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Biomedical subjects

C Reithmann

Publications and source records attributed to C Reithmann.

At least 37 records · Page 2Linked to original sources
PubMed1998

[Repetitive monomorphic ventricular tachycardia (Gallavardin type): clinical and electrophysiological characteristics in 20 patients].

Repetitive monomorphic ventricular tachycardia (RMVT) is defined by the presence of numerous monomorphic isolated, premature ventricular complexes, couplets, and runs of unsustained ventricular tachycardia having the same morphology in patients without structural heart disease. Patients with RMVT mostly demonstrate the typical left bundle branch block morphology with normal or rightward axis during tachycardia. At our institution, 20 patients with RMVT have been systematically studied: a syncope had occurred in 35% of our patients, in three cases a syncope was the first manifestation of the RMVT. Of our RMVT patients, 25% developed sustained episodes (> 3 min) of ventricular tachycardia as documented by Holter ECG. The salvos of ventricular tachycardia are generally short in RMVT. This behavior and the typical exercise dependence differentiates RMVT from paroxysmal sustained idiopathic ventricular tachycardia. Exercise testing is mandatory for correct diagnosis of RMVT. In our institution, 85-90% of RMVT patients demonstrated runs of ventricular tachycardia or sustained ventricular tachycardia while on a treadmill (exercise test) or during isoproterenol infusion. RMVT was inducible by programmed electrical right ventricular stimulation in only 13% of our patients. Therefore, in patients with suspected RMVT programmed electrophysiological stimulation is only useful to differentiate a ventricular tachycardia from a supraventricular tachycardia with bundle brunch block or in patients with unexplained syncope. The prognosis is considered generally good; in our patients no life threatening ventricular tachyarrhythmias were observed during a follow-up of up to 4 years. Verapamil and beta-adrenoceptor antagonists generally offer symptomatic improvement. In some cases treatment with a class III antiarrhythmic agent is necessary. While drug-refractory paroxysmal sustained idiopathic ventricular tachycardia can be abladed with both immediate and long-term success, catheter ablation of RMVT is only rarely indicated.

Adult↗
PubMed1998

Fast pathway ablation in patients with common atrioventricular nodal reentrant tachycardia and prolonged PR interval during sinus rhythm.

AIMS: This study aimed to clarify the safety and efficacy of selective fast pathway ablation in patients with atrioventricular nodal reentrant tachycardia and a prolonged PR interval during sinus rhythm. Such patients have been reported to have an increased incidence of complete atrioventricular block. METHODS AND RESULTS: In this study, the earliest retrograde atrial activation during atrioventricular nodal reentrant tachycardia and right ventricular stimulation was localized. Fast pathway ablation was then performed in five patients with the common form of atrioventricular nodal reentrant tachycardia and a prolonged PR interval. Three of the five patients had almost incessant atrioventricular nodal reentrant tachycardia. Radiofrequency catheter ablation induced a complete ventriculo-atrial block during right ventricular stimulation in four patients and a marked prolongation of ventriculo-atrial conduction during right ventricular stimulation in one. Non-inducibility of common atrioventricular nodal reentrant tachycardia with and without isoproterenol was achieved in all five patients. The PR interval increased from 254 +/- 53 ms to 276 +/- 48 ms and the atrio-His interval from 172 +/- 46 ms to 192 +/- 45 ms. Second- or third-degree atrioventricular block did not occur during the ablation procedure. During the followup of 19 +/- 20 months none of the patients developed symptoms suggestive of atrioventricular nodal reentrant tachycardia or evidence of second- or third-degree atrioventricular block. CONCLUSION: These data suggest that atrioventricular node (retrograde) fast pathway ablation can apparently be safely performed in patients with common atrioventricular nodal reentrant tachycardia and a prolonged PR interval during sinus rhythm.

Adult↗
PubMed1997

A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease.

The aim of this study was to determine whether a defect at the post-receptor level of adenylyl cyclase may also contribute to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease. The severity of congestive heart failure in 31 patients with congenital heart disease was graded by a scoring system which included a description of historical and clinical variables. Patients were divided into a group with no or mild heart failure (score < or = 6) and a group with severe heart failure (score > 6). beta-Adrenoceptor-stimulated adenylyl cyclase activity was significantly decreased by 65% in patients with severe heart failure in comparison to the group of patients with no or mild heart failure. In addition, receptor-independent adenylyl cyclase stimulation by forskolin was reduced by 52% in patients with score > 6 compared to patients with score < or = 6. This post-receptor defect of adenylyl cyclase was apparently due to a decrease in the activity of catalytic subunit of adenylyl cyclase as adenylyl cyclase stimulation by forskolin in the presence of Mn2+ which uncouples catalytic subunit from the G proteins, G(s) and G(i), was also significantly diminished in the patients with severe heart failure. In contrast, the level of inhibitory G protein alpha-subunits was apparently not different in the two groups. In summary, the data indicate that a defect at the catalytic subunit of adenylyl cyclase apparently contributes to the decreased effectiveness of cAMP-increasing agents in severely failing patients with congenital heart disease.

Adenosine Diphosphate↗
PubMed1997

Partial inhibition of protein synthesis by Pseudomonas exotoxin A deranges catecholamine sensitivity of cultured rat heart myocytes.

To elucidate cellular mechanisms of myocardial depression in Pseudomonas sepsis the effects of sublethal concentrations of P. aeruginosa exotoxin A--a main virulence factor--were studied in cultured neonatal rat cardiomyocytes. It is known that this toxin exerts its pathogenic effect by inhibition of protein synthesis via ADP-ribosylation and thereby inactivation of elongation factor 2 (EF-2). Within 48 72 h, half maximal inhibition of protein synthesis occurs at 4-10 ng/ml. The toxin prevents the beta-adrenoceptor(AR)-mediated myosin heavy chain isozyme shift (V3/V1), while the T3-induced myosin shift is not suppressed. While beta 1-AR-downregulation by excess of norepinephrine (NE) is not affected, protein synthesis-dependent receptor upregulation in the recover period after removal of NE is completely suppressed by P. aeruginosa exotoxin A. Thus, a non-lethal, partial inhibition of global cellular protein synthesis by P. aeruginosa exotoxin A: (1) completely prevents beta 1-AR-mediated myosin isozyme shift and beta-AR upregulation: (2) sustains the cardiomyocytes in a catecholamine-refractory contractile state in the recovery period after catecholamine desensitization: (3) suggests cellular mechanisms by which P. aeruginosa exotoxin A might impair heart function in Pseudomonas sepsis: and (4) may help reveal the possible influence of endogenous inhibitors of EF-2.

ADP Ribose Transferases↗
PubMed1997

Tumor necrosis factor alpha (TNF alpha) is cardiodepressant in pathophysiologically relevant concentrations without inducing inducible nitric oxide-(NO)-synthase (iNOS) or triggering serious cytotoxicity.

Cardiac hypertrophy and heart failure are frequently accompanied by elevated plasma levels of tumor necrosis factor alpha (TNF alpha), the pathogenetic relevance of this finding being a matter of debate. In human acute septic cardiomyopathy, on the other hand, the negative inotropic impact of TNF alpha on the heart is well documented and frequently ascribed to the induction of inducible nitric oxide (NO) synthase (iNOS) and an enhanced production of NO in the heart. Yet the present study presents evidence that in cardiomyocytes TNF alpha in non-toxic concentrations specifically depresses contractile performance independent of NO. In spontaneously beating neonatal rat cardiomyocytes, TNF alpha in a low, pathophysiologically relevant concentration (10 U/ml, 1-3 days) does not alter basal pulsation amplitude, but blocks alpha- and beta-adrenoceptor-stimulated increase in contractility and beating irregularity and impairs the impact of high extracellular calcium on contractile performance. However, this low TNF alpha-concentration does not suffice to induce iNOS - documented by reverse transcriptase polymerase chain reaction - or enhance nitrite concentrations in the cell culture supernatants as a measure of cellular NO production, neither in the presence nor absence of dexamethasone (0.1 micro M). Only in high concentration - the specific proinflammatory action being documented by an enhanced release of interleukin-6 from cardiomyocytes - TNF alpha (1000 U/mol; 6, 24 h) weakly induces the mRNA for iNOS, with a consecutive moderate rise in cellular nitrite production. TNF alpha-incubation (10-1000 U/ml) does not alter the morphological appearance of the cells displayed by phase contrast microscopy or evoke gross cytotoxicity.

Animals↗
PubMed1996

Exposure to the n-3 polyunsaturated fatty acid docosahexaenoic acid impairs alpha 1-adrenoceptor-mediated contractile responses and inositol phosphate formation in rat cardiomyocytes.

The beneficial effects of n-3 polyunsaturated fatty acids of fish oil in the prevention of fatal arrhythmias in myocardial ischemia were suggested to be at least in part mediated by a modulation of dihydropyridine-sensitive L-type calcium channels. As cardiac alpha 1-adrenoceptor stimulation has been suggested to have no significant effect on L-type calcium channels, the aim of this study using cultured neonatal rat cardiomyocytes was to investigate whether chronic n-3 polyunsaturated fatty acid exposure may have an influence on alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias. Pretreatment of the rat cardiomyocytes for 3 days in the presence of the n-3 polyunsaturated fish oil-derived fatty acid docosahexaenoic acid (60 mumol/l) markedly decreased alpha 1-adrenoceptor-stimulated increase in contraction velocity and induction of arrhythmias. The increase in contraction velocity of the cardiomyocytes induced by the beta-adrenoceptor agonist isoprenaline was also markedly reduced by the n-3 fatty acid pretreatment. Basal contractile amplitude and spontaneous beating frequency of the cardiomyocytes were not significantly altered by the docosahexaenoic acid exposure. The pretreatment of the rat cardiomyocytes for 3 days in the presence of docosahexaenoic acid (60 mumol/l) decreased alpha 1-adrenoceptor-stimulated formation of the calcium-mobilizing second messenger IP3 and its metabolites IP2 and IP1 by 55%. The depression of IP3 formation by docosahexaenoic acid treatment was not mediated by a decreased uptake of myo-inositol into the cardiomyocytes nor by a decreased synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of phospholipase C. The level of glycerol-3-phosphate, an important substrate of the phosphoinositide cycle, was unaltered by the docosahexaenoic acid pretreatment. Receptor binding studies revealed that the dissociation constant and maximal binding capacity of the alpha 1-adrenoceptor antagonist (3H)prazosin was unchanged by the n-3 polyunsaturated fatty acid exposure. Beta-Adrenoceptor-and forskolin-stimulated adenylyl cyclase activities were not diminished by the docosahexaenoic acid pretreatment. Chronic exposure of the cardiomyocytes to the n-6 polyunsaturated fatty acid arachidonic acid (60 mumol/l) did neither significantly alter alpha 1-adrenoceptor-induced inositol phosphate formation nor alpha 1-adrenoceptor-stimulated increase in contraction velocity. The results presented show that chronic n-3 polyunsaturated fatty acid pretreatment of rat cardiomyocytes leads to a marked impairment of alpha 1-adrenoceptor-induced positive inotropic effects and induction of arrhythmias concomitant with a n-3 fatty acid-induced decrease in IP3 formation. This derangement of the phosphoinositide pathway by chronic n-3 fatty acid exposure may, thus, contribute to the beneficial effects of fish oil-derived fatty acids in the prevention of fatal arrhythmias in myocardial ischemia.

Adenylyl Cyclases↗
PubMed1996

Beta-adrenoceptor desensitization despite cardiac denervation in human failing transplanted myocardium.

The aim of this study, using right ventricular endomyocardial biopsies, was to determine whether adenylyl cyclase activity is decreased-despite cardiac denervation-in human failing transplanted myocardium. beta-Adrenoceptor-stimulated adenylyl cyclase activity in membranes of moderately failing transplanted hearts was significantly decreased by 49% in comparison to non-failing transplanted hearts. Receptor-independent adenylyl cyclase stimulation (forskolin + GTP, forskolin + Mn2+) and the level of inhibitory G protein alpha-subunits were not significantly different in membranes of failing vs. non-failing transplanted myocardium. The results indicate that similar to failing non-transplanted myocardium the responsiveness to beta-adrenoceptor agonists is also decreased in failing transplanted myocardium.

Adenylyl Cyclases↗
PubMed1995

Chronic muscarinic cholinoceptor stimulation increases adenylyl cyclase responsiveness in rat cardiomyocytes by a decrease in the level of inhibitory G-protein alpha-subunits.

Exposure of neonatal rat cardiomyocytes for 3 days to the muscarinic cholinoceptor agonist carbachol led to a concentration-dependent increase in adenylyl cyclase stimulation by the beta-adrenoceptor agonist isoproterenol by up to 115% (at 1 mmol/l carbachol). In addition, direct adenylyl cyclase stimulation by forskolin was increased in carbachol (1 mmol/l)-treated cells by 32%. Pretreatment of the rat cardiomyocytes with pertussis toxin, which enhances adenylyl cyclase activity by a functional inactivation of the inhibitory G-protein (Gi), was performed to investigate the possible role of Gi-proteins in carbachol-induced sensitization of adenylyl cyclase stimulation. After pretreatment of the cells with pertussis toxin, the carbachol-mediated increase in forskolin-stimulated adenylyl cyclase activity was lost and the carbachol-mediated increase in beta-adrenoceptor-stimulated adenylyl cyclase activity was attenuated. Labelling of the 40 kDa pertussis toxin substrates in cardiomyocyte membranes was decreased by carbachol in a concentration-dependent manner by up to 34% (at 1 mmol/l carbachol). The number and affinity of beta 1-adrenoceptors was unaltered following the chronic carbachol treatment. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the carbachol-induced decrease in the level of pertussis toxin-sensitive G-proteins and increase in adenylyl cyclase activity depend on de-novo protein synthesis. Pseudomonas exotoxin A inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of the cells with 1 ng/ml Pseudomonas exotoxin A for 3 days led to a reduction in the subsequent ADP-ribosylation of elongation factor 2 in the cytosol of the heart muscle cells by 57%.(ABSTRACT TRUNCATED AT 250 WORDS)

ADP Ribose Transferases↗
PubMed1994

Tumor necrosis factor alpha decreases inositol phosphate formation and phosphatidylinositol-bisphosphate (PIP2) synthesis in rat cardiomyocytes.

Treatment of neonatal rat cardiomyocytes for 72 h in the presence of tumor necrosis factor alpha (TNF alpha) (10 U/ml) lead to a decrease in basal and alpha 1-adrenoceptor-induced formation of the calcium-mobilizing second messenger inositol trisphosphate (IP3) and its metabolites, IP2 and IP1, by 35 and 26%, respectively. The synthesis of phosphatidylinositol bisphosphate (PIP2), the substrate of PI-specific phospholipase C, was decreased by 45% following the TNF alpha (10 U/ml) exposure. Time courses of TNF alpha (10 U/ml)-induced alterations in rat cardiomyocytes showed a parallel decline of basal inositol phosphate formation and PIP2 synthesis suggesting that the decrease in inositol phosphate formation was due to the reduction in PIP2 synthesis. As the TNF alpha-induced decrease of PIP2 synthesis was associated with a decreased synthesis of the phospholipid phosphatidylinositol (PI), the precursor of PIP2, by 33%, the decreased availability of PIP2 is apparently, at least in part, the result of the decreased synthesis of PI. As an apparent functional consequence of the decrease in IP3 formation following the TNF alpha exposure, the alpha 1-adrenoceptor-mediated induction of arrhythmias by 100 mumol/l noradrenaline + 10 mumol/l timolol was abolished in TNF alpha-pretreated rat cardiomyocytes. To investigate one of the possible mechanisms of the TNF alpha-induced decrease of PIP2 formation, the effect of TNF alpha pretreatment on glycerol-3-phosphate dehydrogenase (GDH), a key enzyme of lipogenesis, was studied: Exposure of the rat cardiomyocytes for 72 h to TNF alpha induced a concentration-dependent decrease in GDH activity by maximally 55%.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Desensitization of rat cardiomyocyte adenylyl cyclase stimulation by plasma of noradrenaline-treated patients with septic shock.

The purpose of this study was to test the possibility that the mechanisms of catecholamine-induced desensitization of cardiac beta-adrenoceptor stimulation are modified in septic shock. Exposure of neonatal rat cardiomyocytes for 48 hr to plasma of noradrenaline-treated patients with septic shock led to a down-regulation of beta-adrenoceptors by 35%, an increase in the level of inhibitory G protein alpha-subunits by 60%, and a decrease in isoproterenol-stimulated adenylyl cyclase activity by 50% in membranes prepared from the rat cardiomyocytes. Similar alterations were observed following pretreatment of the cells with plasma of adrenaline-treated patients with cardiogenic shock. In contrast, exposure of the cardiomyocytes to plasma of intensive care patients without shock, and to plasma of dopamine-treated patients with septic shock did not induce alterations of the cardiomyocyte adenylyl cyclase system. The dosage of the catecholamines had to be increased within the first two days of treatment in the noradrenaline-treated patients, but not in the dopamine-treated patients with septic shock. Thus, this observed tolerance to noradrenaline in the treatment of septic shock may, in part, be due to a desensitization of cardiac beta-adrenoceptor stimulation induced by the beta-adrenoceptor stimulatory effect of noradrenaline.

Adenylyl Cyclases↗
PubMed1992

Distinct pathways for beta-adrenoceptor-induced up-regulation of muscarinic acetylcholine receptors and inhibitory G-protein alpha-subunits in chicken cardiomyocytes.

Exposure of cardiomyocytes from chicken embryos for 3 days to the beta-adrenoceptor agonist, isoproterenol, lead to a down-regulation of beta-adrenoceptors by about 70% and to a decrease in isoproterenol-stimulated adenylyl cyclase activity by about 40% (homologous desensitization). In addition, the isoproterenol treatment induced an increase in the level of muscarinic acetylcholine receptors by about 30% and an increase in pertussis toxin-catalyzed ADP-ribosylation of two about 40 kDa proteins, most probably alpha-subunits of the inhibitory G-protein (Gi), by about a factor of two (heterologous desensitization). The purpose of the present study was to characterize the role of beta-adrenoceptor-dependent and -independent mechanisms in heterologous desensitization of adenylyl cyclase. Therefore, the effect of pretreatment with the beta-adrenoceptor antagonist, propranolol, with the partial agonists, celiprolol and xamoterol, and with the beta-adrenoceptor-independent adenylyl cyclase activators, prostaglandin E1 and forskolin, on beta-adrenoceptors, muscarinic acetylcholine receptors and pertussis-toxin-catalyzed ADP-ribosylation of G-protein alpha-subunits was studied. Pretreatment of the cardiomyocytes for 3 days with xamoterol or celiprolol, but not with propranolol, induced a small decrease in beta-adrenoceptor number and in isoproterenol-stimulated adenylyl cyclase activity by about 15-20%. Exposure to prostaglandin E1 and forskolin lead to a more pronounced decrease in beta-adrenoceptor binding and in isoproterenol-mediated adenylyl cyclase stimulation by about 40-60% (heterologous desensitization). An increase in the level of muscarinic acetylcholine receptors, similar to that induced by isoproterenol exposure, was only observed after pretreatment with the partial agonists, celiprolol and xamoterol, but not after pretreatment with the beta-adrenoceptor-independent agonists, prostaglandin E1 and forskolin, nor after pretreatment with propranolol. In contrast, prostaglandin E1 and forskolin exposure lead to a similar increase in pertussis toxin-catalyzed ADP-ribosylation of about 40 kDa G-proteins as isoproterenol exposure whereas treatment with propranolol, celiprolol and xamoterol had no or only a very small effect on pertussis toxin substrates. In summary, the data suggest that, similar as shown for homologous desensitization, cyclic AMP-dependent and -independent mechanisms are also involved in heterologous desensitization of adenylyl cyclase stimulation. The beta-adrenoceptor-induced upregulation of muscarinic acetylcholine receptors and of the alpha-subunits of pertussis toxin-sensitive G-proteins, most probably of Gi, seem to be mediated via distinct pathways.

Adenylyl Cyclases↗
PubMed1991

Tumor necrosis factor alpha up-regulates Gi alpha and G beta proteins and adenylyl cyclase responsiveness in rat cardiomyocytes.

Treatment of cultured rat cardiomyocytes in serum-free medium for 48 h with recombinant human tumor necrosis factor alpha (TNF alpha) led to a concentration-dependent increase in the level of membrane-inhibitory guanine nucleotide-binding protein (Gi) alpha-subunits and in pertussis toxin-catalyzed [32P]ADP ribosylation of 40 kDa proteins. Both Gi alpha protein subtypes present in rat cardiac myocyte membranes, Gi alpha 40 and Gi alpha 41, were up-regulated by the cytokine, with the maximal increase occurring at 10 U/ml TNF alpha. In contrast to noradrenaline exposure, which causes a similar, but apparently exclusive, increase in alpha i-subunits, treatment with TNF alpha in addition increased the level of membrane G protein beta 36-subunits. Furthermore, while noradrenaline exposure led to a decrease in receptor-dependent and -independent adenylyl cyclase activity, treatment of cardiomyocytes with TNF alpha caused a concentration-dependent increase in cyclase responsiveness to either forskolin, guanosine 5'-O-(3-thiotriphosphate) or isoproterenol, even though beta-adrenoceptor density was decreased by TNF alpha. The increase in adenylyl cyclase activity induced by TNF alpha was completely suppressed when the cells were cocultured with noradrenaline, a condition leading to an additive increase in Gi alpha level. The data indicate that the cytokine TNF alpha can potently modulate G protein-mediated signal transduction in rat cardiac myocytes. Although TNF alpha, like noradrenaline, exposure of the cells increased the level of membrane Gi alpha proteins, it did not decrease but rather caused an increase in adenylyl cyclase responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate Ribose↗
PubMed1991

The oxime HGG-12 as a muscarinic acetylcholine receptor antagonist without intrinsic activity in cardiac membranes.

Direct interactions of the bispyridinium oxime HGG-12 with muscarinic acetylcholine receptors were investigated in porcine cardiac atrial membranes. Competition binding experiments using the radiolabeled muscarinic receptor antagonist (3H)QNB revealed specific binding of HGG-12 to muscarinic acetylcholine receptors of porcine atrial membranes with a dissociation constant of 3.8 x 10(-7) mol/l. Muscarinic acetylcholine receptor-stimulated binding of the radiolabeled GTP analog (35S)GTP[S] to guanine nucleotide binding proteins (G-proteins) was used to study antagonistic and possible agonistic effects of HGG-12 at muscarinic acetylcholine receptors. HGG-12 completely inhibited carbachol- and oxotremorine-stimulated (35S)GTP[S] binding to pertussis toxin sensitive and insensitive G-proteins in a competitive manner. Inhibition constants (K1) of HGG-12 for blockade of carbachol- and oxotremorine-stimulated GTP[S]-binding (9.7 x 10(-7) mol/l and 1.7 x 10(-6) mol/l, respectively) were higher by about a factor of 100 than those of the muscarinic acetylcholine receptor antagonist atropine. In the absence of muscarinic acetylcholine receptor agonists. HGG-12 by itself had no stimulatory effect on (35S)GTP[S] binding in porcine atrial membranes. The results of this study show that the oxime HGG-12 is a competitive antagonist without intrinsic activity at porcine atrial muscarinic acetylcholine receptors. The stimulatory action of HGG-12 on muscarinic acetylcholine receptors which has been described by several authors is, therefore, suggested to be due to partial inhibition of acetylcholinesterase by the oxime rather than to direct agonism at muscarinic acetylcholine receptors.

Animals↗
PubMed1991

Regulation of adenylyl cyclase by noradrenaline and tumour necrosis factor alpha in rat cardiomyocytes.

The regulation of adenylyl cyclase components and of adenylyl cyclase activity by noradrenaline and tumour necrosis factor alpha (TNF alpha) was studied in rat cardiomyocytes. Long-term treatment of rat cardiomyocytes in the presence of noradrenaline leads, in addition to a down-regulation of beta 1-adrenoceptors, to an increase in the level of inhibitory G protein alpha-subunits and to a heterologous desensitization of adenylyl cyclase stimulation. Similar to the noradrenaline exposure, incubation of the cardiomyocytes in the presence of the cytokine TNF alpha (10 U.ml-1) also increases the level of Gi alpha proteins. However, in contrast to the noradrenaline treatment, which apparently induces a selective up-regulation of Gi alpha, the TNF alpha exposure also increases the level or activity of other components of adenylyl cyclase, such as the level of membrane beta 36-subunits of G proteins and, most likely, the level of the alpha-subunits of the stimulatory G protein (Gs alpha) and the activity of adenylyl cyclase catalytic subunit. While noradrenaline treatment desensitizes receptor-dependent and independent adenylyl cyclase activity, treatment of the cells with TNF alpha induces a sensitization of adenylyl cyclase stimulation. The data indicate that only a selective increase in the level of inhibitory G protein alpha subunits decreases adenylyl cyclase activity. The hypersensitivity of adenylyl cyclase induced by TNF alpha exposure may be due to concomitant alterations of other components of the adenylyl cyclase signal transduction system.

Adenylyl Cyclases↗
PubMed1990

Hormonal regulation of Gi alpha level and adenylyl cyclase responsiveness.

Prolonged exposure of cells to adenylyl cyclase stimulatory hormonal factors can cause an increase in the level of membrane inhibitory G protein (Gi) alpha-subunits, while inhibitory receptor agonists have been reported to induce the opposite response. As studied in cultured rat cardiomyocytes, the beta-adrenoceptor-induced increase in the level of Gi alpha proteins is protein synthesis-dependent, is apparently not accompanied by an increase in G protein beta-subunits and results in a decreased adenylyl cyclase responsiveness. On the other hand, a decrease in Gi alpha level apparently results in sensitization of adenylyl cyclase stimulation. These data suggest that the up- or down-regulation of the level and activity of Gi protein alpha-subunits is a rather general cellular response, providing an intracellular negative feedback control against prolonged receptor activation.

ADP Ribose Transferases↗
PubMed1990

Pseudomonas exotoxin A prevents beta-adrenoceptor-induced upregulation of Gi protein alpha-subunits and adenylyl cyclase desensitization in rat heart muscle cells.

Exposure of rat heart muscle cells to noradrenaline (1 microM) for 48 hr led to a decrease in the number of beta 1-adrenoceptors of 50% and a concomitant decrease in adenylyl cyclase stimulation by isoprenaline and forskolin of about 60 and 30%, respectively. In addition, the levels of two inhibitory guanine nucleotide-binding protein (Gi protein) alpha-subunits (Gi alpha 40 and Gi alpha 41) were increased in membranes of noradrenaline-treated cells. Evidence is presented that noradrenaline induces this increase by activation of beta-adrenoceptors. First, the noradrenaline action was mimicked by the beta-adrenoceptor agonist isoprenaline. Second, beta-adrenoceptor blockade by timolol but not alpha-adrenoceptor blockade by prazosin prevented the noradrenaline-induced up-regulation of Gi alpha proteins. Furthermore, timolol but not prazosin abolished the noradrenaline-induced down-regulation of beta 1-adrenoceptors and the decreases in receptor-dependent (isoprenaline) and -independent (forskolin) adenylyl cyclase stimulation. The specific protein synthesis inhibitor Pseudomonas exotoxin A was used to study whether the noradrenaline-induced up-regulation of Gi alpha subunits depends on increased synthesis of these proteins. This toxin inhibits peptide chain elongation by ADP-ribosylating elongation factor 2. Treatment of rat heart muscle cells with Pseudomonas exotoxin A (1 ng/ml) completely prevented the noradrenaline-induced increase in Gi alpha proteins, measured by both pertussis toxin-catalyzed ADP-ribosylation and immunoblotting with anti-Gi alpha antibodies. Most importantly, Pseudomonas exotoxin A also completely prevented the noradrenaline-induced decrease in forskolin-stimulated adenylyl cyclase activity. Furthermore, the noradrenaline-induced decrease in isoprenaline-stimulated adenylyl cyclase activity was significantly attenuated by the toxin, although the down-regulation of beta 1-adrenoceptors caused by noradrenaline treatment was not affected. The data presented suggest that prolonged activation of beta-adrenoceptors in rat heart muscle cells, in addition to causing a receptor down-regulation, induces the synthesis of Gi alpha proteins, which then apparently mediate a decreased adenylyl cyclase responsiveness. The data, additionally, suggest that the synthesis of Gi alpha proteins is under control of the activity of the adenylyl cyclase system and that altered levels of these proteins may play a major role in long term regulation of signal transduction by this enzyme.

ADP Ribose Transferases↗