Search PubMed⌕ Search

Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 235 records · Page 13Linked to original sources
PubMed1987

Synthesis and platelet antiaggregatory activity of trimetoquinol analogs as endoperoxide/thromboxane A2 antagonists.

Trimetoquinol (TMQ) has activity as a beta-adrenergic agonist and as a platelet antiaggregatory agent. Recent reports from this and other laboratories have focused on the mechanism of inhibition of platelet function by TMQ and its analogs. Based on its competitive and stereoselective inhibition of thromboxane mimetic agents, TMQ was proposed as an endoperoxide/thromboxane A2 receptor antagonist; however, this mechanism has been questioned. A radiolabeled TMQ analog with high specific activity would aid in the elucidation of the actual mechanism of action. In the current research, modifications of the trimethoxy ring system of TMQ have been investigated. Replacement of one or two of the methoxy groups with iodine atoms leads to retention of platelet antiaggregatory activity and agonist blocking activity. Thus, these analogs have promise as potential radioligands since iodide exchange labeling can provide 125I-labeled compounds. Further, replacement of a methoxy group with either a nitro or amino functionality leads to decreased activity in platelet systems. These results suggest that the putative sites of interaction for the trimethoxy ring system of TMQ in platelet systems will tolerate large, lipid soluble groups but will not tolerate large changes in the electronic characteristics of the ring system.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1986

Alpha-adrenoceptor-mediated actions of optical isomers and desoxy analogs of catecholimidazoline and norepinephrine in human platelets: in vitro.

Adrenoceptor-mediated effects of the enantiomers of optically active imidazoline, 2-(3,4,alpha-trihydroxybenzyl imidazoline (catecholimidazoline; CI), and norepinephrine (NE), and the corresponding desoxy derivatives, 2-(3,4-dihydroxybenzyl)imidazoline (desoxy-CI) and dopamine, have been investigated in human platelets. Differences between responsiveness of platelets from donor to donor were observed in the presence of the isomers and the desoxy analogs of NE and CI. In certain platelet preparations, all compounds gave concentration-dependent stimulatory responses, whereas in other preparations, only R(-)-NE and R(-)-CI were inducers of platelet aggregation and serotonin release. The rank order of stimulatory potencies (EC50; microM) for CI and NE was R(-)-NE (1.3) greater than R(-)-CI (7.5) greater than S(+)-NE (19) = S(+)-CI (20) = dopamine (22) greater than desoxy-CI (greater than 35). Unlike R(-)-CI, both S(+)-CI and desoxy-CI were either agonists or antagonists of human platelet function. In preparations unresponsive to the S(+)-isomers or desoxy analogs, the potencies (EC50) for R(-)-NE and R(-)-CI were 1.7 and 7.7 microM respectively. The corresponding inactive CIs [S(+)-CI and desoxy-CI] were inhibitors of both primary and secondary phases of aggregation and serotonin release responses to R(-)-CI and R(-)-NE, respectively. In contrast, the aggregation responses to ADP, arachidonic acid or U46619 were not blocked by S(+)-CI or desoxy CI. The rank order of inhibitory potencies for selected alpha-adrenoceptor agents against R(-)-NE was phentolamine greater than clonidine greater than desoxy-CI greater than S(+)-CI. Moreover, the relative inhibitory potencies of phentolamine and desoxy-CI against aggregation responses to R(-)-NE and R(-)-CI, respectively, were the same. These results suggest that the enantiomers and desoxy derivatives of CI and NE mediate their effects in human platelets by an interaction with alpha-adrenoceptors; catecholamines and imidazolines interact with the same alpha-adrenoceptors in human platelets; the stereochemical requirements of both chemical classes for stimulatory activity in human platelets adhere to the Easson-Stedman hypothesis in this alpha 2-adrenoceptor system; and desoxy-CI possessed the highest potency as an antagonist of alpha-adrenoceptors which suggests that the hydroxy group at the benzylic carbon atom of these imidazolines may not be required for maximal binding to adrenoceptors in platelets.

Blood Platelets↗
PubMed1986

Behavioral effects of a dimethylsulfonium analog of dopamine after injection into the nucleus accumbens and the striatum.

We have previously synthesized a chemical analog of dopamine (DA) in which the amine group has been replaced by a permanently charged dimethylsulfonium group. In the present study, we have determined whether this compound can exert DA agonist activity in the nucleus accumbens by comparing its effects with those of DA. When DA was injected into the nucleus accumbens of rats pretreated with nialamide, a monoamine oxidase inhibitor, there was marked stimulation of locomotor activity. Similarly, after intraaccumbens injection, the sulfonium analog also produced a marked stimulation of locomotor activity, and this effect was inhibited by the DA receptor antagonist, haloperidol (0.2 mg/kg, IP). However, the sulfonium analog did not stimulate locomotor activity when rats were pretreated with saline instead of nialamide. In addition, the stimulation of locomotor activity produced by the sulfonium analog in rats pretreated with nialamide was completely inhibited by the DA synthesis inhibitor, alpha-methyl-p-tyrosine. These results suggest that the stimulation of locomotor activity by the sulfonium analog is mediated indirectly through the release of DA. The sulfonium analog was able to produce marked contralateral circling after it was injected into the striatum of rats on the side of the brain in which DA nerve terminals were previously destroyed with 6-hydroxydopamine. Similarly, the sulfonium analog produced a marked stimulation of locomotor activity after it was injected into the nucleus accumbens of rats that were previously injected into this region with 6-hydroxydopamine. These results suggest that the sulfonium analog of dopamine can exert direct as well as indirect DA agonist activity.

Animals↗
PubMed1986

Synthesis and investigation of the beta-adrenoceptor agonist and platelet antiaggregatory properties of 1,7,8-trisubstituted 2,3,4,5-tetrahydro-1H-2-benzazepine analogues of trimetoquinol.

The synthesis and biological evaluation of 7,8-dihydroxy (2) and 7,8-methylenedioxy (3) analogues of 1-[(3,4,5-trimethyoxyphenyl)methyl]-2,3,4,5-tetradhyo-1H-2-b enzazepine on beta-adrenoceptor systems and human platelets were undertaken and compared with trimetoquinol (TMQ, 1). Whereas 1 is a potent beta-adrenoceptor agonist in guinea pig atria and trachea (pD2 = 8.2), analogue 2 was marginally effective at relaxing guinea pig tracheal smooth muscle (pD2 = 4.4) and inactive as an agonist on guinea pig atria. Analogues 2 and 3 were inhibitors of phospholipase C (PLC; from Clostridium perfringens) induced and secondary wave of ADP-induced aggregation responses and inactive against low-dose thrombin-induced or stable endoperoxide (U46619) induced human platelet aggregation. Against ADP-induced serotonin secretion, 3 was 9-fold more active than analogue 2. Further, the rank order of TMQ isomers and 3 as inhibitors of PLC-induced platelet aggregation, serotonin secretion, and phosphatidylinositol degradation was identical (3 greater than (S)-(-)-1 greater than (R)-(+)-1). The results suggest that these compounds are blocking the action of PLC by interfering with phosphatidylinositol turnover in platelet membranes. The inhibition of ADP-induced responses in human platelets by analogues 2 and 3 also suggests a site of inhibition at a level of arachidonic acid release. Thus, ring expansion of 1 as in the benzazepine analogues 2 and 3 has allowed us to develop selective inhibitors of platelet function that lack significant beta-adrenoceptor activity.

Adenosine Diphosphate↗
PubMed1986

Syntheses and beta-adrenergic agonist and antiaggregatory properties of N-substituted trimetoquinol analogues.

Trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7- dihydroxy-1,2,3,4-tetrahydroisoquinoline, TMQ] is a potent beta-adrenergic receptor agonist and inhibitor of human platelet aggregation. Selective cleavage of O-benzyl groups in the presence of an N-benzyl group using HCl and formation of a cyclic sulfite ester from the reaction of a catechol with thionyl chloride were achieved. The N-substituents included methyl, benzyl, and beta-hydroxy- and beta-chloroethyl groups. Each N-substituted TMQ caused a concentration-dependent stimulation of beta 2 (trachea) and beta 1 (atria) adrenoceptor tissues and inhibition of 15(S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13(E)-dienoic acid (U46619, a thromboxane A2 mimetic) mediated human platelet activation. TMQ remained the most potent in the series. Structure-activity results indicated that the larger the N-substituent, the lower the beta-adrenergic activity but the higher the inhibition of platelet aggregatory activity. Thus, the structural requirements of these TMQ analogues for the two types of biological activity are different.

Adrenergic beta-Agonists↗
PubMed1986

Synthesis and biological evaluation of irreversible inhibitors of aldose reductase.

5-Isothiocyanatoalrestatin (1b) and 5-azidoalrestatin (1c) were prepared synthetically and examined as potential affinity and photoaffinity inhibitors of rat lens aldose reductase. Both compound 1b and 1c under appropriate conditions at 10(-4) M produced a 70% irreversible inactivation of aldose reductase within 1 min. The enzyme could, in part, be protected by preincubation with sorbinil 2, a known potent inhibitor of aldose reductase.

Affinity Labels↗
PubMed1986

Absorption of iron from ferric hydroxide polymers introduced into ligated rat duodenal segments.

The availability of iron from 59Fe-labeled polymeric ferric hydroxides and low-molecular-weight ferric complexes (LMW iron) was compared by using ligated rat duodenal segments, in vivo. The effect of iron status was assessed by using iron-adequate (Hb 12.3-15.5 g/dl) and iron-deficient (Hb 8.1-10.6 g/dl) rats for each iron treatment. Analysis of data from the animal experiment showed: less (P less than 0.01) iron from polymers [6.8% (iron adequate) and 7.7% (iron deficient)] was transferred to the carcass than from LMW iron [29.2% (iron adequate) and 47.9% (iron deficient)] and iron-deficient animals absorbed more iron than iron-adequate rats from LMW iron but not from polymeric iron. Solubility studies showed that these data could not be attributed to solubility differences between polymers and LMW iron. The results of this experiment suggest that in the intestine factors or conditions that depolymerize iron or prevent polymer formation could enhance iron absorption.

Animals↗
PubMed1986

Influence of pecan shells and hulls as a roughage source on milk production, rumen fermentation, and digestion in ruminants.

In Experiment 1, 20 lambs (36 kg) were fed five diets containing 0, 5, or 10% pecan shells or hulls to evaluate digestion and nitrogen balance. Digestion was not depressed by diets containing 5% shells. Protein digestibility was not reduced and nitrogen balance was higher for lambs fed 5% hulls than for lambs in other groups. In Experiment 2, 8 Holstein cows (29.3 kg milk/d) were assigned to two diets: basal and basal with 5% shells in the grain mix. Cows fed diets containing shells produced the same amount of milk and milk fat as control cows. In Experiment 3, 12 Holstein cows (27.3 kg milk/d) were assigned to the same two diets used in Experiment 2 and a third treatment received 5% pecan hulls in the grain mix. Cows fed shells or hull diets reduced concentrate intake and milk production. In Experiment 4, 12 Hereford X Angus steers (474.5 kg) were fed diets used in Experiment 3 to examine rumen fermentation, digestion, and passage rates. Steers fed hulls had lower rumen ammonia N and higher rumen pH compared with steers fed the basal diet. Total rumen volatile fatty acid concentration was not different among treatments. Generally, rumen fluid from steers fed hulls had higher proportions of acetate and lower proportions of butyrate. Rumen fluid and particulate passage rates and digestion measurements were not affected by addition of shells or hulls.

Animal Feed↗
PubMed1986

Effects of some carbohydrates on iron absorption.

Two experiments were performed to examine the effects of various carbohydrates (fructose, lactose, corn starch, wheat starch and potato starch) on the utilization of iron, on Fe-depleted rats. These received a single meal that contained the test carbohydrate at a 60% level, labelled with 59Fe. The rest of the experiment the rats were fed a diet which contained glucose at a 60% level as the carbohydrate source. In both experiments rats were fasted overnight, and the dose was offered in the form of a morning meal. To assay for 59Fe, the animals were counted in a "Whole body counter" between two and four hours after dosing, and every day for the following 10 days. Percentage retention and absorption, as well as hemoglobin values were determined. In the first experiment, the replacement of glucose by fructose at a 60% level enhanced significantly iron absorption and retention. An increase in absorption and retention also occurred when glucose was replaced by lactose at a 60% level, but the difference was not statistically significant. Administration of 59Fe as an 59Fe-fructose chelate did not seem to have a significant effect on retention and absorption when compared to the effect of dosing with 59Fe adsorbed onto a fructose diet. This not rule out the possibility that chelation is the mechanism responsible for the enhancing effect of fructose on iron utilization. The complex could have been formed in the stomach, resulting in a significant absorption for both the 59Fe-labelled meal and the 59Fe-carbohydrate complex-labelled meal. In the second experiment, administration of a meal that contained either of the starches resulted in a reduction on retention and absorption of 59Fe. The decrease, however, was statistically significant only for cooked corn starch, wheat starch and cooked wheat starch. The effect of cooking was to reduce even more the retention and absorption of 59Fe, but this reduction was statistically significant only for corn starch. The depressing effects of starches on iron retention and absorption are quite relevant to human nutrition. In the developing countries, diets are generally high in cereal products - often whole grain cereals - and low in animal products. The inhibitory effects of cereals on iron absorption have been traditionally attributed to the presence of phytates and fiber, but the data herein presented suggest that high intakes of starches may be inhibitory as well.

Absorption↗
PubMed1986

Multigated blood-pool tomography: new method for the assessment of left ventricular function.

A technique for the semiautomatic calculation of left ventricular volumes from multigated blood-pool tomograms (MGBPT) was tested in a series of 12 patients undergoing contrast ventriculography within 48 hr of gated tomography. The parameters necessary for the calculation of volume were developed in a chest phantom study performed with a series of 99mTc-filled balloons representing the right and left ventricles. The images were analyzed for volume using a percentage of peak count-threshold of the left ventricular balloon. This technique resulted in a correlation of r = 0.99 of the calculated to the true phantom volumes (y = 0.87x + 27.4, p less than 0.01, s.e.e. = 7.87 ml). The patient studies were recorded at 16 frames/cardiac cycle at each of 60 angles over a 360 degree rotation. Reconstructed data were presented in an endless loop cine format producing a set of sequential "beating tomographic slices" in the transverse, apical four-chamber, short-axis, and long-axis oblique views. Measurements of end systolic volume (y = 0.79x + 30, r = 0.93, p less than 0.001, s.e.e. = 24 ml), end-diastolic volume (y = 0.63x + 60, r = 0.94, p less than 0.0001, s.e.e. = 20 ml) and ejection fraction (y = 0.88x - 0.02, r = 0.92, p less than 0.001, s.e.e. = 0.08) determined from the semiautomated volume method correlated well with those determined by left ventricular contrast angiography. A qualitative comparison of MGBPT, planar imaging, and left ventricular angiography in 12 patients revealed that the visual assessment of wall motion using the 16-frame tomographic slices had significant advantages over planar and single plane angiographic data in the identification of inferior, basal, and septal wall motion abnormalities as well as the extent of involvement by aneurysm formation. A quantitative comparison of wall motion in the long-axis oblique view of the MGBPT to the RAO 30 degree ventriculogram (y = 0.74x + 8.7, r = 0.82, p less than 0.0001, s.e.e. = 14%) confirmed the qualitative similarity of these two views. We conclude that MGBPT is promising as a method for accurately measuring left ventricular volumes and assessing regional wall motion.

Aged↗
PubMed1985

Antagonism of prostaglandin-mediated responses in platelets and vascular smooth muscle by 13-azaprostanoic acid analogs. Evidence for selective blockade of thromboxane A2 responses.

Studies were undertaken to examine the pharmacological properties and stereochemical requirements of a limited series of prostanoic acid analogs for inhibition of arachidonic acid (AA) and/or endoperoxide (U46619)-mediated responses in human platelets and rat aorta. To assess the role of stereochemistry, a set of trans- and cis-isomers of 13-azaprostanoic acid (APA) and 11a-homo-13-azaprostanoic acid (HAPA) were prepared. Each prostanoic acid analog blocked AA- or U46619-induced aggregatory and secretory responses in platelets, and U46619-mediated contractions of rat aorta in a concentration-dependent manner (0.1 to 100 microM). The azaprostanoic acid analogs blocked responses to both inducers of platelet activation with IC50 values ranging from 3.4 to 27.5 microM. Trans-APA was about 2- to 3-fold more active as an antagonist of serotonin release induced by AA or U46619 than the remaining analogs. The rank order of inhibitory potency (IC50; microM) for these analogs against U46619-induced serotonin release in human platelets was trans-APA (3.4) greater than cis-APA (8.9) = cis-HAPA (8.7) = trans-HAPA (9.1). Concentrations of the prostanoic acid analogs required to block these responses to AA and U46619 were similar, and the highest concentration used (100 microM) did not modify AA-induced malondialdehyde production in human platelet preparations. In contrast, the isomers of APA and HAPA were equally active as antagonists of U46619-induced contractions of rat vascular tissue, possessing KB values varying from 7.1 to 13.2 microM. Each azaprostanoic acid analog shifted the concentration-response curve of U46619 in rat aorta to the right, indicating a competitive-type inhibition. In addition, the azoprostanoic acid analog (U51605) was a more potent competitive antagonist of U46619 in this preparation and possessed an average pKB value of 6.18. In summary, the results show that (1) expansion of the five-membered ring of APA to the six-membered ring analogs (HAPA) led to a retention of potent inhibitory activity against U46619 in human platelets and rat vascular smooth muscle, (2) the antiaggregatory and antisecretory actions of the azaprostanoic acid analogs were mediated by a blockade of the responses to AA and U46619, and not by an inhibition of AA metabolism, (3) the blocking activity for the APA isomers was stereoselective (trans greater than cis) whereas the isomers of HAPA were equally effective as inhibitors of platelet function; and (4) these azaprostanoic acid analogs act as selective endoperoxide (U46619)/thromboxane A2 antagonists in these two tissues.

Adult↗
PubMed1985

N-substituted imidazolines and ethylenediamines and their action on alpha- and beta-adrenergic receptors.

A series of N-substituted imidazolines and ethylenediamines were synthesized and examined for their activity in alpha- and beta-adrenergic systems. The length of the intermediate side chain between the catechol and imidazoline ring or the amine of the ethylenediamine segment was shown to affect the adrenergic activity. N-[2-(3,4-Dihydroxyphenyl)ethyl]imidazoline hydrochloride (2) and N-[2-(3,4-dihydroxyphenyl)ethyl]ethylenediamine dihydrochloride (4), both with two methylene groups between the catechol and amine segment, were found to be somewhat selective for alpha 2-adrenergic receptors while 1-(3,4-dihydroxybenzyl)imidazoline hydrochloride (1) and N-2-(3,4-dihydroxybenzyl)ethylenediamine dihydrochloride (3), both with one methylene group between the catechol and amine segment, were more selective for alpha1-adrenergic receptors in a pithed rat model. Of the four compounds examined, only compound 2 showed significant direct activity on beta1- and beta2-adrenergic receptors.

Animals↗