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Biomedical subjects

R E Zipkin

Publications and source records attributed to R E Zipkin.

11 recordsLinked to original sources
PubMed2001

Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain.

In mammals, specific lipids and amino acids serve as crucial signaling molecules. In bacteria, conjugates of lipids and amino acids (referred to as lipoamino acids) have been identified and found to possess biological activity. Here, we report that mammals also produce lipoamino acids, specifically the arachidonyl amino acids. We show that the conjugate of arachidonic acid and glycine (N-arachidonylglycine (NAGly)) is present in bovine and rat brain as well as other tissues and that it suppresses tonic inflammatory pain. The biosynthesis of NAGly and its degradation by the enzyme fatty acid amide hydrolase can be observed in rat brain tissue. In addition to NAGly, bovine brain produces at least two other arachidonyl amino acids: N-arachidonyl gamma-aminobutyric acid (NAGABA) and N-arachidonylalanine. Like NAGly, NAGABA inhibits pain. These findings open the door to the identification of other members of this new class of biomolecules, which may be integral to pain regulation and a variety of functions in mammals.

Alanine↗
PubMed1995

Structural and stereochemical studies of potent inhibitors of glucosylceramide synthase and tumor cell growth.

Analogs and homologs of PDMP were synthesized, based on its structure (D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol). This compound had previously been found to block the synthesis of GlcCer (glucosylceramide). Increasing the acyl chain length from 10 to 16 carbon atoms greatly enhanced the efficacy of the enzyme inhibitor, as did the use of a less polar cyclic amine, especially a pyrrolidine instead of a morpholine ring. Replacement of the phenyl ring by a chain corresponding to sphingosine also yielded a strongly inhibitory material. By using a chiral synthetic route, we showed that the isomers active against GlcCer synthase had the R,R-(D-threo)-configuration. However, strong inhibition of the growth of human cancer cells in plastico was produced by both the threo and erythro racemic compounds, showing involvement of an additional factor (beyond simple depletion of cell glycosphingolipids by blockage of GlcCer synthesis). The growth arresting effects could be correlated with increases in cellular ceramide and diglyceride levels. The aliphatic pyrrolidino compound was strongly inhibitory toward the glucosyltransferase and produced almost complete depletion of glycolipids, but did not inhibit growth or cause an accumulation of ceramide. Attempts were made to see whether the differences in growth effects could be attributed to the influence of the inhibitors on related enzymes (ceramide and sphingomyelin synthase and ceramidase and sphingomyelinase). While some stimulation of enzyme activity was noted, particularly at high inhibitor concentrations (50 microM), these findings did not explain the differing effects of the different inhibitors. The best inhibitors of GlcCer synthase compared favorably in efficacy with some cancer chemotherapeutic drugs in current use when tested with a battery of human cancer cells.

Animals↗
PubMed1994

Comparative study of the angiographic morphology of coronary artery lesions treated with PTCA, directional coronary atherectomy, or high-speed rotational ablation.

To evaluate trends in morphology-based intervention selection, series of 110 consecutive procedures of each of three devices, percutaneous transluminal balloon coronary angioplasty (PTCA), directional coronary atherectomy (DCA), or high-speed rotational ablation (HSRA), were reviewed. PTCA was used mainly in discrete, concentric, smooth, ACC/AHA type A and B1 lesions. PTCA was used less frequently on a bend, branching points or in calcified lesions. Using PTCA as a reference, DCA was used more often for the treatment of discrete, proximal, eccentric, and noncalcified lesions, often complicated with thrombus and located on straight segments. HSRA was used more frequently in diffuse, calcified multiple complicated and B2+C type lesions with frequent side branches and bend points. These results suggest that directional atherectomy and rotational ablation may be helpful in expanding the capacity of the operator to approach prognostically unfavorable lesions.

Aged↗
PubMed1993

Rest/exercise thallium myocardial perfusion imaging: a new and rapid technique to evaluate coronary artery disease.

Twenty-six patients underwent conventional exercise/4-h redistribution thallium myocardial perfusion imaging as well as rest/exercise imaging on different days. For the rest/exercise study, patients were imaged 10 min after receiving 1 mCi thallium at rest. The resting study was immediately followed by symptom-limited treadmill exercise. Patients were injected with 2 mCi thallium at peak exercise and imaged 10 min later. The entire rest/exercise study was completed in 2 h. There was a high degree of correlation between the two studies. Of the 130 segments analysed, 84 were normal and 46 were abnormal by exercise/redistribution imaging whereas 88 were normal and 42 were abnormal by rest/exercise imaging. Among the 14 patients who had coronary arteriography, both exercise/redistribution and rest/exercise imaging correctly identified 23/35 segments as abnormal (sensitivity [pi003] 66%) and 34/35 segments as normal (specificity = 97%). Furthermore, abnormal segments were more likely to be reversible on the rest/exercise study. The results suggest that the accuracy of rest/exercise thallium imaging is equal to conventional exercise/redistribution imaging in the evaluation of coronary artery disease. The significant time economy and possible improvement in assessing myocardial viability are important potential advantages of this new technique.

Aged↗
PubMed1991

Mitral valve replacement in dilated canine hearts with chronic mitral regurgitation. Importance of the mitral subvalvular apparatus.

The importance of the mitral subvalvular apparatus in terms of left ventricular (LV) mechanics and energetic efficiency in the chronically dilated canine heart was assessed in nine dogs with surgically induced mitral regurgitation. Miniature radiopaque tantalum markers were implanted into the myocardium to measure LV volume. Biplane cinefluoroscopic images obtained 1 week and 3 months after creation of mitral regurgitation confirmed the presence of LV dilatation. Mitral valve replacement with preservation of all chordae tendineae was then performed. LV systolic function and derived energetics were then assessed during transient caval occlusion both before and after chordal division by using exteriorized snares. Global LV systolic mechanics, as assessed by the slopes of the end-systolic pressure volume (Ees) and end-systolic stress volume (Ms) relations, fell by 46% (11.7 +/- 2.8 versus 6.3 +/- 1.4 mm Hg/ml, p less than 0.001) and 33% (17.8 +/- 4.0 versus 12.0 +/- 5.1 kdyne/cm5, p = 0.0001), respectively, when the chordae were divided. Chordal severing also increased systolic LV wall stress or LV afterload. In terms of calculated myocardial energetics, the slopes of the stroke work-end-diastolic volume and pressure volume area-end-diastolic volume relations declined significantly by 20% (85 +/- 14 versus 68 +/- 16 mm Hg) and 11% (116 +/- 20 versus 104 +/- 20 mm Hg) after cutting the chordae, thereby indicating reduced external stroke work and mechanical energy generated at any given level of preload. Moreover, the efficiency of energy transfer from pressure volume area to external stroke work fell by 19% (p less than 0.001). Since effective systemic arterial elastance (Ea) did not change, the Ea/Ees ratio (index of ventriculoarterial [V-A] coupling) increased from 0.93 +/- 0.27 to 1.67 +/- 0.62 (p = 0.006). Therefore, chordal division in dilated dog hearts due to chronic mitral regurgitation resulted not only in deterioration of systolic LV mechanics but also deleterious changes in calculated LV energetics and efficiency due to exacerbated mismatch in V-A coupling between the left ventricle and the systemic arterial bed, unfavorable loading conditions, and exhaustion of preload reserve. These observations in the low-pressure, volume-overloaded heart due to chronic mitral regurgitation underscore the importance of the mitral subvalvular apparatus for optimal LV systolic performance and energetic efficiency.

Animals↗
PubMed1990

Direct cardiovascular actions of two metabolites of linoleic acid.

Two newly discovered oxidation products of linoleic acid (i.e., 9,10-epoxy-12-octadecenoate termed Leukotoxin A, and 12,13-epoxy-9-octadecenoate termed Leukotoxin B) are produced by neutrophils in a variety of species. These substances appear to combat bacterial infection although they also have detrimental effects on normal organ function. Administration of Leukotoxin A or B to isolated cat papillary muscles decreased developed force, an index of myocardial contractility, in a concentration-dependent manner. Leukotoxin B was more active in decreasing the developed force than Leukotoxin A at high concentrations. Leukotoxin A or B, when added to isolated perfused cat carotid arteries, produced a significant vasoconstriction which in vivo would result in an increased vascular resistance. Thus, leukotoxins exert significant direct effects on the cardiovascular system in cats. Leukotoxins A and B are both cardiodepressant and vasoactive independent of release of other blood borne mediators.

Animals↗
PubMed1989

Development and application of a membrane receptor assay for leukotriene B4.

5(S),12(R)-dihydroxy-6-cis-8,10 trans-14-cis-eicosatetraenoic acid (LTB4) is a potent inflammatory mediator generated by human cells. A receptor assay using membranes from cultured HL-60 cells has been developed to quantitate LTB4 with a range of sensitivity from 10 pg to 5 ng. The initial metabolite of LTB4, 20-OH LTB4, has a cross reactivity of 28% while other lipoxygenase products do not significantly compete. This assay has been used to study ionomyocin-induced formation of LTB4 by human neutrophils. The use of membranes from HL-60 cells for the measurement of LTB4 provides a sensitive and highly selective alternative to radioimmunoassay for the determination of the levels of this important eicosanoid in biological fluids and should be useful in the development of antagonists of the LTB4 receptor.

Cell Membrane↗
PubMed1989

Preparation of omega trideuterated sulfidopeptide leukotrienes: analysis by FAB/MS.

C-20 Trideuterated leukotriene A4 methyl ester was prepared by Wittig condensation of a deuterated C9-phosphonium salt with a C11-epoxydienal. It was then treated separately with glutathione, cysteinylglycine and cysteine. The resulting esters were saponified to give C-20 trideuterated leukotrienes C4, D4 and E4 respectively. Fast atom bombardment mass spectrometry showed that the synthetic compounds contained from 0.5 to 1.0% protium impurity. Introduction of deuterium at C-20 ensures that it is stable to a wide variety of reagents and reaction conditions. The deuterated leukotrienes will serve as internal standards for the quantitative analysis by mass spectrometry of endogenous sulfidopeptide leukotrienes present in biological fluids.

Deuterium↗
PubMed1987

Metabolism of cyclooxygenase and lipoxygenase products by 15-prostaglandin dehydrogenase from human HL-60 leukemia cells.

A number of prostaglandins and mono-hydroxylated fatty acids were investigated as substrates for NAD-dependent 15-prostaglandin dehydrogenase (15-PGDH) obtained from human HL-60 cells. Lipoxygenase and cyclooxygenase-derived substrates possessing an w-6 hydroxyl moiety (15-HETE, 13-HODD and HHT) were metabolized to corresponding keto derivatives at a rate comparable to that for prostaglandins E2 and F2 alpha. 12-HETE was a poor substrate and 5-HETE was not metabolized. The w-6 hydroxy fatty acids inhibited the metabolism of PGE2 and therefore they may play a role in modulating bioactive prostaglandin levels.

Cell Line↗