Tempol Therapy Attenuates Ventricular Dysfunction And Normalizes Sympathetic Neural Control In Experimental Heart Failure

Chronic heart failure(CHF)is characterized by increased plasma norepinephrine level and enhanced sympathetic tone.The excessive sympathetic activation not only deteriorates the CHF but also is prognostic of death and complications.It has been shown that the enhanced cardiac sympathetic afferent reflex(CSAR)partially contributes to sympathoexcitation in CHF.We have found that the Angâ…¡and AT₁ receptors in paraventricular nucleus(PVN)are involved in the enhanced CSAR in CHF rats,and that the effects of Angâ…¡in the PVN on the CSAR and sympathetic outflow are mediated by the ROS including superoxide anions and hydrogen peroxide in the PVN.The ROS level in the PVN is increased in CHF rats.Microinjection of tempol,a kind of radical scanvenger,into the PVN not only normalizes the enhanced CSAR and sympathetic activities but also abolishes the effect of Angâ…¡on the CSAR in CHF.Therefore,we hypothesis that the elimination of ROS in the PVN might probably plays an important role as a therapeutic target in decreasing overexcitated sympathetic activities in CHF.The present study was to investigate the effects of long-term administration of tempol in rats with experimental CHF induced by coronary arterial ligation(CAL)on the ventricular function,CSAR and sympathetic nerve activity.In addition,the changes of the AT₁ receptor expression and the ROS level in the PVN and RVLM were tested.The rats were randomly subjected to coronary arterial ligation(CAL) to induce CHF or sham operation.CAL group was then randomly divided into tempol group(CAL-Tem)and vehicle group(CAL-Veh).Sham group was also randomly divided into tempol group(Sham-Tem)and vehicle group(Sham-Veh).The tempol was orally administered in drinking water(2 mmol of tempol in a liter of water)for consecutive 6 weeks since the 4^thhour after surgery.Acute researches were carried out at the end of the eighth week.The findings were as follows:1.Mortality and CHF incidence3 of 38 rats in CAL-Veh group but no rat in other groups died of severe heart failure(determined by postmortem examination)during the eight weeks' feeding after tempol or vehicle intervention.33 of 35(94.3 %)CAL-Veh rats developed CHF.However,only 4 of 38(10.5%) CAL-Tem rats developed mild CHF.No rat in Sham group developed CHF.2.Gross pathological changesThe CAL-Veh rats exhibited significantly higher heart weight,lung weight,ratio of heart weight to body weight and ratio of lung weight to body weight compared with Sham-Veh rats.Tempol administration prevented the increased lung weight and lung-to-body weight ratio caused by CAL,but failed in preventing the increased heart weight and heart-to-body weight ratio.Each CAL rat,treated with either vehicle or tempol,had a dense scar in the anterior ventricular wall.There was no significant difference in the infarct area between the CAL-Tem rats and CAL-Veh rats.No infarct was evident in all sham-operated rats.3.Heart function test3.1 Intracardiac catheter methodAll CAL-Veh rats showed obvious left ventricular dysfunction, exhibiting a significantly higher LVEDP,and a significantly lower LVdP/dtmax compared with Sham-Veh rats.There was no significant difference among CAL-Tem rats,Sham-Tem rats or Sham-Veh rats in those parameters.The changes above caused by the CAL were significantly attenuated by tempol but not vehicle.3.2 EchocardiogramThe LVEDD,LVESD,LVEDV and LVESV increased,while the FS and EF decreased in CAL-Veh rats compared with Sham-Veh rats. These changes caused by the CAL were significantly attenuated by tempol but not by vehicle.Tempol had no significant effect on the ventricular function in sham-operated rats.4.Baseline RSNA The baseline RSNA was enhanced in CAL-Veh rats compared with Sham-Veh rats.Tempol therapy normalized the enhanced baseline RSNA in CAL-Tem rats,but had no significant effect on the baseline RSNA in Sham-Tern rats.5.Effects of Angâ…¡Bilateral microinjection of Angâ…¡into the PVN induced pressor and sympathoexcitatory responses in all groups of rats,but the responses were enhanced in CAL-Veh rats compared with Sham-Veh rats.The enhanced responses to Angâ…¡were normalized by tempol treatment in CAL-Tem rats.6.CSARThe CSAR induced by epicardial application of capsaicin was significantly enhanced in CAL-Veh rats compared with Sham-Veh rats. However,tempol treatment normalized the enhanced CSAR in CAL-Tem rats.7.Plasma catecholamineThe plasma norepinephrine level increased in CAL-Veh rats compared with Sham-Veh rats.Tempol therapy normalized the norepinephrine level in CAL-Tem rats.However,there was no significant difference in plasma epinephrine among all groups.8.AT₁ receptor expression in PVN and RVLM The AT₁ receptor expression in both PVN and RVLM increased in CAL-Veh rats compared with Sham-Veh rats.The increased AT₁ receptor expression was normalized by tempol therapy in CAL-Tem rats.9.Superoxide anions in PVN and RVLMThe superoxide anions in both PVN and RVLM were increased in CAL-Veh rats compared with Sham-Veh rats.The increased levels of superoxide anions in both PVN and RVLM were normalized by tempol therapy in CAL-Tem rats.Taken together,it was concluded that tempol administration attenuates ventricular dysfunction,and normalizes sympathetic neural activity in CHF,which involves in the central mechanism of Angiotensionâ…¡and superoxide anions in the PVN and RVLM.