Impaired G(s)alpha and adenylyl cyclase cause beta-adrenoceptor desensitization in chronically hypoxic rat

The effects of beta-adrenoceptor stimulation with isoproterenol on electric ally induced contraction and intracellular calcium ([Ca2+](i)) transient, a nd cAMP in myocytes from both hypertrophied right and nonhypertrophied left ventricles of rats exposed to 10% oxygen for 4 wk, were significantly atte nuated. The increased [Ca2+](i) transient in response to cholera toxin was abolished, whereas increased cAMP after NaF significantly attenuated. The b iologically active isoform, G(s)alpha-small (45 kDa), was reduced while the biologically inactive isoform, G(s)alpha-large (52 kDa), increased. The in creased electrically induced [Ca2+](i) transient and cAMP with 10-100 mu M forskolin were significantly attenuated in chronically hypoxic rats. The co ntent 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 a nd adenylyl cyclase cause b-adrenoceptor desensitization. The impaired func tion of the G(s) protein may be due to reduced G(s)alpha-small and/or incre ased G(s)alpha-large, which does not result from changes in G(i) protein. R esponses to all treatments were the same for right and left ventricles, ind icating that the impaired cardiac functions are not secondary to cardiac hy pertrophy.