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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secretion of beta-endorphin from mouse pituitary AtT20 cells is stimulated by a variety of compounds that raise intracellular cAMP and Ca2+. To investigate the role of cAMP-dependent protein kinases in secretion, AtT20 cells were transfected with an expression vector coding for a regulatory (R) subunit of cAMP-dependent protein kinase containing mutations in both cAMP-binding sites. Expression of the mutant regulatory subunit in stable transformants (RAB cells) results in a dominant inhibition of cAMP-dependent protein kinase activity. Isoproterenol (1 microM) or analogs of cAMP stimulated beta-endorphin secretion from AtT20 cells, but failed to stimulate secretion in RAB cells expressing the mutant R subunit. Secretion in response to CRF (100 nM) was inhibited by 80% in these mutant clones, whereas the secretory response to vasoactive intestinal peptide (VIP; 100 nM) or phorbol ester (100 nM phorbol myristate acetate) was not inhibited by the R subunit mutation. Intracellular cAMP was elevated in response to CRF (11- to 15-fold), isoproterenol (5- to 10-fold), and VIP (4- to 8-fold) in RAB cells. Similar concentrations of VIP were required to evoke beta-endorphin secretion in either RAB cells or AtT20 cells. As with most secretagogues, VIP-induced secretion was inhibited in the presence of either EGTA or a voltage-sensitive Ca2+ channel antagonist, PN200-110. The secretory response to VIP was unaffected by down-regulation of protein kinase-C. These results suggest that CRF and isoproterenol work via cAMP-dependent protein kinase to activate beta-endorphin secretion, whereas VIP can act by a different mechanism that does not involve cAMP-dependent protein kinase or protein kinase-C.
Mol Endocrinol 1991 Feb
PMID:Role of cyclic adenosine 3',5'-monophosphate-dependent protein kinase in hormone-stimulated beta-endorphin secretion in AtT20 cells. 164 51

Catecholamines increase the amplitudes of oscillatory afterpotentials (OAP) and peak magnitude of the transient inward current (Iti) responsible for OAP. The objectives of this study were to determine whether beta-adrenoceptor stimulation can induce Iti, and to determine the mechanism by which beta-adrenoceptor stimulation increases the magnitude of Iti. Experiments were performed using standard two electrode voltage--clamp techniques in isolated rabbit Purkinje fibers. Holding potential was either -50 or -80 mV. The Iti was elicited by repolarizing steps, following 1.5 or 3 s activating steps to potentials near 0 mV. Isoproterenol (ISO) failed to induce the Iti at concentrations from 10(-8) to 10(-6)M. However ISO (10(-7)M) significantly increased peak magnitude of spontaneously occurring Iti (P less than 0.05), or Iti induced by acetylstrophanthidin (AS) (P less than 0.05). ISO also shifted the minimum activation voltage 10 mV more negative (P less than 0.05). The current-voltage relationship demonstrated that ISO significantly increased the range of potentials over which Iti greater than or equal to 5 nA occurred, but did not significantly shift the voltage at which maximum peak current was observed. Effects of ISO on Iti were blocked by 10(-7)M propranolol or atenolol. Mn2+ (2 mM) or verapamil (2 microM) blocked the slow inward current (Isi) more than 80% before substantially decreasing peak Iti. Either agent blocked stimulation of Isi but not Iti by ISO at 10(-7)M. In contrast, quinacrine (20 microM), an inhibitor of Na(+)-Ca2+ exchange, abolished stimulation of Iti by ISO while having no significant effect on Isi. Our results indicate that beta-adrenoceptor stimulation cannot induce Iti in rabbit Purkinje fibers, but can enhance the Iti induced by other means, by stimulating Na(+)-Ca2+ exchange.
J Mol Cell Cardiol 1991 May
PMID:Mechanisms of action of beta-adrenergic agents on the arrhythmogenic transient inward current in rabbit Purkinje fibers. 165 60

We have demonstrated for the first time the isolation of sarcoplasmic reticulum (SR) membranes from adult rat ventricular myocytes obtained from a single rat heart. The myocyte SR preparation exhibits similar Ca(2+)-transport and Ca2+/K(+)-ATPase activity as well as a similar protein profile to SR membranes isolated from intact rat heart tissue. This SR preparation exhibited a Ca2+/K(+)-ATPase activity of 371 +/- 55 nmol/min/mg protein (mean +/- S.E.M.; n = 5) and an oxalate-stimulated Ca(2+)-uptake activity of 103 +/- 4 nmol/min/mg protein (mean +/- S.E.M.; n = 6). Pretreatment of the SR vesicles with 5 microM ruthenium red increased the oxalate-stimulated Ca(2+)-uptake to 204 +/- 12 nmol/min/mg protein demonstrating the presence of junctional SR membranes. Sodium dodecyl sulphate polyacrylamide gel electrophoresis shows that the isolated SR membranes contained protein bands at 430 (Ca(2+)-release channel), 100 (Ca2+/K(+)-ATPase), 55 (calsequestrin and/or calreticulin) and 53 kDa (glycoprotein). Western blots of myocyte SR membranes stained with ruthenium red detected 2 major Ca(2+)-binding protein bands in this preparation at 53-55 kDa (calsequestrin and/or calreticulin) and 97-100 kDa (Ca2+/K(+)-ATPase). The presence of phospholamban, a regulatory protein of the Ca2+/K(+)-ATPase of cardiac SR, was confirmed in the myocyte SR membranes by western blots probed with a monoclonal antibody to phospholamban. Isoproterenol stimulation of intact [32P]orthophosphate equilibriated myocytes was associated with an increase in the phosphorylation of 3 distinct proteins (27, 31 and 152 kDa) in myocyte homogenates. The 27 kDa phosphorylated protein was identified in purified SR membranes as phospholamban my migration on electrophoretic gels and by immunoblotting. The ability to prepare SR membranes from intact isolated adult rat ventricular myocytes makes this system a potentially useful model for the study of SR regulation by protein phosphorylation.
J Mol Cell Cardiol 1991 Oct
PMID:Isolation and characterization of purified sarcoplasmic reticulum membranes from isolated adult rat ventricular myocytes. 166 Sep 35

A given overall level of beta-adrenergic receptor occupancy by agonist can involve either high or low turnover of occupancy with respect to individual receptors, depending on the binding properties of the particular agonist. It was recently demonstrated that, for epinephrine-stimulated adenylate cyclase activation in the S49 cell, a portion of the separation between the beta-adrenergic receptor binding curve and the cyclase response curves is dependent on high occupancy turnover (high binding frequency). By involving a larger number of receptors within a short period of time than are bound at any one instant, the effect of high binding frequency is to increase the rate of GTP-binding protein/adenylate cyclase activation over the rate that is observed when the mobility of the number of receptors occupied at any given instant is the rate-limiting factor. This phenomenon contributes to the normal dose-response curve for epinephrine, according to our analysis, but only in combination with the apparent high efficiency of the receptor in the epinephrine-bound state at cyclase activation. Here we examined the potential combination of the contributions of agonist binding frequency and intrinsic efficiency to the adenylate cyclase activation rate for four other beta-adrenergic agonists (isoproterenol, zinterol, metaproterenol, and dobutamine). This was done by a comparison of the response (1-min cAMP accumulation) between a point on the normal dose versus response curve (control) with the response under conditions in which the concentration of agonist-bound receptors was identical to control but the absolute number of receptors involved in maintaining that concentration was significantly reduced. In the experiments, the majority of the receptors were blocked by the beta-adrenergic antagonist propranolol, which has a relatively long occupancy half-life. The remaining receptors were occupied by agonist such that the concentration of bound receptors was identical to the control condition of low occupancy of the full complement of receptors in the absence of antagonist. Compared with control, the experimental condition was one in which agonist occupancy turnover was inhibited and the potential contribution of agonist binding frequency as a factor contributing to the cyclase activation rate was greatly reduced (producing a point on the receptor mobility-limited dose versus response curve). Isoproterenol and metaproterenol show evidence that their binding frequencies and the efficiency of the receptor when bound to them are of such a combination that the normal dose-response curves for these agonists contain a component that is dependent on the binding frequency.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Pharmacol 1991 Aug
PMID:Comparisons of the combined contributions of agonist binding frequency and intrinsic efficiency to receptor-mediated activation of adenylate cyclase. 167 53

Polyamines are thought to play an essential role in cellular hypertrophy and proliferation. Ornithine decarboxylase (ODC) catalyzes the first and probably the rate-limiting step in biosynthesis of polyamines. In this study, we evaluated the pathophysiological role of the renin-angiotensin system in isoproterenol-induced cardiac hypertrophy, using myocardial ODC activity as an indicator of cardiac hypertrophy. Isoproterenol caused an eight-fold increase of myocardial ODC activity in normotensive Wistar rats within 4 h after injection. Captopril suppressed the induction of ODC by isoproterenol to two-thirds of the control level. These results indicate that the renin-angiotensin system may participate in the induction of myocardial hypertrophy by isoproterenol.
J Mol Cell Cardiol 1991 Jun
PMID:Effect of captopril on isoproterenol-induced myocardial ornithine decarboxylase activity. 171 21

The role of adenosine and its cellular source in isoproterenol-induced coronary vasodilatation was investigated in isolated perfused rat hearts prelabelled with [3H]adenosine. Time courses (times for half-maximal increase) were measured for changes in oxygen consumption (2.23 +/- 0.22 min), coronary flow (3.30 +/- 0.33 min), concentrations of effluent radioactivity (3.92 +/- 0.30 min) and adenosine and its metabolites (inosine, hypoxanthine and xanthine) (2.00 +/- 0.23 min). Isoproterenol stimulation decreased the cellular energy state and increased the concentration of tissue adenosine and its metabolites. Coronary flow was linearly correlated with tissue adenosine (r = 0.85) and phosphorylation potential (r = -0.82) and tissue adenosine also showed a linear correlation with phosphorylation potential (r = -0.84) and tissue free [AMP] (r = 0.79). The specific radioactivities of tissue nucleotides remained constant, but those of adenosine, inosine and hypoxanthine + xanthine were decreased by 42%, 26% and 46%, respectively. Purine compound concentrations increased during isoproterenol stimulation from basal values of 56 +/- 23, 98 +/- 33 and 44 +/- 19 nM to 388 +/- 173, 583 +/- 156 and 178 +/- 27 nM, respectively. The basal specific radioactivity ratio of adenosine:inosine:(hypoxanthine + xanthine) in the effluent perfusate was 1:0.5:7, but the specific radioactivities decreased rapidly upon isoproterenol stimulation, and at 3 min the ratio had changed to 1:2.5:16.5. The time courses of release and the changes in the specific radioactivities of the nucleosides indicate that adenosine release occurred mainly from cardiomyocytes, and that the release of adenosine and its metabolites from the cardiomyocytes preceded that from the endothelium. It is also shown that adenosine release during catecholamine stimulation occurs concomitantly with a decrease in the cellular energy state and AMP accumulation. This is in accord with the adenosine hypothesis of coronary vasoregulation.
J Mol Cell Cardiol 1991 Oct
PMID:Cellular source and role of adenosine in isoproterenol-induced coronary vasodilatation. 174 5

Isoproterenol can induce potentially arrhymthogenic depolarizations of the resting membrane of single guinea-pig ventricular myocytes. This effect on resting potential of single guinea-pig ventricular myocytes differs qualitatively from results obtained by others from intact cardiac muscle preparations and also differs from our experience with single dog ventricular myocytes. We performed experiments on dog and guinea-pig ventricular myocytes in an attempt to clarify the effects of isoproterenol on the resting potential of mammalian ventricular myocytes. Voltage recordings with 40-60 M omega 3 M potassium chloride filled microelectrodes revealed an isoproterenol-induced depolarization of 4.3 +/- 1.0 mV in guinea-pig but no depolarization in dog myocytes. Activation of an outwardly rectifying chloride current is responsible for the isoproterenol-induced depolarization of guinea-pig ventricular myocytes. Our whole cell patch clamp recordings consistently revealed such a current in guinea-pig cells but always failed to demonstrate an isoproterenol-induced chloride current in dog myocytes under identical conditions. In contrast to single cells, isoproterenol did not depolarize intact guinea-pig papillary muscle when potential was recorded with 40-60 M omega 3 M KCl filled electrodes. Furthermore, we saw no depolarization in single guinea-pig myocytes when recording electrodes did not contain chloride. We conclude that: (1) despite activation of a chloride current, isoproterenol does not significantly depolarize guinea-pig ventricular muscle unless the driving force for the current at the resting potential is increased by elevating [Cl]i above physiological levels, and (2) an isoproterenol-induced chloride current, although demonstrable in guinea-pig ventricular cells, is not present in healthy dog ventricular cells.
J Mol Cell Cardiol 1991 Oct
PMID:The isoproterenol-induced chloride current and cardiac resting potential. 174 7

The failure of adenosine receptor antagonists to consistently attenuate metabolic coronary vasodilation suggests that adenosine is not a primary regulator of functional hyperemia. An alternative hypothesis, however, is that metabolic stimulation of the heart in the presence of an adenosine receptor antagonist results in enhanced interstitial levels of adenosine which then might overcome the blockade. To test this hypothesis, interstitial levels of adenosine and inosine were estimated by HPLC analysis of fluid which exudes from the epicardial surface of isolated rat hearts perfused with crystalloid solution at constant flow. Isoproterenol infusion (10 nM) produced increases in heart rate, left ventricular systolic pressure, rate of pressure development, myocardial oxygen consumption and adenosine and inosine concentrations of venous effluent and surface exudate and produced decreases in coronary vascular resistance. The presence of the adenosine receptor antagonist, 8-(4-sulfophenyl) theophylline (spT) (100 microM), in the perfusate had little or no effect upon most of the responses to isoproterenol except that it significantly enhanced the isoproterenol-induced increases in adenosine release and adenosine concentrations in the venous effluent and surface exudate. The isoproterenol-induced change in adenosine concentration per unit change in oxygen consumption was approximately 3-fold greater in the presence of spT than in its absence. This extra adenosine production may tend to overcome the competitive blocking effect of spT and help explain why agents such as spT are not always effective in blocking metabolic vasodilation.
J Mol Cell Cardiol 1991 Aug
PMID:Adenosine receptor blockade enhances isoproterenol-induced increases in cardiac interstitial adenosine. 194 90

A background current induced by isoprenaline, and its modulation by adenosine and ATP, have been studied using the whole cell patch clamp technique in guinea-pig ventricular myocytes. Isoprenaline (1-2000 nM) caused an inward shift of the holding current, in addition to increasing the inward calcium current (ICa). The effect on the background current was maximal earlier than the increase in ICa, but was of shorter duration. The magnitude of the background current was concentration dependent with a EC50 of 8 nM. This current was unaffected by tetrodotoxin 20 microM, Cd 200 microM or verapamil, 10 microM and potassium channel blockade (intracellular Cs, extracellular Cs 20 mM, Ba 2 mM or tetraethylammonium 10 mM). Lowering the chloride content of the electrode solution reduced the magnitude of the background current. The background current was also induced by histamine (1 or 10 microM). Adenosine (10-1000 microM) and and ATP (200 microM) antagonised the isoprenaline induced background current and the increase in ICa. The histamine effects on these currents were also reduced by adenosine. These results suggest that this background current may be carried by chloride ions and may be mediated via an increase in intracellular cyclic AMP concentration. Antagonism of this current may contribute to the antiarrhythmic actions of adenosine and ATP but their mechanisms of action are yet to be determined.
J Mol Cell Cardiol 1990 Dec
PMID:Antagonism by adenosine and ATP of an isoprenaline-induced background current in guinea-pig ventricular myocytes. 208 55

To assess the role of dietary sodium in the regional development and pathogenesis of isoproterenol (ISO)-induced cardiac hypertrophy, male Fischer rats (150-175g n = 65) were divided into control (C) and ISO-treated (I) and three dietary sodium subgroups; low (8.7-13 mEq/kg) (LS), normal (173.9 mEq/kg) (NS) and high (1378 mEq/kg) (HS). Diets began 2 weeks prior to a 7 day continuous infusion of ISO (Alzet miniosmotic pump; 3 mg/kg/day). Mean total heart weight of all I rat groups was larger than in C rats (p less than 0.05). However, low sodium diet ameliorated the percent increase, compared to respective controls, in total heart weight (LSI, 20 +/- 3%; NSI, 26 +/- 6; HSI, 24 +/- 2 (p less than 0.05). Regionally, dietary sodium level did not alter the degree of hypertrophy in the left ventricle plus septum (LVS), but sodium restriction sharply reduced the severe right ventricular (RV) and atrial hypertrophy present in the NSI and HSI rats (LVS: LSI, 18 +/- 2%; NSI, 20 +/- 2; HSI, 15 +/- 2; RV: LSI, 21 +/- 7%; NSI, 45 +/- 9, HSI, 40 +/- 2; atria: LSI, 46 +/- 17; NSI, 73 +/- 23; HSI, 78 +/- 9). Isoproterenol produced diffuse and focal myocardial fibrosis in the subepimyocardium of the LVS with occasional foci of fibrosis in the RV and the subepimyocardium of the LVS. Quantitative analysis demonstrated an increased volume percent of connective tissue limited to the LVS subendomyocardium in all three ISO-treated groups compared to controls (p less than 0.05). These data shows that isoproterenol produces greater hypertrophy of the RV and the atria than the LVS and that dietary sodium restriction selectively decreases the degree of hypertrophy of the RV and the atria produced by ISO. The findings also indicate that the myocardial hypertrophy due to ISO is independent of myocardial injury and is thus, not merely a compensatory response to myocyte loss but rather a direct result of beta-adrenergic stimulation.
J Mol Cell Cardiol 1990 Oct
PMID:Alterations in dietary sodium affect isoproterenol-induced cardiac hypertrophy. 215 37


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