title: A post-receptor defect of adenylyl cyclase in severely failing myocardium from children with congenital heart disease.
abstract: 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.
authors.affiliation: Med. Klinik I, Klinikum Grosshadern, Universität München, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Reithmann
authors.forename: D
authors.initials: D
authors.lastname: Reber
authors.forename: R
authors.initials: R
authors.lastname: Kozlik-Feldmann
authors.forename: H
authors.initials: H
authors.lastname: Netz
authors.forename: G
authors.initials: G
authors.lastname: Pilz
authors.forename: A
authors.initials: A
authors.lastname: Welz
authors.forename: K
authors.initials: K
authors.lastname: Werdan
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000172:deficiency*; D000293:Adolescent; D002462:Cell Membrane / Q000201:enzymology; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006325:Heart Atria / Q000201:enzymology / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000201:enzymology*; D006333:Heart Failure / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D011943:Receptors, Adrenergic, beta; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D000244:Adenosine Diphosphate; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases