Mechanisms Responsible For The Electromechanical Effects Of Magnesium Lithospermate B On Failing Rabbit And Human Ventricular Myocardium

• Main Authors: Lin, Meng -Ying, 林孟穎
• Other Authors: Lin, Cheng-I
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/32065995983388630719

碩士 === 國防醫學院 === 生理學研究所 === 100 === Introduction Magnesium lithospermate B（MLB）,a water-soluble extract from Danshen（Salviae Miltiorrhizae Radix）, has a core structure similar to cardiac glycosides and is assumed to be responsible for treatment of heart failure（HF）.Furthermore, it was found to possess multiple protective pharmacological effects on ischemic heart diseases. However,the molecular mechanisms of MLB on the cardiac contractility remained unclear. Purpose In consideration of the possibility of positive inotropic effect of MLB, we investigated the electromechanical effects of MLB on the rabbit ventricular myocardium, the failing rabbit and human hearts. Meterial and Methods A progressive and reliable model of heart failure was created with the New Zealand white rabbits（3 months male, 2.5~3kg）following a fast pacing of the right ventricular wall with the rate of 380~400 beats/min for 4 weeks. Human failing hearts were obtained at cardiac surgery. The contractile forces were recorded under the stimulition of 1 Hz and 0.5 Hz at 37℃, with or without conditioning of different medications, in isolated rabbit and human ventricular myocardium, respectively. Intracellular Ca2+ transient ([Ca2+]i) was studied in isolated ventricular cardiomyocytes by the Indo-1 fluorimetric ratio technique. The Ca2+ transient and decay portion were measured at a 1 Hz field-stimulation. The western blot method was used to investigate the protein expression and phosphorylation of Ca2+ handling proteins. Results MLB could improve contractility in rabbit and human HF myocardium in a dose-dependent manner. The enhanced contractility of MLB in healthy rabbit myocardium was attenuated with the effect of PKA or Na+-Ca2+ exchanger blocker. Our results indicated MLB had multiple pharmacological involved on various pathways, except through L-type Ca2+ channel. The average amplitudes of Ca2+ transients were significantly increased in MLB treated groups, while the average time constant () for the decay of Ca2+ transient were statistically shortened in MLB treated groups. Western blot demonstrated that MLB could induce a significant increase in the phosphorylation of SR-bound phospholamban. Conclusion MLB had been shown to have positive inotropic effects, related with increase intracellular calcium transient and the upregulated phosphorylation of phospholamban on the normal healthy rabbit hearts, the failing hearts of both rabbits and human. The mechanisms of MLB on enhancing cardiac contractility via the increase in release and uptake of calcium were possibly by way of multiple pathways including PKA and Na+-Ca2+ exchanger.