by procedures described previously. These compounds were compared in selected pharmacological tests in mice, rats, dogs, and cats. The results suggested that methyl substitution in the close proximity of the phenolic hydroxyl group strongly influenced the activity of some cannabinoids, particularly of those which had a planar five-membered alicyclic ring rather than a six-membered ring.

Acoustic Stimulation↗
PubMed1975

Homologs of dopa, alpha-methyldopa, and dopamine as potential cardiovascular drugs.

Starting from 3,4-dimethoxyphenacyl bromide, 2-amino-4-(3,4-dihydroxyphenyl)butyric acid (homodopa) was synthesized in six steps. 5-Hydroxyhomodopa was similarly prepared. alpha-Methylhomodopa was synthesized in four steps from zingerone [4-(4-hydroxy-3-methoxyphenyl)-2-butanone]. alpha-Methylhomodopa showed no antihypertensive activity in the genetic hypertensive rat. Homodopa did not potentiate the behavioral effect of Dopa or inhibit Dopa decarboxylase. Homodopamine, unlike dopamine, did not increase renal blood flow in the dog.

5-Hydroxytryptophan↗