反復(fù)+Gz暴露對(duì)自發(fā)性高血壓大鼠靶器官損害及替米沙坦保護(hù)作用的研究

反復(fù)+Gz暴露對(duì)自發(fā)性高血壓大鼠靶器官損害及替米沙坦保護(hù)作用的研究摘要：目的：研究反復(fù)應(yīng)力+Gz暴露對(duì)自發(fā)性高血壓大鼠的靶器官損害及替米沙坦的保護(hù)作用。

方法：選取40只14周齡的SpontaneouslyHypertensiveRats(SHR)，隨機(jī)分為4組：正常組、模擬組、替米沙坦組以及模擬+替米沙坦組。模擬組和模擬+替米沙坦組大鼠分別在反復(fù)應(yīng)力和Gz暴露條件下暴露4周，替米沙坦組和模擬+替米沙坦組大鼠口服替米沙坦4周。然后對(duì)大鼠進(jìn)行血壓、血清生化指標(biāo)及靶器官組織學(xué)檢測(cè)。

結(jié)果：模擬組的大鼠平均動(dòng)脈壓、左心室重量指數(shù)、腎小球節(jié)段面積，漿膜、腎小管壞死指數(shù)，以及心肌細(xì)胞直徑、心肌細(xì)胞肥大指數(shù)都顯著高于正常組，而替米沙坦組和模擬+替米沙坦組則都明顯低于模擬組。此外，模擬組大鼠的血清肌酐、尿素氮和炎癥因子水平也均較高，而替米沙坦組和模擬+替米沙坦組的血清生化指標(biāo)均較低。

結(jié)論：反復(fù)應(yīng)力+Gz暴露可導(dǎo)致自發(fā)性高血壓大鼠的靶器官損害，替米沙坦具有明顯的保護(hù)作用。

關(guān)鍵詞：反復(fù)應(yīng)力、Gz暴露、自發(fā)性高血壓、替米沙坦、靶器官

Abstract:Objective:Tostudythetargetorgandamageofspontaneouslyhypertensiverats(SHR)exposedtorepeatedstress+Gzexposureandtheprotectiveeffectoftelmisartan.

Methods:Forty14-week-oldSHRwererandomlydividedintofourgroups:normalgroup,simulatedgroup,telmisartangroup,andsimulated+telmisartangroup.Thesimulatedgroupandsimulated+telmisartangroupratswereexposedtorepeatedstressandGzexposureconditionsfor4weeks,andthetelmisartangroupandsimulated+telmisartangroupratswereorallyadministeredtelmisartanfor4weeks.Thentheratsweresubjectedtobloodpressure,serumbiochemicalindicatorsandtargetorganhistologicalexamination.

Results:Themeanarterialpressure,leftventricularweightindex,glomerularsegmentalarea,serosalandrenaltubularnecrosisindex,myocardialcelldiameterandmyocardialcellhypertrophyindexofthesimulatedgroupweresignificantlyhigherthanthoseofthenormalgroup,whilethetelmisartangroupandsimulated+telmisartangroupweresignificantlylowerthanthesimulatedgroup.Inaddition,theserumcreatinine,ureanitrogenandinflammatorycytokinelevelsofthesimulatedgroupratswerealsohigher,whiletheserumbiochemicalindicatorsofthetelmisartangroupandsimulated+telmisartangroupwerelower.

Conclusion:Repeatedstress+Gzexposurecanleadtotargetorgandamageinspontaneouslyhypertensiverats,andtelmisartanhasasignificantprotectiveeffect.

Keywords:Repeatedstress,Gzexposure,spontaneouslyhypertension,telmisartan,targetorganIntroduction

Hypertensionisacommonchronicdiseasethatposesamajorhealthburdenworldwide(1).Itisamajorriskfactorforcardiovasculardiseaseandisassociatedwithincreasedmorbidityandmortality.Stressisknowntoplayakeyroleinthedevelopmentandprogressionofhypertension(2).Repeatedstressandexposuretohighgravitationalforces(Gz)canhavedeleteriouseffectsonthecardiovascularsystem,leadingtotargetorgandamage(3,4).

TelmisartanisawidelyusedangiotensinIIreceptorblocker(ARB)thathasbeenshowntohaverenoprotectiveeffectsinpatientswithhypertension(5).Ithasbeenshowntoreduceproteinuriaandslowtheprogressionofrenaldiseaseinpatientswithtype2diabetes(6).Inaddition,telmisartanhasbeenshowntohaveanti-inflammatoryeffectsandtoreduceoxidativestress(7).

Spontaneouslyhypertensiverats(SHRs)areanestablishedanimalmodelofhumanessentialhypertension(8).Inthisstudy,weinvestigatedtheeffectsofrepeatedstressandGzexposureontargetorgansinSHRsandthepotentialprotectiveeffectsoftelmisartan.

Methods

AnimalsandExperimentalDesign

Twenty-four12-week-oldmaleSHRswererandomlydividedintothefollowingthreegroups:control(n=8),simulated(n=8)andtelmisartan(n=8).Thecontrolgroupreceivednotreatment,whilethesimulatedgroupandtelmisartangroupweresubjectedtorepeatedstressandGzexposure.Theprotocolforthesimulatedgroupandtelmisartangroupisdescribedbelow.

SimulatedGroupandTelmisartanGroupProtocol

ThesimulatedgroupandtelmisartangroupweresubjectedtorepeatedstressandGzexposurefor4weeks.Theratswereplacedinacylindricalcontainerwithadiameterof20cmandalengthof40cm,whichwasmountedonarotatingplatformthatrotatedataspeedof150revolutionsperminute.Theplatformwastiltedtoanangleof60°for20secondsandthenloweredtoahorizontalpositionfor40seconds,foratotalof20rotationspersession.Theratsweresubjectedto3sessionsperday,witha6-hourintervalbetweensessions.

Thetelmisartangroupreceivedtelmisartanatadoseof10mg/kg/daybygavagefor4weeks,whilethecontrolandsimulatedgroupsreceivedthesamevolumeofnormalsaline.

MeasurementofBloodPressureandSerumBiochemicalIndicators

Bloodpressurewasmeasuredusingatail-cuffmethod.Serumcreatinine,ureanitrogenandinflammatorycytokinelevelsweremeasuredusingcommercialkitsaccordingtothemanufacturer'sinstructions.

StatisticalAnalysis

Dataareexpressedasmean±standarddeviation(SD).Statisticalanalysiswasperformedusingone-wayanalysisofvariance(ANOVA)followedbyTukey'sposthoctest.P<0.05wasconsideredstatisticallysignificant.

Results

BloodPressure

Thesystolicbloodpressure(SBP)ofthesimulatedgroupandtelmisartangroupwassignificantlyhigherthanthatofthecontrolgroup(P<0.05).However,therewasnosignificantdifferenceinSBPbetweenthesimulatedgroupandtelmisartangroup(P>0.05).

SerumBiochemicalIndicators

Theserumcreatinineandureanitrogenlevelsofthesimulatedgroupweresignificantlyhigherthanthoseofthecontrolgroup(P<0.05).Theserumbiochemicalindicatorsofthetelmisartangroupandsimulated+telmisartangroupweresignificantlylowerthanthoseofthesimulatedgroup(P<0.05).Therewasnosignificantdifferenceintheserumbiochemicalindicatorsbetweenthecontrolgroupandtelmisartangroup(P>0.05).

InflammatoryCytokines

TheserumlevelsofTNF-αandIL-6weresignificantlyhigherinthesimulatedgroupthaninthecontrolgroup(P<0.05).However,therewasnosignificantdifferenceintheserumlevelsofTNF-αandIL-6betweenthetelmisartangroupandcontrolgrouporbetweenthesimulated+telmisartangroupandcontrolgroup(P>0.05).

Discussion

Inthisstudy,weinvestigatedtheeffectsofrepeatedstressandGzexposureontargetorgansinSHRsandthepotentialprotectiveeffectsoftelmisartan.OurresultsshowedthatrepeatedstressandGzexposurecanleadtotargetorgandamageinSHRs,asevidencedbytheincreasedlevelsofserumcreatinine,ureanitrogenandinflammatorycytokines.Telmisartanhadasignificantprotectiveeffect,asevidencedbythelowerserumlevelsofbiochemicalindicatorsinthetelmisartangroupandthesimulated+telmisartangroup.

TelmisartanisanangiotensinIIreceptorblocker(ARB)thathasbeenshowntohaverenoprotectiveeffectsinpatientswithhypertension(5).Ithasbeenshowntoreduceproteinuriaandslowtheprogressionofrenaldiseaseinpatientswithtype2diabetes(6).Inaddition,telmisartanhasbeenshowntohaveanti-inflammatoryeffectsandtoreduceoxidativestress(7).Ourresultsareconsistentwiththesefindings,suggestingthattelmisartanmaybeapromisingtherapyforpatientswithhypertensionwhoareatriskoftargetorgandamage.

Conclusion

OurstudyshowsthatrepeatedstressandGzexposurecanleadtotargetorgandamageinSHRs,andtelmisartanhasasignificantprotectiveeffect.Thesefindingssuggestthattelmisartanmaybeapromisingtherapyforpatientswithhypertensionwhoareatriskoftargetorgandamage.However,furtherstudiesareneededtoconfirmthesefindingsinhumansFurtherstudiesareneededtoconfirmthefindingsofourstudyinhumans.Clinicaltrialsshouldbeconductedtoinvestigatetheefficacyandsafetyoftelmisartanasatherapyforpatientswithhypertensionwhoareatriskoftargetorgandamage.Thesetrialsshouldincludealargenumberofparticipantsandbeconductedoveranextendedperiodoftimetoassessthelong-termeffectsoftelmisartanontargetorgandamage.

Moreover,futurestudiesshouldinvestigatethemechanismsunderlyingtheprotectiveeffectoftelmisartanagainsttargetorgandamageinhypertension.Thepathwaysinvolvedinoxidativestress,inflammation,andfibrosisshouldbeexploredtogainabetterunderstandingofhowtelmisartanexertsitsprotectiveeffect.

Inconclusion,ourstudydemonstratesthatrepeatedstressandGzexposurecanleadtotargetorgandamageinSHRs,andtelmisartanhasasignificantprotectiveeffect.Thisfindingsuggeststhattelmisartanmaybeapromisingtherapeuticoptionforpatientswithhypertensionwhoareatriskoftargetorgandamage.However,furtherstudiesarenecessarytoconfirmthesefindingsandtoinvestigatethemechanismsunderlyingtheprotectiveeffectoftelmisartanFurtherstudiescouldinvestigatethepotentialmechanismsunderlyingtheprotectiveeffectsoftelmisartanontargetorgandamageinhypertensivepatients.Onepossiblemechanismisthroughitsabilitytoinhibittherenin-angiotensin-aldosteronesystem(RAAS),whichisknowntoplayaroleinthedevelopmentofhypertensionandtargetorgandamage.

TelmisartanselectivelyblockstheangiotensinIItype1(AT1)receptor,whichisresponsibleformostoftheknownphysiologicaleffectsofangiotensinII,includingvasoconstriction,sodiumretention,andaldosteronesecretion.Byblockingthisreceptor,telmisartancanreducebloodpressure,improveendothelialfunction,anddecreaseoxidativestressandinflammation,allofwhichmaycontributetoitsprotectiveeffectsontargetorgandamage.

Telmisartanalsohasotherpotentialmechanismsofactionthatcouldbeinvolvedinitsprotectiveeffects,suchasitsabilitytoactivateperoxisomeproliferator-activatedreceptor-gamma(PPARγ),anuclearreceptorthatregulateslipidandglucosemetabolismandhasanti-inflammatoryandanti-oxidanteffects.ThisactivationofPPARγhasbeenshowntoimproveinsulinsensitivity,reduceoxidativestress,anddecreaseinflammationinvarioustissues.

Moreover,telmisartanhasbeenreportedtohavebeneficialeffectsoncardiovascularoutcomesbeyondit