Chronic hypoxia induces beta-adrenoceptor desensitization in rat hearts via impaired Gs protein and adenylyl cyclase function, independent of hypertrophy.
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 et al. (Wed,) studied this question.