Multiple Hemodynamic Effects Of Endogenous Hydrogen Sulf Ide From Central Nervous System

AIM:Endogenous hydrogen sulfide is recongnized as a new neuromodulator which take part in the regulation of central neurous system phyisology and diseases. To explore the effect of endogenous hydrogen sulfide on hemodynamic effects and its probable mechanism.Method:Rats were given H2S gas saturation buffer and H2S different precursor-L-Cys or MP or CBS inhibitor-HA and different intervention agent by lateral cerebral ventricle(I.C.V.);the mean arterial pressure (MAP) and heart rate (HR) were recorded by Powerlab/4S instruments. To measure left ventricular pressure, the arterial catheters were inserted into the left-ventricle by right carotid arteries, and the left ventricular developed pressure (LVDP), left-ventricle maximal rate of systolic and diastolic pressure development (±LVdp/dtmax) were recorded; respiration were monitored by tracheal intubation. Western blot for MPST and CBS protein concentration; Measurement of H2S production by methylene; Measurement of the Na+-K+-ATPase activity by biological chemistry; Radioimmunoassay for endogenous digitalis like factors。Result:(1) Western blotting data showed, that both CBS and MPST protein expressed in thalamus and cortex; using L-cys as precursor (CBS dependent), the H2S releasing from thalamus and cortex were62.5±5.3and63.8±10.3nmol/min/g tissues; while administrated MP as precursor (MPST dependent), the endogenous H2S generation were approximate to two-fold (125.7±16.8,134.6±17.7nmol/min/g tissues respectively; all P<0.01) in the thalamus and cortex, comparison to L-cys as precursor. Pre-incubated with HA-an inhibitor of CBS, significantly blocked the endogenous H2S production from L-Cys; but not affected H2S production form MP。(2) The exogenous H2S injection by I.C.V. induced a dose-dependent transient hypotension (within in10-240seconds), the time of hypotensive effect was longer in low concentration H2S. After transient hypotension, dramatic MAP increased rapidly in dose-dependent manner were observed and maintained long times (5-20min).(3) Continuously injected H2S gradually increased MAP during2hours. At the end of injection, the MAP increased about30mmHg compared with physiological saline injection, peaked between90min and100min of infusion (P<0.01versus baseline).(4) Bonus injection L-Cys, induced quickly dramatic elevation of MAP, the peak appeared at10-20min, the maximum changes of MAP was about43mmHg and the pulse pressure also increased approximately to1fold. As following, the MAP and pulse pressure recovered gradually. Bonus injection MP, the MAP slowly gradually increased, the maximum changes of MAP was approximate to24mmHg, which continued to60min (the end of observation) without attenuation. Administration with CBS inhibitor-HA block endogenous H2S, lowered the MAP for20min, the maximum reduction of MAP was about20mmHg.(5) I.C.V. administrated the L-Cys induced the heart rate decreased during60min by bonus injection L-Cys, the maximum changes of heart rate was approximate to100bpm (P<0.01versus baseline). Injection HA or intravenous injection H2S did not affect heart rate. Pretreartment with HA blocked CBS activity significantly attenuated the heart rate inhibition by L-Cys (P<0.01). Whereas pre-intravenous injection phentolamine did not affect (p>0.05). Pretreatment with HA inhibition CBS activity in part blocked the effects of L-Cys, The phentolamine also partly blocked the hypertensive effect of L-Cys.(6) Continuously injected different concentration of H2S by I.C.V. and found that increasing CNS endogenous H2S production induced dose-dependently increases left ventricular develop-pressure (LVDP) and±LVdp/dtmax, without affecting left ventricular end of diastolic pressure. Bonus injection H2S precursor L-Cys also increased LVDP and±LVdp/dtmax; on the contrary, HA injection induced a transient decreases of LVDP and±LVdp/dtmax.(7) Intravenous injection phenolamine alpha receptor blocker largely blocked the hypertensive effects of H2S (P<0.01).(8)The I.C.V.injection H2S induced a dose-dependent deeper and slower respiration.(9) Pre-injection KATP channel blocker-glibenclamide by I.C.V), significantly blocked the transient hypotension effects of H2S (P<0.01); whereas did not block the following hypertension effects;(10) The beta receptor blocker metoprolol in part lowered the positive inotropic effect of L-Cys, but not glibenclamide (P<0.05).(11) L-Cys I.C.V. quickly elevated the plasma EDLF level approximately to1fold compared with physiological saline injection control group (P<0.01). HA injection slightly lowered the EDLF level in plasma but no statistical difference.(12) The L-Cys I.C.V. inhibited cardiac and aortic membrane Na+-K+-ATPase, otherwise, HA increased it.Conclusion:Central nervous system endogenous hydrogen sulfide up-regulated mean arterial pressure and cardiac systolic function by activation sympathetic nervous, increase the depth of respiration to slow down the respiratory rate, the activation of central KATP channels, inhibition of the cardiac and abdominal aortic micro-vesicles the Na+-K+-ATPase activity and increase endogenous digitalis like factorrelease.