ABSTRACT
1. This study investigated the effects of BIIE0246, a novel neuropeptide Y (NPY) Y2 receptor antagonist, on the inhibition of cholinergic neuroeffector transmission in rat heart and guinea-pig trachea and purinergic neuroeffector transmission in guinea-pig vas deferens produced by the NPY Y2 receptor agonist, N-acetyl [Leu28,31] NPY 24-36. 2. In pentobarbitone anaesthetized rats, supramaximal stimulation every 30 s, of the vagus nerve innervating the heart, increased pulse interval by approximately 100 ms. This response was attenuated by intravenous administration of N-acetyl [Leu28,31] NPY 24-36 (10 nmol x kg(-1)). 3. Transmural stimulation of segments of guinea-pig trachea at 1 min intervals with 5 s trains of stimuli at 0.5, 5, 10, 20 and 40 Hz evoked contractions which were reduced in force by N-acetyl [Leu28,31] NPY 24-36 (2 microM). 4. In guinea-pig vasa deferentia, the amplitude of excitatory junction potentials evoked by trains of 20 stimuli at 1 Hz was reduced in the presence of N-acetyl [Leu28,31] NPY 24-36 (1 microM). 5. In all preparations BIIE0246 attenuated the inhibitory effect of N-acetyl [Leu28,31] NPY 24-36 but had no effect when applied alone. 6. The findings support the view that the nerve terminals of postganglionic parasympathetic and sympathetic neurones possess neuropeptide Y Y2 receptors which, when activated, reduce neurotransmitter release.
Subject(s)
Arginine/analogs & derivatives , Arginine/pharmacology , Benzazepines/pharmacology , Neuroeffector Junction/drug effects , Receptors, Neuropeptide Y/antagonists & inhibitors , Acetylcholine/metabolism , Action Potentials/drug effects , Animals , Female , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Male , Neuroeffector Junction/physiology , Purines/metabolism , Rats , Rats, Wistar , Trachea/drug effects , Trachea/physiology , Vas Deferens/drug effectsABSTRACT
This study observed the effects of stimulation of the cardiac sympathetic nerve on vagal slowing of the heart in rats, and compared these with any actions of exogenous neuropeptide Y (NPY) and galanin (GAL). In rats anaesthetised with pentobarbitone, stimulation of the cardiac sympathetic nerve for 2 min at 20 Hz in the rat evoked an attenuation of subsequent cardiac vagal action, which could be mimicked by exogenous NPY, but not GAL. The galanin antagonist, GAL1-13/NPY24-36, known to block the inhibitory action of galanin on the cardiac vagus in cats, did not alter the effect of sympathetic stimulation on cardiac vagal activity. We suggest on the basis of results here that in the rat, NPY released during stimulation of the cardiac sympathetic nerve, causes inhibition of acetylcholine release from the vagus nerve.
Subject(s)
Heart/innervation , Parasympathetic Nervous System/physiology , Sympathetic Nervous System/physiology , Anesthesia , Animals , Cats , Electric Stimulation , Female , Galanin/pharmacology , Heart/drug effects , Neuropeptide Y/pharmacology , Parasympathetic Nervous System/drug effects , Rats , Rats, Wistar , Sympathetic Nervous System/drug effects , Vagus Nerve/drug effects , Vagus Nerve/physiologyABSTRACT
Neuropeptide Y (NPY) and a C-terminal analog of NPY, N acetyl [Leu(28,31)] NPY 24-36, act at NPY Y(2) receptors to potently inhibit cardiac vagal activity. The C-terminal analog is equipotent as NPY in inhibiting cardiac vagal activity but does not retain any pressor or Y(1) activity. This study investigates the importance of each amino acid in the 13 residue analog for functional activity by systematically substituting each residue with L-alanine. The inhibitory effect on cardiac vagal action decreased with substitution at residues 25,26,28,29 and 31. No decrease in activity was observed with alanine substitution at residues 24, 27 or 30. Residues 32 and 34 retained activity only at high doses, while residues 33, 35 and 36 were not active following alanine substitution. The difference in potency of the effective analogs suggests secondary structure of the peptide is as important for activity as retaining key amino acids.
