title: Role of altered G-protein expression in the regulation of myocardial adenylate cyclase activity and force of contraction in spontaneous hypertensive cardiomyopathy in rats.
abstract: OBJECTIVE
  The question of this study was whether alterations in the inhibitory guanine-nucleotide binding protein alpha-subunits (G(i)alpha) contribute to alterations in adenylate cyclase regulation in hypertensive cardiomyopathy of spontaneously hypertensive rats (SHR).
  
  
  METHODS
  G(i)alpha was measured by pertussis toxin-catalysed 32P-adenosine 5'-pyrophosphate (ADP)-ribosylation and radioimmunochemically by competition of rat myocardial membrane extracts to DS 4 antiserum binding to the 125I-radiolabelled C terminus of retinal transducin alpha (125I-KENLKDCGLF). Cardiac beta-adrenoceptors, m-cholinoceptors as well as isoprenaline-, guanine-nucleotide [Gpp(NH)p]- and forskolin-stimulated adenylate cyclase activity and inotropic responses to isoprenaline and carbachol were studied in SHR and age-matched Wistar-Kyoto (WKY, control) rats.
  
  
  RESULTS
  In native membranes of SHR there was an increase in pertussis toxin substrates, but a larger increase in the presence of non-ionic detergent Lubrol PX. The radioimmunological quantification of G(i)alpha revealed an increase in membrane extracts of SHR. In addition, myocardial beta-adrenoceptors and myocardial m-cholinoceptors were reduced in SHR compared with in WKY rats. Basal adenylate cyclase, isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylate cyclase activities were also reduced. However, in the presence of 5 mmol/l MnCl2 no differences in adenylate cyclase activities between SHR and WKY rats were detected under either condition.
  
  
  CONCLUSIONS
  The present study shows that the amount of G(i)alpha-proteins and not only pertussis toxin substrates are increased in membranes of hypertrophic hearts from SHR without heart failure. The results obtained with pertussis-labelling depended strongly on the substrate quality of G(i)alpha. Increased G(i)alpha expression and reduced beta-adrenoceptor number might have functional relevance in the regulation of adenylate cyclase activity and force of contraction in SHR. An increase in G(i)alpha expression might play a pathophysiological role, not only in terminal heart failure, but also in hypertrophic cardiomyopathy.
authors.affiliation: Medizinische Klinik I, Universität München, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Böhm
authors.forename: P
authors.initials: P
authors.lastname: Gierschik
authors.forename: A
authors.initials: A
authors.lastname: Knorr
authors.forename: K
authors.initials: K
authors.lastname: Larisch
authors.forename: K
authors.initials: K
authors.lastname: Weismann
authors.forename: E
authors.initials: E
authors.lastname: Erdmann
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D006332:Cardiomegaly / Q000378:metabolism / Q000503:physiopathology; D002462:Cell Membrane / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D006973:Hypertension / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D037342:Pertussis Toxin; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D010566:Virulence Factors, Bordetella
chemical_list: D037361:Adenylate Cyclase Toxin; D010566:Virulence Factors, Bordetella; D002217:Carbachol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol