Prenatal caffeine exposure induces down-regulation of the protein kinase A/ryanodine receptor/large-conductance Ca2+-activated K+ pathway in the cerebral arteries of old offspring rats.

Background/aims: The current study investigated the long-term effects of prenatal caffeine (Caf) exposure on cerebral vessels of old offspring rats.

Methods: Pregnant rats were treated with Caf (20 mg/kg, twice daily) or 0.9% normal saline during gestational days 3.5-19.5, and offspring were tested at 24 months old. Vascular functions of middle cerebral arteries and ion channel activities in smooth muscle cells were examined using myograph system and patch-clamp.

Results: Prenatal Caf exposure decreased isoprenaline (β-adrenergic agonist)-induced dilatation of the middle cerebral artery in the offspring. Treatment with protein kinase A (PKA) inhibitor reduced isoprenaline-mediated vasodilatation to a greater extent in the control. Forskolin-mediated vasodilatation and membrane hyperpolarization were reduced in the Caf group. Large-conductance Ca-activated K (BKCa) channel inhibitor iberiotoxin significantly attenuated forskolin-induced vasodilatation and reduced depolarization in the control, not in the Caf group. The PKA agonist-activated cell-attached single BKCa currents to a greater extent in the control. The mRNA and protein expression levels of PKA-Cα were decreased. The sensitivity of ryanodine receptors to the PKA agonist was blunted in the Caf group, whereas the mRNA expression of ryanodine receptor 2 subunit was reduced. Voltage/Ca sensitivity of BKCa was decreased accompanied by reduced mRNA and protein expression of BKCa-β1 subunits in the Caf group. PKA agonist-stimulated inside-out BKCa currents were weaker in the Caf group.

Conclusion: Prenatal exposure to Caf-affected isoprenaline/forskolin-mediated vascular functions in aged cerebral arteries, related to dysfunction of the PKA/ryanodine receptors/BKCa signaling pathway.