Autonomic receptor-effector coupling during post-natal development

Abstract

In summary, there are marked age-dependent alterations in the myocardial alpha 1-adrenergic, beta-adrenergic and muscarinic signal transduction cascades. With maturation, an inhibitory alpha 1-adrenergic response appears, which differs from the pre-existing excitatory response both with respect to the specific receptor subtype involved and its G protein coupling. Neurally released NPY appears to play a critical role in regulating the expression of the inhibitory alpha 1-adrenergic response. Likewise, sympathetic innervation appears involved in the loss of an excitatory muscarinic response during development. Again, this response, which is M1 mediated, differs in receptor subtype from that of the M2 inhibitory response characteristic of the adult. Both responses are PT-sensitive, which suggests the involvement of a PT-sensitive G protein in each case, although not necessarily the identical G protein. The role of innervation in developmental regulation of the beta-adrenergic response is unknown. While a distinct beta 1-adrenergic response exists through development, and appears to change predominantly only with respect to magnitude, the beta 2-adrenergic cascade would seem to have somewhat more complex regulation. Not only is the adult normally far less sensitive to beta 2-agonists than the neonate, but the classical beta-adrenergic effect to enhance relaxation along with the increase in force is absent in the adult when the beta 2 (but not beta 1) receptors are activated. It is apparent from the above summary that in the case of all three autonomic receptor systems, the functional signal transduction cascades in the neonate seem designed to favor excitation (chronotropic and/or inotropic) over inhibition. The alpha 1-adrenergic system is exclusively excitatory in the newborn, with an opposing inhibitory cascade only becoming evident after the onset of sympathetic innervation. Similarly, prior to sympathetic innervation the muscarinic system exhibits both excitatory and inhibitory effects, with the excitatory response being lost with development. Finally, while the beta-adrenergic system appears exclusively excitatory at all ages, in the neonate the beta 1- and beta 2-cascades both contribute to the total positive inotropic response to low concentrations of agonist, while in the adult the beta 2-component only contributes at high agonist concentrations. While the reasons for the favoring of excitation cascades in the neonate is not known, it is tempting to speculate on this point. In this respect it is worth noting that in the young, increasing heart rate, rather than stroke volume, is the primary mechanism by which cardiac output is increased [62]. In this situation, excitatory autonomic mechanisms may be advantageous. Also, at the time of birth in the rat (and at other times in different species) there is a period of potential autonomic imbalance when the parasympathetic innervation to the heart is established but the sympathetic innervation is not yet well developed. During this period, having a positive chronotropic component to muscarinic action, and a positive rather than negative alpha 1-adrenergic response, could serve to compensate for any imbalance between the two limbs of the autonomic nervous system. Finally, while the sympathetic innervation of the heart is not fully developed at birth, there can be circulating catecholamines from the adrenal medulla, and these would be primarily epinephrine rather than norepinephrine. Since epinephrine has a much higher affinity than norepinephrine for beta 2-adrenergic receptors, the presence of a strong beta 2-adrenergic cascade in the neonate could be designed to respond to the circulating, rather than neuronal, catecholamines. Lastly, one should not forget that the final physiologic response depends not only on the proximal events of receptor-effector coupling, but on more distal elements that provide the substrate for these autonomic agonists.(ABSTRACT TRUNCATED AT 400 WORDS)