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Inhibition of rat platelet aggregation by the diazeniumdiolate nitric oxide donor MAHMA NONOate
Author(s) -
Homer Kerry L,
Wanstall Janet C
Publication year - 2002
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0704971
Subject(s) - thapsigargin , chemistry , soluble guanylyl cyclase , sodium nitroprusside , molsidomine , nitric oxide , serca , adenosine diphosphate , zaprinast , adenosine , platelet , biochemistry , pharmacology , endoplasmic reticulum , atpase , medicine , phosphodiesterase , enzyme , guanylate cyclase , biology , platelet aggregation , organic chemistry
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 (1 H ‐[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. MAHMA NONOate concentration‐dependently inhibited sub‐maximal aggregation responses to collagen (2–10 μg ml −1 ) and adenosine diphosphate (ADP; 2 μ 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. ODQ (10 μ M ) caused only a small shift (approximately half a log unit) in the concentration‐response curve to MAHMA NONOate irrespective of the aggregating agent. The NO‐independent activator of soluble guanylate cyclase, YC‐1 (3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzyl indazole; 1–100 μ M ), did not inhibit aggregation. The cGMP analogue, 8‐pCPT‐cGMP (8‐(4‐chlorophenylthio)guanosine 3′5′ cyclic monophosphate; 0.1–1 m M ), caused minimal inhibition. On collagen‐aggregated platelets responses to MAHMA NONOate (ODQ 10 μ M present) were abolished by thapsigargin (200 n M ). On ADP‐aggregated platelets thapsigargin caused partial inhibition. Results with S‐nitrosoglutathione (GSNO) resembled those with MAHMA NONOate. Glyceryl trinitrate and sodium nitroprusside were poor inhibitors of aggregation. 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.British Journal of Pharmacology (2002) 137 , 1071–1081. doi: 10.1038/sj.bjp.0704971