Combined contribution of endothelial relaxing autacoides in the rat femoral artery response to CPCA: an adenosine A2 receptor agonist.

We examined the contribution of endothelial relaxing factors and potassium channels in actions of CPCA, potent adenosine A(2) receptor agonist, on isolated intact male rat femoral artery (FA). CPCA produced concentration-dependent relaxation of FA, which was notably, but not completely, reduced after endothelial denudation. DPCPX, A(1) receptor antagonist, had no significant effect, while SCH 58261 (A(2A) receptor antagonist) notably reduced CPCA-evoked effect. Pharmacological inhibition of nitric oxide synthase or cyclooxygenase comparably reduced CPCA-evoked action, still in a lesser degree than after denudation. In the presence of buffer with high K(+) (100 mM), CPCA-produced relaxations were almost abolished. TEA (nonselective K(Ca) blocker), glibenclamide (K(ATP) blocker), Ba(++) (K(IR) blocker), or ouabain (Na(+)/K(+)-ATPase inhibitor) did not change CPCA-induced relaxation. Concentration-response curve for CPCA was significantly shifted to the right after the incubation of apamin (SK channel blocker). CPCA produced concentration-dependent relaxation of FA that was partly dependent on endothelial cells. Endothelium-related portion of CPCA-elicited effect was mediated by combined action of endothelial NO, prostacyclin, and EDHF after activation of endothelial A(2A) receptors. Small conductance K(Ca) channels were involved in this action.

Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution.

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators.

[From quantum to integrative physiology].

Physiology studies the functions of different organs, systems and how they maintain the integrity of organisms. Nervous and endocrine systems react to stimulus, causality plays a key role in their activities. Physical and chemical conditions of fluids in the internal environment serve as a background and an active modulator for regulatory influences. Autacoid formation is in many respects based on probable events. It has been proved, that during the formation of regulatory systems in cell evolution the appearance of regulatory molecules was based on statistical probability of quantum events: sporadical appearance in cells during metabolism of peptides, lipids, hydrolysis of larger molecules on fragments, quanta, which received physiological activity in the form of function regulators. These processes in their adapted, according to Darwin's mechanism of natural selection, value were recorded into the genome since synthesis readings of the polypeptides were fixed. The formation of multicellular organisms was promoted by the arise of regulatory systems and their integration under the supervision of the nervous system.

Lipid autacoids in inflammation and injury responses: a matter of privilege.

Host defense is essential to all vertebrates, and programs of inflammation and wound healing must be highly integrated in tissue and organ structures, such as the skin, cornea, and mucosa, that provide crucial barriers and interfaces with the external environment. Certain aspects of inflammation and wound healing have posed a conundrum for biologists, especially to the extent that the two programs may appear to operate in opposition to each other. The recruitment of neutrophils to injured tissue, for example, is essential to inflammation and defense against infection, but can at the same time impair wound healing. One mechanism for regulating this duality is provided by lipid autacoids, which act to restrain leukocyte activation and to promote the resolution of inflammation. Emerging evidence indicates that lipid autacoids also have a central role in wound healing and in fact mediate a privileged injury response, as is observed in the cornea, characterized by rapid healing as well as effective host defense.

Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs.

Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicin-insensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs. Drugs were administered directly to the Krebs buffer perfusing the extrathoracic trachea. Citric acid was applied topically to the tracheal mucosa, directly into the tracheal perfusate in increasing concentrations and at 1-min intervals. Citric acid dose dependently evoked coughing in anesthetized guinea pigs. This was mimicked by hydrochloric acid but not by sodium citrate. The coughing evoked by acid was nearly or completely abolished by TTX or by cutting the recurrent laryngeal nerves. Perfusing the trachea with a low Cl- buffer potentiated the acid-induced cough reflex. In contrast, prior capsaicin desensitization, 10 microM capsazepine, Ca2+-free perfusate, 0.1 microM iberiotoxin, 1 microM atropine, 10 microM isoproterenol, 10 microM albuterol, 3 microM indomethacin, 0.1 microM HOE-140, a combination of neurokinin1 (NK1; CP-99994), NK2 (SR-48968), and NK3 (SB-223412) receptor antagonists (0.1 microM each), a combination of histamine H1 (3 microM pyrilamine) and cysLT1 (1 microM ICI-198615) receptor antagonists, superior laryngeal nerve transection, or epithelium removal did not inhibit citric acid-evoked coughing. These and other data indicate that citric acid-evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels.

Rat model of platelet-activating factor-induced rhinosinusitis.

Platelet-activating factor (PAF) is known to be a potent inflammatory mediator, especially in allergic inflammation. However, the exact role of PAF in the pathogenesis of rhinosinusitis has not been clearly established. To understand the role of PAF in the pathogenesis of rhinosinusitis, it is necessary to develop an animal model of PAF-induced rhinosinusitis. The aim of this study was to develop a rat model of rhinosinusitis induced by intranasally applied PAF. Fifty microliters of 16 microg/mL PAF was applied intranasally through each naris in 4-week-old Sprague-Dawley rats, and the same amount of vehicle was applied in control rats. At 1, 3, or 5 days, the animals were painlessly sacrificed, and the nasal cavity and sinuses were prepared for histologic investigation. The histologic sections were examined in a blind manner for the appearance of neutrophil clusters in the sinonasal air space, and the numbers of eosinophils, areas of epithelial loss, goblet cells, and inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the mucosa. Neutrophil clusters were observed in the air space, and the number of eosinophils, areas of epithelial loss, goblet cells, and iNOS-positive inflammatory cells in the mucosa were increased significantly in the PAF-applied rats. The amount of inflammation varied according to the time interval, showing a peak at day 3. We conclude that intranasally applied PAF induces rhinosinusitis in rats. The histologic evidence of rhinosinusitis revealed the appearance of neutrophil clusters in the sinonasal air space, infiltration of eosinophils and iNOS-positive inflammatory cells in the mucosa, areas of epithelial loss, and goblet cell hyperplasia in the epithelium. This rat model of PAF-induced rhinosinusitis may be applied for better understanding of the role of PAF in the pathogenesis of rhinosinusitis.

Cardiotoxicity of digitalis glycosides: roles of autonomic pathways, autacoids and ion channels.

1 Cardiac glycosides have been used for centuries as therapeutic agents for the treatment of heart diseases. In patients with heart failure, digoxin and the other glycosides exert their positive inotropic effect by inhibiting Na(+)-K(+)-ATPase, thereby increasing intracellular sodium, which, in turn, inhibits the Na(+)/Ca(2+) exchanger and increases intracellular calcium levels. As the therapeutic index of digitalis is narrow, arrhythmias are common problems in clinical practice. The mechanisms and mediators of these arrhythmias, however, are not completely understood. 2 The involvement of the sympathetic and parasympathetic nervous system in digitalis cardiac toxicity is reviewed. 3 Receptors, channels, exchange systems or other cellular components involved in digitalis-induced cardiotoxicity are also reviewed. 4 Possible mediators of digitalis-induced cardiac toxicity are discussed. 5 Management of digitalis toxicity in patients is summarized. 6 The determination of the possible mediators of digitalis-induced cardiac toxicity will enhance our knowledge and lead to the development of new therapeutic strategies to treat these lethal arrhythmias.

[Study of autacoids role in the regulation of circadian rhythm of the human renal function].

The circadian rhythm of urine formation was studied in younger (27 +/- 8 yr) and aged (76 +/- 3 yr) males. In 11 younger healthy examined persons a decrease of diuresis during the night as compared with the day time was due to a rise of solute free water reabsorption. In 31 aged males the change of the urine formation rhythm with increase of the nocturnal diuresis is based on a rise of osmolal clearance combined with an increase of the solute free water reabsorption. It is shown that blockade of autacoid secretion leads to normalization of the diuresis circadian rhythm. In 10 aged men, nocturia was due to a decrease of vasopressin secretion which resulted in a decrease of the solute free water reabsorption and an increase of diuresis. The obtained data are considered as an evidence for the role of renal autacoids, alongside with vasopressin, in regulation of the circadian rhythm of the kidney function.

[Architecture of physiological functions: the same basis but new aspects]. / Arkhitektura fiziologicheskikh funktsii: tot zhe fundament, novye grani.

The principles of physiological functions formulated by J. Barckroft (constancy of the internal medium, reserves, any adaptation as an integration, principle of antagonism, doubling of mechanisms) are compared with principles of modern physiology. The place and role of physiology in the life sciences are discussed. The necessity of taking into consideration 4 level of regulation of functions (the nervous system, hormones, autacoids, physicochemical factors of the extracellular fluid) is substantiated, as well as the necessity of identification of 4 levels of organization of physiological systems. The main role of the water-salt homeostasis in maintaining the cell volume is suggested. Significance of various types of receptors and second messengers in regulation and modulation of functions is shown.

Endogenous morphine and codeine. Possible role as endogenous anticonvulsants.

Exogenously administered morphine can have both convulsive or anticonvulsive effects, depending on the dose and species. The levels of the endogenous opiate alkaloids morphine and codeine were significantly elevated in specific rat brain regions by the convulsive drug, pentylenetetrazole, as well as by the anticonvulsant drugs, carbamazepine and phenytoin. Morphine and codeine levels in peripheral tissues (heart, lung, spleen and adrenal) were unaffected by these drugs. Maximal increases in morphine levels were seen in the hypothalamus and striatum (2-10-fold), while lesser increases occurred in the midbrain and brain stem (2-4-fold). Codeine levels were also markedly increased in hypothalamus (5-10 fold), In contrast to morphine, codeine levels were also increased in the hippocampus (2-10-fold), but were unchanged in the striatum. These studies suggest that the endogenous alkaloids morphine and codeine are involved in the modulation of convulsions and that morphine and/or codeine may act as an endogenous anticonvulsant.

Interaction of endothelial autacoids in microvascular control.

The endothelium releases dilating autacoids, such as nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF). Different mechanisms of interaction between these autacoids have been identified and are briefly reviewed here. NO, which dilates resistance vessels via the second messenger cGMP, also amplifies the responses to vasodilators, which act by elevation of cAMP (e.g., prostaglandins), in a synergistic manner. This amplification is most likely due to a cGMP-dependent inhibition of the breakdown of cAMP. An interaction of these autacoids can not only be found in vascular smooth muscle cells but also in the endothelium. A closer look towards the site of production reveals that prostacyclin attenuates the release of NO, which is achieved by a decrease of the intracellular calcium levels in endothelial cells. This feedback mechanism leads to enhanced NO formation after inhibition of cyclooxygenase. While NO does not seem to modulate prostaglandin synthesis, it has been shown recently in coronary arteries that NO attenuates the release of EDHF. Under conditions of compromised NO formation EDHF might act via this mechanism as a second line of defense. This could help in maintaining endothelium-dependent vasodilation unless an altered smooth muscle responsiveness generally reduces the efficacy of endothelial vasodilators (including EDHF). Convincing experimental evidence for such an impaired relaxation of smooth muscle has been presented recently following exposure to elevated oxLDL levels.