Structural requirements for neuropeptide Y18-36-evoked hypotension: a systematic study

Area of Science:

• Pharmacology
• Neuroendocrinology
• Cardiovascular Physiology

Background:

• Neuropeptide Y (NPY) and its C-terminal fragments induce hypotension and histamine release in vitro.
• Plasma histamine levels correlate with the hypotensive effects of NPY fragments in vivo.
• The specific structural requirements linking NPY18-36's hypotensive action to histamine release remain unclear.

Purpose of the Study:

• To investigate the correlation between NPY18-36's hypotensive response and in vivo histamine elevation.
• To characterize the structural requirements for both hypotensive activity and histamine release of NPY18-36 analogues.

Main Methods:

• Systematic replacement of amino acids in NPY18-36 with their D-isomers.
• Modification of the N- and C-termini of NPY18-36.
• Assessment of hypotensive potency and plasma histamine elevation for synthesized analogues.

Main Results:

• NPY18-36 analogues showed varied hypotensive potencies, with [D-Tyr21]NPY18-36 being significantly more potent.
• A strong correlation was observed between the rank order of potency for hypotension and histamine elevation among tested analogues.
• NPY1-36 induced hypotension but did not elevate plasma histamine, suggesting a different mechanism.

Conclusions:

• The hypotensive magnitude of NPY18-36 analogues is primarily determined by their ability to increase plasma histamine levels.
• A well-defined N-terminal pharmacophore is crucial for NPY18-36's activity, indicated by sensitivity to chiral inversion and N-terminal modifications.
• The mechanism of hypotension induced by NPY1-36 differs from that of NPY18-36 analogues.