Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy.
In myocardial membranes from hearts with dilated cardiomyopathy (DCM), there was a 37% increase of the Gi alpha-protein as measured by 32P-ADP-ribosylation of a approximately 40 kDa pertussis toxin substrate. Immunoblotting techniques also showed increased amounts of Gi alpha in DCM. In hearts with ischemic cardiomyopathy (ICM), Gi alpha was not altered compared with nonfailing myocardium (NF). Basal and Gpp(NH)p-stimulated adenylate cyclase activity was reduced in DCM but not in ICM. The number of beta-adrenoceptors was similarly reduced both in DCM and ICM compared with NF. Alterations of m-cholinoceptors or A1-adenosine receptors did not occur. Consistently, "indirect" negative inotropic effects of the m-cholinoceptor agonist carbachol and the A1-adenosine receptor agonist R-PIA were not different in ICM, DCM, and nonfailing myocardium. In ICM and DCM, there was a marked reduction of the positive inotropic responses to isoprenaline and milrinone. However, there was a further reduction in DCM compared with ICM. It is concluded that the increase of Gi alpha is accompanied by a reduction of basal and guanine-nucleotide-stimulated adenylate cyclase activity. Alterations of m-cholinoceptors and A1-adenosine receptors do not appear to be involved. The further decrease of the positive inotropic effects of isoprenaline and milrinone in DCM provides evidence that the increase of Gi alpha is functionally relevant in DCM but not ICM and hence might contribute to the reduced effects of endogenous catecholamines and exogenous cAMP-dependent positive inotropic agents in the former but not the latter condition.
Böhm
M
M
Medizinische Klinik I, Universität München, FRG.
Gierschik
P
P
Jakobs
K H
KH
Pieske
B
B
Schnabel
P
P
Ungerer
M
M
Erdmann
E
E
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000328:Adult; D002217:Carbachol / Q000494:pharmacology; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003327:Coronary Disease / Q000378:metabolism*; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D037342:Pertussis Toxin; D010660:Phenylisopropyladenosine / Q000494:pharmacology; D011728:Pyridones / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000378:metabolism; D011983:Receptors, Purinergic / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D037361:Adenylate Cyclase Toxin; D002316:Cardiotonic Agents; D011728:Pyridones; D011943:Receptors, Adrenergic, beta; D011950:Receptors, Cholinergic; D011983:Receptors, Purinergic; D010566:Virulence Factors, Bordetella; D000246:Adenosine Diphosphate Ribose; D010660:Phenylisopropyladenosine; D002217:Carbachol; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D020105:Milrinone; D007545:Isoproterenol