INTERACTIONS BETWEEN NEUROPEPTIDE-Y AND THE ADENYLATE-CYCLASE PATHWAYIN RAT MESENTERIC SMALL ARTERIES - ROLE OF MEMBRANE-POTENTIAL

1. Simultaneous measurements of membrane potential and tension were pe rformed to investigate the intracellular mechanisms of neuropeptide Y (NPY) in rat mesenteric small arteries. 2. NPY (0.1 mu M) depolarized arterial smooth muscle cells from -55 to -47 mV and increased wall ten sion by 0.22 N m(-1), representing 11% of the contraction elicited by a high-potassium solution. Isoprenaline (1 mu M) and acetylcholine (1 mu M) evoked hyperpolarizations of 11 and 17 mV, respectively. NPY inh ibited the isoprenaline-induced effects on membrane potential without affecting those of acetylcholine. 3. Forskolin evoked sustained concen tration-dependent hyperpolarizations of small mesenteric arteries. NPY (0.1 mu M) inhibited the responses to 1 mu M forskolin, but did not a lter the stable hyperpolarization elicited by the specific activator o f protein kinase A (PKA) S-p-5,6-DCl- cBIMPS (0.1. mM). Forskolin incr eased the cyclic AMP (cAMP) content of the arteries 21-fold, and NPY i nhibited the forskolin-evoked increase in cAMP levels by 91 %. 4. The hyperpolarization produced by 1 mu M forskolin was not affected by eit her charybdotoxin (0.1 mu M) or 4-aminopyridine (0.5 mM), but glibencl amide (5 mu M) inhibited the hyperpolarization by 70%. Glibenclamide a lso inhibited the hyperpolarization evoked by S-p-5,6-DCl-cBIMPS by 59 %. 5. Neither depolarization nor contraction caused by NPY were signif icantly affected by either glibenclamide (5 mu M) or nifedipine (5 mu M), but they were reduced by gadolinium (IO mu M). However, the blocki ng effect of NPY on forskolin-elicited hyperpolarization was not affec ted by gadolinium. 6. Charybdotoxin (0.1 mu) and 4-aminopyridine (0.5 mM) strongly enhanced the depolarization and contraction caused by NPY (0.1 mu M); and nifedipine (1 mu M) prevented the enhanced responses to NPY in the presence of charybdotoxin. 7. These findings suggest tha t NPY acts through at least two different intracellular mechanisms in mesenteric small arteries: a depolarization of arterial smooth muscle which is probably due to activation of non-selective cation channels, and a marked inhibition of adenylate cyclase activity, which in turn i nhibits the hyperpolarization produced by cAMP accumulation in these a rteries.