Neuronal Regulation of the Development of the a-Adrenergic Chronotropic Response in the Rat Heart

During development, there are changes in the response of automatic cardiac fibers to a-adrenergic agonists. In neonatal rat ventricle, in vitro phenylephrine (1 X 10~* M) induces an increase in automatic rate from 115 ± 12 (mean ± SEM) to 168 ± 10 beats/min, P < 0.05. In contrast, in adult rat ventricle, the rate decreases from 36 ± 8 to 12 ± 12 beats/min, P < 0.05. At both ages, the response is attenuated by the a^antagonist, prazosin (1 X 10~* M). We used cultures of neonatal rat myocytes to determine whether maturation of innervation contributes to the ontogeny of this response. All non-innervated cultures showed a positive chronotropic response to a-stimulation; phenylephrine (1 X 10"' M) increased the rate from 40 ± 2 to 52 ± 2 beats/min, P < 0.05. In contrast, 60% of the myocytes innervated with sympathetic neurons showed a decrease in rate in response to phenylephrine, from 78 ± 6 to 67 ± 6 beats/min, P < 0.05. The negative chronotropic effect of phenylephrine did not result from the release of acetylcholine or adenosine, or the inhibition of presynaptic norepinephrine release by phenylephrine. Furthermore, exposure to neuronal norepinephrine is not responsible for the alteration in muscle cell responsiveness. In conclusion, we have demonstrated the modulation of the myocardial response to aadrenergic stimulation by the occurrence of innervation in tissue culture. This provides an explanation for the previously identified ontogenetic change in a-adrenergjc effects on intact cardiac fibers from excitation to inhibition. (Circ Res 57: 415-423, 1985)