Toxicology and pharmacology of some ruthenium compounds: Vascular smooth muscle relaxation by nitrosyl derivatives of ruthenium and iridium

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Abstract
A series of compounds were synthesized from ruthenium trichloride, and their ip LDSOs were determined in mice: pentamminenitrosylruthenium(II) chloride, 8.9; chloronitrobis(2,2'‐dipyridyl)ruthenium(II), 55;dichlorobis(2,2'‐dipyridyl)ruthenium(II), 63; ruthenium trichloride, 108; and potassium pentachloronitrosylruthenate(II), 127 mg/kg. The two bis‐bipyridyl complexes produced death in convulsions within minutes, whereas the remaining compounds resulted in long, debilitating courses with death occurring in 4–7 d. When given in massive overdoses, however, the compounds with inorganic ligands also produced rapid convulsive death in mice, and when given iv to anesthetized cats, they produced respiratory arrest. The major toxic effects of all the complexes appeared to be due to the metal and not to its associated ligands. Only complexes having a nitrosyl ligand specifically relaxed vascular smooth muscle. Potassium pentabromoiridate(III) also relaxed rabbit aortic strips that had been contracted by adrenergic agonists, but potassium pentachloroiridate(III) did not. None of the complexes was as active as nitroprusside in relaxing aortic strips or in decreasing arterial blood pressure in cats. No compound tested was as potent as cisplatin in antitumor activity. The pentammine‐nitrosylruthenium(II) complex also relaxed guinea pig ileum and frog rectus abdominus when these isolated muscles had been contracted by acetyicholine. It appears that these organoruthenium compounds may produce death in central respiratory arrest, as do the inorganic complexes when given iv or ip in massive overdoses. In minimally lethal doses, the complexes with inorganic ligands may affect a variety of contractile tissues, perhaps by a general mechanism involving Co. These complexes are apt to be generally cytotoxic as well.