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D D Miller

Publications and source records attributed to D D Miller.

At least 91 records · Page 5Linked to original sources
PubMed1996

Iodinated analogs of trimetoquinol as highly potent and selective beta 2-adrenoceptor ligands.

A series of trimetoquinol (1, TMQ) analogs were designed and synthesized based on the lead compound 2, a diiodinated analog of trimetoquinol which exhibits improved selectivity for beta 2-versus beta 1-adrenoceptors (AR). To determine the influence of 1-benzyl substituents of trimetoquinol on beta 2-AR binding affinity and selectivity, we replaced and/or removed the 3'-, 4'-, and 5'-methoxy substituents of trimetoquinol. Replacement of the 4'-methoxy group of 2 with an amino (21c) or acetamido (15) moiety did not significantly alter beta 2-AR and thromboxane A2/prostaglandin H2 (TP) receptor affinity. Substitution with a 4'-hydroxy (18) or -iodo (21b) group did not significantly alter beta 2-AR affinity, but greatly reduced TP receptor affinity (380- and 1200-fold, respectively). Further, the beta 2-AR can accommodate larger substituents such as a benzamide at the 4'-position (26b). Other monoiodo derivatives (24, 26a) have similar or slightly lower affinity to both beta 2-AR and TP receptor compared to their diiodo analogs. Interestingly, removal of the 4'-substituent of 3',5'-diiodo analogs increased beta 2-AR affinity with little or no effect on beta 1-AR and TP binding. Thus, analog 21a displayed highly potent (pKi 9.52) and selective (beta 2/beta 1 = 600) binding affinity for beta 2-AR. On the other hand, trifluoromethyl substituents at the 3'- and 5'-positions (27) essentially abolished binding affinity at beta 2-AR and TP receptors. The differential binding effects of the aforementioned trimetoquinol modifications on the receptor systems may reflect differences in the binding pocket that interacts with the benzyl portion of trimetoquinol analogs. Thus, manipulation of the 1-benzyl moiety of trimetoquinol (1) has resulted in analogs that exhibit potent beta 2-AR binding affinity and significantly lower beta 1-AR and TP receptor affinities.

Adrenergic beta-Agonists↗
PubMed1996

Relationship of vascular thrombosis and inflammatory leukocyte infiltration to neointimal growth following porcine coronary artery stent placement.

BACKGROUND: Superficial and intramural thrombosis are reproducible histopathological features of the porcine coronary oversized stent injury model. Fibrin and its degradation products are chemotactic for mononuclear leukocytes, and promote the proliferation and migration of vascular smooth muscle cells (VSMC) in vitro. The goal of this study was to quantitate the serial histomorphologic evolution of thrombosis, leukocyte infiltration, VSMC proliferation and collagen accumulation following porcine coronary artery stent placement in a porcine model. METHODS: Twenty-four normocholesterolemic swine underwent oversized balloon (3.5-4.0 mm) coronary angioplasty and tantalum metal stent placement. Twenty-six different arterial sites were injured, followed by serial sacrifice at day 4 (n = 6), 8 (n = 6), 14 (n = 6), and 28 (n = 6). Quantitative analysis of the neointima was performed using a high resolution video-microscopy interface and a validated histomorphometric software program. Alpha actin-positive VSMC density (per 10(4) micro(2) neointimal area) and collagen-specific picro-sirius red fluorescence (percent of neointima) were quantitated at sites adjacent to and distant from coronary artery stent placement. RESULTS: The percent of total neointimal area occupied by resolving thrombus material was greater at days 4-8 compared to 14-28 days (59-63% vs. 1-2%; P = 0.001). Mononuclear leukocytes were also significantly increased at days 4 and 8 (92 +/- 1 and 70 +/- 8%) compared to days 14-28 (both 3 +/- 3%; P = 0.001), as a percentage of the total neointimal cellularity. Total neointimal cell density did not change (20 +/- 10, 12 +/- 6, 23 +/- 7 and 20 +/- 3 cells/10(4) micro(2); P-value, NS), despite progressive cross-sectional vascular area stenosis reduction from 7 +/- 3% at day 4 to 72 +/- 14% at day 28 (P = 0.001). Percent neointimal fibrinoid thrombus content and mononuclear leukocyte cellularity were correlated in this model (R = 0.81; P < 0.001). Peri-stent neointimal collagen staining exceeded that at vascular sites distant from porcine coronary stent placement by 14 days (29 +/- 6 vs. 15 +/- 3%), and remained greater at 28 days (35 +/- 11 vs. 16 +/- 12%) (both P < 0.05). CONCLUSIONS: Quantitative serial histomorphometry of porcine coronary vascular stent delivery sites demonstrates early (4-8 day) neointimal mononuclear leukocyte infiltration which is histomorphologically and temporally related to intramural fibrinoid thrombosis. Significant vascular stenosis and collagen deposition occurs by 14-28 days at these vascular injury sites. These data suggest a local interaction between thrombotic and inflammatory elements in porcine coronary neointima following oversized stent injury.

Angioplasty, Balloon↗
PubMed1996

Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine.

A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Adrenergic alpha-Agonists↗
PubMed1996

Pharmacological study of atypical beta-adrenoceptors in rat esophageal smooth muscle.

The chemical specificity for the beta-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective beta-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 118551 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-but an-2-ol] and the beta-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (+/-)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3, 4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [(R* R*)-(+/-)-4-[2'-2-hydroxy 2-(3-chlorophenyl)ethylamino]propyl] phenoxyacetic acid] (8.16) = ICID7114 [(S)-4-(2-hydroxy- 3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) > or = (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3',5'-diiodo-4'-methoxybenzyl)-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1- (3',4',5'-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'- trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline] (6.56) > or = (-)-noradrenaline (6.46) > or = (-)-adrenaline (6.36) > (+/-)-noradrenaline (6.24) > (+/-)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6, 7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- > > (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 microM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical beta/beta 3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical beta/beta 3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical beta/beta 3-adrenoceptors. (-)-Trimetoquinol was as potent as (-)- isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.

Adrenergic beta-1 Receptor Antagonists↗
PubMed1996

Pharmacological activities of trimetoquinol and 1-benzyl halogen-substituted analogues on rat beta-adrenoceptor subtypes.

The beta-adrenoceptor activity profile of trimetoquinol and its 1-benzyl halogen-substituted analogues was studied in rat tissues containing primarily beta 1 (atria)-, beta 2 (trachea)- and atypical beta/beta 3 (distal colon and brown adipose tissue)-adrenoceptors. Functional biological activity resided in the (-)-isomer of trimetoquinol which was 112-, 275-, 372- and 513-fold more potent than (+)-trimetoquinol in trachea, right atria, distal colon and brown adipose tissue, respectively. (+/-)-Trimetoquinol was equally or slightly less active than (-)-trimetoquinol. The 1-benzyl halogen-substituted analogues of trimetoquinol exhibited differential activation of beta-adrenoceptor subtypes. In functional assays, 3'-iodotrimetoquinol was a potent activator of all beta-adrenoceptor subtypes. 3',5'-Diiodotrimetoquinol was 10-fold more potent as an agonist in tissues containing atypical beta/beta 3-adrenoceptors than those tissues containing beta 1- and beta 2-adrenoceptor sites. Furthermore, this drug was a partial agonist as compared to (+/-)-trimetoquinol and 3'-iodotrimetoquinol on beta 1-adrenoceptors. Pharmacological properties of the compounds on rat beta 3-adrenoceptors expressed in Chinese hamster ovary (CHO) cells were consistent with results observed in functional assays. 3',5'-Diiodotrimetoquinol possessed the greatest potency for activation of adenylyl cyclase. Rank order of affinity for rat beta 3-adrenoceptor was 3'-iodotrimetoquinol = 3',5'-diiodotrimetoquinol > (+/-)-trimetoquinol > (-)-isoprenaline. These results suggest that 3',5'-diiodotrimetoquinol is a promising drug for further chemical modification in the development of selective beta 3-adrenoceptor ligands.

Adipose Tissue, Brown↗
PubMed1996

Correlation of poststenotic hyperemic coronary flow velocity and pressure with abnormal stress myocardial perfusion imaging in coronary artery disease.

The functional significance of coronary stenoses is frequently determined by adjunctive noninvasive myocardial perfusion imaging. Poststenotic coronary flow velocity and pressure can be measured directly during routine cardiac catheterization. The aim of this study was to correlate poststenotic (distal) flow velocity and pressure with stress perfusion imaging in patients. Quantitative angiography, basal and hyperemic transstenotic coronary flow velocities, and pressure gradients were measured in 50 patients within 1 week of exercise (n = 29) or of pharmacologic (n = 21) stress perfusion imaging. Twenty-two of 25 patients (88%) with reversible perfusion abnormalities had diminished distal coronary flow velocity reserves (CFVR) of < or = 2.0 x baseline, whereas 22 of 25 (88%) with normal perfusion imaging studies had a normal distal CFVR of > 2.0 (p = 0.000 1). Thirteen of 25 patients (52%) with reversible perfusion abnormalities had transstenotic gradients > or = 20 mm Hg, whereas 20 of 25 (80%) with normal perfusion studies had gradients <20 mm Hg (p = 0.01). Quantitative angiography did not differentiate patients with normal versus abnormal myocardial perfusion imaging. Distal CFVR was correlated more significantly with myocardial perfusion imaging results (kappa = 0.76) than with pressure gradients (kappa = 0.32). Exercise and pharmacologic stress myocardial perfusion imaging abnormalities reflect diminished post-stenotic coronary flow to a greater degree than transstenotic pressure gradients.

Adult↗
PubMed1996

Meta-analysis of intravenous dipyridamole-thallium-201 imaging (1985 to 1994) and dobutamine echocardiography (1991 to 1994) for risk stratification before vascular surgery.

OBJECTIVES: This study evaluated the prognostic value of abnormal test results with pharmacologic stress with regard to perioperative and long-term outcomes in a large population of candidates for vascular surgery. BACKGROUND: Although numerous studies have demonstrated the prognostic value of dipyridamole-thallium-201 myocardial perfusion and dobutamine echocardiography in vascular surgery candidates, a synopsis of predictive estimates is difficult because of individual study variability in pretest clinical risk, sample size and study design. METHODS: A systematic review of published reports on preoperative pharmacologic stress risk stratification from the MEDLINE data base (1985 to 1994) identified 10 reports on dipyridamole-thallium-201 myocardial perfusion (1,994 patients) and 5 on dobutamine stress echocardiography (446 patients). Random effects models were used to calculate summary odds ratios and 95% confidence intervals. RESULTS: Summary odds ratios for death or myocardial infarction and secondary cardiac end points were greater for dobutamine echocardiographic dyssynergy (14- to 27-fold) than for dipyridamole-thallium-201 redistribution (4-fold); wider confidence intervals were noted with dobutamine echocardiography. Pretest coronary disease probability was correlated with the positive predictive value of a reversible thallium-201 defect (r=0.70), increasing sixfold from low to high risk patient subsets. Cardiac event rates were low in patients without a history of coronary artery disease (1% in 176 patients) compared with patients with coronary disease and a normal or fixed-defect pattern (4.8% in 83 patients) and one or more thallium-201 redistribution abnormality (18.6% in 97 patients, p=0.0001). CONCLUSIONS: Meta-analysis of 15 studies demonstrated that the prognostic value of noninvasive stress imaging abnormalities for perioperative ischemic events is comparable between available techniques but that the accuracy varies with coronary artery disease prevalence.

Adrenergic beta-Agonists↗
PubMed1996

Tip-localized calcium entry fluctuates during pollen tube growth.

Studies have been conducted on the dynamics of Ca2+ entry in pollen tubes using ratiometric ion imaging to measure the intracellular gradient and an ion selective vibrating electrode to detect the extracellular influx. A steep tip-focused gradient occurs in all species examined, including Lilium longiflorum, Nicotiana sylvestris, and Tradescantia virginiana. Anlaysis of Lilium pollen tubes loaded with dextran conjugated fura-2 reveals that the gradient derives from Ca2+ entry that is restricted to a small area of plasma membrane at the extreme apex of the tube dome. Since the apical membrane is continually swept to the flanks during tube elongation, either Ca2+ channels are specifically retained at the extreme apex or, as seems more likely, the Ca2+ channels which were active at the tip rapidly inactivate, as new ones are inserted during vesicle fusion. Ratiometric imaging further indicates that the high point of the gradient fluctuates in magnitude from 0.75 to above 3 microM, during measuring intervals of 60 sec, with the elevated points being correlated with an increased rate of tube growth. Independent analysis of the growth at 2- to 3-sec intervals reveals that the rates can fluctuate more than threefold; tubes longer than 700 mu m exhibit oscillations with a period of 23 sec, while tubes shorter than 700 mu m display erratic fluctuations. Inhibition of pollen tube growth caused by mild temperature shock or caffeine (1.5 to 3.0 mM) is correlated with the dissipation of the tip-focused gradient and the Ca2+ influx. Recovery from both treatments is denoted by a global swelling of the pollen tube tip, concomitant with a high transient entry of Ca2+ in the tip. The location of the highest Ca2+ domain within the tip region defines the point from which normal cylindrical elongation will proceed.

Caffeine↗
PubMed1996

Effect of the stress level achieved during symptom-limited exercise technetium-99m sestamibi myocardial tomography on the detection of coronary artery disease.

BACKGROUND: The stress level achieved during exercise thallium 201 myocardial imaging may influence its sensitivity for detecting coronary artery disease (CAD). The effect of exercise adequacy on the accuracy of technetium-99m sestamibi (MIBI) imaging has not been studied. HYPOTHESIS: The study was undertaken to assess the effect of exercise level achieved on sensitivity for detecting CAD. METHODS: A consecutive series of 250 patients (mean age 60 +/- 10 years) with CAD by angiography underwent symptom-limited exercise MIBI single-photon emission computed tomography. Single-vessel CAD was found in 66 patients, double-vessel CAD in 84, triple-vessel CAD in 80, and left main disease in 20. RESULTS: No significant differences were found in sensitivities of an abnormal MIBI scan or a reversible defect among 102 patients reaching 85% of age-predicted heart rate and 148 who did not (82 vs. 89% and 66 vs. 70%, respectively, p = NS). Patients (n = 128) able to exercise < or = 6 min had a higher incidence of abnormal scans and reversible defects than 122 patients with a greater exercise duration (91 vs. 82% and 75 vs. 61%, respectively, both p < 0.05). Sensitivity of an abnormal MIBI scan for multivessel disease was greater than for single-vessel disease in patients who achieved > or = 85% of age-predicted heart rate (91 vs. 59%, p < 0.01) and in those who exercised > 6 min (89 vs. 66%, p < 0.01). No significant differences in the sensitivities of an abnormal MIBI study for multivessel versus single-vessel CAD were seen in patients achieving lower peak levels of exercise. Sensitivity of ischemic ST depression was lower than that of MIBI tomography at all levels of exercise. CONCLUSIONS: The sensitivity of exercise MIBI tomography for angiographic CAD is relatively independent of the peak heart rate achieved. Exercise duration of > 6 min is associated with a significantly higher MIBI abnormality rate than a duration of > 6 min, possibly reflecting the effect of myocardial ischemic burden on exercise ventricular function. Regardless of level of stress or its duration, exercise MIBI tomography improves the sensitivity for CAD detection compared with stress-induced ischemic ST depression.

Adult↗
PubMed1996

Purification and characterization of human heart fatty acid ethyl ester synthase/carboxylesterase.

Fatty acid ethyl ester synthase metabolizes ethanol non-oxidatively in those extrahepatic organs most commonly damaged by alcohol abuse. This study was designed to purify human myocardial fatty acid ethyl ester synthase (FAEES)/carboxylesterase from human heart. The enzyme was purified to homogeneity after chromatography over DEAE-cellulose, Sephadex G-100 and hydroxylapatite. The homogenous enzyme, 62 kDa, has both synthase and carboxylesterase activities. The N-terminal amino acid sequence of the first 17 residues of the purified enzymes were 88% homologous to that of the carboxylesterase from rat liver and adipose tissue. Antibody was raised against pure synthase/carboxylesterase cross-reacted with human cytosolic and microsomal fractions. With a constant oleic acid concentration of 0.25 mM, a calculated apparent Km and Vmax for ethanol were 0.30 M and 3700 nmol/mg protein/h., respectively. With constant ethanol concentrations of 1.2 M, the activity increased with the concentration of oleic acid to 0.17 mM, plateau to 0.25 mM. Because synthase/carboxylesterase esterifies free fatty acids with ethanol to produce its esters with potentially toxic effects, it may now be feasible to establish a link between alcohol consumption and end-organ damage.

Acyltransferases↗
PubMed1996

Comparison of post-junctional alpha-adrenoceptors in iris dilator muscle of humans, and albino and pigmented rabbits.

The relative potency of alpha-adrenoceptor agonists and the dissociation constants of competitive antagonists were studied to characterize the post-junctional alpha-adrenoceptor of the human iris dilator muscle. The data obtained from human iris dilator tissue was compared to that from rabbit. The iris dilator muscle was mounted in an organ bath and tension changes were recorded. (-)-Norepinephrine, (-)-phenylephrine (PE), oxymetazoline and p-aminoclonidine caused contractile responses in albino rabbit, pigmented rabbit and human iris dilator muscle in a concentration-dependent manner. The imidazoline molecules were partial agonists. In rabbit iris dilator, desensitization occurred to repeated oxymetazoline application at an interval of 1 h but recovery to the agonist activity was complete in about 3 h. Exposure to cocaine (10 mumol/l), hydrocortisone (100 mumol/l) and U-0521, a catechol-O-methyltransferase inhibitor (100 mumol/l), significantly potentiated the response to norepinephrine by 92-, 32- and 7 fold in iris dilator tissue of albino rabbit, pigmented rabbit and human, respectively. After block of "uptake1" and "uptake2", the EC50 values of norepinephrine in the albino rabbit, pigmented rabbit and human iris dilator did not differ and ranged from 99 to 195 nmol/l. Small but significant potentiation by uptake blockers was also observed in the responses to PE in the albino rabbit or pigmented rabbit iris dilator. The average maximum tension induced by 100 mumol/l PE was 96 +/- 11 mg (n = 10), 197 +/- 11 mg (n = 11), 45 +/- 5 mg (n = 27) in albino rabbit, pigmented rabbit and human iris dilator, respectively. In human iris dilator, the responses to PE were competitively antagonized by prazosin, 5-methylurapidil and phentolamine with apparent pKB values of 7.3, 6.6 and 7.5, respectively. The pKB values of the prazosin-PE interaction in iris dilator of albino and pigmented rabbit were 8.6 and 6.4, respectively. These results suggest that the post-junctional alpha-adrenoceptors in iris dilator may be similar to that in pigmented rabbit iris. The alpha-adrenoceptor of the human or pigmented rabbit iris dilator may be characterized as alpha 1L-adrenoceptor subtype. The alpha-adrenoceptor of albino rabbit iris dilator appears to be a high affinity subtype. Furthermore, albino rabbit may not be the best strain for the drug research which is relevant to human ocular therapeutics.

Adult↗
PubMed1996

Prognostic value of cardiopulmonary exercise testing using percent achieved of predicted peak oxygen uptake for patients with ischemic and dilated cardiomyopathy.

OBJECTIVES: We tested the hypothesis that percent achieved of predicted peak oxygen uptake (predicted VO2max) improves the prognostic accuracy of identifying high risk ambulatory patients with congestive heart failure considered for heart transplantation compared with absolute peak oxygen uptake (VO2max) in 181 patients with ischemic or dilated cardiomyopathy. BACKGROUND: Peak oxygen uptake during exercise has been shown to be a useful prognostic measurement to risk stratify patients with heart failure. The prognostic value of percent predicted VO2max has not been assessed in these patients. METHODS: We retrospectively studied 181 ambulatory patients referred to the Saint Louis University Heart Failure Unit. Clinical, hemodynamic (137 patients) and coronary angiographic (145 patients) data were recorded, and all patients underwent symptom-limited cardiopulmonary exercise. RESULTS: During a mean follow-up period of 12 +/- 6 months, 26 patients died, and 18 were listed as Status 1 priority for heart transplantation. The actuarial 1- and 2-year survival of the 89 patients who achieved < or = 50% predicted VO2max was 74% and 43%, respectively, compared with 98% and 90% in the 92 who achieved > 50% predicted VO2max (p = 0.001). Multivariable analysis selected < or = 50% predicted VO2max as the most significant predictor of cardiac death (p = 0.007) and cardiac death or Status 1 priority (p = 0.0005). CONCLUSIONS: Percent achieved of predicted VO2max provides important information that can be used to risk stratify ambulatory patients with heart failure with ischemic or dilated etiology that exceeds that provided by measurement of VO2max alone. Patients who achieve > 50% predicted VO2max have an excellent short-term prognosis when treated medically, and heart transplantation can be safely deferred.

Cardiomyopathy, Dilated↗
PubMed1996

Periprocedural Doppler coronary blood flow predictors of myocardial perfusion abnormalities and cardiac events after successful coronary interventions.

Thirty-four consecutive patients had coronary flow velocity assessed under basal and hyperemic conditions in the proximal and distal coronary artery, followed by rest-stress technetium 99m sestamibi myocardial tomography within 3 months of successful coronary angioplasty. In spite of significant angiographic improvement, 29% of patients had a persistent reversible myocardial perfusion defect associated with a residual abnormality of the proximal-to-distal coronary average peak velocity ratio (p/d APV = 2.2 +/- 1.5 vs 1.1 +/- 0.6; p = 0.02). Patients with an abnormal p/d APV ratio (>1.7) had more numerous angioplasty-zone perfusion defects (4.2 +/- 3.3 vs 0.8 +/- 2.0; p = 0.005). Multivariable analysis of clinical, angiographic, coronary flow, and scintigraphic data demonstrated that the relative risk of cardiac events (n = 11) was greatest in patients with a reversible angioplasty-zone perfusion defect (relative risk, 5.5), poststenotic coronary flow reserve <2.0 (relative risk, 8.3) and p/d APV ratio >1.7 (relative risk, 6.2). Residual basal coronary flow-velocity abnormalities are significant physiologic correlates of stress-induced myocardial perfusion defects and are a prognostic covariable associated with future ischemic cardiac events.

Adult↗
PubMed1996

Dipyridamole technetium-99m sestamibi myocardial tomography in patients evaluated for elective vascular surgery: prognostic value for perioperative and late cardiac events.

Dipyridamole thallium-201 myocardial imaging can provide information regarding risk of perioperative cardiac events in patients being considered for vascular surgery. The value for this purpose of myocardial imaging with technetium-99m sestamibi (MIBI), a radiotracer with biokinetic and imaging properties different from thallium-201, has not been established. To this end the prognostic value of dipyridamole MIBI tomography for perioperative and late cardiac events was evaluated in 229 consecutive patients being considered for elective vascular surgery. Vascular surgery was done < or = 3 months after testing in 197 of these patients. Perioperative cardiac events (cardiac death, nonfatal myocardial infarction, unstable angina, or ischemic pulmonary edema) occurred in 9 (5%) patients. The rate of such events was 3% in patients with normal MIBI results, 5% in those with abnormal results, and 6% in patients with a reversible MIBI defect (both p = NS). When patients with abnormal MIBI results who had preoperative cardiac interventions (coronary revascularization or an increase in antiischemic medical therapy) were compared with with those who did not, no significant differences in the occurrence of perioperative cardiac events were found between these two groups either. A group of 172 medically treated patients who survived vascular surgery and did not have a nonfatal perioperative cardiac event was then monitored (mean 21 +/- 14 months) for the occurrence of a serious late cardiac event (nonfatal myocardial infarction or cardiac death). Event-free survival (Mantel-Cox) was significantly less in patients with abnormal studies compared with those with normal scan results. Late cardiac events occurred in 26 (15%) patients, with those having an abnormal MIBI result showing a significantly greater event rate than those with normal results (26% vs 4%, p < 0.0001). The rate of late cardiac events was 33% in patients with a reversible MIBI defect (p < 0.001) and 23% in those with a fixed defect (p < 0.03). Independent Cox multivariable predictors of increased risk of late cardiac events were a history of diabetes mellitus (relative risk [RR] 2.2, 95% confidence interval [CI] 1.0 to 4.9), an abnormal MIBI study (RR 3.7, 95% CI 1.2 to 11.4), and a reversible MIBI defect (RR 2.7, 95% CI 1.2 to 6.1). We conclude that, although its ability to assess increased perioperative cardiac risk remains uncertain, dipyridamole MIBI tomography does provide important prognostic information regarding the risk of serious cardiac events in patients having vascular surgery. The presence of an abnormal MIBI result, specifically one demonstrating a reversible perfusion defect, is associated with significantly increased risk.

Aged↗
PubMed1996

Dipyridamole technetium 99m sestamibi myocardial tomography for preoperative cardiac risk stratification before major or minor nonvascular surgery.

The value of dipyridamole technetium 99m sestamibi (MIBI) tomography for preoperative cardiac risk stratification was assessed in 285 consecutive patients being considered for nonvascular surgery. A "major" (n = 140) or "minor" (n = 89) nonvascular procedure was later done in 229 of these patients < or = 4 months after dipyridamole testing. Perioperative cardiac events (unstable angina, acute ischemic pulmonary edema, nonfatal myocardial infarction, or cardiac death) occurred in 11 (8%) patients undergoing major nonvascular surgery and 1 (1%) undergoing a minor procedure. The only clinical or scintigraphic variables associated with significantly increased perioperative cardiac risk in patients having major surgery were Goldman class > or = II, an abnormal MIBI scan, and a fixed perfusion defect. In these patients, cardiac events occurred in 1% of those who had a normal MIBI study, 14% of those with an abnormal scan (p < 0.01), 12% with a reversible MIBI defect (p = 0.29), and 17% with a fixed MIBI defect (p < 0.01). In the 60 patients whose Goldman class was > or = II, only an abnormal MIBI study and a fixed perfusion defect were associated with incremental risk of a perioperative cardiac event. The incidence of perioperative cardiac events in these patients was 4% with a normal MIBI scan, 27% with an abnormal study (p < 0.05), 24% with a reversible MIBI defect (p = 0.45), and 37% with a fixed defect (p < 0.01). Event rates were low in patients having minor nonvascular surgery; none of the 25 with a normal MIBI study and only 1 of the 64 with an abnormal scan had a perioperative cardiac event (p = not significant (NS). We conclude that dipyridamole MIBI tomography can provide important prognostic information in patients having major nonvascular surgery. A normal MIBI study indicates a low risk of perioperative cardiac events, whereas an abnormal study in patients with Goldman class > or = II undergoing major surgery is associated with significantly increased risk. The prognostic value of MIBI tomography in patients at low clinical risk undergoing minor surgery is limited.

Aged↗
PubMed1996

Cryofixing single cells and multicellular specimens enhances structure and immunocytochemistry for light microscopy.

Cryofixation is widely held to be superior to chemical fixation for preserving cell structure; however, the use of cryofixation has been limited chiefly to electron microscopy. To see if cryofixation would improve sample structure or antigenicity as observed through the light microscope, we cryofixed Nicotiana alata and Lilium longiflorum pollen tubes and Tradescantia virginina stamen hairs by plunge freezing. After freeze-substitution, and embedding in butylmethylmethacrylate, we found using the light microscope that the superiority of cryofixation over chemical fixation was obvious. Cryofixation, unlike chemical fixation, did not distort cell morphology and preserved microtubule and actin arrays in a form closely resembling that of living cells. Additionally, to test further the usefulness of cryofixation for light microscopy, we studied the appearance of cells and the retention of antigenicity in plunge-frozen multicellular organ. Roots of Arabidopsis thaliana were either chemically fixed or plunge frozen, and then embedded in the removable methacrylate resin used above. We found that plunge freezing preserved cell morphology far better than did chemical fixation, and likewise improved the appearance of both actin and microtubule arrays. Plunge-frozen roots also had cells with more life-like cytoplasm than those of chemically fixed roots, as assessed with toluidine-blue staining or high-resolution Nomarski optics. Damage from ice crystal formation could not be resolved through the light microscope, even in the interior of the root, 40-75 microns from the surface. We suggest that plunge freezing would enhance many investigations at the light microscope level, including those of multicellular organs, where damage from ice crystals may be less severe than artefacts from chemical fixation.

Arabidopsis↗
PubMed1996

Actions of imidazolines on bovine ciliary artery.

A segment of bovine ciliary artery exhibits nonlinear biphasic contractile responses to agonists. The maximal responses of oxymetazoline (OMZ) and norepinephrine (NE) were 55% and 45%, respectively (KCl = 100%). The relative potency comparison based on the ED50 of the first component of the dose-response curve was OMZ; 1 > NE; 1/7 > phenylephrine; 1/72. At equipotent doses of NE and OMZ, the t1/2 duration of response of the latter agonist was 43 times greater than that of the former and, after 3 hrs, responses were 95% reproducible. Naphazoline, tetrahydrozoline and para-aminoclonidine did not produce significant contraction of the blood vessel but did antagonize the action of the agonists. As compared to that of NE, naphazoline was selective in blocking responses of OMZ. Phentolamine blocking action of NE was greater than that of OMZ. Nifedipine, 100 nM, reduced the second component of OMZ response. Although the vascular action of NE was blocked by prazosin, the contractile action of OMZ was totally resistant to block by 1 microM of prazosin. These results indicate that ciliary artery contains a subtype of alpha-adrenoceptors (alpha 11) with low sensitivity to prazosin. The tissue also contains a unique OMZ sensitive site or imidazoline receptors which exhibit low affinity to alpha-adrenoceptor blockers.

Adrenergic alpha-Agonists↗