vasoactive-intestinal-peptide and sapropterin

Vasoactive intestinal peptide plays an important role in the trans-synaptic activation of tyrosine hydroxylase in sympathoadrenal tissues in response to physiological stress. Since tyrosine hydroxylase is thought to be subsaturated with its cofactor, tetrahydrobiopterin, we tested the hypothesis that up-regulation of tyrosine hydroxylase gene expression following vasoactive intestinal peptide treatment is accompanied by a concomitant elevation of intracellular tetrahydrobiopterin biosynthesis. We also investigated the second messenger systems involved in vasoactive intestinal peptide's effects on tetrahydrobiopterin metabolism. Our results demonstrate that treatment of PC12 cells for 24 h with vasoactive intestinal peptide induced intracellular tetrahydrobiopterin levels 3.5-fold. This increase was due to increased expression of the gene encoding GTP cyclohydrolase, the initial and rate-limiting enzyme in tetrahydrobiopterin biosynthesis, which was blocked by the transcriptional inhibitor, actinomycin D. Activation of tyrosine hydroxylase and GTP cyclohydrolase by vasoactive intestinal peptide was mediated by cyclic-AMP. Furthermore, stimulation of cyclic-AMP-mediated responses or protein kinase C activity induced the maximal in vitro activities of both tyrosine hydroxylase and GTP cyclohydrolase; the responses were additive when both treatments were combined. Induction of sphingolipid metabolism had no effect on the activation of tyrosine hydroxylase, while it induced GTP cyclohydrolase in a protein kinase C-independent manner. Our results support the hypothesis that intracellular tetrahydrobiopterin levels are tightly linked to tyrosine hydroxylation and that tetrahydrobiopterin bioavailability modulates catecholamine synthesis.

Topics: Alcohol Oxidoreductases; Animals; Antioxidants; Biopterins; Catecholamines; Cyclic AMP; Dactinomycin; Enzyme Activation; Enzyme Induction; GTP Cyclohydrolase; Kinetics; PC12 Cells; Polymerase Chain Reaction; Protein Kinase C; Rats; RNA, Messenger; Second Messenger Systems; Tetradecanoylphorbol Acetate; Transcription, Genetic; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Pyloric stenosis (PS) is a common condition in infancy, which is associated with smooth muscle hypertrophy that results in pyloric outlet obstruction. The author examines the ontogeny of the peptide innervation of the pylorus in fetal tissues and an experimental model in mice and evaluates the histochemical and morphological changes in the pylorus. The data suggest that PS is an intrauterine lesion that occurs by 12 weeks' gestation. This is associated with diminished nitric oxide in human tissues and reduced enzyme activity (resulting from a deficiency in an enzyme cofactor) in mice. Increased vasoactive intestinal polypeptide expression in pyloric myenteric ganglia may be an intrinsic mechanism for resolving this condition.

Topics: Animals; Biopterins; Female; Gestational Age; Humans; Hypertrophy; Infant; Infant, Newborn; Male; Mice; Mice, Inbred Strains; Myenteric Plexus; Nitric Oxide; Nitric Oxide Synthase; Pregnancy; Pyloric Antrum; Pyloric Stenosis; Vagus Nerve; Vasoactive Intestinal Peptide