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We describe a new species of the genus Hebius and provide evidence for the validity of H. septemlineatus comb. nov.. Morphological and molecular analyses of Hebius specimens collected in Yunnan Province, China, revealed three distinct lineages, namely the newly described Hebius weixiensis sp. nov., as well as H. octolineatus (Boulenger, 1904), and H. septemlineatus comb. nov. (Schmidt 1925), which is removed from synonymy with H. octolineatus. Based on mitochondrial genealogy, Hebius weixiensis sp. nov. is sister to H. septemlineatus comb. nov., while H. octolineatus is sister to H. bitaeniatus. The new species and H. septemlineatus comb. nov. showed considerable genetic divergence from their recognized congeners (uncorrected P-distance ≥3.9%). Furthermore, the new species and H. septemlineatus comb. nov. can be diagnosed from closely related congeners by a combination of pholidosis characters.

Embryo implantation is an essential step for a successful pregnancy, and any defect in this process can lead to a range of pregnancy pathologies. The objective of this study was to explore the role of N-myc downregulated gene 1 (NDRG1) in embryo implantation. It was found that uterine NDRG1 expression has a dynamic pattern during the estrous cycle in nonpregnant mice and that uterine NDRG1 expression was elevated during the implantation process in pregnant mice. The distinct accumulation of NDRG1 protein signals was observed in the primary decidual zone adjacent to the implanting embryo during early pregnancy. Furthermore, uterine NDRG1 expression could be induced by activated implantation or artificial decidualization in mice. Decreased uterine NDRG1 expression was associated with pregnancy loss in mice and was associated with recurrent miscarriages in humans. The in vitro decidualization of both mouse and human endometrial stromal cells (ESCs) was accompanied by increased NDRG1 expression and downregulated NDRG1 expression in ESCs effectively inhibited decidualization. Collectively, these data suggest that NDRG1 plays an important role in decidualization during the implantation process, and the abnormal expression of NDRG1 may be involved in pregnancy loss.

Decidualization is an indispensable event in the embryo implantation process, but its underlying molecular mechanisms remain elusive. In this study, we showed that in mice, the uterine expression of N-myc downstream-regulated gene 3 (NDRG3), a member of the α/β hydrolase superfamily, was induced by estradiol and progesterone. During the embryo implantation process, uterine Ndrg3 expression was remarkably upregulated, and its expression level at implantation sites (IS) was significantly higher than that at inter-IS. Increased uterine expression of Ndrg3 was associated with artificial decidualization and the activation of delayed implantation. The in vitro decidualization of mouse endometrial stromal cells (ESCs) induced by estradiol and progesterone was also accompanied by increased Ndrg3 expression, and downregulated Ndrg3 expression in ESCs effectively inhibited decidualization. miR-290b-5p was identified as an upstream regulator of Ndrg3, and the uterine expression level of miR-290b-5p was decreased during the implantation process. Furthermore, overexpression of miR-290b-5p in mouse ESCs inhibited their in vitro decidualization. Taken together, these data suggested that Ndrg3 might play an important role in embryo implantation by regulating decidualization potentially via the estrogen/progesterone/miR-290b-5p pathway.

Purpose To determine whether protein tyrosine phosphatase 1B (PTP1B) is expressed in rat retinal pigment epithelium (RPE) cells, to evaluate whether inhibition of PTP1B contributes to initiation of RPE cells into an active state, and to investigate the signaling pathways involved in this process. Methods Rat retinas were detached by trans-scleral injection of 1.4% sodium hyaluronate into the subretinal space. Immunocytochemistry evaluated the expression of PTP1B in RPE cells located at normal and detached retinas. From the cultured RPE cells treated with TCS-401, cell proliferation was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetracolium bromide assay, and the protein expression levels of cyclin A and cyclin D1 were determined. The effect of TCS-401 on cell differentiation was confirmed by immunostaining for α-smooth muscle actin and by western blot. Cell migration activity and PTP1B signaling mechanism were determined. Migration Assay was used to evaluate cell migration activity. PTP1B signaling mechanism was determined by use of PD98059 and LY294002. Results PTP1B was expressed in the RPE layer of the normal retina. After retinal detachment, weak immunolabeling of PTP1B was seen in the RPE cells. TCS-401 promoted the proliferation and expression of cyclin A and cyclin D1 in RPE cells. TCS-401 induced RPE cells to differentiate toward better contractility and motility. A migration assay proved that inhibiting PTP1B improved the migratory activity of RPE cells. TCS-401 activated extracellular signal-regulated kinase (Erk) and protein kinase B (Akt) phosphorylation. Pretreatment with PD98059 and LY294002 abolished TCS-401-induced activation of Erk, Akt, cell proliferation, and cell migration. Conclusions PTP1B may be involved in regulating the active state of RPE cells. The inhibition of PTP1B promoted the proliferation, myofibroblast differentiation, and migration of RPE cells, and MEK/Erk and PI3K/Akt signaling pathways played important roles in the proliferation and migration process.

Embryo implantation is an essential step for the establishment of pregnancy and dynamically regulated by estrogen and progesterone. NDRG4 (N-myc down-regulated gene 4) is a tumor suppressor that participates in cell survival, tumor invasion and angiogenesis. The objective of this study was to preliminarily explore the role of NDRG4 in embryo implantation. By immunohistochemistry (IHC) and quantitive RT-PCR (qRT-PCR), we found that uterine expression of NDRG4 was increased along with puberal development, and its expression in adult females reached the peak at the estrus stage during the estrus cycle. Furthermore, uterine NDRG4 expression was significantly induced by the treatment of estradiol (E2) both in pre-puberty females and ovariectomized adult females. Uterine expression pattern of NDRG4 during the peri-implantation period in mice was determined by IHC, qRT-PCR and Western blot. It was observed that NDRG4 expression was up-regulated during the implantation process, and its expression level at the implantation sites was significantly higher than that at the inter-implantation sites. Meanwhile, an increased expression in NDRG4 was associated with artificial decidualization as well as the activation of delayed implantation. By qRT-PCR and Western blot, we found that the in vitro decidualization of endometrial stromal cells (ESCs) was accompanied by up-regulation of NDRG4 expression, whereas knockdown of its expression in these cells by siRNA inhibited the decidualization process. In addition, Western blot analysis showed that NDRG4 protein expression was decreased in human villus tissues of recurrent miscarriage (RM) patients compared to normal pregnant women. Collectively, these data suggested that uterine NDRG4 expression could be induced by estrogen, and NDRG4 might play an important role during early pregnancy.

To explore the preventive and therapeutic effects of Faecalibacterium prausnitzii (F. prausnitzii) supernatant on dextran sulfate sodium (DSS) induced colitis in mice.Forty C57BL/6J male mice were randomly divided into four groups: control group, model group, treatment group, and prevention group. Mice were weighed daily. On day 10, the colon length was measured, the colorectal histopathologic damage score (HDS) was assessed, and plasma interleukin (IL)-17A, IL-6, and IL-4 levels were detected by enzyme-linked immunosorbent assay. The expression of transcription factor retinoic acid-related orphan receptor-γt (RORγt) and IL-17A in colon inflammatory mucosa tissue were determined by immunohistochemical assay, and the expression levels of RORγt mRNA, IL-17A mRNA, and IL-6 mRNA were detected by real-time quantitative polymerase chain reaction (PCR). The proportion of Th17 in mononuclear cells in spleen was assayed by fluorescence activated cell sorter.When compared with the model group, the colon length (P0.05) and body weight (P0.01) in the treatment and prevention groups were significantly increased, and the colon HDS was decreased (P0.05 and P0.01). There was no statistical difference between the treatment group and prevention group. After treatment with F. prausnitzii supernatant, the plasma levels of IL-17A and IL-6 (P0.05), the protein and mRNA expression of IL-17A and RORγt, and the Th17 cell ratio of spleen cells (P0.01) were significantly decreased compared to the model group. Plasma IL-4 level in the prevention group was significantly higher than that in the model group (P0.05), but there was no significant difference between these two groups in the expression of IL-6 in both the plasma and colon mucosa tissues.F. prausnitzii supernatant exerts protective and therapeutic effects on DSS-induced colitis in mice, probably via inhibition of Th17 differentiation and IL-17A secretion in the plasma and colon mucosa tissues. It can also improve colitis in mice by downregulating IL-6 and prevent colitis by upregulating IL-4.

To investigate the biological significance of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) involvement in oocyte maturation, we screened for proteins that bound to UCH-L1 in mouse ovaries, and we found that the prostate tumor overexpressed-1 (PTOV1) protein was able to bind to UCH-L1. PTOV1 is highly expressed in prostate cancers and considered as a potential marker for carcinogenesis and the progress of prostate cancer. It was reported that PTOV1 plays an important role in cell cycle regulation, but its role in mammalian oocyte development and meiosis is still unclear. In this paper, it was found that the expression levels of PTOV1 in mouse ovaries progressively increased from prepubescence to adulthood. And we found by immunohistochemistry that PTOV1 spreaded in both the cytoplasm and nuclei of oocytes during prepuberty, but in normal adult mouse oocytes, it concentrated not only in nuclei but also on the plasma membrane, though in some oocytes with abnormal shapes, PTOV1 did not display the typical distribution patterns. In granulosa cells, however, it was found to locate in the cytoplasm at all the selected ages. In postnatal mouse ovaries (28 days), estradiol treatment induced the adult-specific distribution pattern of PTOV1 in oocytes. In addition, UCH-L1 was shown to be associated with CDK1, which participated in the regulation of cell cycle and oocyte maturation. Therefore, we propose that the distribution changes of PTOV1 are age-dependent, and significant for mouse oocyte development and maturation. Moreover, the discovery that PTOV1 is associated with UCH-L1 in mouse oocytes supports the explanations for that UCH-L1 is involved in oocyte development and maturation, especially under the regulation of estrogen.

Uchl1 was found to be involved in spermatocyte apoptosis. The aim of the present study was to test whether Uchl1 and its associated proteins Jab1 and p27(kip1) were involved in spermatogenic damages in response to heat-stress in cryptorchidism. Hematoxylin and eosin (HE) staining and DNA end labeling (TUNEL) were used to observe morphological and apoptotic characteristics of spermatogenic cells; Immunohistochemical analysis was used to detect changes of Uchl1 and its associated proteins Jab1 and p27(kip1) in response to heat-stress from cryptorchidism leading to spermatocyte losses; And protein affinity analysis (pull-down) and immunofluorescence co-localization were used to verify the relevance among the three proteins in spermatocytes. The results showed that, Jab1 and p27(kip1), in parallel to Uchl1, increased in spermatocytes of apoptotic appearances in response to heat-stress, but not in multinucleated giant cells; Jab1 bound to Uchl1 in testis protein extracts, and co-localized with Uchl1 and p27(kip1) specifically in spermatocytes with apoptotic appearances. These results suggest that the accumulation of Uchl1 protein is involved in the heat-stress-induced spermatocyte apoptosis through a new pathway related with Jab1 and p27(kip1), but not the formation of multinucleated giant cells.

Mesenchymal stem cells (MSCs) are non-hematopoietic cells with multi-lineage potential, which makes them attractive targets for regenerative medicine applications. Efficient gene transfer into MSCs is essential for basic research in developmental biology and for therapeutic applications involving gene-modification in regenerative medicine. Adenovirus vectors (Advs) can efficiently and transiently introduce an exogenous gene into many cell types via their primary receptors, the coxsackievirus and adenovirus receptors (CARs), but not into MSCs, which lack CAR expression. To overcome this problem, an Adv coated with cationic polymer polyethyleneimine (PEI) was developed. In this study, we demonstrated that PEI coating with an optimal ratio can enhance adenoviral transduction of MSCs without cytotoxicity. We also investigated the physicochemical properties and internalization mechanisms of the PEI-coated Adv. These results could help to evaluate the potentiality of the PEI-coated Adv as a prototype vector for efficient and safe transduction into MSCs.

This study examined the mttuence of human high density ltpoproteins (HDL) on the intracellular free calcium of cultured bovine aortic endothelial cells (BAECs). Intracellular Ca 2+ concentration ([Ca 2+ ] i ) was determined by a fluorescent calcium indicator, Fura-2. It was found that, in the presence of 1 mmol/L extracellular calcium, HDL resulted in a biphasic elevation of [Ca 2+ ] i in BAECs, consisting of an initial, transient component followed by a lower, but more sustained component. Doses of HDL from 25 to 200 μg protein/ml induced marked concentration-dependent elevations of [Ca 2+ ] i in BAECs. The sustained component was abolished by deprivation of extracellular calcium or by pretreatment of endothelial cells with a calcium influx blocker, NiCl 2 . HDL-induced elevation of [Ca 2+ ] i was attenuated in a concentration-dependent way by an inhibitor of calcium release, tetracaine. Repeated applications of HDL (100 μg protein/ml) markedly blunted the initial peak component of the calcium transient of BAECs. These results demonstrate that both intracellular and extracellular calcium pools are responsible for the biphasic elevation of [Ca 2+ ] i induced by HDL in cultured BAECs.

Apoptosis of abnormal oocytes is essential for defective oocyte elimination during prepubertal ovary development, and the ubiquitin system regulates the cell apoptosis via the degradation of specific proteins. Ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a component of the ubiquitin system, and the UCH-L1-dependent apoptosis is important for spermatogenesis. In the present study, the change in the number of follicles and the expression of UCH-L1 in oocytes were determined in prepubertal mouse ovaries by immunohistochemical techniques. A significant decrease in the follicular pool was found in prepubertal mouse ovaries during the period of day 21 to day 28 after birth, and accordingly, the UCH-L1 protein expression was increased, to some degree in association with Jun activation domain-binding protein 1 (Jab1) and cyclin-dependent kinase inhibitor p27(Kipl). The increased UCH-L1 protein, together with the corresponding changes of Jab1 was detected in morphologically abnormal oocytes of prepubertal ovaries. Through the immunofluorescent colocalization, UCH-L1 was shown concentrating in abnormal oocytes, and a parallel change in Jab1 was also seen. The affinity analysis confirmed the interaction between UCH-L1 and Jab1 in ovaries. These results suggest that UCH-L1 plays an important role, possibly in association with Jab1 and p27(Kipl), in selective elimination of abnormal oocytes during mouse prepubertal development.

Background The study was conducted to investigate the inhibitory effect of 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) on embryo implantation in mice with a view to identifying whether it might be a suitable agent for postcoital contraception. Study Design The anti-implantation efficacy of AEBSF was determined by counting the number of visible implanted embryos on Day 8 of pregnancy following a single intrauterine injection of AEBSF at doses of 30, 300 and 3000 μg per mouse uterine horn on Day 3 of pregnancy. The reversibility of the inhibitory effect of AEBSF on implantation was further evaluated by observing the outcome of a subsequent pregnancy without AEBSF treatment. Results A dose-dependent inhibitory effect of AEBSF on embryo implantation in vivo was observed. Morphological analysis revealed no significant cytotoxicity of AEBSF on the mouse uterine epithelia. Furthermore, the anti-implantation effect of AEBSF was reversible. Conclusion Intrauterine administration of AEBSF at an appropriate dose might provide a basis for the development of novel contraception.

To investigate the effect of aspirin on the apoptosis of cultured bovine aortic endothelial cells (BAEC) and the signal pathways involved in this process.BAEC were cultured and passaged in Dulbecco's modified Eagle's medium culture medium. Morphologic changes and quantification of apoptotic cells were determined using fluorescence microscope after staining the cells with Hoechst 33258. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyltetrazolium bromide (MTT) method. DNA fragmentation was visualized by agarose gel electrophoresis. Phospho-p38 mitogen-activated protein kinase (MAPK) expression was detected by Western blotting.Aspirin at low concentrations from 1X10( -10) mol/L to 1X10( -8) mol/L decreased the apoptosis and p38 MAPK phosphorylation induced by H2O2 in BAEC, while high doses of aspirin (1X10( -7)-1X10( -4) mol/L) induced typical apoptotic changes in BAEC and stimulated the expression of phospho-p38 MAPK in a concentration-dependent manner. SB203580, a specific p38 MAPK inhibitor, blocked such effects.Aspirin exhibits a biphasic effect on the apoptosis in BAEC, reducing apoptosis at low concentration and inducing apoptosis at high concentration. p38 MAPK may be an important signal molecule mediating the effects of aspirin.

We have developed a "combination culture system", composed of primary differentiated granulosa cells, proestrus anterior pituitary lobe and delta-4-androstenedione. This cultured system effectively induce the maturation of oocytes from early tertiary follicles of diethylstilbestrol (DES)-treated rats. After DES stimulation, an average of 189 oocytes were obtained from early tertiary follicles of unilateral ovaries; 78% of these oocytes, when cultured in this culture system, extruded the first polar body, a criterion of oocyte maturation. Of the mature oocytes, the rate of normal fertilization and egg cleavage were 88% and 93%, respectively. After 96 h of culturing in vitro, 59% of the zygotes developed into morulae or blastocysts. Embryos implanted at the two-cell stage were able to develop into healthy individuals. Thus the combination culture system provides an experimental model in which the molecular mechanisms of egg maturation, fertilization, and embryonic development can be studied.

To explore the inhibitory effect of antisense oligonucleotide (ODN) to mitogen activated protein kinase(MAPK) on cardiomyocyte hypertrophy induced by angiotensin II (Ang II).A 17-mer phosphorothioate-protected antisense ODN directed against the initiation of translation sites of the p42 and p44 MAPK isoforms by liposomal transfection was applied to inhibit the translation of p44/p42 MAPK mRNA. The sense and random ODNs to p44/p42MAPK were used as sequence controls. Neonatal cardiac myocytes were exposed to Ang II (10 nmol/L) for 5 min and then harvested in lysis buffer for the measurement of the activity and the phosphorylated protein content of p44/p42MAPK that were tested by P-81 phosphocellulose filter paper method and Western blotting, respectively. The rate of protein synthesis by [3H]leucine incorporation and the diameter of cell were measured after exposure to Ang II for 24 h and 72 h, respectively.In cardiac myocyte Ang II increased p44/p42 MAPK activity and phosphorylated protein content by 140 % and 699 %, and also increased [3H]leucine incorporation and cell diameter by 40 % and 27 %. c-fos and c-myc mRNAs were induced significantly after exposure to Ang II. Antisense ODN to p44/p42MAPK (0.2 micromol/L) reduced Ang II-induced MAPK activity by 30 %, and phophorylated MAPK protein expression by 59 % in cardiac myocyte, and inhibited c-fos and c-myc mRNA expression induced by Ang II by 44 % and 43 %, respectively. The diameter and the rate of protein synthesis of cardiac myocyte induced by Ang II were decreased by 16 % and 22 % after pretreatment with antisense ODN to p44/p42MAPK.Antisense ODN to p44/p42 MAPK inhibited the increase of rate of protein synthesis, and the augmentation of cell diameter and expression of c-fos and c-myc mRNA induced by Ang II in cultured cardiac myocytes. p44/p42 MAPK played a critical role in the hypertrophic response induced by Ang II in cultured neonatal rat cardiac myocytes.

p28, a protein derived from toad (Bufo bufo gargarizans) oocytes, has a high level of sequence homology to mouse UCH L1. We report here that it is a toad ubiquitin carboxyl-terminal hydrolase (UCH), termed tUCH for its ability to hydrolyze the UCH substrate ubiquitin ethyl ester (UboEt). The similarities of secondary structures between tUCH and UCH L1 highlight that they might have common functions. The total extracted proteins both from immature and matured oocytes contain 2% tUCH. The enzyme kinetic constants (Km and Kc) both of the tUCH and UCH L1 reveal that they possess similar catalytic properties on their common substrate Ub-AMC. Anti-tUCH monoclonal antibody (tUCH mAb) can recognize tUCH and dominant-negative tUCH (tUCH C(90)S), but not mouse UCH L1, suggesting that it does not target on the conservative UCH active sites. Furthermore, anti-tUCH mAb when injected into oocytes blocked the progesterone-induced GVBD but anti-tUCH mAb could not inhibit the tUCH catalytic hydrolysis of Ub-AMC, revealing that the implication of tUCH in the oocyte maturation regulation is not dependent on its UCH activity.

p28, a 28kD protein from toad (Bufo bufo gargarizans) oocytes, was identified by using p13 suc1 -agaroseaffinity chromatography. Sequence homology analysis of the full-length cDNA of p28(Gene Bank accessionnumber: AF 314091) indicated that it encodes a protein containing 224 amino-acids with about 55% iden-tities and more than 70% positives to human, rat or mouse UCH-L1, and contains homological functionaldomains of UCH family. Anti-p28 monoclonal antibody, on injecting into the oocytes, could inhibit theprogesterone-induced resumption of meiotic division in a dose-dependent manner. The recombinant pro-tein p28 showed similar SDS/PAGE behaviors to the native one, and promoted ubiquitin ethyl ester hydrolysis,a classical catalytic reaction for ubiquitin carboxyl terminal hydrolases (UCHs). The results in this paperreveal that a novel protein, p28, exists in the toad oocytes, is a UCH L1 homolog, was engaged in the processof progesterone-induced oocyte maturation possibly through an involvement in protein turnover anddegradation.Key words: p28, cDNA clone, recombinant expression, ubiquitin carboxyl terminal hydrolase, oocytematuration.

To investigate the effect of 17beta-estradiol (E2) on TNF-alpha-induced apoptosis in cultured bovine aortic endothelial cells (BAEC) and the underlied mechanism.BAEC were cultured and passaged in Dulbecco's modified Eagle's medium (DMEM). Morphologic changes and quantification of apoptotic cells were determined under fluorescence microscope with Hoechst 33258 staining. Cell viability was detected with MTT method. DNA fragmentation was visualized by agarose gel electrophoresis. The expression of phospho-p38 and phospho-p44/42 Ca2+-calmodulin dependent protein kinase (CCDPK) was measured by Western blotting.TNF-alpha 5000 kU/L elicited typical apoptotic morphologic changes (chromatic condensation, nucleus fragmentation, and DNA fragmentation). E2 0.1 pmol/L-100 nmol/L enhanced the expression of phospho-p44/42 CCDPK induced by TNF-alpha, at the same time, inhibited TNF-alpha induced activation of p38 CCDPK. E2 protected BAEC from apoptosis induced by TNF-alpha in a concentration-dependent manner. DNA fragmentation induced by TNF-alpha 5000 kU/L was also reduced by E2 1 nmol/L. Both the E2-induced upregulation of phospho-p44/42 CCDPK and its anti-apoptotic action were prevented by the specific p44/42 CCDPK inhibitor U0126.Activation of p44/42 CCDPK signaling together with inhibition of p38 CCDPK signaling by E2 appears to be an important mechanism for its survival effect on endothelial cells.

To investigate the effect of VEGF on TNF-alpha- or H2O2-induced apoptosis in cultured bovine aortic endothelial cells (BAEC) and the underlied signal transduction mechanisms related to Ca2+-calmodulin dependent protein kinase (CCDPK).BAEC were cultured and passaged in DMEM. Morphologic changes and quantification of apoptotic cells were determined under fluorescence microscope with Hoechst 33258 staining. Cell viability was detected with MTT method. DNA fragmentation was visualized by agarose gel electrophoresis. The expression of phospho-p38 and phospho-p42/p44 CCDPK was measured by Western blotting.TNF-alpha 5000 kU/L and H2O2 300 micromol/L elicited DNA fragmentation in BAEC. Vascular endothelial growth factor (VEGF) 100 microg/L significantly protected BAEC from apoptosis induced by TNF-alpha or H2O2, as shown in cell viability assay and apoptotic cell counting. DNA fragmentation induced by TNF-alpha or H2O2 was also reduced by VEGF 100 microg/L. VEGF enhanced TNF-alpha and H2O2 stimulated expression of phospho-p42/p44 CCDPK, simultaneously inhibited TNF-alpha- and H2O2-induced activation of phospho-p38 CCDPK. Both the VEGF-induced up-regulation of phospho-p42/p44 CCDPK and its anti-apoptotic action were prevented by the specific p42/p44 CCDPK inhibitor U0126.VEGF protects BAEC from apoptosis induced by TNF-alpha and H2O2, and its co-modulatory effects by activation of p42/p44 CCDPK signaling together with inhibition of p38 CCDPK signaling appear to be an important mechanism for its survival effect on endothelial cells.

Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heart in vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heart in vitro. Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H1 and H2 antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine. We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.

Platelet-activating factor is a novel phospholipid that has been implicated as an important mediator of acute allergic reactions. The intravenous administration of acetyl glyceryl ether phosphorylcholine, a pure, synthetic platelet-activating factor, causes electrocardiographic changes in the rabbit similar to those which are characteristic manifestations of systemic anaphylaxis. To determine whether platelet-activating factor contributes to anaphylactic cardiac dysfunction, we measured platelet-activating factor release from the sensitized guinea pig heart challenged in vitro with specific antigen and compared the resulting cardiac dysfunction with that induced by the injection of acetyl glyceryl ether phosphorylcholine into nonsensitized hearts. The results of these studies document that, during anaphylaxis in the isolated guinea pig heart, a platelet-activating factor is released into the coronary effluent that has physicochemical and functional properties similar to those of acetyl glyceryl ether phosphorylcholine. The intracardiac administration of acetyl glyceryl ether phosphorylcholine (10(-14) to 3 X 10(-9) mol) induced dose-related decreases in left ventricular contractile force (-5 to -85%) and coronary flow (-5 to -85%), as well as impaired atrioventricular conduction. The negative inotropic effect of acetyl glyceryl ether phosphorylcholine also was present in hearts perfused at constant flow. Although, in these hearts, acetyl glyceryl ether phosphorylcholine increased coronary resistance, which may have caused regional shunting and ischemia, it is unlikely that the negative inotropic effect of acetyl glyceryl ether phosphorylcholine was secondary to changes in coronary flow, since acetyl glyceryl ether phosphorylcholine also caused a dose-dependent negative inotropic effect in the electrically paced, noncoronary-perfused left atrium and right ventricular papillary muscle.(ABSTRACT TRUNCATED AT 250 WORDS)