Impaired G(s)alpha and adenylyl cyclase cause beta-adrenoceptor desensitization in chronically hypoxic rat hearts.
The effects of beta-adrenoceptor stimulation with isoproterenol on electrically induced contraction and intracellular calcium ([Ca(2+)](i)) transient, and cAMP in myocytes from both hypertrophied right and nonhypertrophied left ventricles of rats exposed to 10% oxygen for 4 wk, were significantly attenuated. The increased [Ca(2+)](i) transient in response to cholera toxin was abolished, whereas increased cAMP after NaF significantly attenuated. The biologically active isoform, G(s)alpha-small (45 kDa), was reduced while the biologically inactive isoform, G(s)alpha-large (52 kDa), increased. The increased electrically induced [Ca(2+)](i) transient and cAMP with 10-100 microM forskolin were significantly attenuated in chronically hypoxic rats. The content of G(i)alpha(2), the predominant isoform of G(i) protein in the heart, was unchanged. Results indicate that impaired functions of G(s) protein and adenylyl cyclase cause beta-adrenoceptor desensitization. The impaired function of the G(s) protein may be due to reduced G(s)alpha-small and/or increased G(s)alpha-large, which does not result from changes in G(i) protein. Responses to all treatments were the same for right and left ventricles, indicating that the impaired cardiac functions are not secondary to cardiac hypertrophy.
Pei
J M
JM
Department of Physiology, Faculty of Medicine, University of Hong Kong, Hong Kong, China.
Yu
X C
XC
Fung
M L
ML
Zhou
J J
JJ
Cheung
C S
CS
Wong
N S
NS
Leung
M P
MP
Wong
T M
TM
D000262:Adenylyl Cyclases / Q000502:physiology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002772:Cholera Toxin / Q000494:pharmacology; D002908:Chronic Disease; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004558:Electric Stimulation; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000502:physiology*; D006352:Heart Ventricles; D000860:Hypoxia / Q000503:physiopathology*; D007425:Intracellular Membranes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012016:Reference Values; D012969:Sodium Fluoride / Q000494:pharmacology
D002316:Cardiotonic Agents; D020033:Protein Isoforms; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D012969:Sodium Fluoride; D002772:Cholera Toxin; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium