Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently we have been successful in isolating an endogenous negative inotropic factor (ENIF) from porcine left ventricular tissue. In this study, we have characterized its pharmacological properties. The results of the study demonstrated that ENIF produces a concentration-dependent negative inotropic response on both guinea pig left atria and right ventricular trabeculae. The maximal reduction in contractile force produced by 300 ul of ENIF (5 ml bath) on atria and trabeculae were 90.0 +/- 0.8% and 77.5 +/- 6%. Atria, however, was significantly more sensitive to ENIF than trabeculae. The ED 50 of ENIF for atria was found to be 38 ul as opposed to ED 50 of 100 ul of ENIF for trabeculae. Acetylcholine (ACh), a muscarinic receptor agonist, decreased the contractile force of guinea pig atria in a dose-dependent manner with a maximal decline in the contractile force of 90%. However, none of the concentration of ACh used affected the contractile function of the trabeculae. Atropine (1 uM) completely blocked the negative inotropic response on atria of all the doses of ACh used. The same dose of atropine, however, was unable to influence the negative inotropic effect of any of the doses of ENIF used on either the atria or trabeculae preparations in our study. The maximal decline in the contractile force of atria was e.g. 94 and 95% in the presence and absence of atropine respectively. These data demonstrate that the myocardial negative inotropic effect of ENIF is not mediated via the cholinegic receptor mechanism.
Mol Cell Biochem 1998 Jan
PMID:Pharmacological characterization of an endogenous negative inotrophic factor (ENIF) from porcine heart. 954 92

The Flinders sensitive line of rats (FSL rats) have an altered REM sleep pattern which includes a shorter REM sleep latency and an increased percentage of REM sleep [R.M. Benca, D.H. Overstreet, M.A. Gilliland, D. Russell, B.M. Bergmann, W.H. Obermeyer, Increased basal REM sleep but no difference in dark induction or light suppression of REM sleep in Flinders rats with cholinergic supersensitivity, Neuropsychopharmacology 15 (1996) 45-51; P.J. Shiromani, D.H. Overstreet, D. Levy, C.A. Goodrich, S.A. Campbell, J. C. Gillin, Increased REM sleep in rats selectively bred for cholinergic hyperactivity, Neuropsychopharmacology 1 (1988) 127-133]. Cholinergic mechanisms have been implicated in REM sleep generation [reviewed in P.J. Shiromani, J.C. Gillin, S.J. Henriksen, Acetylcholine and the regulation of REM sleep: basic mechanisms and clinical implication for affective illness and narcolepsy, Annu. Rev. Pharmacol. Toxicol. 27 (1987) 137-156]. In the present study, specific aspects of the cholinergic system were examined in the pontine region of the FSL rats. The number of cholinergic neurons in the LDT and PPT were not different in FSL and control rats. Analysis of steady state levels of mRNAs encoding the acetylcholine synthesizing protein, choline acetyltransferase (ChAT) or the m2, m3 and m5 muscarinic receptor subtypes were also comparable in FSL and control rats. These data raise the possibility that the cellular events underlying the altered REM sleep pattern in FSL rats may include mechanisms that effect the muscarinic or nicotinic receptor in the pons.
Brain Res Mol Brain Res 1998 Apr
PMID:Expression of cholinergic markers in the pons of Flinders rats. 958 25

In porcine bronchi, inhibition of both Cl- and HCO3- transport is required to block the anion secretion response to ACh and to cause mucus accumulation within ACh-treated submucosal gland ducts [S. K. Inglis, M. R. Corboz, A. E. Taylor, and S. T. Ballard. Am. J. Physiol. 272 (Lung Cell. Mol. Physiol. 16): L372-L377, 1997]. In this previous study, a combination of three potential HCO3- transport inhibitors [1 mM acetazolamide, 1 mM DIDS, and 0.1 mM dimethylamiloride (DMA)] was used to block carbonic anhydrase, Cl-/HCO3- exchange, and Na+/H+ exchange, respectively. The aim of the present study was to obtain a better understanding of the mechanism of ACh-induced HCO3- secretion in airway glands by determining which of the three inhibitors, in combination with bumetanide, is required to block anion secretion and so cause ductal mucin accumulation. Gland duct mucin content was measured in distal bronchi isolated from domestic pigs. Addition of either bumetanide alone, bumetanide plus acetazolamide, or bumetanide plus DIDS had no significant effect on ACh-induced mean gland duct mucin content. In contrast, glands treated with bumetanide plus DMA as well as glands treated with all four anion transport blockers were almost completely occluded with mucin after the addition of ACh. These data suggest that mucin is cleared from the ducts of bronchial submucosal glands by liquid generated from Cl(-)- and DMA-sensitive HCO3- transport.
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PMID:Effect of anion secretion inhibitors on mucin content of airway submucosal gland ducts. 961 91

We stably transfected human kidney embryonic 293 cells with the rat neuronal nicotinic acetylcholine receptor (nAChR) alpha3 and beta4 subunit genes. This new cell line, KXalpha3 beta4R2, expresses a high level of the alpha3/beta4 receptor subtype, which binds (+/-)- [3H]epibatidine with a Kd value of 304+/-16 pM and a Bmax value of 8942 +/- 115 fmol/mg protein. Comparison of nicotinic drugs in competing for alpha3/beta4 receptor binding sites in this cell line and the binding sites in rat forebrain (predominantly alpha4/beta2 receptors) revealed marked differences in their Ki values, but similar rank orders of potency for agonists were observed, with the exception of anatoxin-A. The affinity of the competitive antagonist dihydro-beta-erythroidine is >7000 times higher at alpha4/beta2 receptors in rat forebrain than at the alpha3/beta4 receptors in these cells. The alpha3/beta4 nAChRs expressed in this cell line are functional, and in response to nicotinic agonists, 86Rb+ efflux was increased to levels 8-10 times the basal levels. Acetylcholine, (-)-nicotine, cytisine, carbachol, and (+/-)-epibatidine all stimulated 86Rb+ efflux, which was blocked by mecamylamine. The EC50 values for acetylcholine and (-)-nicotine to stimulate 86Rb+ effluxes were 114 +/- 24 and 28 +/- 4 microM, respectively. The rank order of potency of nicotinic antagonists in blocking the function of this alpha3/beta4 receptor was mecamylamine > d-tubocurarine > dihydro-beta-erythroidine > hexamethonium. Mecamylamine, d-tubocurarine, and hexamethonium blocked the function by a noncompetitive mechanism, whereas dihydro-beta-erythroidine blocked the function competitively. The KXalpha3 beta4R2 cell line should prove to be a very useful model for studying this subtype of nAChRs.
Mol Pharmacol 1998 Aug
PMID:Rat alpha3/beta4 subtype of neuronal nicotinic acetylcholine receptor stably expressed in a transfected cell line: pharmacology of ligand binding and function. 968 74

Fluoxetine is used in the treatment of a variety of clinical disorders including depression and obesity, and of cocaine detoxification or alcoholism. It is generally believed that fluoxetine exerts its clinical effects because it selectively blocks 5-hydroxytryptamine (5HT) reuptake into nerve terminals. In here we describe that fluoxetine antagonized the neuronal homomeric alpha 7 nicotinic acetylcholine receptors (nAChR) expressed in Xenopus oocytes, with an IC50 of 43 microM, when fluoxetine was coapplied with ACh, and of 1.6 microM when the oocytes were pretreated briefly with fluoxetine. A similar block occurred in oocytes expressing L247T alpha 7 mutant nAChR. Furthermore, blockage of mutant alpha 7 receptors appeared non-competitive and was stronger with cell membrane hyperpolarization. Cell-attached single channel recordings in oocytes expressing L247T alpha 7 mutant nAChR showed that the voltage-dependence of the blockage by fluoxetine could be due to a drastic decrease in channel opening frequency accompanied by marked channel flickering and reduced channel conductance. We conclude that fluoxetine behaves as a reversible blocker of both wild and mutant alpha 7 receptors; and that the Leu-247T mutation in the channel domain renders the blockage of alpha 7 nAChR by fluoxetine voltage-dependent. These effects of fluoxetine on alpha 7 receptors may be clinically important.
Mol Psychiatry 1998 Jul
PMID:Effects of fluoxetine on wild and mutant neuronal alpha 7 nicotinic receptors. 970 46

This study employs the pancreas of normal and diabetic rats to investigate the relationship between the endocrine and exocrine pancreas in the control of exocrine secretion employing enzyme and immunohistochemical and physiological techniques. Acetylcholine esterase (ACh-E) positive nerves were distributed in the interacinar regions of the pancreas lying close to the exocrine cells. There was no difference between the cholinergic innervation of the pancreas in normal and diabetic rat. Insulin (INS) immunopositive cells were observed in the peripheral and central portions of the Islet of Langerhans in the pancreas of normal rat. In the diabetic animals the number of INS-positive cells were decreased. In contrast, glucagon (GLU) and somatostatin (SOM)-immunopositive cells were identified mainly in the peripheral parts of the Islets of Langerhans and their numbers increased markedly in the diabetic pancreas. Insulin alone had no significant effect on amylase secretion in the normal pancreas whereas GLU and SOM evoked small increases in amylase out compared to basal. In contrast, the islet hormones have no detectable secretory effect on the diabetic pancreas compared to control. Both electrical field stimulation (EFS) of intrinsic secretomotor nerves and exogenous application of acetylcholine (ACh) resulted in marked increases in amylase secretion. In pancreatic acini and acinar cells ACh evoked dose-dependent increases in amylase release. In normal pancreatic segments a combination of either INS or GLU with EFS or ACh resulted in marked potentiation of amylase output. In contrast, SOM inhibited the EFS-evoked amylase output but enhanced the secretory response to ACh. In pancreatic acini and acinar cells from normal rat and in pancreatic segments from diabetic rats, the islet hormones had no potentiating effect on the ACh-evoked secretory response. Similarly, in the diabetic rat the islet hormone had no effect on EFS-evoked amylase output. In fura-2 loaded pancreatic acinar cells ACh-induced a marked increase in intracellular free calcium concentration [Ca2+]i compared to basal. Either INS or GLU, but not SOM, elicited a small increase in [Ca2+]i. Combining either INS or GLU with ACh resulted in a potentiation of [Ca2+]i compared with ACh alone. In contrast, SOM had no significant effect on the ACh-induced [Ca2+]i compared to the response obtained with ACh alone. In pancreatic acinar cells of diabetic rat ACh-elicited similar magnitude of [Ca2+]i compared to acinar cells of normal rat. However, when the islet hormones were combined with ACh there was no enhancement of [Ca2+]i compared to ACh alone. The results indicate that the potentiation of either EFS or ACh-evoked secretory responses by the islet hormones seem to occur only in pancreatic segments which have intact viable Islets of Langerhans and not in either acini and acinar cells or from the pancreas of diabetic rat. Moreover, it is apparent that cellular Ca2+ is involved with the interaction of ACh with either INS or GLU.
Int J Mol Med 1998 Mar
PMID:Effects of islet hormones on nerve-mediated and acetylcholine-evoked secretory responses in the isolated pancreas of normal and diabetic rats. 985 77

Ethanol, at physiologically relevant concentrations, significantly enhanced high-affinity neuronal nicotinic acetylcholine receptor (NnAChR) currents insensitive to alpha-bungarotoxin (alpha-BuTX-ICs) in cultured rat cortical neurons in a fast and reversible manner, as determined by standard whole-cell patch-clamp recording techniques. The enhancement was (mean +/- S.D.) 7.7 +/- 5% to 192 +/- 52% upon coapplication of 3 to 300 mM ethanol with 1 to 3 microM ACh. No plateau for this ethanol-induced enhancement of alpha-BuTX-ICs was reached. The maximal alpha-BuTX-IC evoked by very high concentrations of ACh also was increased upon coapplication of ethanol. In contrast, ethanol weakly inhibited low-affinity NnAChR currents sensitive to alpha-BuTX (alpha-BuTX-SCs) (5 +/- 4% to 29 +/- 6% inhibition by 10 to 300 mM ethanol at 300 to 1000 microM ACh). This neuronal preparation also enabled comparison of ethanol action on NnAChRs with its action on N-methyl-D-aspartate receptor currents and gamma-aminobutyric acid receptor currents within the same neurons. Ethanol (100 mM) was more potent at enhancing NnAChR alpha-BuTX-ICs (61 +/- 9% enhancement) than it was at enhancing gamma-aminobutyric acid receptor current (3 +/- 3% enhancement-not statistically significant) or at inhibiting N-methyl-D-aspartate receptor currents (approximately 35 +/- 7% inhibition). Thus, NnAChRs, particularly those insensitive to alpha-BuTX, may be sensitive conduits through which ethanol can mediate some of its actions in the brain.
Mol Pharmacol 1999 Jan
PMID:Ethanol modulation of nicotinic acetylcholine receptor currents in cultured cortical neurons. 988 96

Adenosine triphosphate (ATP) and catecholamine (CA) released from cultured porcine adrenal chromaffin cells were continuously measured with an ATP photometer (luciferin-luciferase method) and electrochemical detector, respectively. Application of acetylcholine (ACh, 0.1 mM) or high K+ (60 mM) caused increases of ATP and CA in perfused effluent with the same time course. The peak molar ratio of CA to ATP in the effluent was about 10 for ACh and high K+ stimulation. The high-performance liquid chromatographic (HPLC) analysis of adenine nucleotides in the collected effluent revealed that the relative amounts of ATP, ADP and AMP were almost the same throughout the period of stimulation, suggesting that ATP breakdown in the effluent was constant. Changes in the peak molar ratio of CA to ATP appearing in the effluent did not occur with repetitive high K+ or sustained Ba2+ stimulation (5 mM). The similarity between the time courses of ATP and CA appearing in the effluent suggests that releasable chromaffin granules have a constant molar ratio of CA to ATP. The on-line system developed is a simple and rapid method for examining ATP and CA secretion, simultaneously.
Comp Biochem Physiol A Mol Integr Physiol 1999 Mar
PMID:On-line measurement of adenosine triphosphate and catecholamine released from adrenal chromaffin cells. 1035 64

During development of mammalian neuromuscular junctions, the expression of ACh receptors (AChRs) switches from an embryonic form to an adult form, which provides a higher Ca2+ permeable channel. The lack of this switch can prevent normal development of neuromuscular junctions. In non-mammalian species, however, the switch appears not to occur. The results of the present study show that Ca2+ entry through non-mammalian AChR channels was controlled by differential phosphorylation rather than a subunit switch. This finding provides support for the hypothesis that localized Ca2+ influx through AChR channels has a critical role in the formation and maintenance of neuromuscular junctions.
Brain Res Mol Brain Res 1999 Jun 08
PMID:Positive- and negative-regulation of Ca2+ entry through ACh receptor channels by phosphorylation. 1036 52

After myocardial infarction (MI), nitric oxide (NO)-mediated vasorelaxation is attenuated in both conduit and resistance arteries. To determine if the attenuated vasorelaxation after MI is due to downregulation of eNOS protein, pharmacological, immunoblotting, and gene transfer of eNOS were performed in rats 3 weeks after MI. Gene transfer was accomplished using a "first-generation" serotype 5, replication-deficient, adenoviral vector (1.2 x 10(9) pfus) containing eNOS cDNA in the hindlimb vasculature for 30 min. Five days after infection, overexpression of eNOS protein was confirmed by immunohistochemical staining and immunoblotting. Recombinant gene expression was localized primarily to the vascular endothelial cells. After MI, eNOS protein level decreased (3.3 +/- 0.9 vs 2.1 +/- 0.8 intensity units/microg protein, n=6, P<0.05); after gene transfer it increased (P<0.05) two-fold to 4.3 +/- 1.2 intensity units/microg protein, n=5. There were no changes in hemodynamics in MI rats transfected with eNOS. Acetylcholine (ACh)-stimulated vasorelaxation was decreased (P<0.05) by 30% after MI and was restored to normal with eNOS transfection. Addition of 100 microm NG-nitro-L-arginine methyl ester (L-NAME) abolished the difference between sham, MI, and MI transfected rats. L-arginine (1 mm) restored the ACh-response in MI-transfected rats toward control, but it did not eliminate the difference between MI and sham rats. We conclude that the attenuated endothelial NO-mediated vasorelaxation in the hindlimb after MI is due to a downregulation of eNOS protein and overexpression of eNOS transgene restores normal endothelial NO-mediated vasorelaxation.
J Mol Cell Cardiol 1999 Jun
PMID:Overexpression of endothelium nitric oxide synthase reverses the diminished vasorelaxation in the hindlimb vasculature in ischemic heart failure in vivo. 1037 98


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