Modifications of cardiac contractility by redox cycling alkylating and mixed redox cycling/alkylating quinones.
The effects of redox cycling, alkylating and mixed redox cycling/alkylating benzo- and naphthoquinones were examined in electrically driven guinea pig left atria. Cardiac microsomal and mitochondrial NAD(P)H-dependent metabolism of the quinones and consequent generation of superoxide anion (O2.-) were also measured. Mixed redox cycling/alkylating 2-methyl-1,4-naphthoquinone, redox cycling 2,3-dimethoxy-1,4-naphthoquinone and alkylating p-benzoquinone determined concentration-dependent positive inotropic responses, whereas redox cycling 2,3,5,6-tetramethyl-p-benzoquinone had no effect. The positive inotropic effect of 2,3-dimethoxy-1,4-naphthoquinone was completely catecholamine-mediated, that of 2-methyl-1,4-naphthoquinone was approximately 70% adrenergic and 30% direct. p-Benzoquinone acted directly on heart muscle. In time, quinones with alkylating properties caused increases in the resting force of atria, whereas redox cycling quinones did not produce toxic effects. Mitochondrial NADH-oxidoreductase accounted for 90 to 95% of the metabolism of all quinones, whereas the contribution of the microsomal pathway was negligible. Considerable amounts of O2.- were produced by mitochondrial biotransformation of 2-methyl-1,4-naphthoquinone and 2,3-dimethoxy-1,4-naphthoquinone but not of 2,3,5,6-tetramethyl-p-benzoquinone and p-benzoquinone, suggesting a kind of relation between O2.- generation and the release of catecholamines.
Floreani
M
M
Department of Pharmacology, University of Padova, Italy.
Carpenedo
F
F
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects; D016227:Benzoquinones / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006325:Heart Atria / Q000187:drug effects; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D008929:Mitochondria, Heart / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D009285:Naphthoquinones / Q000378:metabolism / Q000494:pharmacology; D010084:Oxidation-Reduction; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology*; D015219:Substrate Cycling / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014812:Vitamin K / Q000378:metabolism / Q000494:pharmacology
D000477:Alkylating Agents; D016227:Benzoquinones; D009285:Naphthoquinones; D011809:Quinones; D013481:Superoxides; D014812:Vitamin K; C063002:2,3-dimethoxy-1,4-naphthoquinone; D009247:NADH, NADPH Oxidoreductases; C034257:duroquinone