| Obstructive sleep apnea syndrome (OSAS) is a common sleep-relatedbreathing disorder presenting with the clinical hall-marks of snoring andwitnessed nocturnal sleep apnea. OSAS in patients promotes chronicallyelevated sympathetic nerve activity (SNA) and mean arterial pressure (MAP)with exaggerated sympathetic responses to acute hypoxia. Animal models ofchronic intermittent hypoxia (CIH) have been developed to mimic theintermittent hypoxaemia produced with OSAS and determine the short-andlong-term mechanisms underlying the CIH-induced changes of SNA and MAP.The development of hypertension in patients with OSAS and in rodents withCIH appears to be initiated by over excited of the carotid sinus nerves, whichgenerate chemoreflex-mediate increases in SNA. The mechanisms thatunderying CIH-induced hypertension is not been absolutely definited,however ET-1is confirmed to be a directley excitable neurotransmitter tocarotid body chemoreceptor and problely regulate SNA through chemoreflex.In this study, we observed the MAP and RSNA responses in CIH groupby injecting ET-1to carotid artery to stimulate carotid body chemoreceptordirectly. Meanwhile we tried to explain the effect of ET-1in CIH-relatedhypertension.Objective: We observe the effects of ET-1induced MAP and RSNAchanges in normoxic and CIH rats and underlying the effect of ET-1inCIH-induced hypertension.Method: SPF male Sprague-Dawley rats (n=120) were divided into twogroups: Normoxia and CIH. During hypoxic exposure, animals were placeddaily in commercial hypoxic chambers that were flushed with100%N2todecrease the fraction of inspired O2(FiO2) to nadir of9%for1.5min. The FiO2gradually returned to21%over the remainder of each cycle. Theexposure cycle was repeated every3min for8h/day for21days during theanimal’s sleeping hours. Normoxic animals underwent identical handling andexposure, but chambers were flushed with room air rather than N2. The twogroup rats underwent tail-cuff method for the noninvasive measurement of tailartery blood pressure before and after21days of CIH. After the exposure cyclewas completed, animals were randomly assigned to physiologicalinvestigation.The indices as follow: The two group rats were anesthetized and wereunderwent femal artery and vein caunulation and ventilaed artificially. A thirdcaunulation was injected to carotid artery to arterial injection. The protocolswere as follow (1) Normoxia baroreceptor-impaired rats were submitted toadministration of ET-1-1(0.1,0.3,1,3,10nmol/kg) to observe the responses ofRSNA.(2) Resting and changes of RSNA were recorded5min before and aftercarotid artery injectin of1nmol/kg ET-1in both carotid sinus and aorticdenervated normoxia rats.(3) In two distinct groups of rats, normoxia andCIH, the removal of baroreceptor was used to evaluate the role of thechemoreflex in the MAP and RSNA responses to application of ET-1andreceptors antagonist or signal passway antagonist in both groups.Results1The effects of CIH on tail MAPCompared with Normoxic rats (110.3±3.81mmHg), CIH (145.7±5.74mmHg) significantly increase the tail MAP (P <0.01).2The effects of CIH on resting MAP and RSNACompared with Normoxic rats (94.18±5.58mmHg), CIH (110.12±4.93mmHg) significantly increase the resting MAP (P <0.01). Compared withNormoxic rats (37.03±3.88mv.s), CIH (52.24±2.98mv.s) significantlyincrease the resting RSNA (P <0.01).3The effects of diverse concentration of ET-1on RSNA in Normoxicbaroreceptor-impaired ratsET-1caused a concentration-dependent response of RSNA which characterised by an increase and sustained after reaching its maximalamplitude. The concentration of1nmol/kg elicited suitable changes in RSNAand sustained after reaching its maximal amplitude.4The effects of ET-1on RSNA in both carotid sinus and aortic denervatedNormoxic ratsThe injection of ET-1was unable to elicit any significant difference inRSNA.5The effects of ET-1on MAP and RSNA in baroreceptor-impaired Normoxicand CIH rats.Compared with baroreceptor-impaired Normoxic rats (10.92±1.84%),CIH (15.05±2.04%) significantly augment the ET-1induced increase ofMAP (P <0.01). Compared with baroreceptor-impaired Normoxic rats (7.34±1.77%), CIH (11.78±1.55%) significantly augment the ET-1induced increaseof RSNA (P <0.01).6The effects of BQ123and BQ788on ET-1induced increase of MAP andRSNA in CIH ratsIn baroreceptor-impaired rats, injection of ET-115mins afteradministrated of ETAreceptor antagonist BQ123. Compared withbaroreceptor-impaired Normoxic rats (85.47±10.9%), CIH (97.3±12.3%)significantly inhibit ET-1induced increase of MAP (P <0.01). Compared withbaroreceptor-impaired Normoxic rats (175.46±13.6%), CIH (224.61±15.9%)significantly inhibit the ET-1induced increase of RSNA (P <0.01). Inbaroreceptor-impaired rats, injection of ET-115mins after administrated ofETBreceptor antagonist BQ788. Compared with baroreceptor-impairedNormoxic rats (25.24±2.3%), CIH (65.10±5.6%) significantly augmentET-1induced increase of MAP (P <0.01). Compared withbaroreceptor-impaired Normoxic rats (31.17±5.9%), CIH (172.63±11.6%)significantly augment ET-1induced increase of RSNA (P <0.01).7The effects of SB203580and Chelerythine on ET-1induced increase ofMAP and RSNA in CIH ratsIn baroreceptor-impaired rats, injection of ET-115mins after administrated of P38MAPK signal pathway antagonist SB203580. Comparedwith baroreceptor-impaired Normoxic rats (40.65±5.7%), CIH (41±6.3%)significantly inhibit ET-1induced increase of MAP (P <0.01). Compared withbaroreceptor-impaired Normoxic rats (34.18±3.6%), CIH (33.27±3.3%)significantly inhibit ET-1induced increase of RSNA (P <0.01). Inbaroreceptor-impaired rats, injection of ET-115mins after administrated ofPKC signal pathway antagonist Chelerythine. Compared withbaroreceptor-impaired Normoxic rats (61.90±6.3%), CIH (62±7.2%)significantly inhibit ET-1induced increase of MAP (P <0.01). Compared withbaroreceptor-impaired Normoxic rats (50.24±5.7%), CIH (51.03±6.2%)significantly inhibit ET-1induced increase of RSNA (P <0.01).Conclusions: CIH signigicantly increase the MAP and RSNA comparedwith Normoxic rats; ET-1increase the MAP and RSNA and the changes weregreater in CIH group; ETAreceptor, P38MAPK and PKC signial passwayantagonist BQ123, SB203580and Chelerythine prevented the ET-1inducedincrease of MAP and RSNA, ETBreceptor antagonist BQ788augment theET-1induced increase of MAP and RSNA. |
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