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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 217 records · Page 12Linked to original sources
PubMed1988

Use of [3H]trimetoquinol as a radioligand in human platelets: interaction with putative endoperoxide/thromboxane A2 receptor sites.

We have recently shown that trimetoquinol [1-(3,4,5-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline; TMQ] is a potent and stereoselective [R(+)-isomer greater than S(-)-isomer] antagonist of aggregation induced by thromboxane A2 and stable epoxymethano PGH2 analogues (U46619; U44069) in human platelets. The present study was undertaken to characterize the pharmacological specificity of binding sites for racemic- [3H]TMQ in washed human platelets. Specific binding of [3H]TMQ, determined by addition of 100 microM R(+)-TMQ, accounted for 12-26% of the total binding at 1.0 microM. Saturation data suggested two binding sites with apparent dissociation constants of 2.8 nM and 1.4 microM for the high and low affinity binding sites, respectively. Maximal binding densities (pmol/mg protein) were 2.3 and 42.9 for the respective high and low affinity sites. The optical isomers of TMQ, cis and trans-isomers of 13-azaprostanoic acid (13-APA), and U46619 inhibited [3H]TMQ specific binding to the low affinity site. R(+)-TMQ was 32-fold more potent than S(-)-TMQ at inhibiting [3H]TMQ binding, and the stereoselective potency difference and concentrations needed to inhibit binding were similar to those required for inhibition of U46619-induced platelet aggregation and serotonin secretion. Similarly, trans-13-APA was 90-fold more potent than cis-13-APA as a competitor of [3H]TMQ binding. U46619 also inhibited TMQ binding at concentrations (IC50 = 0.4 microM) similar to those required for aggregation (EC50 = 0.16 microM) and secretion (EC50 = 0.23 microM). At 1 mM, arachidonic acid inhibited [3H] TMQ binding by only 25%. Our studies indicate that [3H]TMQ interacts with specific binding sites with characteristics indicative of putative endoperoxide/thromboxane A2 receptors in human platelets.

Blood Platelets↗
PubMed1988

Synthesis and thromboxane A2 antagonist activity of N-benzyltrimetoquinol analogues.

It is currently believed that the platelet thromboxane A2 (TXA2/PGH2) receptor is different from the vascular TXA2/PGH2 receptor. While the majority of TXA2 receptor antagonists are structurally related to the prostaglandins, trimetoquinol (TMQ) represents a unique nonprostanoid antagonist. TMQ also possesses beta-adrenergic activity; however, an N-benzyl substituent on TMQ has been shown to impart some selectivity for platelet antiaggregatory activity versus beta-adrenergic activity. In this study, we examined the synthesis and TXA2 antagonist activity of a series of substituted N-benzyl analogues of TMQ. While these analogues showed an apparent direct correlation between platelet antiaggregatory activity and electron-donating ability of the N-benzyl substituents, no such correlation could be demonstrated for the inhibition of contractile responses. Thus, nonprostanoid TXA2 antagonists can be used to demonstrate differences between platelet and vascular TXA2/PGH2 responses.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

Fatty acid analogue accumulation: a marker of myocyte viability in ischemic-reperfused myocardium.

A 3-methyl substituted radioiodinated long chain fatty acid analogue was evaluated as an agent for the noninvasive detection of altered fatty acid uptake in reperfused, postischemic myocardium. This iodinated fatty acid analogue, 15-(para-iodophenyl)-3-methyl pentadecanoic acid, was given intravenously at 3 hours of reperfusion following 15 minutes (Group 1, n = 5 dogs) or 60 minutes (Group 2, n = 5 dogs) of left anterior descending coronary artery occlusion. Myocardial blood flow (MBF) was measured during occlusion and reperfusion with radiolabeled microspheres administered via the left atrium. Paired ultrasonic subendocardial crystals were placed in the ischemic perfusion bed to assess regional left ventricular systolic function at baseline, during ischemia and reperfusion. Electron microscopic analysis and staining with triphenyltetrazolium chloride (TTC) was performed. Groups 1 and 2 dogs had similar (p = NS) myocardial blood flows during occlusion. TTC positive 1 g endocardial segments from Group 1 (n = 98) and Group 2 (n = 71) had 37% greater fatty acid analogue activity (0.26 +/- 0.04 vs. 0.19 +/- 0.09 percent injected dose per gram; p less than 0.05) compared with TTC negative segments from Group 2 dogs (n = 37). When fatty acid analogue activity was related to near simultaneous reperfusion blood flow, this ratio was 27% greater (p less than 0.05) in TTC positive segments (0.38 +/- 0.1) compared with TTC negative (0.30 +/- 0.16) segments, and 9% greater than normal (0.35 +/- 0.09; p less than 0.05). While ischemic regions from both Groups 1 and 2 dogs became similarly dyskinetic during occlusion (systolic shortening, -11 +/- 6 vs. -11 +/- 2%; p = NS), TTC negative segments remained akinetic (= 1 +/- 7%) at 3 hours of reperfusion while TTC positive zones had recovered partial systolic function (8 +/- 22%). Electron microscopy confirmed the presence of reversible ultrastructural changes in TTC positive regions. A 60-minute occlusion, 3-hour reperfusion model adapted for in vivo single photon emission computed tomography showed a similar excess of 123I fatty acid activity over flow when compared to perfusion (as measured with 201Tl) in the ischemic border zone of 4/4 canine myocardial infarcts. We conclude that the accumulation of this non-beta-oxidized fatty acid analogue noninvasively identifies zones of discordance between fatty acid and flow distribution that are characteristic of ischemically "stunned" but viable myocardium.

Animals↗
PubMed1988

Activation of alpha-1 adrenoreceptors of rat aorta by analogs of imidazoline.

New analogs of desoxycatecholimidazoline were synthesized for elucidating the steric requirements for the activation of alpha-1 adrenoreceptors. The compounds tested on rat thoracic aorta in this study were: desoxycatecholimidazole with and without bridge carbon hydroxyl group, analogs of desoxycatecholamidazoline with fluorine substitution at position 2, 5 or 6 of the catechol ring and hydroxybenzyl group at carbon-4 of the imidazoline part of the molecule. The addition of a double bond in the imidazoline to give an imidazole results in a decrease in potency and the introduction of benzylic hydroxyl group also reduces its activity by 4- and 6-fold, respectively. 2-Fluoro and 5-fluoro catecholimidazoline possess full agonist activity; their potencies being even higher than the parent molecule. The 6-fluoro analog is a partial agonist inasmuch as it produces a response that is only 30% of the maximum response produced by other analogs of imidazoline. In the present study, 4-substituted imidazolines retain their agonist activity, although weaker than desoxycatecholimidazoline. The potency of R- and S-isomers of 4-substituted catecholbenzyl imidazoline were similar. Although these isomers exhibit apparent chemical similarity to catecholamines, small differences between the activity of stereoisomers indicate that the mode of interaction of these molecules at alpha adrenoreceptor may differ from that of stereoisomers of epinephrine.

Animals↗
PubMed1988

Increased exercise thallium-201 lung uptake: a noninvasive prognostic index in two-vessel coronary artery disease.

To determine the physiologic impact of two-vessel coronary artery disease and its effect on prognosis, a series of clinical, angiographic, exercise and quantitative thallium-201 (Tl-201) imaging parameters were analyzed in 85 consecutive two-vessel coronary artery disease patients followed for 52 +/- 27 months after coronary angiography and Tl-201 scintigraphy. End points were cardiac death (n = 3), myocardial infarction (n = 6) and coronary bypass graft surgery more than three months after testing (n = 16). Using Cox Hazards survival analysis, early cardiac events were not predicted by: myocardial infarction or anginal history; resting left ventricular function; exercise blood pressure response; angina or severity of ECG ST segment depression (mm); Tl-201 defect size; redistribution or clearance; angiographic patterns; or the presence of proximal left anterior descending disease. Significant predictors of adverse cardiac events were: increased exercise lung to heart Tl-201 ratio (0.59 +/- 0.12 versus 0.46 +/- 0.1; P less than 0.0001); ECG lead extent of ST segment depression (P less than 0.03); and exercise heart rate response (P less than 0.047). Event-free survival for patients with normal and abnormally increased lung to heart Tl-201 ratios at 48 months was 76% versus 63% (P less than 0.003). It was concluded that two-vessel coronary artery disease survival correlates with exercise Tl-201 uptake which reflects exercise induced left ventricular dysfunction.

Actuarial Analysis↗
PubMed1987

Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane antagonist properties of N-substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist and U46619 (a thromboxane A2 agonist) antagonist properties of trimetoquinol (TMQ, I) and its optical isomers, and N-substituted TMQ analogues (methyl, II; 2-hydroxyethyl, III; cyclic sulfite N-2-chloroethyl, IV; 2-chloroethyl, V; benzyl, VI) were studied in guinea pig atria and trachea and rat aorta, respectively. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than II greater than III greater than IV greater than V greater than VI. Whereas N-substitution reduced potency for beta-agonism, the beta 2/beta 1-selectivity ratio was enhanced by increasing the size of the N-substituent. All analogues possessed equal or greater (up to 41-fold more) beta 2-selectivity than I. Propranolol was a competitive antagonist of selected TMQ analogues in guinea pig trachea and atria, thus confirming the beta-adrenoceptor actions of these drugs. The optical isomers of TMQ gave a rank order of agonist potency of S(-)-TMQ greater than R(+)-TMQ, and a beta 2/beta 1-selectivity equal to or greater than racemic-TMQ. Each TMQ analogue also blocked the contractile responses of U46619 in rat aorta in a competitive manner, and the rank order of inhibition of U46619-induced contraction in rat aorta was I greater than VI greater than II = III greater than IV greater than V. N-Benzyl TMQ (VI) possessed the greatest potency for U46619 blockade and beta 2/beta 1-selectivity ratio of the N-substituted analogues. The results show that varying the N-substituents on TMQ produces compounds which retain beta 2-selectivity and give a different activity profile for beta-adrenoceptor activation vs. endoperoxide/thromboxane A2 antagonism.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1987

Left ventricular ejection fraction response during exercise in asymptomatic systemic hypertension.

To study the effect of mild-to-moderate elevations in diastolic blood pressure (BP) on systolic left ventricular (LV) function, 28 hypertensive patients and 20 normal subjects underwent upright exercise first-pass radionuclide angiography. All were asymptomatic, had normal rest and exercise electrocardiographic findings and no evidence of LV hypertrophy or coronary artery disease. LV function at rest was similar in the 2 groups, but with exercise hypertensive patients had a greater end-systolic volume (69 +/- 19 vs 51 +/- 19 ml, p less than 0.002) and lower ejection fraction (EF) (0.59 +/- 0.09 vs 0.72 +/- 0.07, p less than 0.0001), stroke volume (101 +/- 28 vs 130 +/- 36 ml, p less than 0.005) and peak oxygen uptake (23 +/- 7 vs 33 +/- 9 ml/kl/min, p less than 0.05). Hypertensive patients were separated into 3 groups: group 1-12 patients with an increase in EF with exercise greater than or equal to 0.05; group 2-7 patients with a change in EF with exercise less than 0.05; and group 3-9 patients with a decrease in EF with exercise greater than or equal to 0.05. Group 3 hypertensive patients were older, had a higher heart rate at rest and lower peak oxygen uptake. Rest LV function was similar in the 3 hypertensive subgroups, but exercise end-systolic volumes were higher in groups 2 and 3. Exercise thallium-201 images was normal in all but 1 of 14 hypertensive group 2 or 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1987

Synthesis and application of 13C enriched phenylisothiocyanate as a 13C NMR protein probe.

Phenylisothiocyanate, enriched with 13C at the isothiocyanate carbon, has been synthesized and utilized as a 13C NMR probe of proteins for the first time. The reagent has been used to label the amino groups of oxidized glutathione, and the resulting 13C NMR spectrum shows a prominent thiocarbonyl peak after a single NMR scan. The reagent is also capable of differentiating amino groups on the insulin molecule with distinct peaks corresponding to the amino groups on the A and B chains of insulin. This study illustrates the potential of using a new 13C label to functionalize amino groups of proteins and to study the labeled proteins with 13C NMR.

Carbon Isotopes↗
PubMed1987

Interaction of enantiomers of hydroxy tolazoline with adrenoceptors.

Adrenoceptor-mediated effects of the enantiomers of hydroxytolazoline and tolazoline (i.e., desoxy derivative) have been investigated in vitro. The enantiomers and tolazoline were partial agonists of postjunctional alpha 1-adrenoceptors in rat aorta. The rank order of potencies of the compounds in this system was as follows: tolazoline greater than R(-)-hydroxytolazoline greater than S(+)-hydroxytolazoline. The efficacy of R(-)-hydroxytolazoline was higher than that of tolazoline, though its affinity for the receptor was less. The KB values for prazosin against these agonists were nearly equal, which indicated that these imidazolines activate the same type of receptor in rat aorta. The S(+)-isomer, however, produced both a prazosin sensitive and resistant component of the response. The interactions of the derivatives with presynaptic alpha 2-adrenoceptors were studied in field-stimulated myenteric plexus-longitudinal muscle of guinea-pig ileum. These substances were blockers at presynaptic alpha 2-adrenoceptors. Based on KB values, the order of affinity in this system was as follows: tolazoline greater than S(+)-isomer greater than or equal to R(-)-isomer. beta-Adrenoceptor mediated activity was quantitated in guinea-pig and rat atria. R(-)-hydroxytolazoline lacked chronotropic effects either in guinea pig or rat atria. At 3 X 10(-4) M the isomer did not antagonize the effect of isoproterenol in the atria. On the other hand, S(+)-hydroxytolazoline produced a variable chronotropic effect in guinea-pig atria, but failed to show any significant activity in rat atria. Thus, the beta-adrenoceptor mediated action appears to be insignificant. Steric aspects of alpha-adrenoceptor mediated events are discussed.

Animals↗
PubMed1987

Prognostic value of computer-quantitated exercise thallium imaging early after percutaneous transluminal coronary angioplasty.

To develop an approach to predicting adverse events after percutaneous transluminal coronary angioplasty (PTCA), 50 patients had thallium-201 exercise testing within 1 month after successful single vessel coronary angioplasty and were followed up for a mean of 18 months. Adverse events were: 1) clinical events consisting of recurrent angina (17 patients) and myocardial infarction (1 patient); 2) treatment events consisting of repeat coronary angioplasty (10 patients) and coronary bypass surgery (1 patient); and 3) restenosis, defined as a greater than 30% increase in luminal stenosis (15 of 38 recatheterized patients). There were no deaths. Of the clinical, exercise, angiographic and thallium scan variables analyzed by stepwise logistic regression, postangioplasty gradient greater than 20 mm Hg predicted clinical events and treatment events, and the number of segments with slower thallium clearance predicted clinical events, treatment events and restenosis. Using Cox Hazards model regression of survival without events, the number of transient qualitative thallium defects also predicted clinical events and restenosis. At 1 year after angioplasty, 24% of patients with these variables had restenosis compared with only 6% of those without these variables and 36% of patients with these variables had a clinical or treatment event compared with 8% of patients without these variables. Three measures of the adequacy of myocardial perfusion (post-angioplasty gradient, reduced thallium clearance and transient thallium defects) were additive predictors of adverse events after coronary angioplasty with the relative risk being approximately four times greater in patients with these variables than in those without. Such adverse events, therefore, are usually a consequence of inadequate revascularization.

Adult↗
PubMed1987

5-fluoro- and 8-fluorotrimetoquinol: selective beta 2-adrenoceptor agonists.

The 5-fluoro and 8-fluoro analogues of trimetoquinol, TMQ, have been synthesized and evaluated for beta 2- and beta 1-adrenoceptor activity in guinea pig trachea and atria, respectively. The fluoro analogues of TMQ maintained potent beta 2-adrenoceptor agonist activity but had reduced beta 1-adrenoceptor agonist activity. The changes in beta 1-activity of these compounds were correlated to differences in phenolic pKa's. The beta 1- and beta 2-adrenoceptor actions of 2 and 3 were blocked in a competitive manner by propranolol. The enhanced beta 2/beta 1 selectivity for the analogues was found to be 8-fluoro analogue 3 greater than 5-fluoro analogue 2 greater than trimetoquinol (1).

Adrenergic beta-Agonists↗
PubMed1987

Dopamine agonists: effects of charged and uncharged analogues of dopamine.

Dopamine, at physiological pH, may exist as either an uncharged amine or a charged ammonium species. In order to gain insight as to which species is better suited for interaction with the dopamine receptor, we have synthesized dopamine analogues in which the nitrogen atom is replaced with a neutral methyl sulfide, a neutral methyl selenide, a charged dimethylsulfonium iodide, and a charged dimethylselenonium iodide. These analogues were tested for their ability to inhibit the K+-stimulated release of [3H]acetylcholine from striatal slices. At 30 microM concentration, the charged sulfonium and selenonium salts possessed significant agonist activity while the corresponding neutral species were inactive, suggesting that a charged species is optimal for dopamine agonist activity. In addition, the methyl sulfide was converted into the corresponding sulfoxide and sulfone; however, neither of these oxidation products possessed significant activity as dopaminergic agonists.

Acetylcholine↗
PubMed1987

Charged analogues of chlorpromazine as dopamine antagonists.

Chlorpromazine (1, CPZ) is a potent dopamine antagonist that has been used widely as an antipsychotic agent. Since dopaminergic antagonists, like dopaminergic agonists, exist in solution as the charged and uncharged molecular species, it is not clear which form of the amine is most important for interaction with the dopamine receptor. Previous work from our laboratory has indicated that a variety of permanently charged species could replace the amine/ammonium moiety of dopamine and retain dopamine agonist activity. This paper describes the synthesis and dopamine antagonist activity of both the trimethylammonium iodide and the dimethylsulfonium iodide analogues of chlorpromazine. The permanently uncharged methyl sulfide analogue was also synthesized; however, due to its lack of aqueous solubility, its pharmacological activity could not be evaluated. Binding of both the dimethylsulfonium iodide and the trimethylammonium iodide analogues to D-2 dopamine receptors of rat striatal tissue was observed. The observed relative order of binding was CPZ greater than CPZ sulfonium analogue greater than CPZ ammonium analogue. These compounds had a similar order of activity in antagonizing the apomorphine-induced inhibition of potassium-induced release of [3H]acetylcholine from mouse striatal slices.

Acetylcholine↗
PubMed1987

Long-term prognosis of patients with variant angina.

The long-term prognosis of variant angina and the factors influencing it were assessed in 217 consecutive patients hospitalized in our coronary care unit and followed for a mean of 65 months (range 2 to 123). Cardiac death occurred in 30 patients and an additional 54 experienced a nonfatal myocardial infarction. Survival at 1 and 5 years was 95% and 89%, respectively; survival without infarction was 83% and 69%. Coronary disease and the degree of disease activity were strong predictors of survival by Cox analysis. Survival at 1 year was 99%, and that at 5 years was 95% and 94%, respectively, for patients with one-vessel disease (n = 81) and for those without stenoses of 70% or greater (n = 87). Survival at 1 and 5 years was only 87% and 77% for those with multivessel disease (n = 40). The Cox analysis selected left ventricular function, initial treatment, extent score, duration of angina at rest, and disease activity as multivariate predictors of survival without infarction. Coronary disease was a strong predictor (p less than .0001) of survival without infarction by univariate analysis. Treatment with nifedipine, diltiazem, or verapamil improved survival without infarction compared with other medical treatment (p = .002). Myocardial infarction occurred most commonly soon after diagnosis in patients with a short history of angina at rest. Late coronary events were almost never preceded by resting angina.

Adult↗
PubMed1987

Asymmetric catecholimidazolines and catecholamidines: affinity and efficacy relationships at the alpha adrenoreceptor in rat aorta.

The epinephrine (EPI) stereoisomers interact with the alpha adrenoreceptor according to the Easson-Stedman model with an order of potency of (-)-EPI greater than (+)-EPI = Epinine. A series of catecholimidazolines (CI) and catecholamidines (CA) were compared with the EPI series for the relationship of stereoisomerism to potency, affinity and efficacy. Within each group of desoxy compound and stereoisomers obtained by -OH substitution at the benzylic position, differences in potency were found to be due solely to differences in affinity; differences in efficacy were not significant. The stereoisomers of the CI and CA series followed the order of potency predicted by the Easson-Stedman model: (-)-isomer greater than (+)-isomer. The desoxy analogs, in contrast to the prediction based on the Easson-Stedman hypothesis, were equal (CI) or greater (CA) in potency than the more potent (-)-isomer of each series. Possible explanations for this include differences in physical properties in the desoxy analogs of CI and CA compared with the corresponding enantiomers. Methyl or benzyl substitution at C-4 of the imidazoline ring decreased potency over 100-fold; potency differences between enantiomers were negligible. Thus, the Easson-Stedman model cannot be extended to either the CI or CA series of alpha adrenoreceptor agonists.

Amidines↗