| Summary: | 碩士 === 國立臺灣大學 === 藥理學研究所 === 83 === HTW-3, -4 and -5,are synthetic tetrahydro furoquinolines found to have positive inotropic and negative chronotropic effect on rat cardiact issues. Current clamp revealed that HTW-3, -4 and-5 prolonged of the action potential duration with a concomitant decrease in action potential upstroke (dV/dt)max. The relative potency to prolong the action potential duration was HTW-3> HTW-4>>HTW-5. Voltage clamp study revealed that the relative sensitivity of ionic current to block by HTW-3, -5 was Ito>INa> ICa≒IK1, but Ito ≒ >INa≒Ca≒K1 by HTW-4. The reduction of Ito by HTWs was associated with a marked acceleration of its inactivation. The fractional inhibition of Ito by HTWs increased with the time of epolarization,suggesting that HTWs may inter act with open Ito channels. However, the inhibition of Ito was also associated with a negative shift of its steady-state inactvation curve and slowing of the rate of recovery of Ito from inactivation. The results suggest that HTWs may also interact with inactivated Ito channels. At lower concentration, HTW-3, -5 had the activities of class I and calss III-like anti- arrhythmic agents. The class I activity was characterized by the reduction of INa and a negative shift of the steady-state inactivation curve. IK1 was almost unaffected under the same concentration range. Atenolol (3 μM) only partially inhibited the inotropic effect of high dose HTW-3,-4 (100 μM). In conclusion, HTWs prolonged APD and caused positive inotropic action mainly by inhibition of Ito. The positive inotropic action of high concentration HTW-3, -4, but not HTW-5, was partially mediated by activation of β-adrenoceptors. The results suggested that ortho Cl substitution on N-methylbenzyl group (HTW-5)may lead to the loss of β effect. Whether ortho substitution of proton by other functional groups can have the same effect remains to be investigated in the future.
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