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  • 1
    Electronic Resource
    Electronic Resource
    Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy (1996)
    Springer
    Journal of molecular medicine 74 (1996), S. 321-332 
    Details
    ISSN: 1432-1440
    Keywords: Heart failure ; Human left ventricle ; Sarcoplasmic reticulum Ca2+ATPase ; Phospholamban ; cAMP
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Giα2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P〈0.01) and from patients with ICM (37%, P〈0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P〈0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P〈0.001 for DCM; 31%, P〈0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins. Giα2 mRNA and protein levels were both significantly increased in failing mycocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or posttranslational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00207509
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    β-Adrenergic signal transduction in the failing and hypertrophied myocardium (1997)
    Springer
    Journal of molecular medicine 75 (1997), S. 842-848 
    Details
    ISSN: 1432-1440
    Keywords: Key words β-Adrenoceptors ; Adenylyl cyclase ; Cardiac hypertrophy ; Heart failure ; G proteins ; Sympathetic activation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A strong sympathetic activation has been observed in heart failure and is the cause of β-adrenergic desensitization in this condition. On the receptor level there is downregulation of β1-adrenergic receptors and uncoupling of β2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of β-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. β3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein α subunits (Giα) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein α and βγ subunits, have been observed to be unchanged. Recent evidence shows that increases in Giα also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Giα can suppress adenylyl cyclase in the absence of β-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Giα may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001090050175
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    Paper (German National Licenses)
    Fulltext
  • 3
    Electronic Resource
    Electronic Resource
    Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 308-312 
    Details
    ISSN: 1432-1912
    Keywords: Key words Nitric oxide ; cGMP ; M-cholinoceptors ; Force of contraction ; Heart failure ; Human myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-L-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37° C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 μmol/l) was studied in the presence of the β-adrenoceptor agonist isoprenaline (0.03 μmol/l). After stimulation with isoprenaline, carbachol significantly (P〈0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to β-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 μmol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 μmol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue. The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168562
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 4
    Electronic Resource
    Electronic Resource
    Evidence against a role of nitric oxide in the indirect negative inotropic-effect of M-cholinoceptor stimulation in human ventricular myocardium (1995)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 352 (1995), S. 308-312 
    Details
    ISSN: 1432-1912
    Keywords: Nitric oxide ; cGMP ; M-cholinoceptors ; Force of contraction ; Heart failure ; Human myocardium
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Nitric oxide (NO) has been reported to mediate several effects in response to muscarinic cholinergic stimulation in cardiovascular tissues. Recently, an attenuation of guinea pig cardiac myocyte contraction by NO has been described. The aim of the present study was to determine whether the indirect negative inotropic effect of M-cholinoceptor stimulation in human myocardium is in part due to an effect of endogenous NO. Therefore, the effect of carbachol was studied under control conditions and during inhibition of NO-synthase by pretreatment with NG-monomethyl-l-arginine (NMMA). Functional experiments were performed in isolated, electrically driven (1 Hz, 37°C) left ventricular papillary muscle strips of human myocardium. Since cytokines have been reported to be increased in the serum of patients with heart failure and could induce NO-synthase activity in failing myocardium, we compared samples from nonfailing and terminally failing (classified as NYHA IV) hearts. The indirect negative inotropic effect of carbachol (10 μmol/l) was studied in the presence of the \-adrenoceptor agonist isoprenaline (0.03 μmol/l). After stimulation with isoprenaline, carbachol significantly (P 〈 0.05) reduced force of contraction. This effect was diminished in failing myocardium compared to nonfailing, probably due to the diminished inotropic response most likely due to the lower cAMP levels in response to \-adrenoceptor stimulation in the former condition. Pretreatment with NMMA (100 μmol/l) altered the antiadrenergic effect of carbachol neither in nonfailing nor in failing preparations. Furthermore, inhibition of guanylyl cyclase, the target enzyme of NO, by preincubation with methylene blue (10 μmol/l) for 30 min had no effect on the carbachol-induced decrease in force of contraction. Basal force of contraction, as well as the positive inotropic effect of isoprenaline remained unaffected by NMMA or methylene blue. The present study provides evidence that the indirect negative inotropic effect of M-cholinoceptor agonists is not due to an effect of NO in the human myocardium. Furthermore, the well known enhancement of cGMP in response to M-cholinoceptor stimulation appears not to be involved in this antiadrenergic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168562
    Library Location Call Number Volume/Issue/Year Availability
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    Paper (German National Licenses)
    Fulltext
  • 5
    Electronic Resource
    Electronic Resource
    Role of G-proteins in altered β-adrenergic responsiveness in the failing and hypertrophied myocardium (1996)
    Springer
    Basic research in cardiology 91 (1996), S. 47-51 
    Details
    ISSN: 1435-1803
    Keywords: Heart failure ; hypertensive cardiac hypertrophy ; adenylyl cyclase activity ; β-adrenergic receptor-G-proteins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the heart and other tissues, β-adrenergic desensitization occurs during treatment with catecholamines. In heart failure, a strong sympathetic activation has been observed and is the cause of β-adrenergic desensitization in this condition. On the receptor level, there is a downregulation of β1-adrenergic receptors as well as an uncoupling of β2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of β-ARK2 in failing myocardium leading to phosphorylation and uncoupling of receptors. In addition, an increase of inhibitory G-protein α-subunits (Giα) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G-protein α-subunits and βγ-subunits have been observed to be unchanged. Recently, evidence has been raised that increases of Giα also depress adenylyl cyclase in compensated cardiac hypertrophy in monogenic and polygenic as well as in secondary hypertension. These increases of Giα can suppress adenylyl cylase in the absence of β-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure these observations indicate that adenylyl cyclase desensitization by Giα could be a pathophysiologically relevant mechanism to contribute to the progression from compensated cardiac hypertrophy to heart failure.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00795362
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
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