| BackgroundExcessive sympathetic activity contributes to haemodynamic deterioration in chronicheart failure (CHF). The cardiac sympathetic afferent reflex (CSAR) is known toincrease sympathetic activity and blood pressure and the enhanced CSAR is involvedin the sympathetic over-activation in CHF. The enhanced CSAR in CHF attributes tothe increased activity of cardiac sympathetic afferents and the potentiated central gainof this reflex. The paraventricular nucleus (PVN) of hypothalamus is an importantcomponent of the central neurocircuitry of the CSAR and plays an important role inregulating the sympathetic and cardiovascular activity. Angiotensin II (Ang II) in thePVN augments the CSAR and increases the sympathetic outflow and blood pressure,which is mediated by Ang II type1(AT1) receptors in the PVN in CHF rats. However,experimental animals were subjected to bilateral cervical vagotomy (VT) andbaroreceptor denervation (BD) to minimize the confounding effects of baroreceptorand vagal afferent activities on the CSAR and sympathetic drive in these experiments. One key issue to be resolved is whether the sympatho-excitatory CSAR is stillenhanced in intact CHF rats. The effects of the arterial baroreceptor and vagalafferents on the enhanced CSAR in CHF rats are unknown. Furthermore, the impactsof arterial baroreceptor and vagal inputs on the effects of Ang II in the PVN in CHFare unknown.ObjectiveTo determine whether the CSAR is enhanced in intact CHF rats and whether thebaroreceptor and vagal afferents inhibit the enhanced CSAR and theCSAR-enhancing effects of Ang II in the PVN in CHF rats.MethodsExperiments were carried out in male Sprague-Dawley rats. The rats were dividedinto CHF rats and Sham rats at random. Acute experiment was carried out7weeksafter coronary ligation or sham surgery. Either Sham or CHF rats were randomlydivided into four groups, which were subjected to be vagotomized (VT), baroreceptordenervated (BD)+VT or cardiac sympathetic denervated (CSD), or were kept intact(INT). The coordinates for PVN were determined in a stereotaxic instrumentaccording to the Paxinos and Watson rat atlas. All the drugs were bilaterallymicroinjected into PVN. Renal sympathetic nerve activity (RSNA), mean arterialpressure (MAP) and heart rate (HR) were recorded in vivo on a PowerLab dataacquisition system. The CSAR was evaluated by the RSNA responses to epicardialapplication of capsaicin.Protocols:1. To determinate the effects of the pretreatment with VT, BD+VT or CSD on theCSAR in CHF rats. 2. To determinate the effects of the pretreatment with VT, BD+VT or CSD on thePVN Ang II-induced enhancement in the CSAR, RSNA and MAP in CHF rats.Results1. The mean infarct area was34.0%of the left ventricle in CHF rats but no obviousinfarct was found in Sham rats. The heart weight and the heart-to-body weight ratiowere increased in CHF rats, suggesting myocardial hypertrophy in the non-infarctedregion of the myocardium. The systolic arterial pressure, left ventricle peak systolicpressure and maximal rise rate of the LV pressure (+LV dP/dtmax) deceased, but leftventricle end-diastolic pressure (LVEDP) increased in CHF rats.2. No significant difference in MAP and HR was found1hour after treatment withINT, VT, BD+VT or CSD between Sham rats and CHF rats. However, the CSDtreatment decreased the HR in CHF rats but not in Sham rats.3. Capsaicin increased the RSNA and MAP in INT, VT or BD+VT rats, but decreasedthe RSNA and MAP in CSD rats. In INT-, VT-or BD+VT-treated rats, the excitatoryresponses of capsaicin were greater in CHF rats than Sham rats. In either Sham orCHF rats, the RSNA and MAP responses to capsaicin were greater in VT-treated ratsthan INT rats. In CHF rats, the responses were greater in BD+VT-treated rats thaneither INT rats or VT rats.4. In INT, VT or BD+VT-treated rats, the PVN microinjection of Ang II causedgreater increases in the RSNA and MAP in CHF rats than that in Sham rats. CSDattenuated Ang II-induced increases in RSNA and MAP in CHF rats but not in Shamrats.5. The PVN microinjection of Ang II significantly augmented the RSNA and MAPresponses to epicardial application of capsaicin in Sham rats treated with BD+VT and in CHF rats treated with INT, VT or BD+VT. The enhanced RSNA and MAPresponses to capsaicin after Ang II were significantly greater in CHF rats than Shamrats. The effects of Ang II in the PVN on the RSNA and MAP responses to capsaicinwere augmented by VT, and further augmented by BD+VT.ConclusionsThe CSAR is enhanced in intact CHF rats. The activities of the arterial baroreceptorand vagal afferents inhibit the CSAR and the enhanced CSAR responses to Ang II inthe PVN. BackgroundExcessive sympathetic activity contributes to haemodynamic deterioration in chronicheart failure (CHF). Inhibition of sympathetic overactivity appears to be a therapeutictarget in treating CHF. The enhanced cardiac sympathetic afferent reflex (CSAR) is involved in the sympathetic over-activation in CHF. The paraventricular nucleus(PVN) of hypothalamus is an important component of the central neurocircuitry ofthe CSAR and plays an important role in regulating the sympathetic andcardiovascular activity. PVN is also involved in the enhanced CSAR and sympatheticactivity in CHF. Hydrogen sulfide (H2S), as a gaseous transmitter, has peripheralcardiovascular actions including protective effects against cardiacischemia–reperfusion injury and vasodilatory effects. Endogenous formation of H2Sis achieved mainly by cystathionine-β-synthase (CBS) in the brain. As an animportant integrative site of the sympathetic activity, cardiovascular effects of H2S inthe PVN are not well identified. And it is not yet known whether H2S in the PVNmodulates the CSAR and sympathetic activity in CHF.ObjectiveTo determine whether H2S in the PVN modulates the blood pressure, sympatheticactivity and CSAR in CHF.MethodsExperiments were carried out in male Sprague-Dawley rats. The rats were dividedinto CHF rats and Sham rats at random. Acute experiment was carried out7weeksafter coronary ligation or sham surgery. The coordinates for PVN were determined ina stereotaxic instrument according to the Paxinos and Watson rat atlas. All the drugswere bilaterally microinjected into PVN. Renal sympathetic nerve activity (RSNA),mean arterial pressure (MAP) and heart rate (HR) were recorded in vivo on aPowerLab data acquisition system. The CSAR was evaluated by the RSNA responsesto epicardial application of capsaicin. The H2S and CBS levels as well as CBSactivity in the PVN were measured with ELISA. Protocols:1. To determine the time effects of1%DMSO, a H2S donor GYY4137(2nmol) or aCBS inhibitor hydroxylamine (HA,3nmol) microinjected in the PVN on the RSNA,MAP and HR in normal rats.2. To determine the release of H2S from GYY4137. After the PVN microinjection ofsaline,1%DMSO or GYY4137(0.01,0.1,1,2or4nmol) in normal rats, the PVNtissues from individual rats were quickly collected for the measurement of the H2Slevel using ELISA method.3. To determine the dose effects of GYY4137in the PVN on the CSAR, baselineRSNA and MAP in Sham and CHF rats.4. To determine the dose effects of HA in the PVN on the CSAR, baseline RSNA andMAP in Sham and CHF rats.5. To determine the effects of cardiac afferent stimulation on the H2S and CBS levelsas well as CBS activity within the PVN. The Sham and CHF rats were separatelytreated with successive epicardial application of saline or capsaicin three times. Thenthe PVN tissues from individual rats were quickly collected for the measurement ofthe H2S and CBS levels as well as CBS activity using ELISA method.Results1. The mean infarct area was30.1%of the left ventricle in CHF rats but no obviousinfarct was found in Sham rats. The heart weight and the heart-to-body weight ratiowere increased in CHF rats, suggesting myocardial hypertrophy in the non-infarctedregion of the myocardium. The systolic arterial pressure, left ventricle peak systolicpressure and maximal rise rate of the LV pressure (+LV dP/dtmax) deceased, but leftventricle end-diastolic pressure (LVEDP) increased in CHF rats. 2. Microinjection of1%DMSO or HA (3nmol) into the PVN resulted in no changesin the RSNA, MAP and HR in normal rats. GYY4137(2nmol) caused the increasesin the RSNA, MAP and HR2min after PVN administration and these enhancementsreached the peak at about4min. The changes in the RSNA, MAP and HRrecuperated8min or so after PVN administration of GYY4137.3. Compared with saline or DMSO, microinjection of low doses of GYY4137(0.01or0.1nmol) into the PVN resulted in no changes in the PVN H2S level. Moderatedose of GYY4137(1nmol) caused a tendency in enhancing the PVN H2S level(P>0.05). The PVN administration of high doses of GYY4137(2or4nmol) resultedin the significant increase in the PVN H2S level.4. Compared with DMSO, microinjection of low doses of GYY4137(0.01or0.1nmol) into the PVN resulted in no changes in the baseline RSNA and MAP as well asthe CSAR in both Sham and CHF rats. Moderate dose of GYY4137(1nmol) causedthe increases in the baseline RSNA and MAP in Sham and CHF rats, but had noinfluence on the CSAR. The PVN administration of high doses of GYY4137(2or4nmol) resulted in the greater enhancements in the baseline RSNA and MAP as well asthe CSAR.Compared with Sham rats, the PVN microinjection of DMSO and low doses of GYY4137(0.01or0.1nmol) as well as moderate dose of GYY4137(1nmol) enhancedthe CSAR bot not the baseline RSNA and MAP in CHF rats. The PVN administrationof high doses of GYY4137(2or4nmol) resulted in the enhancements in the baselineRSNA and MAP as well as the CSAR.5. Compared with DMSO, microinjection of HA (0.3or03nmol) into the PVN hadno influences on the baseline RSNA and MAP as well as the CSAR in both Sham andCHF rats.Compared with Sham rats, the PVN administration of DMSO or HA (0.3or 3nmol) enhanced the CSAR bot not the baseline RSNA and MAP in CHF rats.6. Compared with epicardial application of saline, epicardial application of capsaicinsignificantly decreased the H2S level and CBS activity in the PVN in both Sham andCHF rats, but had no influences on the CBS content in the PVN in both Sham andCHF rats. Compared with Sham rats, there were significant decreases in the H2S leveland CBS activity in the PVN in CHF rats after epicardial application of saline, butthere was no significant change on the CBS content in the PVN in CHF rats.ConclusionsExogenous H2S in the PVN increases sympathetic outflow and enhances the CSAR inCHF rats, while endogenous H2S in the PVN is not involved in the enhaced CSARand sympathetic activity in CHF rats. |
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