大鼠延髓腹外侧部微量注射心房钠尿肽的心血管效应

在麻醉大鼠观察了延髓腹外侧部的谷氨酸敏感区(GSA)应用ANP对血压和心率的影响。在GSA应用α-hANP,血压和心率明显降低。低浓度的APⅢ(10~(-6)mol/L)仅引起血压减低而不伴有心率减慢效应,而高浓度的APⅢ对血压和心率均有抑制效应。这些结果提示,ANP可能具有抑制延髓交感中枢作用并可能作为动脉压力感受器中枢通路的一种化学递质或调质。     

心房钠尿因子对麻醉家兔局部血流的影响

在42只麻醉家兔,观察了静脉注射心房肽Ⅱ(AtriopeptinⅡ,APⅡ)对局部血流量以及动脉内注射 AP Ⅱ 对局部血管阻力的影响。结果如下:(1)静脉注射 APⅡ(30μg/kg)5min后,平均动脉压(MAP)降低11.0±1.5mmHg(n=8,M±SE,下同),与溶剂对照组相比有明显差异(P相似文献   

Interaction of poly(ADP-ribose) polymerase 1 with apurinic/apyrimidinic sites within clustered DNA damage

To study the interaction of poly(ADP-ribose) polymerase 1 (PARP1) with apurinic/apyrimidinic sites (AP sites) within clustered damages, DNA duplexes were created that contained an AP site in one strand and one of its analogs situated opposite the AP site in the complementary strand. Residues of 3-hydroxy-2-hydroxymethyltetrahydrofuran (THF), diethylene glycol (DEG), and decane-1,10-diol (DD) were used. It is shown for the first time that apurinic/apyrimidinic endonuclease 1 (APE1) cleaves the DNA strands at the positions of DEG and DD residues, and this suggests these groups as AP site analogs. Insertion of DEG and DD residues opposite an AP site decreased the rate of AP site hydrolysis by APE1 similarly to the effect of the THF residue, which is a well-known analog of the AP site, and this allowed us to use such AP DNAs to imitate DNA with particular types of clustered damages. PARP1, isolated and in cell extracts, efficiently interacted with AP DNA with analogs of AP sites producing a Schiff base. PARP1 competes with APE1 upon interaction with AP DNAs, decreasing the level of its cross-linking with AP DNA, and inhibits hydrolysis of AP sites within AP DNAs containing DEG and THF residues. Using glutaraldehyde as a linking agent, APE1 is shown to considerably decrease the amount of AP DNA-bound PARP1 dimer, which is the catalytically active form of this enzyme. Autopoly(ADP-ribosyl)ation of PARP1 decreased its inhibitory effect. The possible involvement of PARP1 and its automodification in the regulation of AP site processing within particular clustered damages is discussed.     

Decrease in the lower limit of the rat brain vital activity by the physiological method]

The brain temperature, at which the cessation of the lung respiration occurs in the cooled animals, can be named the lower temperature limit of the brain functional competence, since at this temperature the spontaneous respiration is not restored on its own, and without special artificial undertakings the animals perish. In this study upon the total cooling of the rat bodies their lung respiration stopped completely as the temperature of the medulla oblongata in the region of the respiratory center decreased to 18.18 +/- 0.17 degrees C. This occurred simultaneously with an abrupt decrease in the heart rate and in the arterial blood pressure (AP) to 42 +/- 1 mm Hg. Upon an isolated cooling of the rat head the heart rate and AP were maintained at a comparatively high level. Under such conditions the lung respiration did not stop even as the temperature of the medulla oblongata decreased to 17.23 +/- 0.25 degrees C. It retained rhythmicallity, a particular rate, and a comparatively high amplitude. It is suggested that an intensive blood supply of the cooled brain decreases the lower temperature limit of its vital activity.     

Regulation of apoptosis in the endocardial cushions of the developing chick heart

During the early stages of heartdevelopment, there are two main foci of cell death: outflow tract (OT)and atrioventricular (AV) endocardial cushions. These tissuescontribute to the septa and valves of the mature heart and receive cellpopulations from neural crest (NC) cell migration and epicardial cellinvasion. We examined embryonic chick hearts for expression, in thecushions, of bcl-2 family members, caspase-9, and the caspase substrate poly(ADP-ribose) polymerase. Antiapoptotic bcl-2 is expressed heavily in the OT and AV regions throughout embryonic days (ED) 4-7, with a decrease in levels at ED 4 and 5 in OT and AVcushions, respectively. Proapoptotic bax predominantly associatedwith the prongs of the NC-derived aorticopulmonary (AP) septum but was expressed throughout the AV cushions. Proapoptotic bak alsoassociated with the prongs of the AP septum in the OT, while proteinlevels were upregulated at ED 4-5 and 4-6 in OT and AVcushions, respectively. Bid expression showed a similar time course. Wefound the 10-kDa cleavage fragment of active caspase-9 at ED 4-8and 5-8 in OT and AV cushions, respectively, and the 24-kDacleavage fragment of poly(ADP-ribose) polymerase throughout ED 3-8and 7-8 in OT and AV cushions, respectively. Caspase-3 cleavageoccurred throughout the time period examined. Using cushion cellcultures, we found that inhibitors of caspases-3 and -9 and a universalcaspase inhibitor significantly reduced apoptosis, as didretroviral overexpression of bcl-2 using an RCAS expression vector.Premigratory NC cells were fluorescently labeled in vivo with1,1-didodecyl-3,3,3',3'-tetramethylindocarbocyanine. Subsequent nuclearstaining of cushion cells with 4,6-diamidino-2-phenylindole revealedthe presence of apoptotic nuclei in the NC cells in the OT cushionsand in the prongs of the AP septum. These results demonstrate adevelopmentally regulated role for the bcl-2 and the caspase familiesof molecules in the endocardial cushions of the developing heart andlend support to the possibility that some of the dying cells in thecushions are derived from the NC.

     

Effect of stretching on the action potentials of the human and rabbit ventricular myocardium

The effect of stretching from L0 to Lmax on the electrical activity was studied on human myocardial preparations from patients with heart disease and on strips of rabbit ventricular myocardium. Muscular deformation was shown to decrease the amplitude and velocity of depolarization in slow action potentials. The action potentials (AP) possessing a fast depolarization phase were not sensitive to physiological stretching. Antiarrhythmic drugs--ethmozin (2 X 10(-5) M) and ethacizin (2 X 10(-6) M)--caused a decrease in the rate of AP depolarization, thus increasing AP sensitivity to deformation. It is suggested that stretching under the action of ethmozin and ethacizin reduced cardiomyocyte excitability due to suppression of slow Ca-current.     

Effect of atrial peptide on gastric acid secretion in rats

The effect of synthetic rat atriopeptin (AP) II was examined on basal, vagally and carbachol-induced gastric acid secretion in anesthetized rats. AP II infusion, at stepwise increasing doses of 2, 20 and 100 ng/kg/min, had no effect on basal acid secretion. At doses of 2 and 20 ng/kg/min, AP II augmented vagally induced acid secretion significantly. The secretory response to vagal stimulation + AP II 20 ng/kg/min was completely abolished by atropine. In contrast a higher dose of AP II (50 ng/kg/h) reduced vagally induced acid secretion significantly. This dose of AP II also reduced acid secretion during direct cholinergic stimulation by carbachol, while the lower dose of 20 ng/kg/min had no effect on carbachol-induced acid secretion. The present data demonstrate for the first time an effect of atrial peptide on gastric acid secretion. At lower doses AP II augments the vagal influence on parietal cell function perhaps by augmenting vagally induced acetylcholine release. At higher doses AP II exerts an inhibitory effect on parietal cell function during vagally and carbachol-induced acid secretion, suggesting different and as yet unknown mechanisms of action. These results raise the possibility that the heart can exert a hormonally mediated influence on the regulation of gastric acid secretion.     

Effect of a new beta-blocker (CM 6805) on the action potential of guinea pig atrial fiber

CM6804 effect has been studied about some parameters of the intracellular action potential (AP) of guinea pig autorythmic auricle. Auricle was preserved alive under Tyrode oxygenated solution at 37 degrees C. AP is measured by a fluctuating intracellular glass microelectrode. At a concentration of 5 . 10(-5) M, CM doesn't alter the resting membrane potential, it causes a small overshoot reduction, it decreases the maximum depolarization rate and the heart rate, it increases the action potential duration. Overshoot and maximum depolarization rate decrease prove that CM modifies the membrane permeability probably by a diminution of the sodium rapid inward current. CM action is similar to others aryl-oxy-propyl propanolamine like propranolol.     

Autonomic control of the cardiovascular system during acclimatization to high altitude: effects of sildenafil.

Both acute hypoxia and sildenafil may influence autonomic control through transient cardiovascular effects. In a double-blind study, we investigated whether sildenalfil (Sil) could interfere with cardiovascular effects of hypoxia. Twelve healthy men [placebo (Pla) n = 6; Sil, n = 6] were exposed to an altitude of 4,350 m during 6 days. Treatment was continuously administered from 6 to 8 h after arrival at altitude (3 x 40 mg/day). The autonomic control on the heart was assessed by heart rate variability (HRV) during sleep at sea level (SL) and between day 1-2 and day 5-6 in hypoxia. Arterial pressure (AP) and total peripheral resistances (TPR) were obtained during daytime. There was no statistical difference between groups in HRV, AP, and TPR throughout the study. Hypoxia induced a decrease in R-R interval and an increase in AP in both groups. Low frequency-to-high frequency ratio increased at day 1-2 (Pla, P = 0.04; Sil, P = 0.02) and day 5-6 (Pla and Sil, P = 0.04) vs. SL, whereas normalized high-frequency power decreased only in Pla (P = 0.04, day 1-2 vs. SL). Normalized low-frequency power increased at high altitude (Pla and Sil, P = 0.04, day 5-6 vs. SL). TPR decreased at day 2 in Pla (P = 0.02) and tended to normalize at day 6 (P = 0.07, day 6 vs. day 2). Acute hypoxia induced a decrease in parasympathetic and increase in sympathetic tone, which tended to be reversed with acclimatization. Sil had no deleterious effects on the cardiovascular response to high-altitude exposure and its control by the autonomic nervous system.     

Effect of medium change on poly(ADP-ribose) synthesis in friend erythroleukemic cells

In Friend leukemic cells cultured in the presence of 5 mM hexamethylene bisacetamide, a potent differentiation-inducer, poly(ADP-ribose) synthesis was reduced to about one-third of that in control cells. Replacing the original culture medium with fresh medium resulted in a decrease of poly(ADP-ribose) synthesis in confluent control cultures, while cells induced to differentiate were not affected by the medium change. This is not attributable to the difference of the level of poly(ADP-ribose) synthesis in different cell cycle stages, since DNA synthesis and cell growth in differentiating cells were maintained at the same level with those of control cells. In control cultures, a medium change during the log-phase effected a prolongation in the rise of poly(ADP-ribose) synthesis. When conditioned medium was substituted during log-phase growth, poly(ADP-ribose) synthesis was stimulated in control cells. This stimulating effect was not lost by dialysis but was lost by heat-treatment or trypsin-digestion. Results suggest that poly(ADP-ribose) synthesis is regulated by some factor(s) released into the culture medium.     

Effect of DNA on poly (ADP-ribose) glycohydrolase and the degradation of histone H1-poly (ADP-ribose) complex from HeLa cell nuclei.

A poly(ADP-ribose)-H1 histone complex has been isolated from HeLa cell nuclei incubated with NAD. The rate of poly(ADP-ribose) glycohydrolase catalyzed hydrolysis of the polymer in the complex is only 1/9 that of free poly(ADP-ribose), indicating that the polymer is in a protected environment within the complex. Comparison of the rate of hydrolysis of free poly(ADP-ribose) in the presence or absence of H1 to that in the complex synthesized de novo indicates a specific mode of packaging of the complex. This is further indicated by the fact that alkaline dissociation of the complex followed by neutralization markedly exposes the associated poly(ADP-ribose) to the glycohydrolase. The complex also partially unfolds when it binds to DNA as evidenced by a 2-fold increase in the rate of glycolytic cleavage of poly(ADP-ribose). This effect of DNA is not due to a stimulation of the glycohydrolase per se since hydrolysis of free polymer by the enzyme is strongly inhibited by DNA, especially single-stranded DNA. Inhibition of glycohydrolase by DNA results from the binding of the enzyme to DNA and conditions which decrease this binding (increased ionic strength or addition of histone H1 which competes for DNA binding) relieve the DNA inhibition.     

心房钠尿多肽对麻醉大鼠血压和肾神经传出放电的影响

本实验观察了心房肽Ⅱ(Atriopeptin Ⅱ,APⅡ)对麻醉大鼠血压(AP)、心率(HR)和肾交感神经传出放电(RSNA)的影响,并与硝普钠对 AP 和 RSNA 的影响作比较。结果如下:(1)缓冲神经完整和迷走神经完整条件下(n=12)静脉注射 APⅡ(50μg/kg)后,动脉收缩压(SAP)降低23.0±1.66 mmHg(Μ±SE,p<0.001),HR 减慢9±3.5b/min(p<0.05),RSNA 降低4.89±2.95%(P>0.05)。迷走神经切断后,静脉注射 APⅡ引起的~⊿SAP 虽有所减小,但与切断迷走神经前的反应比较,无统计学意义,HR 减慢不再出现,而 RSNA 则有所增加;(2)缓冲神经切断和迷走神经完整条件下(n=7),静脉注射 APⅡ时 SAP 降低27.4±3.25mmHg(P<0.001),HR 减慢13±3.1b/min(P<0.01),RSNA 降低11.67±1.95%(P<0.001)。切断迷走神经后,静脉注射 APⅡ引起的 SAP 降低程度有明显減小(P<0.01),HR减慢不再出现,RSNA 则反而增加(3)无论在迷走神经完整还是切断条件下,静脉注射硝普钠(n=6) SAP 均明显降低,同时伴有 RSNA 的反射性增加。以上结果表明:APⅡ的降压效应,部分是通过迷走神经传入纤维;在切断缓冲神经条件下,APⅡ可经由迷走神经传入纤维的激活而反射地抑制 RSNA。     

Down-regulation of AP1 activities after polarization of vas deferens epithelial cells correlates with androgen-induced gene expression

Vas deferens epithelial cell subcultures were used to study the sequential regulation of jun/fos proto-oncogene expression and AP1 activities during cell proliferation, polarization and androgen-induced expression of a terminal differentiation marker, i. e. the mvdp gene. Proliferation of epithelial cells is associated with a high expression in the nucleus of most Jun and Fos oncoproteins. After cell seeding on an extracellular matrix which allows polarization and expression of the mvdp gene in response to androgens, AP1 protein accumulation is greatly altered and consists in a loss of JunB, Fra1, FosB and a decrease in c-Fos, c-Jun and Fra2, while JunD remained at the same level. This was correlated with a drop in AP1 binding activity as evaluated by gel shift assay using either AP1 consensus sequence or AP1 binding sites of the mvdp gene promoter region, and in AP1 transactivating activity, as estimated by stable transfection experiments using an AP1 responsive promoter (TRE-TK-luc). Androgens did not significantly influence AP1 activities. On the contrary, stimulation of AP1 proteins by the tumor-promoting phorbol ester caused a decrease in androgen-induced mvdp mRNA accumulation, and this effect was reversed by staurosporine, a potent inhibitor of PKC. Our data suggest that a down-regulation of AP1 activities induced by epithelial cell differentiation is a prerequisite to androgen-induced mvdp gene expression. The high AP1 activities observed during proliferative state or induced in TPA-treated polarized cells, exert a repressive effect on androgen action.     

Paticipation of cannabinoid receptors in the regulation of cardiac rhythm and cardiac contractility

It has been found that i. v. administration of cannabinoid receptor (CB) agonists (HU-210, ACPA, anandamide, methanandamide) induced a decrease in the heart rate (HR) in anesthetized rats. Pretreatment with CB1 receptor antagonist SR141716A completely abolished a negative chronotropic effect of CB receptor agonist HU-210. The CB2 receptor antagonist SRI 44528 did not prevent a HU-210-induced decrease in the HR. Pretreatment with the ganglion blocker hexamethonium had no effect on the negative chronotropic action of HU-210. Addition of HU-210 (100 nM) to perfusion solution induced a decrease in the HR, left ventricular development pressure, rate of contractility and relaxation of isolated perfused rate heart without change in end diastolic pressure. These data suggest that cardiac CBI receptor activation induces a decrease in the HR both in vivo and in vitro. An occupancy of the same receptors mediates a negative inotropic effects of cannabinoids.     

Modulation of c-myc expression in the HL-60 cell line

A decrease in the expression of the myc proto-oncogene of HL-60 cells has been reported as an accompaniment of myeloid differentiation induced by either dimethylsulfoxide or retinoic acid. We report herein that several inhibitors of poly(ADP-ribose)-polymerase induced myeloid differentiation in HL-60 cultures. Studies on the expression of the c-myc gene in total cell RNA populations indicate that expression of this gene is inversely correlated with the state of differentiation, either myeloid or monocytic, of the cultured cells independent of the inducer and the rate of cell proliferation.     

Selective pharmacological blocking of synaptic transmission through the parasympathetic ganglia: Effects on the cardiovascular system

In acute experiments on rats and dogs, compounds IEM-1556 and IEM-1678, the blockers of transmission through the parasympathetic ganglia, reduced the negative chronotropic effect of stimulation of the vagus nerve (VN), while practically not changing the heart rate (HR). In chronic experiments on dogs, these compounds increased the HR, substantially reduced the respiratory heart arrhythmia, did not change the arterial blood pressure (AP), and reduced the chronotropic effects of VN stimulation. IEM-1556 exerted more strong and long-lasting blocking effects on vagal heart control than IEM-1678 did, but in anesthetized animals could evoke a drop in the AP. Acetylcholine, if administered during the action of the above compounds, inhibited heart activity. It is concluded that both IEM-1678 and IEM-1556 are selective parasympatholytics (although IEM-1556 may produce a side effect). The above compounds block synaptic transmission through the intracardiac parasympathetic ganglia and do not affect neuro-effector transmission in the heart.Neirofiziologiya/Neurophysiology, Vol. 28, No. 2/3, pp. 151–159, March–June, 1996.     

Poly(ADP-ribose) metabolism in ultraviolet irradiated human fibroblasts

Exposure of human fibroblasts to 5 J/m2 of UV light resulted in a rapid increase of up to 1500% in the intracellular content of poly(ADP-ribose) and a rapid depletion of its metabolic precursor, NAD. When added just prior to UV treatment, the poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, totally blocked both the increase of poly(ADP-ribose) and decrease in NAD for up to 2.5 h. Addition of 3-aminobenzamide at the time of maximal accumulation of poly(ADP-ribose) resulted in a decrease to basal levels with a half-life of approximately 6 min. The rates of accumulation of poly(ADP-ribose) and depletion of NAD were increased in the presence of either 1-beta-arabinofuranosylcytosine or hydroxyurea. Since these agents are known to cause an additional accumulation of DNA strand breaks following UV irradiation, these data provide evidence for a mechanism in which the rate of poly(ADP-ribose) synthesis following DNA damage is regulated in intact cells by the number of DNA strand breaks. Under conditions in which the synthesis of poly(ADP-ribose) was blocked, DNA repair replication induced by UV light was neither stimulated nor inhibited.     

Disorder of electromechanical coupling in the cells of the myocardium in protracted crush syndrome

Experiments on papillary muscles of normal (control) rabbits and of those with the compression syndrome (CS) were made to explore the action of the control and "syndromic" blood plasma on electric and contractile activity of the myocardium. Isometric contractions of myocardial preparations were recorded at varying stimulation frequencies (0.1-2 Hz). Intracellular rest potentials (RP) and action potentials (AP) were led away with the aid of glass microelectrodes filled with 2.5 M KCl. The replacement of Tyrode solution by the control plasma raised the amplitude of papillary muscle contractions, that being greater as regards the muscles from rabbits with the CS. The "syndromic" plasma (diluted by Tyrode solution in a 1:1 ratio) markedly inhibited the amplitude of contractions of papillary muscles from both the control rabbits and animals with the CS. Reduction of the contractions induced by the "syndromic" plasma seen in all the preparations was followed by two patterns of changes in electrical activity of myocardial fibers. In one pattern, the RP, the amplitude and duration of the AP declined. In the other, on the contrary, the changes were reduced to a greater AP duration. The conclusion is made about the absence of a direct relationship between the decrease in myocardial contractility and changes in intracellular potentials induced by the "syndromic" plasma. It is suggested that the "syndromic" plasma deranges the process of stimulation and contraction coupling in heart papillary muscles.     

Poly(ADP-ribose) turnover in quail myoblast cells: Relation between the polymer level and its catabolism by glycohydrolase

The concerted action of poly(ADP-ribose) polymerase (PARP) which synthesizes the poly(ADP-ribose) (pADPr) in response to DNA strand breaks and the catabolic enzyme poly(ADP-ribose) glycohydrolase (PARG) determine the level of polymer and the rate of its turnover. In the present study, we have shown that the quail myoblast cells have high levels of basal polymer as compared to the murine C3H10T1/2 fibroblasts. We have conducted this study to investigate how such differences influence polymer synthesis and its catabolism in the cells in response to DNA damage by alkylating agent. In quail myoblast cells, the presence of high MNNG concentration such as 200 \sgmaelig;M for 30 min induced a marginal decrease of 15% in the NAD content. For C3H10T1/2 cell line, 64 \sgmaelig;M MNNG provoked a depletion of NAD content by approximately 50%. The induction of the polymer synthesis in response to MNNG treatment was 6-fold higher in C3H10T1/2 cells than in quail myoblast cells notwithstanding the fact that 3-fold higher MNNG concentration was used for quail cells. The polymer synthesis thus induced in quail myoblast cells had a 4-5 fold longer half life than those induced in C3H10T1/2 cells. To account for the slow turnover of the polymer in the quail myoblast cells, we compared the activities of the polymer catabolizing enzyme (PARG) in the two cell types. The quail myoblast cells had about 25% less activity of PARG than the murine cells. This difference in activity is not sufficient to explain the large difference of the rate of catabolism between the two cell types implicating other cellular mechanisms in the regulation of pADPr turnover.