Effect Of Hypoxia And CO₂ On Cardiorespiratory Activity In Juvenile Spontaneously Hypertensive Rats And Its Mechanism Involved

Hypertension is one of the most commonly uninfected diseases and the mobility of essential hypertension approximately accounts for 95%.However,the pathogenic mechanism of hypertension remains elusive so far.Accumulating evidence demonstrates the presence of sympathetic overactivity in the majority of hypertensive patients and the development of hypertension is positively correlated with the sympathetic strength.The sympathetic overactivity is capable of increasing vascular resistance and cardiac output,mobilizing renin-angiotensin-aldosterone system,contributing insulin resistance and central or peripheral inflammatory responses,with the outcome of high blood pressure.It has been demonstrated recently that abnormal respiratory-sympathetic coupling（RSC）contributes to the onset and development of hypertension.RSC serves as homeostatic mechanism of the regulation of ventilation/perfusion ratio through anatomical and functional coupling between breathing and sympathetic nerve system.Hypoxia or hypercapnia can not only activate respiratory chemoreceptor reflexes but also simultaneously trigger cardiovascular reflexes through central neural circuits.Accumulated data indicate that in patients with sleep apnea syndrome and animal models,the carotid body（CB）chemoreceptors are closely correlated with sympathetic activation.In spontaneously hypertensive rats（SHRs）,the CB denervation before onset of hypertension reduces considerably resting blood pressure and breathing frequency,suggesting the amplified RSC by overactivation of CBs.In addition,activation of central respiratory chemoreceptors also contributes to sympathetic overactivity.These findings therefore support that the occurrence of hypertension is associated with sympathetic overactivity resulting from enhanced sensitivity of peripheral and central respiratory chemoreceptors.However,little is known concerning whether the enhanced sensitivity of respiratory chemoreceptors occurs prior to onset of hypertension.Hence,the present study aims to investigate effects of activation of peripheral and central respiratory chemoreceptors on cardiorespiratory activity and attempted to underpin its mechanism involved.Objective:To investigation effects of hypoxia and hypercapnia on cardiorespiratory activity in juvenile SHRs and its mechanism involved.Methods:The experiment was performed in male juvenile SHRs aged4⁵ weeks and age-matched male Wistar-Kyoto rats（WKY）.The combination of whole body plethysmography and radio telemetry system was used to simultaneously measure tidal volume（TV）,breathing frequency（BF）,minute ventilation（MV）,systolic blood pressure（SBP）,diastolic blood pressure（DBP）,mean arterial pressure（MAP）and heart rate（HR）.Cardiorespiratory activities were assessed by activation of peripheral and central respiratory chemoreceptors under hypoxic and hypercapnic conditions.Using immunofluorescence staining,comparisons were made between SHRs and WKYs in cell counts of CO₂-sensitive neurons in the nucleus tractus solitarii（NTS）.Western blot was used to quantitatively analyze the expression level of acid-sensitive ion channels（ASIC）and TASK-2 channels.Results:1.During exposure to room air,no significant difference was found in TV,BF and MV between SHRs and WKYs.Exposure to 10%O₂ raised TV,BF and MV in either SHRs or WKYs but the insignificant difference was found between two phenotypes.Such effects were retained in two groups of rats submitted to chemodenervation,suggesting that insignificant difference was found in the hypoxic ventilatory response between two phenotypes.2.Exposure to 10%O₂ reduced remarkably SBP,DBP,MAP and HR in juvenile WKYs,without considerable effects on the above parameters in SHRs.Hypoxia-stimulated change in amplitude of MAP was less in SHRs than that observed in WKYs and such a change was statistically significant.Hypoxia reduced markedly HR in WKYs,with unchanged effect in SHRs,and therefore such a change in HR was statistically significant between two groups.In two groups of rats with CB’s denervation,hypoxia reduced SBP,DBP and MAP,with no statistical difference in MAP;Hypoxia increased HR in SHRs but decreased in WKYs,with a notable difference in HR between two phenotypes.3.During exposure to 100%O₂,no significant difference in TV and MV was found between SHRs and WKYs.In the presence of 5%and 8%CO₂,SHRs exhibited greater TV,BF and MV compared to WKYs.The chemodenervation did not affect the stimulatory effect of CO₂ on breathing parameters in both phenotypes,ruling out the involvement of CBs.It is concluded that the SHR exhibits enhancement of hypercapnic ventilatory responses mediated most likely by central respiratory chemoreceptors.4.During exposure to 5%and 8%CO₂,the increment of amplitude of MAP and HR was greater in SHRs in relative to WKYs.The above effect was retained at 8%CO₂ even in the absence of CBs.Therefore,the central chemoreceptors but not CBs contributes mainly to the stimulatory effect of hypercapnia on cardiovascular activity,suggesting presence of amplified RSC in SHRs.5.The number of CO₂-activated NTS neurons was greater in SHRs compared with WKYs.6.Quantitative analysis revealed upregulation of ASIC2,ASIC3 and TASK-2 channel expressions.Conclusions:Amplified RSC occurs in SHRs before onset of hypertension and the enhanced sensitivity of central but not peripheral respiratory chemoreceptors contributes mainly to such a role.The hypersensitivity of central respiratory chemoreceptors is closely associated with an increase in the number of CO₂-activated NTS neurons and upregulation of ASIC2,ASIC3 and TASK-2 channel expressions.In summary,amplified RSC in juvenile SHRs contributes most likely to the occurrence and development of hypertension.