Role of beta-adrenoceptor-adenylate cyclase system in the developmental decrease in sensitivity to isoprenaline in foetal and neonatal rat heart.

1. The inotropic and chronotropic sensitivity to noradrenaline and isoprenaline (Iso) of foetal and neonatal rat heart decreases as the heart becomes sympathetically innervated. In the present study, we have examined adenylate cyclase (AC) activation and beta-adrenoceptor binding to determine whether a developmental decrease in sensitivity was demonstrable in the beta-receptor-AC system of atrial and ventricular membranes from the 15 day foetus and 1 day and 7 day neonates. 2. While the maximum activation of AC by Iso increased with age, the sensitivity expressed in terms of pD2 values decreased from the 15th foetal day to the first day after birth in the atria, and from the first day to the 7th day after birth in the ventricle. 3. In contrast, activation of AC by forskolin was almost identical at all ages both in atria and ventricle. 4. The maximum equilibrium binding of [3H]-dihydroalprenolol decreased with age, the dissociation constant being about the same at all ages in both the atria and ventricle. 5. In conclusion, we have demonstrated a developmental decrease in the sensitivity of AC to Iso in myocardial membrane fractions consistent with the developmental decrease in chronotropic and inotropic sensitivity to beta-adrenoceptor agonists. Although a reduction in beta-adrenoceptor number partly accounts for the decrease in sensitivity, some other factors such as decreased coupling to AC may largely be responsible.