In the heart, neuropeptide Y (NPY) released during stimulation of the sympathetic nerve attenuates vagal-evoked bradycardia for a prolonged period. The inhibitory action of NPY is proposed as being Y2 receptor mediated. In rat and mouse, anaesthetised with sodium pentobarbitone, the selective Y2 receptor antagonist BIIE0246 reduced the inhibition of cardiac vagal activity evoked by a Y2 agonist, N-acetyl [Leu28, 31] NPY 24-36. BIIE0246 also reduced the inhibitory effect on vagal action evoked by stimulation of the sympathetic nerve. Deletion of the receptor in Y2 receptor-knockout mice abolished all NPY mediated inhibition of cardiac vagal-evoked bradycardia. These findings strongly support the proposal that NPY released during stimulation of the sympathetic nerve acts via Y2 receptors on the vagus nerve to decrease the slowing effect on the heart evoked by vagal stimulation. Examination of the structural components within NPY, using NPY, related PP peptides and structurally altered analogs, showed proline residues in the N-terminal polyproline region of NPY were found to influence the level of presynaptic activity while residues in the PP fold region further enhanced activity. NPY fragments, as long or longer than 3-36 NPY, possessed full inhibitory activity whereas short C-terminal analogs, such as 24-36 did not. The two leucine residues in agonist N-acetyl [Leu28, 31] NPY 24-36 was found to alter the structure and enhance the amphipathic nature of the a-helix in the shortened fragment. Arginine residues in the helix were also found to be important for activity. The leucine residues in N-acetyl [Leu28, 31] NPY 24-36 are proposed to stabilise the molecule producing an over all linear conformation. Although the conformation adopted by NPY at the receptor is unknown, it is plausible to suggest that the interaction between the proline residues and the a-helix stabilise the molecule in the same way that leucine substitution does in N-acetyl [Leu28, 31] NPY 24-36. Results obtained in Y2 receptor-knockout mice infer by their faster heart rates, an inhibitory role for the receptor in regions of the brain able to effect sympathetic outflow to the heart. Therefore knowledge of the structural requirements required of agonists and antagonists for Y2 receptor activation is likely to be of practical significance in drug design for the treatment of diseases affecting both parasympathetic and sympathetic innervation of the heart.
| Identifer | oai:union.ndltd.org:ADTP/187838 |
| Date | January 2003 |
| Creators | Smith-White, Margaret A., Medical Sciences, Faculty of Medicine, UNSW |
| Publisher | Awarded by:University of New South Wales. School of Medical Sciences |
| Source Sets | Australiasian Digital Theses Program |
| Language | English |
| Detected Language | English |
| Rights | Copyright Margaret A. Smith-White, http://unsworks.unsw.edu.au/copyright |
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