Neuropeptide Y is a prejunctional inhibitor of vagal but not sympathetic inotropic responses in guinea-pig isolated left atria

1 The effects of NPY and related peptides were examined on basal contractil e force and nerve-mediated inotropic responses to electrical field stimulat ion of the guinea-pig isolated left atrium. 2 Electrical field stimulus (EFS)-inotropic response curves were constructe d by applying 1-64 trains of four field pulses (200 Hz, 0.1 ms duration, 10 0 V) across isolated left atria (paced at 4 Hz, 2 ms, 1-4 V) within the atr ial refractory period. Curves were constructed in presence of vehicle, prop ranolol (1 mu M) or atropine (1 mu M) to determine appropriate stimulus con ditions. 3 The effects of PYY (1-10,000 nM), NPY (0.01-10 mu M), N-Ac-[Leu(28,31)]NP Y(24-36) (N-A[L]NPY(24-36); 0.01-10 mu M) and clonidine (0.1-1000 nM) were examined on the positive and negative inotropic responses to EFS (eight tra ins, four pulses per refractory period). 4 NPY-related peptides had no effect on basal force of contraction nor on t he inotropic concentration-response curves to bethanechol or isoprenaline. All three peptides inhibited vagally-mediated negative inotropic responses; rank order of potency PYY > NPY greater than or equal to N-A[L]NPY(24-36) was consistent with an action at prejunctional Y-2-receptors. Clonidine con centration-dependently inhibited sympathetic inotropic responses. However, PYY, NPY and N-A[L]NPY(24-36) failed to mediate any significant inhibition of the positive inotropic response to EFS. 5 These data demonstrate that NPY is an effective inhibitor of vagal but no t sympathetically-mediated inotropic responses in the guinea-pig isolated l eft atria. This may suggest that endogenously co-released NPY is important in mediating cross talk between efferent components of the autonomic nervou s system modulating cardiac contractility, acting overall to sustain positi ve inotropic responses.