Abstract
This report contains results of studies designed to determine whether quinine has direct effects on myofilament Ca2+sensitization in addition to effects on Ca2+. Quinine decreased the EC50 value and maximal contraction of intact arterial strips to histamine. Incubation of arterial strips with indomethacin or 1H-[1,2,4]oxadiazole[4,3-α]quinoxalin-1-one did not alter quinine inhibition, suggesting that the effect is not mediated via cyclooxygenase or cGMP. Pretreatment of strips with quinine had no effect on the histamine-dependent increases in myosin light chain phosphorylation levels. Quinine inhibited Ca2+-induced contraction in α-toxin permeabilized strips, but not the Ca2+-induced contraction in Triton X-100 permeabilized strips. Pretreatment of the α-toxin permeabilized strips with quinine before stimulation with guanosine-5′-O-(3-thio)triphosphate (GTPγS) did not have any effect on the response. In conclusion, quinine inhibited Ca2+-dependent contractions of the α-toxin permeabilized strips, which retain modulatory pathways both upstream and downstream from the contractile proteins but did not inhibit GTPγS-dependent contraction of the α-toxin permeabilized preparation important in upstream modulation of the contraction. Moreover, quinine did not inhibit the Ca2+-dependent contractions of the Triton X-100 permeabilized strips, which are devoid of all modulatory pathways. This suggests that quinine does not act upstream from or directly on the contractile proteins. A more likely site of action may be downstream of the contractile proteins and specifically at the coupling of the contractile proteins with the physiological endpoint of force development.
Footnotes
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This study was supported in part by National Institutes of Health Grants HL 37956 and DK 57252 (to R.S.M.).
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DOI: 10.1124/jpet.102.042101
- Abbreviations:
- MLC
- myosin light chain
- MOPS
- 3-(N-morpholino)propanesulfonic acid
- DTT
- dithiothreitol
- ODQ
- 1H-[1,2,4]oxadiazole[4,3-α]quinoxalin-1-one
- GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- Received July 23, 2002.
- Accepted September 26, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
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