β-Adrenoceptor mediated signal transduction in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters
In view of the lack of information regarding the status of β-adrenoceptor mediated signal transduction mechanisms at severe stages of congestive heart failure, the status of β-adrenoceptors, G-proteins and adenylyl cyclase activities was examined in 220–275 day old cardiomyopathic hamster hearts. Although no changes in the Kd values for β1- and β2-adrenoceptors were seen, the number of β1-adrenoceptors, unlike that of β2-adrenoceptors, was markedly decreased in cardiac membranes from failing hearts. The activation of adenylyl cyclase in the failing hearts by different concentrations of isoproterenol was also attenuated in comparison to the control preparations. The basal adenylyl cyclase activity in cardiac membranes from the failing hearts was not altered; however, the stimulated enzyme activities, when measured in the presence of forskolin, NaF or Gpp(NH)p were depressed significantly. The functional activity of Gs-proteins (measured by cholera toxin stimulation of adenylyl cyclase) was depressed whereas that of Gi-proteins (measured by pertussis toxin stimulation of adenylyl cyclase) was increased in the failing hearts. Not only were the Gs- and Gi-protein contents (measured by immunoblotting) increased, the bioactivities of these proteins as determined by ADP-ribosylations in the presence of cholera toxin and pertussis toxin, respectively, were also higher in failing hearts in comparison to the control values. Northern blot analysis revealed that the signals for Gs- and Gi-protein mRNAs were augmented at this stage of heart failure. These results indicate that the loss of adrenergic support at severe stages of congestive heart failure in cardiomyopathic hamsters may involve a reduction in the number of β1-adrenoceptors, and an increase in Gi-protein contents as well as bioactivities in addition to an uncoupling of Gs-proteins from the catalytic site of adenylyl cyclase in cardiac membrane.
Key wordscardiac β-adrenoceptors adenylyl cyclase in heart myocardial G-proteins signal transduction mechanisms congestive heart failure cardiomyopathic hamsters
Unable to display preview. Download preview PDF.
- 3.Dhalla NS, Elimban V, Rupp H, Takeda N, Nagano M: Role of calcium in cardiac cell damage and dysfunction. In: N. Sperelakis (ed.). Physiology and Pathophysiology of the Heart. 3rd ed. Kluwer Academic Publishers, Boston, 1995, pp 605–623Google Scholar
- 24.Sethi R, Panagia V, Dhalla KS, Beamish RE, Jasmin G, Dhalla NS: Status of β-adrenergic mechanisms during the development of congestive heart failure in cardiomyopathic hamsters (UM-X7.1). In: M. Nagano, N. Takeda, N.S. Dhalla (eds). The Cardiomyopathic Heart. Raven Press, New York, 1994, pp 73–86Google Scholar
- 25.Dhalla NS, Lee SL, Shah KR, Elimban V, Suzuki S, Jasmin G: Behavior of subcellular organelles during the development of congestive heart failure in cardiomyopathic hamsters (UM-X7.1). In: M. Nagano, N. Takeda, N.S. Dhalla (eds). The Cardiomyopathic Heart. Raven Press, New York, 1994, pp 1–14Google Scholar
- 27.Brodde DE, Zerkowski HR, Doetsch N, Motomura S, Khamssi M, Michel MC: Myocardial beta-adrenoceptor changes in heart failure: concomitant reduction in beta1- and beta2-adrenoceptor function related to the degree of heart failure in patients with mitral valve disease. J Am Coll Cardiol 14: 323–331, 1989PubMedCrossRefGoogle Scholar
- 31.Dixon IMC, Dhalla NS: Alterations in cardiac adrenoceptors in congestive heart failure secondary to myocardial infarction. Coronary Artery Disease 2: 805–814, 1991Google Scholar
- 39.Reithmann C, Gierschik P, Sidiropoulos D, Werdan K, Jakobs KH: Mechanism of noradrenaline-induced heterologous desensitization of adenylate cyclase stimulation in rat heart muscle cells: increase in the level of inhibitory G-protein α-subunits. Eur J Pharmacol 172: 211–221, 1989PubMedCrossRefGoogle Scholar
- 40.Horn EM, Bilezekian JP: Mechanisms of abnormal transmembrane signalling of the β-adrenergic receptor in congestive heart failure. Circulation 82 (Suppl I): 26–34, 1990Google Scholar