Cell culture studies demonstrate an increase in cardiac L-type Ca2+ current (I-Ca,I-L) density on sympathetic innervation in vitro and suggest the effect depends on neurally released neuropeptide Y (NPY). To determine if a similar mechanism contributes to the postnatal increase in I-Ca,I-L in vivo, we prepared isolated ventricular myocytes from neonatal and adult mice with targeted deletion of the NPY gene (Npy(-/-)) and matched controls (Npy(+/+)). Whole-cell voltage clamp demonstrates I-Ca,I-L density increases postnatally in Npy(+/+) (by 56%), but is unchanged in Npy(-/-). Both I-Ca,I-L density and action potential duration are significantly greater in adult Npy(+/+) than Npy(-/-) myocytes, whereas I-Ca,I-L density is equivalent in neonatal Npy(+/+) and Npy(-/-) myocytes. These data indicate NPY does not influence ICa,L prenatally, but the postnatal increase in I-Ca,I-L density is entirely NPY-dependent. In contrast, there is a similar postnatal negative voltage shift in the I-V relation in Npy(+/+) and Npy(-/-), indicating NPY does not influence the developmental change in I-Ca,I-L voltage-dependence. Immunoblot analyses and measurements of maximally activated I-Ca,I-L (in presence of forskolin or BayK 8644) show that the differences in current density between Npy(+/+) and Npy(-/-) cannot be attributed to altered Ca2+ channel alpha(1C) subunit protein expression. Rather, these results suggest that the in vivo NPY-dependent postnatal increase in I-Ca,I-L density in cardiac myocytes results from regulation I-Ca,I-L properties by NPY.
|Titolo:||Neuropeptide Y is an essential in vivo developmental regulator of cardiac I-Ca,I-L|
BARBUTI, ANDREA FRANCESCO (Secondo)
|Parole Chiave:||neuropeptide Y ; development ; Ca2+ channel ; innervation ; ventricle|
|Data di pubblicazione:||14-nov-2003|
|Digital Object Identifier (DOI):||10.1161/01.RES.0000099244.01926.56|
|Appare nelle tipologie:||01 - Articolo su periodico|