Chrial Selective Effects Of Doxazosin And Its Enantiomers On The Rabbit Isolated Cardiac Tissue And Intestinal Smooth Muscle

Objective: To study the effects of rac-doxazosin (rac-DOX) and its enantiomers (S-doxazosin, S-DOX and R-Doxazosin, R-DOX) on the rabbit isolated atrial and ventricular strips and ileum and duodenal smooth muscle.Methods: The strips of the rabbit isolated right atrium, left atrium and right ventricle were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively administered into the organ bath containing the rabbit isolated atrial strips, but they were non-cumulatively administered into the organ bath containing the rabbit isolated right ventricular strips. The effects of doxazosin and its enantiomers on contractile force and heart rate were observed.The rabbit isolated ileum, ileum longitudinal muscle strips and circular muscle strips were prepared. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively given into the organ bath containing the rabbit isolated ileum, ileum longitudinal muscle. Doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively administered into the organ bath containing the rabbit isolated ileum circular muscle, then carbachol at 20μmol·L^-1 was applied. Effects of doxazosin and its enantiomers on the contractile force, contractile frequency and carbachol-induced responses were observed in the rabbit isolated ileum preparations.The rabbit isolated duodenal smooth muscle preparations were prepared, and doxazosin and its enantiomers (3, 10, 30μmol·L^-1) were cumulatively given into the organ bath containing the rabbit isolated duodenum. Effects of doxazosin and its enantiomers on the contractile force and contractile frequency were observed in the rabbit isolated duodenal smooth muscle.Results:1 Effects of doxazosin and its enantiomers on the heart rate in the rabbit isolated right atriumIn 23% of the used atrial preparations, the cardiac arrest was induced by R-DOX at 30μmol·L^-1, but S-DOX and rac-DOX at the same concentration did not induce the same effect. S-DOX at 30μmol·L^-1 did not affect the heart rate of the rabbit isolated right atrium, R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the heart rate. R-DOX and rac-DOX at 30μmol·L^-1 decreased the heart rate by 25.7±10.5% and 23.6±7.7%, respectively.2 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right atrium S-DOX did not affect the contractile force of the rabbit isolated right atrium. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the contractile force of the rabbit isolated right atrium and both of them at 30μmol·L^-1 decreased the contractile force by 78.6±8.6% and 56.7±11.7%, respectively. The negative inotropic effect in the right atrium by R-DOX was stronger than that by rac-DOX.3 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated left atriumS-DOX did not affect the contractile force of the rabbit isolated left atrium. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration-dependently decreased the contractile force of the rabbit isolated left atrium and both of them at 30μmol·L^-1 decreased the contractile force by 89.9±4.9% and 45.4±15.6%, respectively. The negative inotropic effect in the left atrium by R-DOX was stronger than that by rac-DOX.4 Effects of doxazosin and its enantiomers on the contractile force in the rabbit isolated right ventricular stripsS-DOX at 30μmol·L^-1 increased the contractile force of the rabbit isolated right ventricular strips, and S-DOX at 30μmol·L^-1 increased the contractile force by 26.7±21.5%. R-DOX (3³0μmol·L^-1) and rac-DOX (3³0μmol·L^-1) concentration -dependently decreased the contractile force of the rabbit isolated right ventricular strips and both of them at 30μmol·L^-1 decreased the contractile force by 38.1±28.1% and 29.4±24.4%, respectively. The negative inotropic effect in the ventricular strips by R-DOX was stronger than that by rac-DOX.5 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated ileum smooth muscleDoxazosin and its enantiomers (3³0μmol·L^-1) did not affect the spontaneous contractile force in the rabbit isolated ileum. S-DOX only at 30μmol·L^-1 decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum, R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frequency from 10.3cycles·min-1 to 7.1cycles·min-1 and from 10.6cycles·min-1 to 6.8cycles·min-1, respectively.Doxazosin and its enantiomers (3³0μmol·L^-1) did not affect the spontaneous contractile force in the rabbit isolated ileum longitudinal muscle strips. S-DOX only at 30μmol·L^-1 decreased the contractile frequency from 12.9cycles·min-1 to 10.1cycles·min-1 in the rabbit isolated ileum longitudinal muscle. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated ileum longitudinal muscle strips, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frequency from 13.9cycles·min-1 to 9.7cycles·min-1 and from 13.0cycles·min-1 to 9.0cycles·min-1, respectively.Doxazosin and its enantiomers (3³0μmol·L^-1) did not affect the contractile force and contractile frequency of the contraction induced by carbachol in the rabbit isolated ileum circular muscle strips.6 Effects of doxazosin and its enantiomers on the contractile force and contractile frequency in the rabbit isolated duodenal smooth muscleS-DOX only at 30μmol·L^-1 decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenum. R-DOX (10³0μmol·L^-1) and rac-DOX (10³0μmol·L^-1) decreased the contractile frequency of spontaneous contraction in the rabbit isolated duodenal smooth muscle, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the contractile frquency from 17.5cycles·min-1 to 14.2cycles·min-1 and from 15.1cycles·min-1 to 12.5cycles·min-1, respectively.Doxazosin and its enantiomers (10³0μmol·L^-1) all decreased the spontaneous contractile force in the rabbit isolated duodenal muscle. S-DOX at 30μmol·L^-1 decreased the spontaneous contractile force from 3.81g to 0.75g, and R-DOX and rac-DOX at 30μmol·L^-1 decreased the spontaneous contractile force from 4.12g to 0.71g and from 3.96g to 0.87g, respectively.Conclusion: R-DOX produces a negative chronotropic effect in the rabbit isolated right atrium more potently than rac-DOX, and it even causes cardiac arrest at higher concentration. S-DOX does not affect the heart rate. R-DOX produces a negative inotropic effect in the rabbit isolated atrial and ventricular strips more potently than rac-DOX. On the contrary, S-DOX produces the positive inotropic effect.Doxazosin and its enantiomers do not affect the spontaneous contractile force in the rabbit isolated ileum and ileum longitudinal muscle, and do not affect the contraction induced by carbachol in the rabbit isolated ileum circular muscle, but decrease the spontaneous contractile force in the rabbit duodenal muscle. Doxazosin and its enantiomers decrease the spontaneous contractile frequency in the rabbit isolated ileum, ileum longitudinal muscle and duodenum muscle, and the inhibitory effect by S-DOX is weaker.