Cyclic GMP‐independent relaxation of rat pulmonary artery by spermine NONOate, a diazeniumdiolate nitric oxide donor

In rat pulmonary artery pre‐contracted with phenylephrine, the mechanisms of relaxation to the nitric oxide (NO) donor, spermine NONOate, were investigated. Responses to spermine NONOate were only partially blocked by the soluble guanylate cyclase inhibitor, ODQ (1 H ‐[1,2,4]Oxadiazolo‐[4,3,‐ a ]quinoxalin‐1‐one) at concentrations up to 30 μ M . Ten μ M ODQ gave maximal inhibition. Endothelium removal had no effect on the potency of spermine NONOate or its inhibition by ODQ. The protein kinase G inhibitor, Rp‐8‐Br‐cGMPS (100 μ M ), caused minimal inhibition of spermine NONOate despite causing marked inhibition of glyceryl trinitrate and isosorbide dinitrate. Spermine NONOate (100 μ M ) caused a 35 fold increase in guanosine 3′5′ cyclic monophosphate (cyclic GMP) above basal levels in pulmonary artery rings. ODQ (3 μ M ) abolished this cyclic GMP production but did not inhibit corresponding relaxant responses. Similar results were seen with another NONOate (MAHMA NONOate; 10 μ M ). ODQ‐resistant relaxation to spermine NONOate (i.e. relaxation seen in the presence of 10 μ M ODQ) was inhibited by potassium (80 m M ), charybdotoxin (300 n M ), iberiotoxin (300 n M ), apamin (100 n M ), ouabain (1 m M ) or thapsigargin (100 n M ) but not by 4‐aminopyridine (3 m M ), glybenclamide (10 μ M ) or diltiazem (10 μ M ). Potassium, charybdotoxin, ouabain and thapsigargin also inhibited ODQ‐resistant relaxation to FK409 ((±)‐ E ‐4‐ethyl‐2‐[ E ‐hydroxyimino]‐5‐nitro‐3‐hexenamide). We conclude that, on rat pulmonary artery, spermine NONOate can produce cyclic GMP‐independent relaxation that involves, at least in part, activation of Na + /K + ‐ATPase, sarco‐endoplasmic reticulum Ca 2+ ‐ATPase and calcium‐activated potassium channels.British Journal of Pharmacology (2000) 131 , 673–682; doi: 10.1038/sj.bjp.0703613