Prenatal Caffeine Exposure Induced Down-regulation Of PKA/RyRs/BK_Ca Pathway In Cerebral Artery Of Aged Rat Offspring

Aims:Prenatal caffeine exposure could affect cardiovascular functions in offspring.This study aimed at the long-term influence of prenatal caffeine on cerebral vessels in aged offspring.Methods:Pregnant rats were treated with high dose of caffeine（Caf:20 mg/kg,twice daily）or Saline（Con）from gestational day 3.5-19.5,their 24-month-old male offspring were tested.Results:Prenatal caffeineexposuredecreasedisoprenaline（ISO）-induced vasodilatation in middle cerebral arteries in the offspring.Protein kinase A（PKA）inhibitor decreased ISO-mediated vasodilatation more significantly in Con.Forskolin-mediated vasodilatation was reduced accompanied by decreased membrane hyper-polarization in Caf.Iberiotoxin(BK_Cachannel inhibitor)significantly attenuated Forskolin-induced vasodilatation and reduced depolarization in Con,not in Caf.PKA agonist activated cell-attached single BK_Cacurrents more significantly in Con.The mRNA and protein expression of PKA-Cαwere decreased.The sensitivity of RyRs to PKA agonist was blunt in Caf,while the mRNA expression of RyR2 was reduced.Voltage/Ca²⁺sensitivity of BK_Caa were decreased accompanied by reduced mRNA and protein expression of BK_Ca-β1subunits in Caf,PKA agonist-stimulated inside-out BK_Cacurrents was weaker too.Conclusions:The results indicate that prenatal caffeine induced down-regulation of PKA/RyR/BK_Capathway,providing new information for further understanding increased risks in aged cerebrovascular diseases in developmental origins.