Involvement of soluble guanylate cyclase and calcium-activated potassium channels in the long-lasting hyporesponsiveness to phenylephrine induced by nitric oxide in rat aorta.
Excessive nitric oxide (NO) production by inducible NO synthase has been implicated in the hyporesponsiveness to vasoconstrictors present in septic shock. Here we show that a brief incubation (30 min) of rat aorta rings with NO donors renders the vessels hyporesponsive to phenylephrine for several hours. Contraction of rings without endothelium by phenylephrine (0.1 nM to 100 microM) was decreased by 50-60% after incubation (30 min) with sodium nitroprusside (3-300 microM) or S-nitroso-acetyl-D,L-penicillamine (SNAP; 70-200 microM). This decrease was characterized by reductions in maximal response and rightwards shifts of phenylephrine concentration/response curves, present even 130 min after NO donor removal. Soluble guanylate cyclase inhibitors methylene blue ( 10 microM) and 1H-(1,2,4)-oxadiazol-(4,3-a)quinoxalin-1-one (ODQ, 1 microM) or the potassium channel blockers TEA (tetraethylammonium; 10 mM) and charybdotoxin (100 nM) inhibited the hyporesponsiveness to phenylephrine induced by the NO donors. In contrast, 4-aminopyridine (1 mM) and glibenclamide (10 microM) had no effect. Our results show that incubation with NO donors reproduces the hyporesponsiveness to phenylephrine and that NO alone accounts for most, if not all, the refractoriness to vasoconstrictors present in septic shock. In addition, soluble guanylate cyclase activation and opening of potassium channels, more specifically the calcium-activated subtype, play a predominant role in this NO-induced hyporesponsiveness to phenylephrine in the rat aorta.
Terluk
M R
MR
Department of Pharmacology, Universidade Federal de Santa Catarina, Florianopolis, Brazil.
da Silva-Santos
J E
JE
Assreuy
J
J
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology; D004342:Drug Hypersensitivity / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology*; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D051381:Rats; D017208:Rats, Wistar; D051640:Small-Conductance Calcium-Activated Potassium Channels
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D051640:Small-Conductance Calcium-Activated Potassium Channels; D010656:Phenylephrine; D009569:Nitric Oxide; D006162:Guanylate Cyclase