Unified description of endoreversible cycles.
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Journal Article↗
Biomedical subjects
Z Yan
Publications and source records attributed to Z Yan.
Control of vascular permeability and vascular smooth muscle in the respiratory tract by multiple neuropeptides.
Recent evidence suggests that a population of primary afferent neurons which terminate in the upper and lower airways contains several coexisting peptides. Thus, substance P was found to coexist with at least three structurally related tachykinins, viz. neurokinin A, neuropeptide K and an eledoisin-like peptide. Furthermore, calcitonin gene-related peptide which is structurally not related to tachykinins is also present in the same neurons which innervate a variety of peripheral tissues. Substance P, neurokinin A, eledoisin-like peptide and calcitonin gene-related peptide can simultaneously be released from central and peripheral branches of primary sensory neurons, whereas a release of neuropeptide K could not be demonstrated. Local inflammatory mediators like bradykinin or histamine also released multiple peptides in the airways and caused vascular protein leakage which is partly dependent on intact sensory nerves. In experimental animals, tachykinins as well as calcitonin gene-related peptide caused vasodilatation, whereas tachykinins but not calcitonin gene-related peptide caused an increase in vascular protein leakage. In humans, intranasally administered substance P (but not calcitonin gene-related peptide) lead to nasal obstruction as measured by rhinomanometry, and to secretion. It is suggested that activation of peripheral endings of perivascular primary sensory neurons causes vasodilatation and increase in vascular protein leakage by simultaneous action of several neuropeptides including tachykinins and calcitonin gene-related peptide.
Animals↗
Effects of clonidine and yohimbine on a C-fibre-evoked blood pressure reflex in the rat.
1. The involvement of alpha 2-adrenoceptors in a capsaicin-induced depressor reflex in the rat has been investigated. 2. The reflex fall in blood pressure following an intra-arterial injection of capsaicin was partially blocked by an intrathecal infusion of clonidine (1 microgram) at the spinal cord level L4-L5, an effect which was abolished by the prior intrathecal infusion of yohimbine (5 micrograms). 3. Clonidine (1 microgram) given intracisternally blocked the depressor reflex almost completely; however, it also produced a gradual, prolonged fall in mean carotid pressure. 4. Yohimbine (20 micrograms) given intracisternally did not change mean blood pressure but had a dual effect on the depressor reflex in response to the capsaicin injection: a short period of enhanced reflex response was followed by a long lasting inhibition of the response. 5. It was concluded that alpha 2-adrenoceptors in the spinal cord inhibit the capsaicin-evoked depressor reflex and that pre- and postsynaptic alpha 2-adrenoceptors in the brain stem modulate this reflex.
Animals↗
Release of multiple tachykinins from capsaicin-sensitive sensory nerves in the lung by bradykinin, histamine, dimethylphenyl piperazinium, and vagal nerve stimulation.
Recent evidence suggests that activation of airway C-fibers, besides causing afferent transmission, also causes release of transmitters from peripheral endings, probably via local axon reflexes, resulting in effects on vascular and bronchial smooth muscle, i.e., vasodilatation, increase in vascular permeability, and bronchoconstriction. In the present study, the release of tachykinins was investigated in the perfused guinea pig lung by various ways of neuronal activation. Substance-P-like immunoreactivity (SP-LI) and neurokinin-A-like immunoreactivity (NKA-LI) was determined by radioimmunoassay in the perfusates. A significantly increased outflow of both SP-LI and NKA-LI was observed during perfusion of the lung with high potassium concentration (60 mM), the C-fiber activator capsaicin (1 microM), bradykinin (1 microM), histamine (100 microM), or the nicotinic agonist dimethylphenyl piperazinium (DMPP) (32 microM). Release of both SP-LI and NKA-LI could also be achieved by electrical stimulation of vagal nerves. The percental increase varied from 80 to 1,000% depending on the kind of stimulus. The release of tachykinins by K+ or capsaicin was greatly reduced in calcium-free medium. Release by histamine was completely inhibited by 1 microM mepyramine, and release by DMPP was abolished by 20 microM hexamethonium. High performance liquid chromatography indicated that NKA-LI consisted of several cross-reacting substances, presumably other peptides of the tachykinin family. Among the isolated mammalian tachykinins, NKA was the most potent one to contract tracheal smooth muscle of guinea pigs in vitro, followed by neurokinin B and by SP. Both NKA and SP relaxed the guinea pig pulmonary artery with similar potency.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Metabolic assessment in liver microsomes by co-activating cytochrome P450s and UDP-glycosyltransferases.
A "dual-activity" microsomal system in which both CYPs and UGTs were active was evaluated for studies of metabolic stability and in-vitro metabolite profiling. In this "dual-activity" system, alamethicin, a pore-forming peptide, was used to activate UGTs in human liver microsomes without affecting CYP activity. Interference studies indicated that CYP cofactors had little effect on UGT surrogate activity as measured by glucuronidation of acetaminophen and trifluoperazine. Further, UGT cofactor, UDPGA (< 2 mM), did not inhibit the marker activity of five major CYPs including 1A2, 2C9, 2C19, 2D6 and 3A4, suggesting that both oxidation and glucuronidation can be co-activated in microsomes. In a comparison study, compounds with significant glucuronidation showed distinct stability profiles in the "dual-activity" system, compared to the conventional microsomal incubation in which only CYPs were active. For compounds with minor or no glucuronidation, the metabolic stability remained similar between the "dual-activity" system and the conventional microsomal incubation. The feasibility of this "dual-activity" system utilized for metabolite profiling was also investigated using tramadol as a model drug. It was found that oxidative metabolites of tramadol generated in the "dual-activity" system matched those detected in the conventional microsomal incubation. However, tramadol glucuronide was observed in the "dual-activity" system but not in the conventional micromosal incubation. Results clearly suggest that the "dual-activity" system is a valuable in vitro model for metabolism studies in drug discovery.
Alamethicin↗
Rapidly distinguishing reversible and irreversible CYP450 inhibitors by using fluorometric kinetic analyses.
In this study we have evaluated the reliability of a fluorescence-based method used for rapid identification of irreversible CYP inhibitors (mechanism-based inhibitors). This was accomplished by comparing the time-dependence pattern of IC50 values from fluorometric kinetic measurements. For irreversible CYP inhibitors, IC50 values decreased as incubation proceeded. This was due to progressive inactivation of corresponding enzymes by reactive metabolites generated during the incubation. This change pattern was confirmed using a number of known irreversible CYP inhibitors, including furafylline, midazolam, erythromycin, clarithromycin, oleandomycin, 17alpha-ethynylestradiol and verapamil. The pattern was different in reversible inhibition, depending upon the compounds tested in the fluorometric kinetic assay. For some compounds, such as clotrimazole, IC50 values remained relatively stable, whereas other compounds, such as miconazole, terfenadine and ketoconazole showed a significant increase with incubation time. Monitoring tested compounds by LC-MS/MS during the incubation confirmed that increases of IC50 were probably caused by the loss of inhibitors, resulting from either metabolic degradation, or non-specific binding to microsomal proteins.
Chromatography, Liquid↗
A low-power, "architectural," clue to the follicular variant of papillary thyroid adenocarcinoma in aspiration biopsy.
OBJECTIVE: To search for low-power, or "architectural," clues to the diagnosis of the follicular variant of papillary thyroid adenocarcinoma (FVP) in Diff-Quik-stained aspiration biopsy smears in order to aid in the rapid diagnosis of FVP, especially as a complement to frozen sections. STUDY DESIGN: The smears of 23 cases, each with tissue-proven FVP, were compared to those of 23 cases of classic papillary thyroid adenocarcinoma (PTA), 23 cases of tissue-proven follicular neoplasms (FN) (i.e., adenoma or well-differentiated adenocarcinoma) and 23 samples of colloid nodules (CN). The low-power (10x) features of the four groups were studied and compared. RESULTS: Our study showed that FVP exhibited monolayered cellular sheets with branched, irregular contours, which can be distinguished from the uniform microfollicles with smooth contours formed in FN and the large, round or oval monolayered sheets of follicular cells found in CN. FVP shared all of the features of classic PTA except for the larger, complex sheets of epithelial cells and psammoma bodies found in the latter. CONCLUSION: The branched sheets of epithelial cells evident during low-power examination of Diff-Quick-stained smears of thyroid aspirates are a ready first clue to the rapid diagnosis of FVP. The diagnosis can be confirmed by subsequent careful evaluation of nuclei in Papanicolaou-stained smears and sections of tissue.
Adenocarcinoma, Papillary↗
Overexpression of inducible nitric oxide synthase by neointimal smooth muscle cells.
The formation of a neointima represents an important repair mechanism in response to vascular injury. It is associated with the expression of a specific set of genes by the intimal smooth muscle cells. Recently, expression of the inducible isoform of NO synthase (iNOS) has been identified in injured arteries during neointimal formation, suggesting that intimal SMCs have a unique mechanism for regulating NO production. Therefore, we have analyzed the expression of iNOS in intimal SMCs. Although first expressed in the media within 1 day after injury, iNOS was confined to neointimal smooth muscle cells at 1 to 2 weeks after injury. Isolated intimal SMCs were found to consistently reexpress iNOS in reaction to proinflammatory mediators. This was associated with a 5- to 8-fold higher output of NO in comparison with SMCs derived from the media of uninjured arteries. Western blot and Northern blot analyses likewise revealed that the high production of NO by intimal SMCs was due to overexpression of iNOS. Moreover, the same stimuli induced a higher transcriptional activity in intimal than in medial SMCs, as detected by transfection of a reporter gene under the iNOS promoter. Induction of iNOS led to a reduced proliferation in both medial and intimal SMCs. This inhibitory effect was, however, less pronounced in intimal than in medial SMCs. Similarly, intimal cells were less sensitive to NO-induced inhibition of mitochondrial respiration. When SMC clones were analyzed, there was no correlation between iNOS expression and growth pattern, suggesting that iNOS expression is independent of the morphological phenotype of SMCs. Together, our data show that the intimal SMC is the main iNOS-expressing cell type in the injured artery, that it responds more vividly to iNOS-inducing cytokines because of a more efficient activation of the iNOS promoter, and that it is more resistant to the actions of NO compared with medial SMCs. Intimal production of NO via the inducible pathway may be important for the restoration of vascular homeostasis after injury.
Animals↗