MATURATION OF PORCINE TRACHEAL CHOLINERGIC AND INHIBITORY NONADRENERGIC, NONCHOLINERGIC INNERVATION

It is known that both excitatory cholinergic neural activity and nitri c oxide (NO) release from inhibitory non-adrenergic, non-cholinergic ( iNANC) nerves are important determinants of adult human airway smooth muscle tone. However, the level of cholinergic and iNANC activity in t he newborn is unknown. Therefore, isolated trachealis muscle strips we re obtained from neonatal, 10-day-old, and adult pigs. To quantify cho linergic nerve activity, isometric contractions were elicited by stimu lating the nicotinic receptors of the cholinergic intramural ganglia w ith dimethyl-phenyl-piperazinium (DMPP). After ganglionic blockade wit h hexamethonium, the post-ganglionic cholinergic nerves were subjected to electrical field stimulation (EFS). To assess whether DMPP and EFS were also stimulating nitric oxide release from iNANC nerves, the sti mulations were repeated after NO-synthase inhibition with 3 x 10(-5) M N-G-monomethyl-L-arginine acetate (LNMMA). All responses were express ed as a percentage of maximal response to 10(-4) M acetylcholine. Alth ough no significant age-related differences in the contractile respons es to DMPP were demonstrated between the three age groups, the EFS res ponses were significantly different. At EFS frequencies of 1 and 2 Hz the responses of all three groups were different (P < 0.05, unpaired t -test). At frequencies of 0.125 and 0.5 Hz the contractile responses i n the neonatal and 10-day-old groups were less than in the adult anima l tissues (P < 0.05, unpaired t-test). At 4 Hz and above, the response s of the 10-day-old and adult groups became greater than the neonatal (P < 0.05, unpaired t-test). LNMMA did not significantly increase the contractile responses to DMPP at any age. Only in the neonatal and 10- day-old groups was a significant increase of the EFS frequency respons es by LNMMA demonstrated (140.4 +/- 38.2% and 144.2 +/- 41.2%, respect ively, at 0.5 Hz, ANOVA, P < 0.001). In conclusion, the DMPP responses suggest that the neonatal porcine cholinergic innervation is mature a t birth. This contrasts with a frequency-dependent increase in EFS res ponses from birth. This may be due in part to a relative increase in i NANC modulation of post-ganglionic cholinergic activity at birth. This mechanism is not responsible for the increase in higher EFS frequency responses with post-natal maturation. Inhibitory NANC activity may se rve a protective role in the newborn, given the reported hyper-respons iveness of airway smooth muscle, small airway caliber, and high chest wall compliance at this age. (C) 1997 Wiley-Liss, Inc.