| Objective: To detect selectively antagonizing effects of (-)doxazosin [(-)Dox], (+)doxazosin [(+)Dox], (-)alfuzosin [(-)Alf] and (+)alfuzosin [(+)Alf] on the functionalα1-adrenoceptor subtypes, and analyse their effects on contractile force in the rat isolated left atrium and relevant mechanism.Methods: We prepared the isolated preparations of mouse thoracic aorta, rat spleen strip and rat vas deferens. Cumulative concentration-contraction curves for phenylephrine (Phe) in the thoracic aorta, and those for noradrenaline (NA) in spleen strips and vas deferens were constructed. Effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf on contractile responses to Phe or NA were observed, and pKB values were determined. Strips of the rat isolated left atrium were prepared, and the effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf (3, 10 and 30μmol·L-1) on contractile force were observed in the rat isolated atrium.Results:1 Effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf on the contractile responses to Phe in the mouse isolated thoracic aortaPhe (0.0001100μmol·L-1) produced the concentration-dependent contractile responses in the mouse isolated thoracic aorta. Solvent did not significantly affect the values of Emax and EC50 obtained from the second to the fourth concentration-response curves for Phe in the mouse isolated thoracic aorta (P>0.05). Concentration-response curves for Phe were shifted to the right in a parallel manner without significant decrease in Emax values (P>0.05) by (-)Dox and (-)Alf at 0.01 and 0.1μmol·L-1, and Schild plot analysis indicated that (-)Dox and (-)Alf competitively inhibited the concentration-dependent responses to Phe. Concentration-response curves for Phe were shifted to the right by (+)Dox at 0.001 and 0.01μmol·L-1 and (+)Alf at 0.01 and 0.1μmol·L-1, and Schild plot analysis indicated that (+)Dox and (+)Alf non-competitively inhibited the concentration-dependent responses to Phe. Moreover, the pKB value (9.268) of (+)Dox was significantly larger than that (8.452) of (-)Dox (P<0.01). However the pKB value of (+)Alf was not significantly different from that of (-)Alf (P>0.05).2 Effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf on the contractile responses to NA in the rat isolated spleen stripsNA (0.0110000μmol·L-1) produced the concentration-dependent contractile responses in the rat isolated spleen strips. Solvent did not significantly affect the values of Emax and EC50 obtained from the second to the fourth concentration-response curves for NA in the rat isolated spleen strips (P>0.05). Concentration-response curves for NA were shifted to the right in a parallel manner without significant decrease in Emax values (P>0.05) by (-)Dox at 0.03 and 0.3μmol·L-1, and Schild plot analysis indicated that (-)Dox competitively inhibited the concentration-dependent responses to NA. Concentration-response curves for NA were shifted to the right by (+)Dox at 0.003 and 0.03μmol·L-1, (-)Alf and (+)Alf at 0.03 and 0.3μmol·L-1; and Schild plot analysis indicated that (+)Dox, (-)Alf and (+)Alf non-competitively inhibited the concentration-dependent responses to NA. Moreover, the pKB value (8.678) of (+)Dox was significantly larger than that (7.750) of (-)Dox (P<0.01). However the pKB value of (+)Alf was not significantly different from that of (-)Alf (P>0.05).3 Effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf on the contractile responses to NA in the rat isolated vas deferensNA (0.0110000μmol·L-1) produced the concentration-dependent contractile responses in the rat isolated vas deferens. Solvent did not significantly affect the values of Emax and EC50 obtained from the second to the fourth concentration-response curves for NA in the rat isolated vas deferens (P>0.05). Concentration-response curves for NA were shifted to the right in a parallel manner without significant decrease in Emax values (P>0.05) by (+)Dox at 0.01 and 0.1μmol·L-1 and (-)Alf at 0.1 and 1μmol·L-1, and Schild plot analysis indicated that (+)Dox and (-)Alf competitively inhibited the concentration-dependent responses to NA. Concentration-response curves for NA were shifted to the right by (-)Dox and (+)Alf at 0.1 and 1μmol·L-1, and Schild plot analysis indicated that (-)Dox and (+)Alf non-competitively inhibited the concentration- dependent responses to NA. Moreover, the pKB value (7.748) of (+)Dox was significantly larger than that (6.963) of (-)Dox (P<0.01). However the pKB value of (+)Alf was not significantly different from that of (-)Alf (P>0.05).4 Effects of (-)Dox, (+)Dox, (-)Alf and (+)Alf on the contractile force in the rat isolated left atriumThe contractile force before treatment in the rat isolated left atrium was not significantly different among the expreiment groups treated with solvent or drugs, and solvent did not affect the contractile force (P>0.05). (-)Dox (330μmol·L-1) significantly increased the contractile force in a concentration-dependent manner, and each concentration increased the contractile force by (14.55±19.61) %, (47.11±36.82) % and (72.46±31.23) % (P<0.01). However, (+)Dox (330μmol·L-1) significantly decreased the contractile force by (-15.93±13.13) %, (-38.05±22.04) % and (-58.82±52.00) % (P<0.01). Each concentration of (-)Alf and (+)Alf (330μmol·L-1) did not affect the contractile force in the rat isolated left atrium (P>0.05).Conclusion:1 Enantiomers of doxazosin and alfuzosin have selective effects on functionalα1-adrenoceptor subtypes, and the antagoning effect of each enantiomer onα1D-adrenoceptors is the strongest among the three subtypes.2 The antagoning effects of (+)doxazosin onα1A-,α1B- andα1D-adrenoceptors are significantly stronger than those of (-)doxazosin, however pKB values of (+)alfuzosin on the threeα1-adrenoceptor subtypes are not significantly different from those of (-)alfuzosin.3 (-)Doxazosin or (+)doxazosin significantly increases or decreases the contractile force of the rat isolated left atrium. Alfuzosin enantiomers, however, have no effects on atrial contractile force at the same concentrations as doxazosin enantiomers. These results suggest that the inotropic effects by doxazosin enantimors are not related to their antagonizing effects onα1-adrenoceptors.
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