Trends in Pharmacological Sciences
ReviewContractile elements in endothelial cells as potential targets for drug action
Abstract
It is now evident that vascular permeability to macromolecules is subject to a direct pressure-independent physiological and pharmacological regulation. Mediator-stimulated increases in vascular permeability and edema formation may be prevented by treatment with endothelial cell stabilizers which function as physiological mediator antagonists. These unique anti-permeability agents inhibit increases in vascular permeability produced by various inflammatory mediators. Since large junctional gap formation in venules is a characteristic feature of inflammation and so many chemically diverse inflammatory mediators participate in inflammatory responses, the development of a novel class of anti-inflammatory agents which act directly on the venular endothelial cell to inhibit mediator-stimulated increases in vascular permeability may well be warranted. George Grega reviews the evidence for supporting this proposal.
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Cited by (20)
Histamine H<inf>3</inf> receptors regulate vascular permeability changes in the skin of mast cell-deficient mice
2003, International ImmunopharmacologyThe participation of histamine H3 receptors in the regulation of skin vascular permeability changes in mast cell-deficient mice was studied. Although intradermal injection of histamine H3 antagonists, iodophenpropit and clobenpropit, at a dose of 100 nmol/site caused significant increases in skin vascular permeability in both mast cell-deficient (WBB6F1 W/Wv) and wild-type (WBB6F1 +/+) mice, this response was significantly lower in mast cell-deficient mice than in the wild-type controls. Histamine also caused dose-related increases in skin vascular permeability in both wild-type and mast cell-deficient mice. Significant effects were observed at doses of 10 and 100 nmol/site, and no significant difference in skin vascular permeability was observed between mast cell-deficient and wild-type mice. However, histamine contents of dorsal skin in mast cell-deficient mice were significantly lower than in wild-type mice. In addition, the H1 antagonists diphenhydramine and chlorpheniramine and the NK1 antagonists, l-732,138 and l-733,060, were able to antagonize H3 antagonist-induced skin vascular permeability. These results indicated that blockade of H3 receptors by H3 antagonists induce skin vascular permeability through mast cell-dependent mechanisms. In addition, histamine and, to a lesser extent substance P are involved in the reaction.
Efficacy of oral doxepin and piroxicam treatment for interstitial cystitis
2002, European UrologyObjective: To establish the efficacy of a multidrug oral treatment with the tricyclic antidepressant agent doxepin and the cyclooxygenase (COX) inhibitor piroxicam in patients with interstitial cystitis (IC), who had failed standard therapy in an open, prospective, nonrandomized study.
Methods: A total of 37 patients diagnosed with IC received 75 mg doxepin and 40 mg piroxicam daily. The treatment was termed DOXCAM. Effectiveness of therapy was assessed with frequency–volume charts, an IC symptom score and with cystometry prior to treatment, 8 weeks after the start and 4 weeks after termination of drug treatment.
Results: Medication was not tolerated by five patients. Twenty-six of 32 patients have experienced virtual total remission of symptoms (81%) and six patients had significant relief (19%). DOXCAM treatment resulted in a significant percent decrease in pain (65% versus 21%). Daytime frequency decreased from 17.6±5.7 to 11.3±3.6 voids while nocturia did not improve significantly. Twenty-three of the 26 patients who became symptom free and four of the six patients who showed significant improvement had a return of symptoms after cessation of therapy.
Conclusion: It is reasonable to consider oral treatment with DOXCAM in those patients who have failed first-line therapies.
Pathophysiology of the kallikrein-kinin system in mammalian nervous tissue
1998, Pharmacology and TherapeuticsThe nervous system and peripheral tissues in mammals contain a large number of biologically active peptides and proteases that function as neurotransmitters or neuromodulators in the nervous system, as hormones or cellular mediators in peripheral tissue, and play a role in human neurological diseases. The existence and possible functional relevance of bradykinin and kallidin (the peptides), kallikreins (the proteolytic enzymes), and kininases (the peptidases) in neurophysiology and neuropathological states are discussed in this review. Tissue kallikrein, the major cellular kinin-generating enzyme, has been localised in various areas of the mammalian brain. Functionally, it may assist also in the normal turnover of brain proteins and the processing of peptide-hormones, neurotransmitters, and some of the nerve growth factors that are essential for normal neuronal function and synaptic transmission. A specific class of kininases, peptidases responsible for the rapid degradation of kinins, is considered to be identical to enkephalinase A. Additionally, kinins are known to mediate inflammation, a cardinal feature of which is pain, and the clearest evidence for a primary neuronal role exists so far in the activation by kinins of peripherally located nociceptive receptors on C-fibre terminals that transmit and modulate pain perception. Kinins are also important in vascular homeostasis, the release of excitatory amino acid neurotransmitters, and the modulation of cerebral cellular immunity. The two kinin receptors, B2 and B1, that modulate the cellular actions of kinins have been demonstrated in animal neural tissue, neural cells in culture, and various areas of the human brain. Their localisation in glial tissue and neural centres, important in the regulation of cardiovascular homeostasis and nociception, suggests that the kinin system may play a functional role in the nervous system.
Kinins and kinin receptors in the nervous system
1995, Neurochemistry InternationalKinins, including bradykinin and kallidin, are peptides that are produced and act at the site of tissue injury or inflammation. They induce a variety of effects via the activation of specific B1 or B2 receptors that are coupled to a number of biochemical transduction mechanisms. In the periphery the actions of kinins include vasodilatation, increased vascular permeability and the stimulation of immune cells and peptide-containing sensory neurones to induce pain and a number of neuropeptide-induced reflexes. Mechanisms for kinin synthesis are also present in the CNS where kinins are likely to initiate a similar cascade of events, including an increase in blood flow and plasma leakage. Kinins are potent stimulators of neural and neuroglial tissues to induce the synthesis and release of other pro-inflammatory mediators such as prostanoids and cytotoxins (cytokines, free radicals, nitric oxide). These events lead to neural tissue damage as well as long lasting disturbances in blood-brain barrier function. Animal models for CNS trauma and ischaemia show that increases in kinin activity can be reversed either by kinin receptor antagonists or by the inhibition of kinin production. A number of other central actions have been attributed to kinins including an effect on pain signalling, both within the brain (which may be related to vascular headache) and within the spinal dorsal horn where primary afferent nociceptors can be stimulated. Kinins also appear to play a role in cardiovascular regulation especially during chronic spontaneous hypertension. Presently, however, direct evidence is lacking for the release of kinins in pathophysiological conditions of the CNS and it is not known whether spinal or central neurones, other than afferent nerve terminals, are sensitive to kinins. A more detailed examination of the effects of kinins and their central pharmacology is necessary. It is also important to determine whether the inhibition of kinin activity will alleviate CNS inflammation and whether kinin receptor antagonists are useful in pathological conditions of the CNS.
Local intravenous treatments for reflex sympathetic dystrophy of the hand : buflomedil versus guanethidine, long-term follow-up
1990, Annales de Chirurgie de la MainLes résultats des traitements de l'algodystrophie de la main par blocs segmentaires pharmacologiques au buflomédil (51 cas) et à la guanéthidine (30 cas), ont été comparés. Ils sont similaires : 65 % (tous stades confondus) de résultats satisfaisants à excellents pour le buflomédil ; 63 % pour la guanéthidine ; et d'autant meilleurs que le délai entre le début de l'algodystrophie et le bloc est plus court. Sur le plan angioscintigraphique, quand la technique est efficace, on assiste à une normalisation de l'hémovélocité et du volume vasculaire correspondant à l'amélioration clinique. Les fixations osseuses précoce et tardive, évoluent indépendamment du traitement. Les techniques de blocs doivent toujours être associées à des techniques physiothérapiques actives douces et éventuellement à des orthèses dynamiques pour prévenir les séquelles fonctionnelles avec rétraction capsulo-aponévrotique.
This report compares the results obtained after treatment of reflex sympathetic dystrophies (algodystrophies) of the hand by pharmacological segmental blocks with buflomedil (51 cases) versus guanethidine (30 cases). The results were similar for all the different stages of algodystrophies treated : 65 % satisfactory to excellent results with buflomedil, versus 63 % with guanethidine. The sooner the algodystrophy is treated after its onset, the better the results. On TPBS, when the technique is effective, both hemovelocity and blood pool return to normal, along with the improvement in the patient's condition. Early and delayed bone fixations evolve independently of the treatment. These techniques should always be associated with active, mild physiotherapy, and in some cases with dynamic splints in order to prevent the development of functional sequelae in the form or capsulo-aponeurotic retraction.
Los resultados del seguimiento de la algodistrofia de la mano por bloqueos segmentarios farmacológicos con buflomedil (51 casos) y con guanetidina (30 casos) se compararon. Son similares : 65 % (todos los estados mezclados) de resultados satisfactorios a excelentes para el buflomedil ; 63 % para la guanetidina, siendo mejor si el tiempo entre el comienzo de la algodistrofia y el comienzo de los bloqueos es más corto. Desde el punto de vista de la angioescintigrafía, cuando la técnica es buena, se observa una normalización de la velocidad sanguinea y del volúmen vascular correspondiendo a una mejoría clinica. La fijación ósea precoz y tardía evolucionan independientemente del tratamiento. Las técnicas de bloqueo siempre deben ser asociadas a técnicas de fisioterápia activa suave y eventualmente a ortésis dinámicas para prevenir las secuelas funcionales con retracción capsulo-aponeurótica.
Ultrastructural localization of choline acetyltransferase in the rat rostral ventrolateral medulla: evidence for major synaptic relations with non-catecholaminergic neurons
1989, Brain ResearchPharmacological and biochemical studies suggest that interactions between cholinergic and catecholaminergic neurons, particularly those of the C1 adrenergic cell group, in the rostral ventrolateral medulla (RVL) may be important in cardiovascular control. Ultrastructural localization of choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine, and its relation to neurons exhibiting immunoreactivity for catecholamine- (tyrosine hydroxylase; TH) or adrenaline (phenylethanolamine-N-methyltransferase; PNMT) -synthesizing enzymes were examined in the RVL using dual immunoautoradiographic and peroxidase anti-peroxidase (PAP) labeling methods. By light microscopy, the ChAT-immunoreactive neurons were located both dorsally (i.e. the nucleus ambiguus) and ventromedially to those labeled with TH or PNMT (TH/PNMT). A few ChAT-labeled processes were dispersed among TH/PNMT-containing neurons with the majority of overlap immediately ventral to the nucleus ambiguus. By electron microscopy, ChAT-immunoreactivity (ChAT-I) was detected in neuronal perikarya, dendrites, axons and axon terminals and in the vascular endothelial cells of certain blood vessels. The ChAT-labeled perikarya in the ventromedial RVL were medium-sized (15–20 μm), elongated, contained abundant cytoplasm and had slightly indented nuclei. Synaptic junctions on ChAT-immunoreactive perikarya and dendrites were primarily symmetric with 64% (45 out of 70) of the presynaptic terminals unlabeled. The remaining terminals were immunoreactive for ChAT (30%) or TH/PNMT (6%). Terminals with ChAT-I were large (0.8–2.0 μm) and contained numerous small clear vesicles and 1–2 dense core vesicles. Seventy-seven percent (112 out of 145) of the ChAT-labeled terminals formed symmetric synapses with unlabeled perikarya and dendrites, whereas only 8% were with TH/PNMT-labeled perikarya and dendrites, and 15% were with ChAT-immunoreactive perikarya and dendrites. We conclude (1) that cholinergic neurons in the RVL principally terminate on and receive input from non-catecholaminergic neurons, and (2) that the reported sympathetic activation following application of cholinergic agents to the RVL may be mediated by cholinergic inhibition of local inhibitory interneurons. The observed synapses between ChAT and TH/PNMT-containing neurons suggests that cholinergic and adrenergic neurons additionally may exert a minor reciprocal control on each other and thus may modulate their response to the more abundant input from afferents containing other transmitters.