[硫化氢抑制自发性高血压大鼠中钙离子诱导的线粒体通透性转换孔开放]

[Hydrogen sulfide inhibits Ca(2+)-induced mitochondrial permeability transition pore opening in spontaneously hypertensive rats].

作者信息

Strutyns'ka N A, Dorofeieva N O, Vavilova H L, Sahach V F

出版信息

Fiziol Zh (1994). 2013;59(1):3-10.

Abstract

In experiments in vivo and in vitro on the mitochondria isolated from the control and spontaneously hypertensive rats (SHR) hearts, we studied the effects of a donor of hydrogen sulfide (H2S), NaHS, and H2S biosynthesis substrate, L-cysteine, on the sensitivity of the mitochondrial permeability transition pore (mPTP) opening to its natural inductor, Ca2+. We found that NaHS (10(-4), 10(-5) and 5 10(-5) mol/l) influenced the mitochondrial swelling in a concentration-dependent manner in control and spontaneously hypertensive rats. The H2S donor NaHS used in physiological concentrations (10(-6), 10(-5) and 5 10(-5) mol/l) exerted the inhibiting effect on the Ca(2+)-induced mPTP opening in control hearts (corresponding values of such effect were 31, 76, and 100%, respectively), while in spontaneously hypertensive rats hearts the protector effect of NaHS was observed only at its concentration of 10(-5) - 10(-4) mol/l. In experiments in vivo, single intraperitoneal injections of L-cysteine (10(-3) mol/kg) resulted in a decrease in the sensitivity of mPTP to it's inductor Ca2+ in control rats and SHR. In experiments in vivo in which we used a specific blocker of cystathionine-gamma-lyase, propargylglycine (10(-4) mol/kg), with the further injections of L-cysteine we observed a decrease in the threshold Ca2+ concentration (that induce the mitochondrial swelling) by three orders of magnitude in SHR, but in control rats did not effect of L-cysteine. Thus, both endogenous and exogenous hydrogen sulfide inhibits Ca(2+)-induced mitochondrial permeability transition pore opening, indicating its protective effect on pore formation in spontaneously hypertensive rats hearts. Therefore, our studies are indicative of the involvement of H2S in modulation of changes in the permeability of mitochondrial membranes, which can be an important regulatory factor in the development of cardiovascular diseases.

摘要

在对从对照大鼠和自发性高血压大鼠（SHR）心脏分离出的线粒体进行的体内和体外实验中，我们研究了硫化氢（H₂S）供体硫氢化钠（NaHS）和H₂S生物合成底物L-半胱氨酸，对线粒体通透性转换孔（mPTP）开放对其天然诱导剂Ca²⁺敏感性的影响。我们发现，NaHS（10⁻⁴、10⁻⁵和5×10⁻⁵mol/L）在对照大鼠和自发性高血压大鼠中以浓度依赖的方式影响线粒体肿胀。生理浓度（10⁻⁶、10⁻⁵和5×10⁻⁵mol/L）的H₂S供体NaHS对对照心脏中Ca²⁺诱导的mPTP开放具有抑制作用（这种作用的相应值分别为31%、76%和100%），而在自发性高血压大鼠心脏中，仅在NaHS浓度为10⁻⁵ - 10⁻⁴mol/L时观察到其保护作用。在体内实验中，单次腹腔注射L-半胱氨酸（10⁻³mol/kg）导致对照大鼠和SHR中mPTP对其诱导剂Ca²⁺的敏感性降低。在体内实验中，我们使用了胱硫醚-γ-裂解酶的特异性阻滞剂炔丙基甘氨酸（10⁻⁴mol/kg），在进一步注射L-半胱氨酸后，我们观察到SHR中线粒体肿胀的阈值Ca²⁺浓度降低了三个数量级，但在对照大鼠中L-半胱氨酸没有作用。因此，内源性和外源性硫化氢均抑制Ca²⁺诱导的线粒体通透性转换孔开放，表明其对自发性高血压大鼠心脏中孔形成具有保护作用。因此，我们的研究表明H₂S参与了线粒体膜通透性变化的调节，这可能是心血管疾病发生发展中的一个重要调节因素。