Effect of Cholecystokinin-8 (CCK-8) on Blood Pressure and Blood Content of Calcitonin-Gene-Related Peptide (CGRP) in Rats with Hypertension Caused by Fructose or Inhibition of Nitric Oxide Synthesis.

We studied the effect of CCK-8 on BP and blood content of CGRP in rats with hypertension caused by fructose or inhibition of NO synthase with L-NAME. The decrease in the CGRP content was found during the development of fructose-induced hypertension, but not L-NAME-caused hypertension. Administration of CCK-8 to fructose-fed animals reduced BP and increased the content of CGRP. In rats with hypertension caused by NO deficit, CCK-8 lowered BP, but did not affect the content of CGRP. These findings suggest that CGRP mediates the hypotensive effect of CCK-8 in fructose-induced hypertension, but not in NO-deficient hypertension.

Effect of Transcutaneous Electrical Stimulation of Nerves on Blood Pressure and Blood Content of Neuropeptide CGRP and Nitric Oxide in Hypertensive Rats with Metabolic Disturbances.

The development of arterial hypertension in male Wistar rats with fructose-induced metabolic syndrome (12.5% of fructose solution as the only drinking source for 10 weeks) along with impaired glucose tolerance and increased serum concentration of triglycerides and LPO products caused a decrease in the content of serum blood calcitonin gene-related peptide (CGRP). Low-frequency transcutaneous electrical nerve stimulation (1 mA, 2 Hz, 10 min daily for 2 weeks) performed in 8 weeks after the beginning of fructose treatment reduced systolic BP and serum concentration of triglycerides and LPO produces and improved glucose tolerance. After stimulation, CGRP content in rats maintained on fructose diet returned to normal values and the content of nitric oxide metabolites increased. We hypothesize that CGRP and nitric oxide are involved in mechanisms mediating the therapeutic effect of low-frequency transcutaneous electrical nerve stimulation on arterial hypertension developing in metabolic syndrome.

[ROLE OF CAPSAICIN-SENSITIVE NERVES IN THE REGULATION OF DEHYDROEPIANDROSTERONE SULFATE BLOOD CONTENT UNDER NORMAL AND FRUCTOSE-INDUCED METABOLIC SYNDROME].

The effects of the stimulation of capsaicin-sensitive nerves (capsaicin, 1 mg/kg, s/c) and their eafferentation (capsaicin, 150 mg/kg, s/c) on the blood content of dehydroepiandrosterone sulfate (DHEAS) was investigated in normal rats and rats with fructose-induced metabolic syndrome (12.5% fructose solution, 10 weeks). An increase in blood of tryglyceride, lipid peroxidation, glucose (fasting and after loading glucose, 2 mg/kg, i/p) was considered as symptoms of metabolic syndrome. It was shown that in normal rats drinking tap water the stimulation of capsaicin-sensitive nerves resulted in the increase of DHEAS content while their deafferentation reduced the concentration of this hormone in the blood. The fructose diet caused the decrease in content of DHEAS, triglyceridemia, lipid peroxidation, impaired tolerance glucose. In rats with the metabolic syndrome the stimulation capsaicin-sensitive nerves prevented the fructose-induced decrease of DHEAS content as well as decreased the symptoms of metabolic syndrome. In fructose fed rats the stimulation-induced effects were prevented by the deafferentation of capsaicin-sensitive nerves. It is suggested that capsaicin-sensitive nerves contribute both to the regulation of blood content of DHEAS under normal and fructose-induced metabolic syndrome.

[The effect of destruction of rat capsaicin-sensitive nerves on blood pressure in rats with metabolic syndrome].

The effect of destruction of capsaicin-sensitive nerve (capsaicin 150 mg/kg, s/c) on blood pre- ssure was investigated in rats with metabolic syndrome induced by fructose (12.5% in drinking water for 10 weeks). The blood plasma concentrations of glucose, triglyceride (TG) and products of lipid perioxidation were defined in these rats. The systolic blood pressure was measured by non-invasive method using the Coda system (Coda, Kent Scientific, USA). The fructose diet caused impaired tolerance glucose, arterial hypertension, increased the contents of TG and products of lipid peroxidation. In capsaicin--pretreated rats (deafferentiation of capsaicin-sensitive nerve) the fructose intake did not evoke impairment tolerance glucose, the increase of systolic blood pressure and the plasma content of triglyceride. The increase of lipid perioxidation in fructose fed rats was not prevented by capsaicin pretreatment. The authors suggest that capsaicin-sensitive nerves contribute to the development of insulin resistance and arterial hypertension in the metabolic syndrome.

[Effects of capsaicin on oxidative modification of blood plasma proteins and arterial blood pressure in fructose-fed rats].

The influence of the activation of capsaicin-sensitive nerves with capsaicin on the oxidative modification of blood plasma proteins and arterial blood pressure was studied in Wistar rats fed with 12.5% fructose in drinking water for 10 weeks. The obtained results indicate that fructose feeding induces an increase in the arterial blood pressure and the content of plasma blood protein carbonyl derivates. At the same time, in hypertensive rats, the stimulation of sensory nerves by capsaicin (1 mg/kg, i.p.) decreases the content of oxidized proteins in the plasma and normalizes the arterial blood pressure. It is suggested that capsaicin-sensitive nerves are involved in the regulation of oxidative destruction of proteins as well as in blood pressure control under metabolic disturbances produced by prolonged fructose feeding.

[Morphological parameters of the liver in rats during changes in nitric oxide content and deafferentation with capsaicin].

The aim of this investigation was to study the morphological changes of rat liver during the blockade of nitric oxide (NO) synthesis and its increased content in the intact rats and after the damage of capsaicin-sensitive nerves. It was shown that the damage of capsaicin-sensitive nerves resulted in dystrophic and necrotic changes in the liver, associated with the inflammatory reaction. These changes were enhanced by the blockade of NO-synthase. NO deficiency, caused by NO-synthase blockade, lead to disturbances of vascular bed control, resulting in ischemia and hypoxia, and, as a consequence, in dystrophic and necrotic changes in hepatocytes. The data obtained indicate that in the development of dystrophic changes after the modification of the function of capsaicin-sensitive nerves, along with the decrease in the sensory neuropeptide content, the significant role is played by NO-dependent machanisms. Administration of NO precursor, L-arginine, after deafferentation with capsaicin, inhibited the inflammatory reactions in the liver.

[Oxidative modification of rat blood proteins after destruction capsaicin-sensitive nerve and change of nitric oxide level].

Content of blood protein carbonyl derivates in rats are determined to assess oxidative modification of protein after destruction of capsaicin-sensitive nerve and change of nitric oxide (NO) level. Deafferentation of these nerves produces increase of the protein carbonyl derivates content. The increase of NO by L-arginine does not affect protein oxidative destruction produced by ablation of capsaicin-sensitive nerve. Selective inhibitor of neuronal synthase NO (n-NOS) 7-nitroindazole (7-NI) results in similar effect. L-NAME increased oxidative destruction of proteins. These results demonstrate that deafferentation of capsaicin-sensitive nerve induces oxidative destruction of proteins. NO has party to mediating oxidative modification of proteins.

[Disturbed microvascular permeability in the eye caused by capsaicin microinjections into the trigeminal caudalis nucleus].

Capsaicin microinjection into the trigeminal caudalis nucleus (the central projection area of trigeminal capsaicin-sensitive nerve) increase extravasation of proteins in rat eye. The effect was inhibited by ruthenium red introduction (a capsaicin receptor antagonist) and by blocking the effector functions of capsaicin-sensitive nerve endings. It is suggested that capsaicin stimulation of central terminations of trigeminal capsaicin-sensitive afferents induce an increase in the microvascular permeability of the eye, which is mediated through the effector function of capsaicin-sensitive nerves.

Role of nitric oxide in the regulation of activity of proteinase inhibitors alpha(1)-antitrypsin and alpha(2)-macroglobulin by capsaicin-sensitive nerves.

Regulation of activity of serine proteinase inhibitor a1-antitrypsin and nonspecific proteinase inhibitor alpha(2)-macroglobulin in the blood by nitric oxide was studied in intact rats and animals with damage to capsaicin-sensitive nerves. Nonselective nitric oxide synthase inhibitor L-NAME produced a dose-dependent increase in alpha(1)-antitrypsin activity in intact animals. Neuronal NO synthase inhibitor 7-nitroindazole increased alpha(2)-macroglobulin activity. Deafferentation with capsaicin was followed by a decrease in alpha(1)-antitrypsin activity. Both inhibitors of nitric oxide synthase increased activity of alpha(1)-antitrypsin in capsaicin-receiving rats. Nitric oxide precursor L-arginine had a normalizing effect on reduced activity of alpha(1)-antitrypsin after capsaicin deafferentation. Our results suggest that nitric oxide has a modulatory effect on activity of proteinase inhibitors and is involved in the effector influence of capsaicin-sensitive nerves on alpha(1)-antitrypsin activity.

Blood protein reactions to ablation of capsaicin-sensitive neurons.

The effects of ablation of afferent neurons with neurotoxic doses of capsaicin (150 mg/kg) on protein levels in plasma fractions were studied by polyacrylamide gel electrophoresis in Wistar rats at different times points after administration of capsaicin and in inflammatory reactions induced by zymosan (10 mg/100 g). Administration of neurotoxic doses of capsaicin induced biphasic changes in protein levels in plasma fractions. During the initial period (up to seven days), "acute-type" changes in protein content were seen; at 11-30 days, there were chronic increases in the albumin level with decreases in alpha(1), alpha(2), and gamma globulins. Defunctionalization of capsaicin-sensitive nerves 14-30 days before induction of inflammation prevented the "acute-phase" changes in protein contents in the albumin, alpha(1), alpha(2), and beta globulin fractions in response to induction of inflammation with zymosan.

[Alternative changes of activity of alpha2-macroglobulin and alpha1-antitrypsin in rat blood following damage in capsaicin-sensitive nerves].

Effects of functional ablation of peptidergic sensory nerves with neurotoxic doses of capsaicin (150 mg/kg, s/c) as well as of their stimulation with small doses of capsaicin (5 mg/kg, i/p) on activity of proteinase inhibitors: alpha1-antitrypsin (alpha1-AT)-serine proteinase inhibitor and alpha2-macroglobulin (alpha2-MG)-nonspecific inhibitor were investigated in rat blood. The present results indicate alternative changes in activity of these proteinase inhibitors after damage of capsaicin-sensitive nerves: increasing decline in activity of alpha1-AT 1 and 3 or 14 days after administration of capsaicin and increase in activity of alpha2-MG land 3 day after the injection. The stimulation of afferent nerves with capsaicin did not change activity of the proteinase inhibitors 1 and 24 hours after the injection. It is suggested that the stable decrease in activity of alpha1-AT during a long period after the damage of capsaicin-sensitive nerves indicates an important role for these nerves in the regulating alpha1-AT that may exert a tonic effect on the activity alpha1-AT.

[The response of the blood proteins to ablation of the capsaicin-sensitive nerves].

Effects of neurotoxic doses of capsaicin (150 mg/kg) on the protein content in electrophoretic fractions (PAAG) in the Wistar rat plasma were studied. In early period (7 days) after administration of capsaicin, an increase of the alpha1-, alpha2-globulins and a decrease of the albumin, gamma-globulins, were observed. After 14-30 days, increase of the albumin and decrease of the alpha1-, gammay-globulins were detected. The ablation of the capsaicin-sensitive nerves abrogated the changes of positive and negative acute phase reactants induced by zymosan and diminished the content of gamma-globulins.

Effect of cysteine protease inhibitor Ep-475 on TNF-alpha-independent cyclophosphamide-induced apoptosis in mouse lymphosarcoma LS cells.

Cyclophosphamide 1.5-2.0-fold increased activity of cathepsins B and L in tumor tissue of mouse lymphosarcoma LS and caused tumor regression. The effect was most pronounced on day 5 after treatment. Twofold treatment with a selective cathepsin inhibitor Ep-475 slightly stimulated tumor growth in control mice and significantly reduced the antitumor effect of cyclophosphamide. Lysosomal cysteine proteases cathepsins B and L are involved, but do not play a key role in TNF-alpha-independent apoptosis in LS cells induced by cyclophosphamide.

[Effect of damages of capsaicin-sensitive nerves on alpha1-antitrypsin activity in the rat blood]. / Vliianie povrezhdeniia kapsaitsin-chuvstvitel'nykh nervov na aktivnost' al'fa1-antitripsina v krovi krys.

Systemic administration of capsaicin (a neurotoxin of afferent nerves) in a dose of 150 mg/kg led to a decrease in the activity of alpha 1-antitrypsin (alpha 1-AT) in the blood of male Wistar rats. This effect is related to impairment of the local effector function of capsaicin-sensitive nerves in the liver, which is the main source of alpha 1-AT in the blood. Analogous results were obtained upon cutting of the hepatic branch of the vagus nerve involving capsaicin-sensitive afferent fibers of the liver.

[Comparative characteristic of serpin--alpha-1 proteinase inhibitor in human and mice serum]. / Sravnitel'naia kharakteristika serpina--alfa-1-proteinaznogo ingibitora syvorotki krovi cheloveka i myshei.

Serpin alpha-1-proteinase inhibitor have been studied in human subjects and in mice of different lines as acute phase reactant and during tumor development. In humans, there was no difference of serpin activity between men and women. Increased activity was noted in men with acute trauma (acute phase reaction). Comparatively to male, in female mice of different lines decreased activity of serum alpha-1-proteinase inhibitor, was shown. There was no increase of alpha-1-proteinase inhibitor activity during inflammation induced by zymosan administration in mice. alpha-1-proteinase inhibitor belongs to acute phase reactants in humans but not in mice; for mice alpha-2-macroglobulin is a more typical acute phase reactant as compared to alpha-1-proteinase inhibitor. Murine tumor development (hepatoma HA-1, lymphosarcoma LS, Lewis lung adenocarcinoma) was followed by a decreased activity of serum alpha-1-proteinase inhibitor both in successfully treated and untreated groups. According to data of literature, similar dated were obtained in humans with tumors. It was suggested that changes of expressiln of alpha-1-proteinase inhibitor by tumors and its secretion were involved in decreased activity of alpha-1-proteinase inhibitor.

The effects of stimulation and lesioning of afferent nerves on blood glucose and free fatty acid contents in rats in conditions of changing glycemia.

Studies were performed on the effects of activation of afferent nerves with capsaicin (5 mg/kg i.p.) and lesioning of these nerves with neurotoxic doses of capsaicin (50 mg/kg, s.c. in two-day-old rats and 200 mg/kg s.c. in adult rats) on serum glucose and free fatty acid (FFA) concentrations in conditions of changing glucose levels induced by administration of insulin and glucose to starved (16 h) Wistar rats. These studies showed that capsaicin stimulation of intact rats decreased the hypoglycemic action of insulin, increased hyperglycemia following glucose dosage, increased FFA levels, and prevented the FFA-lowering effect of insulin. Neonatal treatment with capsaicin decreased the hypoglycemic effect of insulin but had no effect on hyperglycemia following glucose doses, but decreased FFA levels. Treatment of adult rats with neurotoxic doses of capsaicin did not alter the effect of insulin on glucose levels and decreased FFA concentrations. Capsaicin stimulation in rats following treatment with neurotoxic doses had no effect on the hypoglycemic action of insulin, but prevented it from affecting the FFA concentration.

[Effects of stimulation and damage of afferent nerves on the glucose and free fatty acid levels in the rat blood under various glycemic conditions]. / Vliianie stimuliatsii i povrezhdeniia afferentnykh nervov na soderzhanie gliukozy i svobodnykh zhirnykh kislot v krovi krys pri izmenenii glikemii.

Capsaicin stimulation of afferent neurones increased hyperglycaemic responses to glucose and decreased hypoglycaemia in control rats. Elevation of the free fatty acids level occurred following both the stimulation alone and that combined with insulin. Neonatal capsaicin pre-treatment decreased the hypoglycaemic response effect of insulin and the FFA level. Treatment of adult rats with capsaicin did not affect hypoglycaemia following insulin administration but did decrease the FFA level. In capsaicin pre-treated rats, the capsaicin stimulation exerted no effect upon the hypoglycaemia following insulin administration but abolished the insulin effect on the FFA level. The findings suggest that the capsaicin-sensitive nerves play a major role in mediating the glucose and the FFA metabolic responses.

[Structural changes in the tissues of white rats after capsaicin administration]. / Strukturnye izmeneniia tkanei belykh krys posle vvedeniia kapsaitsina.

Tissue structure of albino rat lung, skin and cornea changing after administration of capsaicin (neurotoxin isolated from red pepper) was studied using light and electron microscope. 5 mg/kg dose causes tissue swelling and microcirculatory bed reaction. 200 mg/kg dose leads to more significant dystrophic tissue alterations. Fibrosclerosis signs were found in certain cases. Microcirculatory disorders are proposed as the main reason for tissue structure alterations observed, although the mechanism of their development is still unclear.

[Reaction of cells of subcutaneous connective tissue to the activation and blockade of the peptidergic system]. / Reaktsiia kletok podkozhnoi soedinitel'noi tkani na aktivatsiiu i blokadu peptidergicheskoi sistemy.

Changes in the quantitative composition of subcutaneous connective tissue cells were examined after activation and blockade of the peripheral peptidergic system with capsaicin. The activating dose (5 mg/kg) of the agent was found to increase the quantity of mast cells in the subcutaneous connective tissue. Its toxic dose (200 mg/kg) elevated the histiocytic and fibroblastic index while the number of mast cells reduced. The same reaction was seen in surgically impaired tissue innervation. It is concluded that peptidergic capsaicin-sensitive neurons play a role in the development of neurogenic dystrophy and this process involves connective tissue cell elements.