Prenatal hypoxia leads to growth restriction and increased risk of adult cardiovascular disease. We have previously demonstrated that prenatal hypoxia desensitizes the 5 week chicken heart, but has no effect in the 2 week heart. This indicates that there is a programming effect of prenatal hypoxia on βAR signaling. It has been shown in a rat model that the β1AR/β2AR ratio and increased Gai expression is related to decreased βAR sensitivity measured by cAMP production after βAR stimulation. Thus, the aim of this study was to determine whether the observed decrease in βAR sensitivity in the prenatally hypoxic 5 week chicken heart is linked to changes in β1AR/β2AR ratio and Gai expression and what effects it has on the cAMP accumulation due to βAR stimulation.
We incubated eggs in normoxia (N, 20.95% O2) or hypoxia from day 0 (H, 14% O2) and raised the post-hatchlings to 5 weeks of age in normoxic conditions. The hearts were sampled and the β1AR/β2AR ratio in intact heart slices was assessed through competitive binding of [3H]CGP-12177 with specific β1AR or β2AR blockers (CGP-20712A and ICI-118,551 respectively). Gas and Gai expression was assessed by Western blot and an immunoassay was used to determine the cAMP accumulation after βAR stimulation with isoproterenol. We found that there is indeed a decrease in β1AR/β2AR ratio. Surprisingly, Gas increased in prenatally hypoxic hearts and not Gai as hypothesized. cAMP levels after isoproterenol stimulation of βARs was lower in H than in N.
In conclusion, the desensitization of βARs to epinephrine in 5 week chickens exposed to prenatal hypoxia was confirmed by significantly lower cAMP production in response to βAR stimulation compared to the controls. Furthermore, the β1AR/β2AR ratio in prenatally hypoxic animals was decreased similarly to the β1AR/β2AR ratio change seen in heart failure. Gas expression was increased, but again considering the lower cAMP accumulation in response to βAR stimulation, the increased Gas seems to be inactive. We speculate that the 5 week chicken exposed to prenatal hypoxia might be displaying early signs of heart failure.