Inhibition of rat platelet aggregation by the diazeniumdiolate nitric oxide donor MAHMA NONOate.
1. Inhibition of rat platelet aggregation by the nitric oxide (NO) donor MAHMA NONOate (Z-1-N-methyl-N-[6-(N-methylammoniohexyl)amino]diazen-1-ium-1,2-diolate) was investigated. The aims were to compare its anti-aggregatory effect with vasorelaxation, to determine the effects of the soluble guanylate cyclase inhibitor, ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one), and to investigate the possible role of activation of sarco-endoplasmic reticulum calcium-ATPase (SERCA), independent of soluble guanylate cyclase, using thapsigargin. 2 MAHMA NONOate concentration-dependently inhibited sub-maximal aggregation responses to collagen (2-10 micro g ml(-1)) and adenosine diphosphate (ADP; 2 micro M) in platelet rich plasma. It was (i). more effective at inhibiting aggregation induced by collagen than by ADP, and (ii). less potent at inhibiting platelet aggregation than relaxing rat pulmonary artery. 3. ODQ (10 micro M) caused only a small shift (approximately half a log unit) in the concentration-response curve to MAHMA NONOate irrespective of the aggregating agent. 4. The NO-independent activator of soluble guanylate cyclase, YC-1 (3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole; 1-100 micro M), did not inhibit aggregation. The cGMP analogue, 8-pCPT-cGMP (8-(4-chlorophenylthio)guanosine 3'5' cyclic monophosphate; 0.1-1 mM), caused minimal inhibition. 5. On collagen-aggregated platelets responses to MAHMA NONOate (ODQ 10 micro M present) were abolished by thapsigargin (200 nM). On ADP-aggregated platelets thapsigargin caused partial inhibition. 6. Results with S-nitrosoglutathione (GSNO) resembled those with MAHMA NONOate. Glyceryl trinitrate and sodium nitroprusside were poor inhibitors of aggregation. 7. Thus inhibition of rat platelet aggregation by MAHMA NONOate (like GSNO) is largely ODQ-resistant and, by implication, independent of soluble guanylate cyclase. A likely mechanism of inhibition is activation of SERCA.
Homer
Kerry L
KL
Department of Physiology and Pharmacology, The University of Queensland, Brisbane, Queensland 4072, Australia. k.homer 1@mailbox.uq.edu.au
Wanstall
Janet C
JC
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D002374:Catalase / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006834:Hydrazines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects
C105785:1-hexanamine-6-(2-hydroxy-1-methyl-2-nitrosohydrazine)-N-methyl; C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D006834:Hydrazines; D007191:Indazoles; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D011810:Quinoxalines; D013873:Thionucleotides; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C055656:8-((4-chlorophenyl)thio)cyclic-3',5'-GMP; D026422:S-Nitrosoglutathione; D000244:Adenosine Diphosphate; D019284:Thapsigargin; D003094:Collagen; D002374:Catalase; D013482:Superoxide Dismutase; D006162:Guanylate Cyclase; D006152:Cyclic GMP