Artesunate is a derivative of qinghaosu, with a sesquiterpene structure. The specific action and the clinical uses of artesunate are on the preliminary stage. On the one hand, artesunate has specific action of both an...Artesunate is a derivative of qinghaosu, with a sesquiterpene structure. The specific action and the clinical uses of artesunate are on the preliminary stage. On the one hand, artesunate has specific action of both antiinflammation and antivirus, and also has protective effect on the pulmonary alveolar macrophages, which may be advantageous to the treatment of the airway non specific inflammation of asthma. On the other hand, qinghaosu has the activities to relax vascular smooth muscle and to cause hypotension. The expectorant action, the antitussive action and the antiasthmatic action of qinghaosu were reported. Artesunate may also have antiasthmatic activity, because the antimalarial potency of artesunate is stronger than that of qinghaosu, and Artesunate can block Ca 2+ influx by inhibiting calcium dependent chloride current. The main aims of this paper are to investigate the site, the mode, and the mechanism of artesunate action on isolated tracheal smooth muscle from the guinea pig. The isolated tracheal smooth muscle and isolated aortic strip circle were suspended in 10 ml Thornton and 5 ml Krebs solution gassed with 95% O 2+5% CO 2 at 37℃ respectively, and stretched with an initial tension of 1.5 g. After a stabilization period of over two hours, drug effects were plotted from cumulative doses. The tension changes were recorded by a forcedisplacement transducer connected to a two pen recorder (XWTD 264 made in Shanghai Dahua Apparatus Factory). Our experiments on isolated tracheal smooth muscle have demonstrated that artesunate is able to relax tracheal smooth muscle by its action on the tracheal smooth muscle cells. In concentrations ranging from 10 pmol·L 1 to 100 nmol·L 1 , artesunate can reduce the tone of the trachea in a concentration dependent manner. Its pD 2 is 8.76±0.74 (epithelium removed, n=6) and its potency is seventy four percent of isoprenaline′s. Artesunate is able to antagonize noncompetitively the effects of spasmogens like acetylcholine and histamine on trachea in a concentration dependent fashion, its pD′ 2 is 9.99±0.71 (n=8) and 11.69±0.53 (n=8), respectively. Timolol, a non selective blocker of the beta adrenergic receptors, does not inhibit the relaxant action of artesunate on trachea (n=6). Artesunate is also able to antagonize the constrictive effect on the trachea by KCl 100 mmol·L 1 in a concentration dependent manner, and its IC 50 is 0.81±0.67 nmol·L 1 (n=6). In the experiment of antagonizing the contractive action on trachea by acetylcholine 100 μmol·L 1 , artesunate was found to be more potent than nicardipine (n=7, P <0.01). Their inhibition rates (%) were 67.51±13.06% and 23.71±11.94% respectively. Nicardipine had no synergistic effect on the potency of artesunate (only increase the inhibition rate of artesunate from 65.71±11.06% to 73.94±11.78%, P>0.05, n=7). Artesunate had no effect on specific binding of 3H QNB on M 3 subtype of mAChR of salivary gland of rats (n=3). In the experiment of isolated aortic strip circle from the rats, artesunate did not block the intracellular Ca 2+ release, but partially inhibited Ca 2+ influx induced by phenylephrine 10 μmol·L 1 in a concentration dependent fashion. Its IC 50 was 1.64±0.38 mmol·L 1 (n=7). The intracellular Ca 2+ transient was determined using Fura 2 by fluorospectrophotometer (RF 5000 made in Japan). The excitation wavelengths were 340 and 380 nm and the emission wavelength was 510 nm. The intracellular Ca 2+ levels were calculated using the formula∶ [Ca 2+ ] i=Kd [(R t R min )/(R max R t)]×(Sf2/Sb2). In the cultured traheal smooth muscle cells, artesunate 100 μmol 1 had no effects on both intracellular Ca 2+ release and nonvoltagedepended Ca 2+ influx induced by cyclopiazonic acid (a Ca 2+ pump inhibitor of endoplasmic reticulum) 10 μmol·L 1 (n=3) (which was determined by using Fura 2). The cyclic AMP levels of the tracheal tissue were展开更多
文摘Artesunate is a derivative of qinghaosu, with a sesquiterpene structure. The specific action and the clinical uses of artesunate are on the preliminary stage. On the one hand, artesunate has specific action of both antiinflammation and antivirus, and also has protective effect on the pulmonary alveolar macrophages, which may be advantageous to the treatment of the airway non specific inflammation of asthma. On the other hand, qinghaosu has the activities to relax vascular smooth muscle and to cause hypotension. The expectorant action, the antitussive action and the antiasthmatic action of qinghaosu were reported. Artesunate may also have antiasthmatic activity, because the antimalarial potency of artesunate is stronger than that of qinghaosu, and Artesunate can block Ca 2+ influx by inhibiting calcium dependent chloride current. The main aims of this paper are to investigate the site, the mode, and the mechanism of artesunate action on isolated tracheal smooth muscle from the guinea pig. The isolated tracheal smooth muscle and isolated aortic strip circle were suspended in 10 ml Thornton and 5 ml Krebs solution gassed with 95% O 2+5% CO 2 at 37℃ respectively, and stretched with an initial tension of 1.5 g. After a stabilization period of over two hours, drug effects were plotted from cumulative doses. The tension changes were recorded by a forcedisplacement transducer connected to a two pen recorder (XWTD 264 made in Shanghai Dahua Apparatus Factory). Our experiments on isolated tracheal smooth muscle have demonstrated that artesunate is able to relax tracheal smooth muscle by its action on the tracheal smooth muscle cells. In concentrations ranging from 10 pmol·L 1 to 100 nmol·L 1 , artesunate can reduce the tone of the trachea in a concentration dependent manner. Its pD 2 is 8.76±0.74 (epithelium removed, n=6) and its potency is seventy four percent of isoprenaline′s. Artesunate is able to antagonize noncompetitively the effects of spasmogens like acetylcholine and histamine on trachea in a concentration dependent fashion, its pD′ 2 is 9.99±0.71 (n=8) and 11.69±0.53 (n=8), respectively. Timolol, a non selective blocker of the beta adrenergic receptors, does not inhibit the relaxant action of artesunate on trachea (n=6). Artesunate is also able to antagonize the constrictive effect on the trachea by KCl 100 mmol·L 1 in a concentration dependent manner, and its IC 50 is 0.81±0.67 nmol·L 1 (n=6). In the experiment of antagonizing the contractive action on trachea by acetylcholine 100 μmol·L 1 , artesunate was found to be more potent than nicardipine (n=7, P <0.01). Their inhibition rates (%) were 67.51±13.06% and 23.71±11.94% respectively. Nicardipine had no synergistic effect on the potency of artesunate (only increase the inhibition rate of artesunate from 65.71±11.06% to 73.94±11.78%, P>0.05, n=7). Artesunate had no effect on specific binding of 3H QNB on M 3 subtype of mAChR of salivary gland of rats (n=3). In the experiment of isolated aortic strip circle from the rats, artesunate did not block the intracellular Ca 2+ release, but partially inhibited Ca 2+ influx induced by phenylephrine 10 μmol·L 1 in a concentration dependent fashion. Its IC 50 was 1.64±0.38 mmol·L 1 (n=7). The intracellular Ca 2+ transient was determined using Fura 2 by fluorospectrophotometer (RF 5000 made in Japan). The excitation wavelengths were 340 and 380 nm and the emission wavelength was 510 nm. The intracellular Ca 2+ levels were calculated using the formula∶ [Ca 2+ ] i=Kd [(R t R min )/(R max R t)]×(Sf2/Sb2). In the cultured traheal smooth muscle cells, artesunate 100 μmol 1 had no effects on both intracellular Ca 2+ release and nonvoltagedepended Ca 2+ influx induced by cyclopiazonic acid (a Ca 2+ pump inhibitor of endoplasmic reticulum) 10 μmol·L 1 (n=3) (which was determined by using Fura 2). The cyclic AMP levels of the tracheal tissue were
