Biomedical subjects

D J Miller

Publications and source records attributed to D J Miller.

At least 37 records · Page 2Linked to original sources

PubMed2001

Short communication: effects of increased expression of alpha-lactalbumin in transgenic mice on milk yield and pup growth.

Lactose synthase (a complex of beta1,4-galactosyltransferase and alpha-lactalbumin) forms lactose in the Golgi complex of mammary epithelial cells. To determine whether alpha-lactalbumin is a limiting component in this complex, transgenic mice that expressed bovine alpha-lactalbumin were studied. Transgenic mice produced 0.5 to 1.5 mg/ml of bovine alpha-lactalbumin in their milk, 5- to 15-fold more alpha-lactalbumin than in milk of control mice. Transgenic and control mice produced milk with the same concentrations of lactose, cream, and total solids, and showed similar mammary gland growth, morphology, and histology. Milk from transgenic mice had 0.6% less protein than milk from control mice (P < 0.05). The in vitro lactose synthase activity in mammary gland homogenates from alpha-lactalbumin transgenic mice was increased (P < 0.05), demonstrating that bovine alpha-lactalbumin could interact with murine beta1,4-galactosyltransferase. Pups reared by lactating transgenic mice showed a 4% increase in growth on d 10 of lactation, suggesting that milk production was increased (P = 0.06). Milk volume, estimated using the weigh-suckle-weigh technique, tended to be higher (although not significantly) in transgenic mice (P = 0.11). These results suggest that augmenting alpha-lactalbumin expression in the dam increases the growth of suckling offspring.

Animals↗

PubMed2001

The search is on: finding accurate molecular markers of male fertility.

Diagnosis of the fertility potential of a semen sample is essential for consistently high reproductive efficiency. The use of subfertile or infertile semen can have devastating consequences for those selling or using the semen. Therefore it is crucial to develop and use accurate diagnostic tests to determine the fertility of males and of individual semen samples. These diagnostic tests must be economically practical and provide consistent results. The goal of this review is to explore areas of fertility diagnostic research, including what we have termed functional and molecular tests, and consider the accuracy of each test. In this article, literature from several species is cited, and it is noteworthy that each diagnostic test may not be valuable in all species. Multiple functional and molecular tests will likely be needed to effectively characterize male fertility in each species.

Animals↗

PubMed2001

Gamete adhesion molecules.

Despite the importance of fertilization for animal production, species preservation and controlling reproduction, the molecular basis underlying fertilization is not well understood. More progress has been made in mice than in other mammals, but targeted deletion of specific genes in the mouse has often yielded unexpected results. The pig is also a useful animal to study, as large numbers of pig gametes can be acquired easily. However, it appears that the pig zona pellucida proteins that bind to spermatozoa may not be homologues of ZP3, the mouse zona pellucida protein that spermatozoa bind to. Therefore, a zona pellucida receptor on spermatozoa that is important for mouse fertilization may be redundant, along with other receptors, in pig fertilization. In this review, the important steps of fertilization in pigs are discussed and the binding of pig gametes is compared with that of mouse gametes. In addition, the molecules that may be important for gamete adhesion are considered. New technical advances and creative ideas offer the opportunity to make important advances in this crucial area.

Acrosome Reaction↗

PubMed2000

The 6-OH group of D-inositol 1-phosphate serves as an H-bond donor in the catalytic hydrolysis of the phosphate ester by inositol monophosphatase.

Inositol monophosphatase plays a pivotal role in the biosynthesis of secondary messengers and is believed to be a target for lithium therapy. It is established how a lithium ion works in inhibiting the enzyme but details of the mechanism for the direct magnesium ion activated hydrolysis of the substrate have been elusive. It is known that substrates require a minimal 1,2-diol phosphate structural motif, which in D-myo-inositol 1-phosphate relates to the fragment comprising the 1-phosphate ester and the 6-hydroxy group. Here it is shown that inhibitors that are D-myo-inositol 1-phosphate substrate analogues possessing 6-substituents larger than the 6-hydroxy group of the substrate, for example, the 6-O-methyl analogue, are able to bind to the enzyme in a congruous manner to the substrate. It is demonstrated, however, that such compounds show no substrate activity whatsoever. It is also shown that a 6-amino group is able to fulfil the role of the 6-hydroxy group of the substrate in conferring substrate activity and that a 6-methylamino group is similarly able to support catalysis. The results indicate that a 6-substituent capable of serving as a hydrogen-bond donor is required in the catalytic mechanism for hydrolysis. It has recently been shown that inositol is displaced from phosphorus with inversion of stereochemistry and we expect that the nucleophilic species is associated with Mg(2+)-1. It is proposed here that the role of the 6-hydroxy group of the substrate is to H-bond with a water molecule or hydroxide ion located on Mg(2+)-2. From this analysis, it appears that the water molecule bound to Mg(2+)-2 serves as a proton donor for the inositolate leaving group in a process that stabilises the alkoxide product and retards the back-reaction.

Animals↗

PubMed2000

Comparisons of soxhlet extraction, pressurized liquid extraction, supercritical fluid extraction and subcritical water extraction for environmental solids: recovery, selectivity and effects on sample matrix.

Extractions of a polycyclic aromatic hydrocarbon (PAH)-contaminated soil from a former manufactured gas plant site were performed with a Soxhlet apparatus (18 h), by pressurized liquid extraction (PLE) (50 min at 100 degrees C), supercritical fluid extraction (SFE) (1 h at 150 degrees C with pure CO2), and subcritical water (1 h at 250 degrees C, or 30 min at 300 degrees C). Although minor differences in recoveries for some PAHs resulted from the different methods, quantitative agreement between all of the methods was generally good. However, the extract quality differed greatly. The organic solvent extracts (Soxhlet and PLE) were much darker, while the extracts from subcritical water (collected in toluene) were orange, and the extracts from SFE (collected in CH2Cl2) were light yellow. The organic solvent extracts also yielded more artifact peaks in the gas chromatography (GC)-mass spectrometry and GC-flame ionization detection chromatograms, especially compared to supercritical CO2. Based on elemental analysis (carbon and nitrogen) of the soil residues after each extraction, subcritical water, PLE, and Soxhlet extraction had poor selectivity for PAHs versus bulk soil organic matter (approximately 1/4 to 1/3 of the bulk soil organic matter was extracted along with the PAHs), while SFE with pure CO2 removed only 8% of the bulk organic matrix. Selectivities for different compound classes also vary with extraction method. Extraction of urban air particulate matter with organic solvents yields very high concentrations of n- and branched alkanes (approximately C18 to C30) from diesel exhaust as well as lower levels of PAHs, and no selectivity between the bulk alkanes and PAHs is obtained during organic solvent extraction. Some moderate selectivity with supercritical CO2 can be achieved by first extracting the bulk alkanes at mild conditions, followed by stronger conditions to extract the remaining PAHs, i.e., the least polar organics are the easiest organics to extract with pure CO2. In direct contrast, subcritical water prefers the more polar analytes, i.e., PAHs were efficiently extracted from urban air particulates at 250 degrees C, with little or no extraction of the alkanes. Finally, recent work has demonstrated that many pollutant molecules become "sequestered" as they age for decades in the environment (i.e., more tightly bound to soil particles and less available to organisms or transport). Therefore, it may be more important for an extraction method to only recover pollutant molecules that are environmentally-relevant, rather than the conventional attempts to extract all pollutant molecules regardless of how tightly bound they are to the soil or sediment matrix. Initial work comparing SFE extraction behavior using mild to strong conditions with bioremediation behavior of PAHs shows great promise to develop extraction methodology to measure environmentally-relevant concentrations of pollutants in addition to their total concentrations.

Chromatography↗

PubMed2000

Static subcritical water extraction with simultaneous solid-phase extraction for determining polycyclic aromatic hydrocarbons on environmental solids.

A rapid and very simple method for extracting polycyclic aromatic hydrocarbons (PAHs) from soils, sediments, and air particulate matter has been developed by coupling static subcritical water extraction with styrene-divinylbenzene (SDB-XC) extraction discs. Soil, water, and the SDB-XC disc are placed in a sealed extraction cell, heated to 250 degrees C for 15 to 60 min, cooled, and the PAHs recovered from the disc with acetone/methylene chloride. If the cells are mixed during heating, all PAHs with molecular weights from 128 to 276 are quantitatively (>90%) extracted and collected on the sorbent disc and are then recovered by shaking with acetone/methylene chloride. After water extraction, the sorbent discs can be stored in autosampler vials without loss of the PAHs, thus providing a convenient method of shipping PAH extracts from field sites to the analytical laboratory. The method gives good quantitative agreement with standard Soxhlet extraction, and with certified reference materials for PAH concentrations on soil, sediment (SRM 1944), and air particulate matter (SRM 1649a).

Environmental Pollutants↗

PubMed2000

Zona pellucida protein binding ability of porcine sperm during epididymal maturation and the acrosome reaction.

In many mammals, the first interaction between gametes during fertilization occurs when sperm contact the zona pellucida surrounding the egg. Although porcine sperm first contact the zona pellucida via their plasma membrane, the regions of the sperm surface that display zona receptors have not been determined. We have used the Alexa 488 fluorophore conjugated to solubilized porcine zona pellucida proteins to observe zona receptors on live boar sperm. Zona proteins bound live, acrosome-intact sperm on the anterior portion of the sperm head, concentrated in a thin band over the acrosomal ridge. When sperm membranes were permeabilized by fixation or acrosome reactions induced by the ionophore A23187, zona binding was extended to a broad area covering the entire acrosomal region. Zona binding proteins were present in the acrosomes of sperm from all regions of the epididymis. In contrast, zona binding sites were found on the plasma membrane of most sperm from the corpus and cauda epididymis, but on only 6% of caput epididymal sperm. In conclusion, acrosome-intact boar sperm exhibit concentrated zona protein binding over the acrosomal ridge and acquire this binding in the corpus region of the epididymis, correlating with the developmental stage at which sperm gain the ability to fertilize oocytes.

Acrosome Reaction↗

PubMed2000

Impact of HIV-1 infection on VH3 gene repertoire of naive human B cells.

B cells of the largest Ig variable heavy chain gene (VH) family, VH3, are reportedly decreased in patients with late stage HIV-1 disease. This deficit may contribute to their impaired responses to infections and vaccines. We confirmed that the VH3 family was underrepresented in serum IgM proteins, with a 45% decrease in patients with advanced HIV-1 disease. However, the proportion of VH3 within VH(1-6) IgM mRNA from peripheral B cells did not differ from that of control subjects (mean +/- SD, 57.1 +/- 9.7 vs 61.1 +/- 8. 7%). Similarly, within VH(1-6) IgD mRNA, which even more closely represents the unstimulated naive repertoire, the relative expression of VH3 mRNA was comparable in the two groups. Moreover, the frequency of individual genes within the VH3 family for IgD, particularly genes which encode putative HIV-1 gp120 binding sites, also was normal in HIV-1-infected patients. However, VH3 family expression for IgG mRNA was significantly decreased (17%) and VH4 IgG was increased (33%) relative to other VH families in advanced HIV-1-infected patients. Thus, the changes in VH family expression were more readily apparent in previously activated IgG "memory" B cell populations and, likely, in cells actively producing IgM rather than in resting naive cells. The presence of a relatively normal naive VH3 IgM and IgD mRNA repertoire in resting cells supports the prospect that with proper stimulation, particularly in conjunction with effective antiviral therapy, vigorous humoral immune responses to infections and vaccines may be elicited in this high-risk population.

B-Lymphocyte Subsets↗

PubMed2000

Pax gene diversity in the basal cnidarian Acropora millepora (Cnidaria, Anthozoa): implications for the evolution of the Pax gene family.

Pax genes encode a family of transcription factors, many of which play key roles in animal embryonic development but whose evolutionary relationships and ancestral functions are unclear. To address these issues, we are characterizing the Pax gene complement of the coral Acropora millepora, an anthozoan cnidarian. As the simplest animals at the tissue level of organization, cnidarians occupy a key position in animal evolution, and the Anthozoa are the basal class within this diverse phylum. We have identified four Pax genes in Acropora: two (Pax-Aam and Pax-Bam) are orthologs of genes identified in other cnidarians; the others (Pax-Cam and Pax-Dam) are unique to Acropora. Pax-Aam may be orthologous with Drosophila Pox neuro, and Pax-Bam clearly belongs to the Pax-2/5/8 class. The Pax-Bam Paired domain binds specifically and preferentially to Pax-2/5/8 binding sites. The recently identified Acropora gene Pax-Dam belongs to the Pax-3/7 class. Clearly, substantial diversification of the Pax family occurred before the Cnidaria/higher Metazoa split. The fourth Acropora Pax gene, Pax-Cam, may correspond to the ancestral vertebrate Pax gene and most closely resembles Pax-6. The expression pattern of Pax-Cam, in putative neurons, is consistent with an ancestral role of the Pax family in neural differentiation and patterning. We have determined the genomic structure of each Acropora Pax gene and show that some splice sites are shared both between the coral genes and between these and Pax genes in triploblastic metazoans. Together, these data support the monophyly of the Pax family and indicate ancient origins of several introns.

Amino Acid Sequence↗

PubMed2000

Direct magneto-optical observation of a structural phase transition in thin films of manganites.

The spontaneous formation of twins in La(2/3)Ca(1/3)MnO3 films below T(S) approximately 105 K is observed by a magneto-optical technique. The twins are revealed as stripes along the {110} directions where magnetization tilts out of the film plane due to the stresses in twins. Their appearance is associated with a martensitic phase transition in the film triggered by the cubic-to-tetragonal transition in the SrTiO3 substrate. It is found that magnetization of the films proceeds by inhomogeneous rotation of magnetic moments. This is due to the presence of microscopic structural inhomogeneities. Their dominating role in the low-temperature transport can explain small effects of the transition at T(S) on the resistivity.

Journal Article↗

PubMed2000

1,25-dihydroxyvitamin D3 treatment decreases macrophage accumulation in the CNS of mice with experimental autoimmune encephalomyelitis.

Sunlight, which is required for vitamin D biosynthesis, may be protective in multiple sclerosis (MS), due to the immunoregulatory functions of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3), the hormonally active vitamin D metabolite. This hypothesis provided the impetus for the experiments reported here investigating mechanisms whereby 1,25-(OH)2D3 may inhibit murine experimental autoimmune encephalomyelitis (EAE). Severe EAE was induced, 1,25-(OH)2D3 or mock treatment was administered, and clinical disease, histopathological disease, and encephalitogenic cells in the central nervous system (CNS) were analyzed within 24-72 h of the treatment. The mock-treated mice remained paralyzed (stage 3 EAE) while most hormone-treated animals regained the partial use of both hind limbs (stage 2 EAE) within 72 h of treatment. A histopathological examination showed the hormone-treated mice had a 50% decrease in white matter and meningeal inflammation at 72 h post treatment. A flow cytometric analysis of cell surface markers on spinal cord cells recovered 24 h post treatment showed the mock-treated mice with EAE had about 7.0 +/- 2.3 million Mac-1+ cells/cord, whereas the hormone-treated mice had about 2.1 +/- 2.6 million Mac-1+ cells/cord, which was not significantly different from the unmanipulated control mice. Otherwise, the flow cytometric analysis detected no significant differences between the groups with respect to CD4+ or CD8+ T cells or B cells or macrophages in draining lymph nodes or spinal cords. These results are discussed with regard to possible fates for the 5 million Mac-1+ cells that were rapidly lost from the inflamed CNS in the 1,25-(OH)2D3-treated mice, and the possible beneficial effect of hormone treatment in resolving acute MS.

Animals↗

PubMed2000

Static subcritical water extraction combined with anion exchange disk sorption for determining chlorinated acid herbicides in soil.

Static subcritical water extraction (SbWE) was coupled with collection on a strong anion exchange (SAX) disk for the determination of chlorinated acid herbicides and their esters in soil. With 100-150 degrees C water, esters were hydrolyzed into their acid form, and the herbicide acids extracted by subcritical water were trapped onto/into a SAX disk as the extraction cell was cooled. The trapped solutes were then derivatized for gas chromatographic (GC) analysis by placing the disk into a GC autosampler vial containing 1 mL of N,O-bis(trimethylsilyl)trifluoroacetamide derivatizing reagent. With the static SbWE/SAX disk extraction, nearly quantitative recoveries (typically over 80%) were obtained at 100 degrees C for 30 min in the extraction of herbicide acids and esters spiked on several different soils covering a range of organic content from 0.3 to 12%. Good agreements were reached between this method and EPA method 8151 for aged spiked soils. Detection limits of the static SbWE/SAX disk extraction were from 0.05 to 0.5 ppm and from 0.01 to 0.5 ppm using GC/electron capture detector and GC/mass spectrometry, respectively. The method is fast and simple and uses a small amount of organic solvent.

Chlorine↗

PubMed2000

The coral Acropora: what it can contribute to our knowledge of metazoan evolution and the evolution of developmental processes.

The diploblastic Cnidaria form one of the most ancient metazoan phyla and thus provide a useful outgroup for comparative studies of the molecular control of development in the more complex, and more often studied, triploblasts. Among cnidarians, the reef building coral Acropora is a particularly appropriate choice for study. Acropora belongs to the Anthozoa, which several lines of evidence now indicate is the basal class within the phylum Cnidaria, and has the practical advantages that its reproduction is predictable, external and accessible and that the base content of its genome is not strongly biased. The Acropora system has already provided insights into ancestral linkages of homeobox genes and the evolution of the Pax genes, and has the potential to provide further new perspectives on the age, role in development, and evolution of these and other gene families.

Animals↗

PubMed2000

Hemangioblastomas and other uncommon intramedullary tumors.

Astrocytoma and ependymoma make up 90% of intramedullary tumors between them. However, a host of less common tumors form the remaining 10%: these include hemangioblastomas, subependymomas, gangliogliomas and other neuronal variants, metastases from extraneural cancers, and a host of other lesions that typically occur intracranially but which present on rare occasions in the intramedullary location. Most neurosurgeons will encounter the unusual tumors of the spinal cord described in this review only a few times during their professional careers, but it is nevertheless important to recognize the distinct radiological and intraoperative features of those for which significant series of patients have been accumulated. Metastases and germinomas aside, the other neoplasms described here are relatively benign in their clinical and histological behavior, and can be meaningfully resected by careful microsurgical technique.

Ganglioglioma↗

PubMed2000

Examination of species boundaries in the Acropora cervicornis group (Scleractinia, cnidaria) using nuclear DNA sequence analyses.

Although Acropora is the most species-rich genus of the scleractinian (stony) corals, only three species occur in the Caribbean: A. cervicornis, A. palmata and A. prolifera. Based on overall coral morphology, abundance and distribution patterns, it has been suggested that A. prolifera may be a hybrid between A. cervicornis and A. palmata. The species boundaries among these three morphospecies were examined using DNA sequence analyses of the nuclear Pax-C 46/47 intron and the ribosomal DNA Internal Transcribed Spacer (ITS1 and ITS2) and 5.8S regions. Moderate levels of sequence variability were observed in the ITS and 5.8S sequences (up to 5.2% overall sequence difference), but variability within species was as large as between species and all three species carried similar sequences. Since this is unlikely to represent a shared ancestral polymorphism, the data suggest that introgressive hybridization occurs among the three species. For the Pax-C intron, A. cervicornis and A. palmata had very distinct allele frequencies and A. cervicornis carried a unique allele at a frequency of 0.769 (although sequence differences between alleles were small). All A. prolifera colonies examined were heterozygous for the Pax-C intron, whereas heterozygosity was only 0.286 and 0.333 for A. cervicornis and A. palmata, respectively. These data support the hypothesis that A. prolifera is the product of hybridization between two species that have a different allelic composition for the Pax-C intron, i.e. A. cervicornis and A. palmata. We therefore suggest that A. prolifera is a hybrid between A. cervicornis and A. palmata, which backcrosses with the parental species at low frequency.

Alleles↗

PubMed2000

Can relative spermatozoal galactosyltransferase activity be predictive of dairy bull fertility?

The best and poorest bovine semen samples used commercially for artificial insemination in dairy cattle typically differ in pregnancy rates by 20 to 25% but are within a range that pregnancy rates cannot be predicted consistently by commonly used laboratory assays. Sperm motility and morphology are the characteristics most often evaluated. Laboratory assays that measure other functional traits of sperm may be useful as supplemental assays to increase the reliability of predicting fertility. One such functional trait is the ability of sperm to bind to the zona pellucida, a process mediated by complementary receptors on each gamete. On mouse sperm, beta1,4-galactosyltransferase acts as a receptor for the zona pellucida. Beta1,4-galactosyltransferase is expressed on sperm from many mammals, including bovine sperm, and is a candidate for a zona pellucida receptor. The ability of sperm to bind to the zona pellucida may be related to the amount of beta1,4-galactosyltransferase present on sperm. The aim of this work was to determine if bull sperm beta1,4-galactosyltransferase activity was related to fertility. Beta1,4-galactosyltransferase enzyme assays were performed on sperm from 24 bulls whose fertility was estimated by nonreturn rate and on sperm from a second group of seven bulls whose fertility was ranked by in vivo competitive fertilization. Beta1,4-galactosyltransferase activity varied between individual bulls but was not correlated to fertility as estimated by nonreturn rate or by competitive fertilization. These results demonstrate that beta1,4-galactosyltransferase activity on sperm varies between animals, but that beta1,4-galactosyltransferase activity alone is not an accurate indicator of fertility in dairy bulls.

Animals↗

PubMed2000

Coaxial double-lumen methylmethacrylate reconstruction in the anterior cervical and upper thoracic spine after tumor resection.

OBJECT: A unique method of anterior spinal reconstruction after decompressive surgery was used to prevent methylmethacrylate-dural contact in cancer patients who underwent corpectomy. The purpose of this study was to assess the efficacy and stability of polymethylmethacrylate (PMMA) anterior surgical constructs in conjunction with anterior cervical plate stabilization (ACPS) in these patients. METHODS: Approximately 700 patients underwent spinal surgery at The University of Texas M. D. Anderson Cancer Center over a 4-year period. The authors conducted a retrospective outcome study for 29 of these patients who underwent anterior cervical or upper thoracic tumor resections while in the supine position. These patients were all treated using the coaxial, double-lumen, PMMA technique for anterior spinal reconstruction with subsequent ACPS. No postoperative external orthoses were used. Twenty-seven patients (93%) harbored metastatic spinal lesions and two (7%) harbored primary tumors. At 1 month postsurgery, significant improvement was seen in spinal axial pain (p<0.001), radiculopathy (p<0.001), gait (p = 0.008), and Frankel grade (p = 0.002). A total of nine patients (31%) underwent combined anterior-posterior 360 degrees stabilization. Twenty-one patients (72%) experienced no complications. Complications related to instrumentation failure occurred in only two patients (7%). There were no cases in which the patients' status worsened, and there were no neurological complications or infections. The median Kaplan-Meier survival estimate for patients with spinal metastases was 9.5 months. At the end of the study, 13 patients (45%) had died and 16 (55%) were alive. Postoperative magnetic resonance images consistently demonstrated that the dura and PMMA in all patients remained separated. CONCLUSIONS: The anterior, coaxial, double-lumen, PMMA reconstruction technique provides a simple means of spinal cord protection in patients in the supine position while undergoing surgery and offers excellent results in cancer patients who have undergone cervical vertebrectomy.

Adult↗

PubMed2000

Vascular smooth muscle actions of carnosine as its zinc complex are mediated by histamine H(1) and H(2) receptors.

The endogenous dipeptide carnosine (beta-alanyl-L-histidine), at 0.1-10 mM, can provoke sustained contractures n rabbit saphenous vein rings with greater efficacy than noradrenaline. The effects are specific; anserine and homocarnosine are ineffective, as are carnosine's constituent amino acids histidine and beta-alanine. Zinc ions enhance the maximum carnosine-induced tension (to 127 +/- 13% of control at 10 microM Zn(total)) and muscle sensitivity is potentiated (mean K(0.5) reduced from 1.23 mM to 17 microM carnosine with 15 microM Zn(total)). The dipeptide acts as a Zn-carnosine complex (Zn. Carn). The effects of carnosine at 1 microM-10 mM (total) in the presence of 1-100 microM Zn(2+) (total) can be described as a unique function of [Zn. Carn] with an apparent K(0.5) for the complex of [7.4)(10(-8)] M. Contractures are reduced at low [Ca(2+)], unaffected by adrenoceptor antagonists, but can be blocked by antagonists to several receptor types. The most specific effect is by mepyramine, the H(1) receptor antagonist. With Zn present, carnosine can inhibit the H(1)-specific binding of [(3)H]mepyramine to isolated Guinea pig cerebella membranes. This effect of carnosine can be described as a function of the concentration of Zn. Carn with an apparent IC(50) of 2.45 microM. Like histamine, carnosine evoked an H2-mediated (cimetidine-sensitive) relaxation in the presence of mepyramine, but was less potent (10.8 +/- 3.1% of initial tension remaining at 10 mM carnosine compared with 13.4 +/- 7.5% remaining at 0.1 mM histamine). Preliminary studies with a Zn-selective fluorescent probe indicate that functionally significant levels of Zn can be released from adventitial mast cells that could modulate actions of carnosine in the extravascular space as well as those of histamine itself. We conclude that carnosine can act at the smooth muscle H(1)-receptor to provoke vasoconstriction and that it also has the potential to act at H(1)-receptors in the central nervous system. Carnosine's mode of action is virtually unique: a vascular muscle receptor apparently transduces the action of a dipeptide in the form of a metal chelate. The functional relationship of carnosine with histamine and the possible physiological relevance of Zn ions for the activity of both agents have not previously been reported.

Animals↗