Abstract
Hydrogen sulfide (H2S) is a novel gasotransmitter that inhibits L-type calcium currents (I Ca, L). However, the underlying molecular mechanisms are unclear. In particular, the targeting site in the L-type calcium channel where H2S functions remains unknown. The study was designed to investigate if the sulfhydryl group could be the possible targeting site in the L-type calcium channel in rat cardiomyocytes. Cardiac function was measured in isolated perfused rat hearts. The L-type calcium currents were recorded by using a whole cell voltage clamp technique on the isolated cardiomyocytes. The L-type calcium channel containing free sulfhydryl groups in H9C2 cells were measured by using Western blot. The results showed that sodium hydrosulfide (NaHS, an H2S donor) produced a negative inotropic effect on cardiac function, which could be partly inhibited by the oxidant sulfhydryl modifier diamide (DM). H2S donor inhibited the peak amplitude of I Ca, L in a concentration-dependent manner. However, dithiothreitol (DTT), a reducing sulfhydryl modifier markedly reversed the H2S donor-induced inhibition of I Ca, L in cardiomyocytes. In contrast, in the presence of DM, H2S donor could not alter cardiac function and L type calcium currents. After the isolated rat heart or the cardiomyocytes were treated with DTT, NaHS could markedly alter cardiac function and L-type calcium currents in cardiomyocytes. Furthermore, NaHS could decrease the functional free sulfhydryl group in the L-type Ca2+ channel, which could be reversed by thiol reductant, either DTT or reduced glutathione. Therefore, our results suggest that H2S might inhibit L-type calcium currents depending on the sulfhydryl group in rat cardiomyocytes.
Highlights
In addition to the gasotransmitters nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third biologic signal gaseous molecule and is recognized as an important physiologic regulator in the circulatory, nervous, endocrine and immune systems [1]
In addition to the fact that LV 6dp/ dtmax and DLVP did not change during perfusion with 100 mmol/ L DTT for 5 min as compared with controls (P.0.05, Fig. 1C), we found that continuous perfusion of K-H solution with 100 mmol/L NaHS for 10 min in the presence of DTT obviously decreased the LV 6dp/dtmax and DLVP, compared to DTT perfusion without NaHS treatment (P,0.01, Fig. 1C)
The results showed that the H2S donor inhibited the I Ca, L in cardiomyocytes, which is accordant to the previous results [6]
Summary
In addition to the gasotransmitters nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third biologic signal gaseous molecule and is recognized as an important physiologic regulator in the circulatory, nervous, endocrine and immune systems [1]. In the investigation of broad physiological functions, the cardio-protective effect of H2S was first found and drew much attention in the field of life sciences. In vitro and in vivo experiments showed that H2S induced negative cardiac inotropic effects and played a cardio-protective role in various models of diseases. It was found that exogenous H2S post-conditioning successfully protected isolated rat hearts against ischemia-reperfusion injury [3] and played a protective role in chronic heart failure [4]. The mechanism responsible for the negative cardiac inotropic effects of H2S has not been fully understood
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