Relaxation to authentic nitric oxide and SIN-1 in rat isolated mesenteric arteries: variable role for smooth muscle hyperpolarization

1 Authentic nitric oxide (NO; 0.1-10 mu moles) caused transient, dose-depen dent relaxation of phenylephrine-induced tone without changing membrane pot ential in mesenteric arteries. Larger doses, above 10 mu moles, did not evo ke more relaxation (maximal relaxation to 150 mu moles NO in denuded arteri es, 69 +/- 17%, n=8) but stimulated muscle hyperpolarization (maximum 19 +/ - 3 mV, n=5). 2 The soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinox alin-1- one (ODQ; 10 muM), abolished relaxation to low doses of NO (n=4), b ut did not modify hyperpolarization with higher doses of NO (n=4). The pota ssium channel blocker charybdotoxin (ChTX; 50 nM) abolished hyperpolarizati on to high doses of NO and significantly reduced the maximal relaxation (to 43 +/- 6%, n=4; P < 0.01). ODQ and ChTX together abolished tension and mem brane potential change to all doses of NO (n=4). 3 All relaxations to 3-morpholino-sydnonimine (SIN-1; 0.01-10 muM) were ass ociated with hyperpolarization. When the endothelium was intact, ChTX inhib ited hyperpolarization and relaxation to SIN-1 (n=5), while iberiotoxin (Ib TX; 50 nM) or 4-aminopyridine (4-AP; 500 muM) reduced relaxation by 40% and 20%, respectively and by 80% in combination (n=6 in each case). 4 In denuded arteries, relaxation to SIN-1 was unaffected by either ChTX or ODQ alone, but abolished by the inhibitors together (n=6). Alone, 4-AP did not alter relaxation, but in the presence of ODQ it reduced the maximal re sponse by around 45% (n=6; P < 0.01). 4-AP, ODQ and IbTX together inhibited relaxation to SIN-1 by 75% (n=6; P < 0.01). 5 Therefore, cyclic guanosine 3 ' ,5 ' -monophosphate (cyclic GMP)-independ ent smooth muscle hyperpolarization, possibly involving direct activation o f calcium-activated and voltage-sensitive potassium channels, contributes t o relaxation evoked by authentic NO and SIN-1. However, the importance of e ach pathway depends on the source of NO and with SIN-1 the relative contrib ution from each pathway is modified by the endothelium.