Hydrogen Sulfide On The Role And Mechanism Of Myocardial Cell Contraction

Hydrogen sulfide (H₂S) is well known as a toxic gas with the characteristic smell of rotten eggs. But it is becoming increasingly clear that mammalian cells also produce H₂S. The H₂S concentration in rat serum is about 46μmol/L. Endogenous H₂S is synthesized naturally in the body from L-cysteine mainly by the activity of two enzymes, cystathionineβ-synthase (CBS) and cystathionineγ-lyase (CSE). CBS seems to be main H₂S -forming enzyme in the brain and nervous system, whereas CSE is the main H₂S -synthesizing enzyme in the cardiovascular system. It is reported that physiological concentrations of H₂S specifically potentiate the activity of the N-methyl-D-aspartate (NMDA) receptor, facilitate the induction of hippocampal long-term potentiation. In cardiovascular system, exogenous administration of H₂S has been reported to be cardioprotective in various disease models. For example, administration of NaHS significantly decreases the duration and severity of ischemia/reperfusion-induced arrhythmias and increased the viability of cardiomyocytes in isolated perfused rat hearts. NaHS treatment reduces infarct size in a rat model of coronary artery ligation. Chronic treatment with NaHS for 3 months decreases medial thickening of intramyocardial coronary arterioles, interstitial fibrosis and reactive oxygen species (ROS) production in spontaneously hypertensive rats (SHR). H₂S was important in hypertension , and the first ATP senstive K⁺ channel opener, the decreasing blood pressure effect of H₂S maybe through the magnism. Recently H₂S was found that it can inhibit the contraction of heart in vitro.However, the mechanisms that mediate the observed cardiac effects of H₂S remain unknown.The endogenous metabolism and physiological functions of H₂S made this gas well known in the novel family of gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO).Calcium homeostasis plays a pivotal role in myocardial physiology and diseases. The influx of Ca²⁺ through the L-type Ca²⁺ channels is a trigger for the ryanodine-dependent calcium release from the sarcoplasmic reticulum, which plays an essential role in the excitation-contraction coupling in cardiomyocytes. To date, there is no information about the potential role of H₂S in regulating calcium channels in the heart. We hypothesize that H₂S may regulate cardiac function and interact with the pathophysiological pathways by regulating calcium channels in cardiomyocytes. Therefore, the present study aimed to investigate the role of H₂S in regulating L-type calcium current (I_Ca,L), intracellular calcium transient ([Ca²⁺]i) and contraction in rat cardiomyocytes. Our results said that H₂S can decrese the [Ca²⁺]i and inhibit the contraction of cardiomyocytes.Since H₂S has been shown to be an opener for the Katp channels in vascular smooth muscle cells(VSMCs), the potential role of H₂S on the the K_ATP channels in cardiomyocytes was also examined and found lower concention can not open the K_ATP. Additionally, cAMP and cGMP, the well recognized intracellular secondary messengers which regulate I_Ca,L in cardiomyocytes, were also measured. H₂S has no effect on the level of cAMP and cGMP; To assess whether H₂S exerts differential effects in regulating I_Ca,L and contraction in normal and hypertrophied cardiac myocytes, we examined the effects of H₂S in cardiomyocytes isolated from both Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR).In summary, NaHS inhibited the contraction of single cardiomyocytes and isolated papillary muscles. Electric field-induced [Ca²⁺]i transient were reduced by NaHS. In contrast, caffeine induced an increase in [Ca²⁺]i and was not altered by NaHS. Bath application of NaHS significantly reduced the time required for the depolarization of the action potential. Inhibition of the peak I_Ca,L by NaHS was determined to be concentration dependent. NaHS had no effect on the Katp current or the levels of cAMP and cGMP in the current study. H₂S is a novel inhibitor of L-type calcium channels in cardiomyocytes. Moreover, H₂S-induced inhibition of [Ca²⁺]i appears to be a secondary effect due to its initial action towards I_Ca,L. The inhibitory effect of H₂S on I_Ca,L requires further investigation to develop novel therapeutic approaches to treat cardiac diseases.