| Background and Objective:Hypertension is the leading cause of various cardiovascular and cerebrovascular diseases and deaths.More than one third hypertensives are resistant to antihypertensive drugs,which is called resistant hypertension.Carotid baroreflex plays a crucial role in the regulation of arterial pressure.Based on this knowledge,electrical stimulation of carotid sinus(ESCS)was designed for treating resistant hypertension.Although there have been proven obvious reductions of blood pressure,the clinical implication of ESCS is largely restrained due to obvious invasiveness.Magnetic stimulation is an emerging noninvasive technology based on the principle of electromagnetic transduction.The alternating magnetic fields can penetrate tissues and converge to an in vivo target where the therapeutic eddy currents might be generated due to magnetoelectric effect.The induced currents may further change the electrical activity within cells,tissue and neural pathway,and leading to relevant metergasis.Magnetic stimulation has been widely used in treating neurological and psychiatric disorders.However,the possibility that magnetic stimulation may activate carotid baroreflex,and then lower arterial pressure has not been evaluated to date.To test this hypothesis,we explored the acute reactions of blood pressure and heart rate to extracorporeal magnetic stimulation of carotid sinus(MSCS)in normotensive rabbits,and to explore the potential mechanism,which may provide new strategy for lowering arterial pressure,especially for resistant hypertension.Methods:Healthy male New Zealand white rabbits weighted 3.0±0.5 kg were used in this study.The rabbits were initially anaesthetized with 30 mg/kg pentobarbital sodium through ear margin vein.The femoral artery was separated and cannulated for recording arterial pressure and heart rate,which were continuously recorded before,during and after stimulation.All data were achieved by PowerLab system(AD Instruments,Australia).The magnetic coil was placed over the body surface projections of the right carotid sinus.We observed the effects of different magnetic stimulation parameters on hemodynamics and related changes of hormone levels.The study included the following parts.1.At 1 Hz frequency,MSCS with graded stimulation intensities were systematically attempted to test its effects on arterial pressure and heart rate.The intensities were measured as percentages to motor threshold(MT),including 100%MT,150%MT,200%MT and 250%MT groups.The decreases of arterial pressure and heart rate among each group were compared.2.With determined optimal stimulation intensity,MSCS with different stimulation frequencies were systematically attempted to test its effects on arterial pressure and heart rate,including low frequency(0.5 Hz and 1 Hz)and high frequency(5 Hz and 10 Hz).The stimulation pattern was uniform for low frequency and intermittent block for high frequency.The decrements of arterial pressure and heart rate among each group were compared.3.With determined optimal stimulation intensity and frequency,MSCS with different stimulation locations(unilateral or bilateral)were compared in decreasing arterial pressure and heart rate.4.Sinoaortic denervation(SAD)was performed to confirm the involvement of carotid baroreflex in the expected hemodynamic responses to MSCS.5.To explore the influence of MSCS on neurohormonal,blood samples were taken before,during(1 minute after stimulation initiation)and after the stimulation(10 and 30 minutes)to measure the plasma levels of aldosterone,epinephrine,norepinephrine and dopamine.6.To explore the influence of MSCS on heart rate variability(HRV)and baroreflex sensitivity(BRS).7.Statistical analysis:Mean arterial pressure(MAP)was used to represent arterial pressure.Results were expressed as mean ± SEM or as median with inter-quartile ranges when appropriate.One-way ANOVA or Kruskal-Wallis was performed for multiple comparisons.Linear regression analysis was used to determine the relationship between reduction level of arterial pressure and stimulation intensity.Results:1.The effect of stimulation intensity on hemodynamics.The arterial pressure decreased immediately after the initiation of magnetic stimulation,thereafter it restored slightly and maintained in a platform,which was still lower than the baseline level.When intensity increased from 100%MT to 250%MT,the mean decrement of MAP from baseline increased from 3.6±1.0 mm Hg to 10.4± 2.3 mm Hg(r = 0.802,P=9.7×10-8).Similarly,the maximal decrement of MAP increased from 11.9±3.0 mm Hg to 28.0±3.0 mm Hg(r=0.817,P=3.6×10-8),which usually occurred within the initial 1 minute of stimulation.When the magnetic stimulation was terminated,arterial pressure returned to the baseline levels immediately.Multiple comparisons showed that the mean MAP reduction(12.3±1.2 mm Hg)and max MAP reduction(28.6±2.5 mm Hg)in 200%MT group was much significant.The trend of heart rate was similar to that of arterial pressure,however,there was no difference between baseline and stimulation of each group.2.The effect of stimulation frequency on hemodynamics.When stimulation intensity was fixed at 200%MT,multiple comparisons showed that the MAP reduction in 1 Hz was much higher[10.8(8.6-14.9)mm Hg],while the heart rate reductions in 0.5 Hz[3.1(1.9-4.5)bpm]and 5 Hz[2.9(-0.1-26.4)bpm]groups were more significant.3.The effect of stimulation location on hemodynamics.At 200%MT stimulation intensity and 1 Hz frequency,there were similar reduction responses of MAP(right/left/bilateral:12.3 ± 1.2 mm Hg,11.2±0.8 mm Hg,11.0±0.9 mm Hg,respectively,P=0.611)and heart rate(right/left/bilateral:3.0 ± 0.4 bpm,2.0±0.4 bpm,1.8±0.5 bpm,respectively,P=0.153)to different stimulation locations.4.The effect of SAD on MSCS.When stimulated on ipsilateral side of SAD with 200%MT and 1 Hz frequency,both mean and maximal MAP decrement was remarkably attenuated compared with that in sham group(7.0 ± 0.8 mm Hg versus 13.0 ± 1.1 mm Hg,P = 0.001;17.3 ± 1.1 mm Hg versus 30.5±2.1 mm Hg,P ＝0.003).The maximal reduction of heart rate was significant lower than that in sham group(21.3±2.1 bpm versus 33.1±4.1 bpm,P = 0.032).Compared to sham group,there was no much difference of MAP and heart rate reduction when MSCS was performed on the contralateral side of SAD.5.The effect of MSCS on neurohormonal.Compared to baseline,the plasma epinephrine level increased significantly after the initiation of stimulation(88.1 ± 9.6 versus 33.9± 5.5 pg/ml,P=0.002),However,the concentration of plasma dopamine level decreased obviously after the initiation of stimulation(16.2 ± 1.7 versus 50.7±3.2 pg/ml,P=4.5×10-6).There were no significant changes in aldosterone concentration during or after the stimulation.(详细)6.The effect of MSCS on HRV and BRS.HRV in terms of total power was increased during MSCS(4.84±0.33 versus 2.40± 0.14 ms2,P = 0.00003)and after MSCS(4.29±0.29 versus 2.40±0.14 ms2,P = 0.0004),There were no obvious changes in low frequency power,high frequency power,and low frequency/high frequency power ratio.And there was a significant increase of BRS during stimulation compared to that at baseline(1.12±0.17 versus 0.67±0.04 ms/mm Hg,P = 0.039).Conclusions:This study demonstrated the efficacy of MSCS in decreasing arterial pressure,which might be caused by the activation of carotid baroreflex.Also,the lowering arterial pressure effect was related to magnetic stimulation parameters,including intensity and frequency.These preliminary results warrant further explorations to establish MSCS as a potential noninvasive treatment for refractory hypertension. |
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