Quinine inhibits vascular contraction independent of effects on calcium or myosin phosphorylation.

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-alpha]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 alpha-toxin permeabilized strips, but not the Ca2+-induced contraction in Triton X-100 permeabilized strips. Pretreatment of the alpha-toxin permeabilized strips with quinine before stimulation with guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) did not have any effect on the response. In conclusion, quinine inhibited Ca2+-dependent contractions of the alpha-toxin permeabilized strips, which retain modulatory pathways both upstream and downstream from the contractile proteins but did not inhibit GTPgammaS-dependent contraction of the alpha-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.