Noradrenergic modulation of the medullary respiratory rhythm generator in the newborn rat: an in vitro study.

1. Superfused brain stem-spinal cord preparations of newborn rats, which continue to show a rhythmic respiratory activity in vitro, were used to analyse the mechanisms whereby the A5 noradrenergic area modulates the activity of the medullary respiratory rhythm generator in the newborn. 2. In preparations including the pons (ponto-medullary preparations), noradrenaline (NA, 25-100 microM) added to the bathing medium either increased (n = 29/50) or decreased (n = 21/50) the respiratory frequency and elicited a tonic discharge in the cervical ventral roots in 50% of the experiments. Double-bath experiments showed that the increases in respiratory frequency were due to NA acting on the pons, whereas the decreases in respiratory frequency were due to NA acting on the medulla. The NA-induced increases in respiratory frequency were attributed to inhibition of A5 neurons by NA and therefore to withdrawal of A5 inhibition on the medullary rhythm respiratory generator. The NA-induced decreases in respiratory frequency seemed to mimic the effects of endogenous NA on the A5 medullary targets. 3. Noradrenaline-induced tonic activity (i) could be induced after elimination of the pons but not on isolated spinal cord, (ii) could be elicited by alpha 1- but not alpha 2-agonists, (iii) could be blocked by alpha 1- but not alpha 2-antagonists. The tonic activity therefore originated from activation of alpha 1 receptors located in the medulla but its importance in respiratory function is doubtful. 4. In medullary preparations (elimination of the pons by transection), the effects of NA agonists and antagonists on respiratory frequency were analysed. Significant decreases in respiratory frequency were induced by NA, adrenaline, phenylephrine and alpha-methyl-NA, but not by the agonists classified as alpha 2 (clonidine and guanfacine), alpha 1 (6-fluoro-NA) and beta (isoprenaline). Since yohimbine, idazoxan and piperoxane (alpha 2 antagonists) blocked the NA-induced decreases in respiratory frequency whereas prazosin (alpha 1-antagonist) did not, it is postulated that alpha 2-receptors may be involved in modulating respiratory frequency. 5. Stimulation, lesion and NA microejection experiments showed the complexity of the mechanisms mediating NA-induced changes in respiratory activity but suggested that the main site of NA action is located in the rostral ventrolateral medulla, where electrical stimulations triggered inspiration prematurely, lesions suppressed the NA-induced decrease in respiratory frequency, and localized application of NA led to an immediate decrease in the respiratory frequency.(ABSTRACT TRUNCATED AT 400 WORDS)