Effects of 2-methyl-1,4-naphthoquinone (menadione) on myocardial contractility and cardiac sarcoplasmic reticulum Ca-ATPase.
(1) In electrically driven guinea-pig left atria, menadione (2-methyl-1,4-naphthoquinone) (1 to 20 mumol/l) and menadione sodium bisulfite (30 to 200 mumol/l) produced marked positive inotropic effects. Endogenously released catecholamines and histamine contributed to 80-85% of the effect, the residual 15-20% appearing as a direct effect. (2) In electrically driven guinea-pig ventricular strips, low micromolar concentrations of menadione (0.05 to 0.3 mumol/l) exerted a catecholamine-mediated small positive inotropic effect. (3) In both myocardial preparations, the increase in force of contraction was followed by a non-reversible rise of resting force. In its effects on cardiac contractility menadione resembled the thiol group blocking agent p-chloromercuribenzoate and H2O2. Pretreatment of atria with glutathione prevented the increase in resting force, while dithiothreitol only slightly delayed it. By contrast, the pretreatment with the NAD(P)H-quinone reductase (DT-diaphorase) inhibitor, dicumarol, markedly increased the rate of appearance of the toxic effect of menadione. (4) Among enzymatic and transport systems involved in the onset and control of cardiac contractility, sarcoplasmic reticulum Ca-ATPase was significantly inhibited by menadione after a long contact time. The inhibition was concentration-dependent and persistent, and was antagonized by addition of glutathione. (5) On the basis of these results, the increase in resting force caused by menadione appears to be related to an impairment of the thiol groups of proteins (Ca-ATPase), presumably caused by the drug per se.
Floreani
M
M
Dipartimento di Farmacologia, Università di Padova, Italy.
Santi Soncin
E
E
Carpenedo
F
F
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D004558:Electric Stimulation; D005978:Glutathione / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008566:Membranes / Q000201:enzymology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D014812:Vitamin K / Q000494:pharmacology*
D014812:Vitamin K; D012964:Sodium; D010727:Phosphoric Diester Hydrolases; D000252:Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; D007545:Isoproterenol; D002118:Calcium; D004229:Dithiothreitol; D015056:1-Methyl-3-isobutylxanthine